Professional Documents
Culture Documents
CONSULTING EDITOR
RICHARD H. HAUG, DDS
Professor and Chief, Oral and Maxillofacial Surgery, Carolinas
Center for Oral Health, Charlotte, North Carolina
EDITOR
DEAN M. DeLUKE, DDS, MBA
Associate Professor and Director of Predoctoral Oral and
Maxillofacial Surgery, Virginia Commonwealth University
School of Dentistry and Virginia Commonwealth University
Medical Center, Richmond, Virginia
AUTHORS
DAVID ALFI, DDS, MD
iii
iv
Contributors
ROMAN G. MEYLIKER, DMD
Contents
Dedication
ix
xi
Dean M. DeLuke
Craniosynostosis Syndromes
103
103
104
106
106
111
Stephen A. Sachs
Osteopetrosis
Osteopathia striata with cranial sclerosis
Infantile cortical hyperostosis: Caffey Silverman syndrome
Segmental regional odontomaxillary dysplasia
Cherubism
Syndromic brous dysplasia: McCune Albright syndrome
Osteogenesis imperfecta
Marfan syndrome
Cleidocranial dysplasia (dysostosis)
Congenital hemolytic anemias
111
113
113
114
115
116
117
118
119
120
123
Victor Nannini
Fabry disease
Williams syndrome
Hurler syndrome
Hunter syndrome
Heerfordt syndrome
Sjogren
syndrome
123
124
125
126
127
128
135
Ioannis G. Koutlas
Ehlers-Danlos syndromes
Parry-Romberg syndrome
Witkop syndrome
Ectodermal dysplasia syndromes
Hypohidrotic ectodermal dysplasia
Osler-Rendu-Weber syndrome
Ascher syndrome
Behcet syndrome
Felty syndrome
135
137
139
139
140
141
143
143
145
vi
Contents
Reactive arthritis
Stevens-Johnson syndrome
Progeria
145
147
148
Hamartoneoplastic Syndromes
153
Klippel-Trenaunay-Weber
syndrome
Sturge-Weber syndrome
Peutz-Jeghers syndrome
Cowden syndrome
Multiple Endocrine Neoplasia syndromes
Proteus syndrome
Neurobromatosis
Tuberous sclerosis
153
154
155
156
157
158
159
160
161
162
167
Mobius
syndrome
Clefting Syndromes
167
168
171
175
Stephanie J. Drew
Velocardiofacial syndrome (Shprintzen syndrome)
Van Der Woude syndrome 1 and 2
Pierre Robin sequence
CHARGE syndrome
Stickler syndrome
178
179
179
180
181
183
Chromosomal Syndromes
183
184
185
187
187
188
190
191
192
197
Rita Shiang
Down syndrome
Klinefelter syndrome
Turner syndrome
197
198
200
Contents
Syndromes with Unusual Facies
205
205
205
207
207
209
211
John E. Fantasia
Papillon-Lefevre syndrome
Hereditary gingival bromatosis type 1
Klippel-Feil syndrome
Oral-facial-digital syndrome type I
Oligodontia
Taurodontism
211
212
213
214
215
217
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viii
PREVIOUS ISSUES
March 2015
March 2014
September 2015
September 2013
Craniomaxillofacial Trauma
David Bitoni, Editor
Oral and Maxillofacial Surgery Clinics of North America, November 2013, Volume 25, Issue 4
Trauma and Reconstruction
David S. Precious, Editor
Dedication
To: Dr. Dominick J. DeLuke and Dr. Leon Eisenbud.
In recognition of their many contributions to the profession, and with thanks for allowing me to see a little further by
standing on their shoulders.
oralmaxsurgeryatlas.theclinics.com
Preface
The purpose of this issue of the Atlas of the Oral and Maxillofacial Surgery Clinics of North America is to serve as an aid
to identification of the more common syndromes of the head
and neck. As such, it should be useful to a varied audience,
including not only the oral and maxillofacial surgeon but also
the oral pathologist, the practitioner of oral medicine, and
members of the craniofacial teamdthe orthodontist, pediatric dentist, speech and language specialist, geneticist, plastic surgeon, ENT specialist, pediatrician, nurse coordinator,
and others.
In keeping with the established format for the Atlas of the
Oral and Maxillofacial Surgery Clinics of North America, it was
necessary to limit the size and scope of this work. We have
therefore included 70 of the more important head and neck
syndromes and organized them using the same nosology as
in the landmark text of Robert Gorlin, first published with
Pindborg in 1964. Each syndrome is presented in a highly
capsulized format, with sections devoted to
Inheritance patterns
Clinical features (with histology, if relevant)
Differential diagnosis
Treatment considerations
While the emphasis in this issue is mainly on identification, clinical applications have also been presented wherever
pertinent. For consistency when identifying the syndromes,
we followed the custom of not using the possessive form,
even though we might sometimes be more accustomed
(incorrectly, I might add) to seeing the possessive form of the
E-mail address:
dmdeluke@vcu.edu
oralmaxsurgeryatlas.theclinics.com
Craniosynostosis Syndromes
Carolyn Dicus Brookes, DMD, MD, Brent A. Golden, DDS, MD,
Timothy A. Turvey, DDS*
KEYWORDS
Craniofacial dysostosis Craniosynostosis syndromes Crouzon Apert Pfeiffer Muenke
KEY POINTS
Craniosynostosis syndromes have wide phenotypic variability. Understanding of the underlying genetic causes continues to
develop.
Children with these syndromes are best managed at a multidisciplinary craniofacial center.
Early management focuses on airway protection, preservation of vision and hearing, and feeding.
Timing of craniofacial reconstruction is driven by growth and development of the area of interest.
In the past, intellectual disability was assumed. However, many patients with craniofacial dysostosis syndromes live rich
lives and have normal or even exceptional intellect provided they are raised in a nurturing, stimulating environment.
Crouzon syndrome
Genetics
FGFR2 mutations
Autosomal dominant; complete penetrance, variable
expressivity
Occasionally de novo
1.6:100,000; 4.5% of craniosynostosis cases2,10
Clinical features
Cardinal features:
Craniosynostosis
Midface/orbital hypoplasia
Clinically normal hands/feet
Crouzon syndrome, like all craniofacial dysostosis syndromes,
is classically characterized by premature fusion of the coronal
and frontosphenoidal sutures and the sphenoethmoidal synchondrosis.11 Fusion results in brachycephaly; midface deficiency; and a short, wide anterior cranial base. The forehead is
prominent because of compensatory growth at unaffected sutures. Additional sutures may be involved and rarely there is no
sutural involvement (Fig. 1).6,12,13
Exophthalmos is always present, largely because of orbital
hypoplasia with retruded supraorbital, infraorbital, and lateral
orbital rims. The widened cranial base can result in hypertelorism. Most patients have exotropia;14 orbital dystopia and
strabismus can be observed.15 Approximately 20% of patients
develop optic atrophy.14
Anteroposterior and vertical midface hypoplasia are
consistent features. Dental crowding, crossbite, and apertognathia are typical. Cleft lip and palate are rare.15
oralmaxsurgeryatlas.theclinics.com
104
Fig. 1 Crouzon syndrome. Frontal views of a child with Crouzon syndrome. The only prior procedures performed were placement of PET
and VP shunt. PET, pressure equalization tubes; VP, ventriculoperitoneal.
Other features
Typically normal intellect
Hydrocephalus (up to 30%); occasional nonprogressive
ventriculomegaly16,17
Hearing loss common18
Classically normal limbs/axial skeleton (occasional mild
anomalies)19e23
Cardiovascular anomalies rare
Differential diagnosis
If choanal atresia is present, consider Crouzon syndrome with
acanthosis nigricans. Apert, Pfeiffer, Jackson-Weiss, and
Saethre-Chotzen syndromes are diagnostic considerations.6
Apert syndrome
Genetics
FGFR2 mutations
Specific mutations linked to clinical features (ie, severe
craniofacial involvement)24
Most are de novo
Sometimes
autosomal
dominant;
complete
penetrance.2
1:100,000; 4% to 5% of craniosynostosis cases2,25,26
Clinical features
Cardinal features:
Craniosynostosis
Midface/orbital hypoplasia
Bilateral syndactyly of hands/feet (minimally second to
fourth digits)
Craniosynostosis Syndromes
105
Fig. 2 Apert syndrome. (AeC) Frontal, lateral and superior views of a 3-D CT reconstruction of an infant with Apert syndrome. Note the
wide midline calavarial defect and turribrachycephaly.
Fig. 3 Apert syndrome. (A) Frontal and profile views of another infant with Apert syndrome. (B) Hands and feet of the same child
demonstrating polysyndactyly. (C) Palatal view of the same patient as a teenager. Note the significant crowding, lateral palatal swellings,
and highly arched palate.
106
Differential diagnosis
Crouzon, Pfeiffer, Saethre-Chotzen, Jackson-Weiss, and Carpenter syndromes are considered, but the pattern of syndactyly usually clinches the diagnosis.6
Pfeiffer syndrome
Genetics43e45
FGFR2 mutations
Type 1 subset: FGFR1 mutation
Frequently no identifiable mutation
Type 1: autosomal dominant; complete penetrance, variable expressivity
Some type 1, types 2 and 3: de novo
Combined prevalence 1:100,0002,44
Clinical features
Cardinal features
Craniosynostosis
Midface/orbital hypoplasia
Broad thumbs/great toes (rarely thumbs normal)4,46
Variable partial soft tissue syndactyly (second and third
digits)44
Three phenotypic types of Pfeiffer syndrome have been
delineated.43
Patients with type I Pfeiffer syndrome are most likely to
have normal intelligence, although mild mental retardation
can be seen.43 The skull is turribrachycephalic. Midface retrusion, exophthalmos, hypertelorism, and nasal bridge
depression are variable. Strabismus is common, as is a high
arched palate with dental crowding.45,47
Features of type 2 Pfeiffer syndrome include cloverleaf skull,
severe exophthalmos, and central nervous system involvement
such as hydrocephalus. Elbow ankylosis or synostosis, choanal
atresia, and cleft palate may be present. Intellectual disability
is common. Patients often die early.2,6,43
Patients with type 3 Pfeiffer syndrome have a more severe
phenotype than those with type 1 with severe exophthalmos
and a very short anterior cranial base without cloverleaf skull.
Visceral anomalies and elbow ankylosis may be present. Early
death is common.43
Conductive hearing loss affects more than 80% of patients
regardless of subtype. Tracheostomy is often required for patients with types 2 and 3. Hydrocephalus and acquired tonsillar
herniation have been reported in most patients with type 1 and
all patients with type 3.48 Cervical fusion (typically C2eC3) is
seen more in types 2 and 3 (Fig. 4).49,50
Classical prognosis is poor for patients with types 2 and 3
Pfeiffer syndrome; however, some of these patients show
normal or only mildly delayed neurodevelopment.2
Differential diagnosis
Differential diagnosis includes Saethre-Chotzen and JacksonWeiss syndromes, although in the latter thumbs are
unaffected.43
Muenke syndrome
Genetics
FGFR3 mutation
Autosomal dominant; incomplete penetrance, variable
expressivity
Sometimes de novo51
1:30,00052; 8% of craniosynostosis cases9
Clinical features
Coronal synostosis (usually bilateral) and various minor anomalies characterize Muenke syndrome.
Phenotypic variation is considerable: additional sutures may
be involved or patients may be simply macrocephalic or even
normocephalic (Figs. 5 and 6).51e53 Females are affected more
severely.52e54 Mild midface hypoplasia, downslanting palpebral
fissures, mild ptosis, and high arched palate may be seen.
Strabismus is common.52 Ventriculomegaly, hydrocephalus,
and cervical spine anomalies are rare.16,55
Minor clinical anomalies of the hands and feet (brachydactyly, clinodactyly) affect some. Soft tissue syndactyly is
rare. Radiographic hand and foot abnormalities may be noted
despite an unremarkable clinical examination.51,55
Almost all patients have sensorineural hearing loss.53
Normal intellect is typical, although developmental delay affects roughly one-third of patients.51,52
Differential diagnosis
Muenke syndrome may be confused with other craniofacial
dysostosis syndromes or nonsyndromic craniosynostosis; genetic testing for all patients with coronal synostosis is thus
Craniosynostosis Syndromes
107
Fig. 5 Muenke syndrome. (A) Frontal and profile views of an infant with Muenke syndrome. (B) Frontal and lateral views of a 3-D CT
reconstruction of the same patient.
Fig. 6 Muenke syndrome. Frontal, lateral, and superior views of a 3-D CT reconstruction of another patient with Muenke syndrome. Note
the dramatic phenotypic variation.
108
Fig. 7
Other systems
A comprehensive medical evaluation is performed early in life.
Exophthalmos increases risk for corneal abrasion, exposure
keratitis, and globe trauma. Unaddressed strabismus can lead
to amblyopia. Early assessment by a pediatric ophthalmologist
is indicated, for these reasons and to monitor for papilledema.
Ocular lubrication, tarsorrhaphy, or early fronto-orbital
advancement are strategies to protect the globes.
Patients require regular evaluation for middle ear disorders
and hearing loss, which are common.
Timing of cleft palate repair depends on speech acquisition;
it may be delayed relative to routine cleft management.
Dental development should be monitored by a pediatric
dentist and an orthodontist.
Limb anomalies are managed by pediatric orthopedists.
Visceral anomalies are managed by the appropriate specialists.
Genetic evaluation and counseling are crucial.
The potential psychosocial and educational impact of these
conditions necessitates ongoing monitoring by a trained psychiatrist or psychologist.
Beaten copper skull appearance on a child with Crouzon syndrome prior to surgical intervention.
Craniosynostosis Syndromes
and orbital expansion, and forehead and orbital bandeau
reshaping, is typically performed in the first year of life.
Posterior expansion by conventional osteotomy or distraction may also be indicated. Reoperation is performed as
indicated.
Midfacial advancement to address orbital and zygomatic
deformities is performed in early childhood (after 5e7 years of
age), at which time the cranial vault and orbits approximate
90% of adult size.60 Midfacial advancement techniques include
monobloc advancement, facial bipartition, and subcranial Le
Fort III osteotomy; a technique is selected based on the individual patients situation. The anteroposterior deficiency at
the orbital rim and the dentate level nearly always differ;
treatment at this phase is directed toward correction of the
orbital and forehead deficiencies.
Further midfacial advancement and onlay grafting is nearly
always required at skeletal maturity. Orthodontic decompensation and orthognathic surgery are then performed.
Esthetic nasal and soft tissue surgery are best delayed until
after orthognathic surgery.
Summary
The craniosynostosis syndromes are varied but they share
several common features and therefore share guiding principles of management. Individual care is best rendered through a
multidisciplinary team with established protocols that offer
flexibility for and attention to individual patient needs. This
collaborative care model has significantly improved outcomes
in patients with these conditions. Decades ago it was common
for these patients to be condemned to asylums or sheltered in
homes with no social interaction. Today many are well
educated, productive members of society. These changes have
occurred because of comprehensive team care and recognition
that these conditions are often more socially than intellectually incapacitating.
Early priorities are airway management, protection of vision
and hearing, and nutritional support. Craniofacial surgical
intervention is staged with cranial vault reconstruction in the
first year of life, correction of the total midface and orbital
deficiency after 5 to 7 years of age, and maxillomandibular
advancement in the teenage years. Given the low incidence of
these syndromes, critical evaluation of outcomes by those
involved with the care of these patients is crucial to ensure
optimal outcomes.
References
1. Kimonis V, Gold JA, Hoffman TL, et al. Genetics of craniosynostosis. Semin Pediatr Neurol 2007;14:150.
2. Robin NH, Falk MJ, Haldeman-Englert CR. FGFR-related craniosynostosis syndromes. In: Pagon RA, Adam MP, Bird TD, et al,
editors. GeneReviews [Internet]. Seattle (WA): University of
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at: http://www.ncbi.nlm.nih.gov/books/NBK1455/. Accessed
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3. Forrest CR, Hopper RA. Craniofacial syndromes and surgery. Plast
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4. Cohen MM. Craniosynostoses: phenotypic/molecular correlations.
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5. Posnick JC, Ruiz RL. The craniofacial dysostosis syndromes: current surgical thinking and future directions. Cleft Palate Craniofac J 2000;37:433.
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6. Hennekam RC, Krantz ID, Allanson JE. Gorlins syndromes of the
head and neck. 5th edition. New York: Oxford University Press;
2010. p. 732e91.
7. Roscioli T, Elakis G, Cox TC, et al. Genotype and clinical care
correlations in craniosynostosis: findings from a cohort of 630
Australian and New Zealand patients. Am J Med Genet C Semin
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8. Heike C, Seto M, Hing A, et al. Century of Jackson-Weiss syndrome: further definition of clinical and radiographic findings in
lost descendants of the original kindred. Am J Med Genet 2001;
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9. Morriss-Kay GM, Wilkie AO. Growth of the normal skull vault and
its alteration in craniosynostosis: insights from human genetics
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10. Cohen MM, Kreiborg S. Birth prevalence studies of the Crouzon
syndrome: comparison of direct and indirect methods. Clin Genet
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11. Burdi AR, Kusnetz AB, Venes JL, et al. The natural history and
pathogenesis of the cranial coronal ring articulations: implications in understanding the pathogenesis of the Crouzon craniostenotic defects. Cleft Palate J 1986;23:28.
12. Kreiborg S, Marsh JL, Cohen MM, et al. Comparative threedimensional analysis of CT-scans of the calavaria and cranial base
in Apert and Crouzon syndromes. J Craniomaxillofac Surg 1993;
21:181.
13. Kreiborg S, Cohen MM. Is craniofacial morphology in Apert and
Crouzon syndromes the same? Acta Odontol Scand 1998;56:339.
14. Kreiborg S, Cohen MM. Ocular manifestations of Apert and Crouzon syndromes: Qualitative and quantitative findings. J Craniofac
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15. Cohen MM, Kreiborg S. A clinical study of the craniofacial features
in Apert syndrome. Int J Oral Maxillofac Surg 1996;25:45.
16. Collmann H, Sorensen N, Krauss J. Hydrocephalus in craniosynostosis: a review. Childs Nerv Syst 2005;21:902.
17. Cinalli G, Sainte-Rose C, Kollar EM, et al. Hydrocephalus and
craniosynostosis. J Neurosurg 1998;88:209.
18. Orvidas LJ, Fabry LB, Diacova S, et al. Hearing and otopathology
in Crouzon syndrome. Laryngoscope 1999;109:1372.
19. Proudman TW, Moore MH, Abbot AH, et al. Noncraniofacial
manifestations of Crouzons disease. J Craniofac Surg 1994;5:218.
20. Hemmer KM, McAlister WH, Marsh JL. Cervical spine anomalies in
the craniosynostosis syndromes. Cleft Palate J 1987;24:328.
21. Anderson PJ, Hall C, Evans RD, et al. The cervical spine in Crouzon
syndrome. Spine 1997;22:402.
22. Anderson PJ, Hall CM, Evans RD, et al. The elbow in syndromic
craniosynostosis. J Craniofac Surg 1998;9:201.
23. Murdoch-Kinch CA, Ward RE. Metacarpophalangeal analysis in
Crouzon syndrome: additional evidence for phenotypic convergence with the acrocephalosyndactyly syndromes. Am J Med
Genet 1997;73:61.
24. Von Gernet S, Golla A, Ehrenfels Y, et al. Genotype-phenotype
analysis in Apert syndrome suggests opposite effects of the two
recurrent mutations on syndactyly and outcome of craniofacial
surgery. Clin Genet 2000;57:137.
25. Tolarova MM, Harris JA, Ordway DE, et al. Birth prevalence, mutation rate, sex ratio, parents age, and ethnicity in Apert syndrome. Am J Med Genet 1997;72:394.
26. Cohen MM, Kreiborg S, Lammer EJ, et al. Birth prevalence study
of the Apert syndrome. Am J Med Genet 1992;42:655.
27. Cohen MM, Kreiborg S. Growth pattern in the Apert syndrome. Am
J Med Genet 1993;47:617.
28. Smith RJ, Jackson IT. Anatomy and significance of the temporal fat pad in Apert syndrome. Cleft Palate Craniofac J 1994;
31:224.
29. Khong JJ, Anderson P, Gray TL, et al. Ophthalmic findings in Apert
syndrome prior to craniofacial surgery. Am J Ophthalmol 2006;
142:328.
30. Tay TM, Martin F, Rowe N, et al. Prevalence and causes of visual
impairment in craniosynostosis syndromes. Clin Experiment Ophthalmol 2006;34:434.
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31. Farkas LG, Kolar JC, Munro IR. Craniofacial disproportions in
Apert syndrome: an anthropometric study. Cleft Palate J 1985;
22:253.
32. Solomon LM, Medenica M, Pruzansky S, et al. Apert syndrome and
palatal mucopolysaccharides. Teratology 1971;8:287.
33. Peterson SJ, Pruzansky S. Palatal anomalies in the syndromes of
Apert and Crouzon. Cleft Palate J 1974;11:394.
34. Letra A, Fraga de Almeida AL, Kaizer R. Intraoral features of
Aperts syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 2007;103:e38.
35. Kreiborg S, Cohen MM. The oral manifestations of Apert syndrome. J Craniofac Genet Dev Biol 1992;12:41.
36. Quintero-Rivera F, Robson CD, Reiss RE, et al. Intracranial
anomalies detected by imaging studies in 30 patients with Apert
syndrome. Am J Med Genet 2006;140A:1337.
37. Gould HJ, Caldarelli DD. Hearing and otopathology in Apert syndrome. Arch Otolaryngol 1982;108:347.
38. Rajenderkumar D, Bamiou DE, Sirimanna T. Audiological profile in
Apert syndrome. Arch Dis Child 2005;90:592.
39. Cohen MM, Kreiborg S. Hands and feet in the Apert syndrome. Am
J Med Genet 1995;57:82.
40. Cohen MM, Kreiborg S. Visceral anomalies in the Apert syndrome.
Am J Med Genet 1993;45:758.
41. Margolis S, Siegel IM, Choy A, et al. Oculocutaneous albinism
associated with Aperts syndrome. Am J Ophthalmol 1977;84:830.
42. Cohen MM, Kreiborg S. Letter to the editor: cutaneous manifestations of Apert syndrome. Am J Med Genet 1995;58:94.
43. Cohen MM. Pfeiffer syndrome update, clinical subtypes, and
guidelines for differential diagnosis. Am J Med Genet 1993;45:300.
44. Vogels A, Fryns JP. Pfeiffer syndrome. Orphanet J Rare Dis
2006;1:19.
45. Greig AV, Wagner J, Warren SM, et al. Pfeiffer syndrome: analysis
of a clinical series and development of a classification syndrome.
J Craniofac Surg 2013;24:204.
46. Kerr NC, Wilroy RS, Kaufman RA. Type 3 Pfeiffer syndrome with
normal thumbs. Am J Med Genet 1996;66:138.
47. Cohen MM. An etiologic and nosologic overview of craniosynostosis syndromes. Birth Defects Orig Artic Ser 1975;11:137.
48. Fearon JA, Rhodes J. Pfeiffer syndrome: a treatment evaluation.
Plast Reconstr Surg 2009;123:1560.
49. Moore MH, Lodge ML, Clark BE. Spinal anomalies in Pfeiffer syndrome. Cleft Palate Craniofac J 1995;32:251.
50. Anderson PJ, Hall CM, Evans RD, et al. Cervical spine in Pfeiffers
syndrome. J Craniofac Surg 1996;7:275.
51. Muenke M, Gripp KW, McDonald-McGinn DM, et al. A unique point
mutation in the fibroblast growth factor receptor 3 gene (FGFR3)
defines a new craniosynostosis syndrome. Am J Hum Genet 1997;
60:555.
52. Agochukwu NB, Doherty ES, Muenke M. Muenke syndrome. In:
Pagon RA, Adam MP, Bird TD, et al, editors. GeneReviews
53.
54.
55.
56.
57.
58.
59.
60.
Further readings
Forrest CR, Hopper RA. Craniofacial syndromes and surgery. Plast
Reconstr Surg 2012;131:86e.
Hennekam RC, Krantz ID, Allanson JE. Gorlins syndromes of the
head and neck. 5th edition. New York: Oxford University Press;
2010. p. 732e91.
McCarthy JG, Warren SM, Bernstein J, et al. Parameters of care for
craniosynostosis. Cleft Palate Craniofac J 2012;49:1S.
Posnick JC, Ruiz RL. The craniofacial dysostosis syndromes: current
surgical thinking and future directions. Cleft Palate Craniofac J
2000;37:433.
Robin NH, Falk MJ, Haldeman-Englert CR. FGFR-related craniosynostosis
syndromes. In: Pagon RA, Adam MP, Bird TD, et al, editors. GeneReviews [Internet]. Seattle (WA): University of Washington; 1998.
p. 1993e2013. Updated 2011 Jun 7. Available at: http://www.ncbi.
nlm.nih.gov/books/NBK1455/. Accessed December 22, 2013.
Introduction
This article is a clinical description of genetic diseases that
affect facial bones, giving rise to dysmorphic facies. It is by no
means complete, rather it is meant to serve as an outline of
skeletal anomalies that can provide structure for oral and
maxillofacial surgeons to screen the patients that they
encounter. The reader should have access to other sources,
such as Gorlin Syndromes of the Head and Neck, Sixth Edition;
Smiths Recognizable Patterns of Human Malformation by
Jones; and The Management of Genetic Syndromes by Cassidy
and Allanson.
When evaluating bone diseases of the jaws and considering
a syndromic etiology, the clinician needs to first characterize
what is observed. Is the process radiolucent or radiopaque?
Does this condition result in skeletal dysplasia, hyperplasia, or
hypoplasia? Is this a local, monostotic, regional, or polyostotic
phenomena? Finally, what other abnormalities are present in
this patient. Is this observed bony pathology a component of a
constellation of findings, that is, a syndrome involving multiple
pathologic entities? If there are multiple disorders, are they
associated with potential for genetic transmission?
Although today there seems to be a limited number of
conditions that affect the maxillofacial skeleton that are truly
genetic in order, as our ability to understand the human
genome and characterize individuals and their genetic
sequence increases, undoubtedly many more clusters of
genetically coded phenotypic expressions will be identified. In
addition, what appears outwardly as an external independent
source of disease or deformity may turn out to be genetically
predetermined. For example, there is no doubt that medication-related osteonecrosis of the jaw (MRONJ) can be related
Disclosure: None.
The New York Center for Orthognathic and Maxillofacial Surgery,
State University of New York at Stony Brook, Hofstra North Shore-Long
Island Jewish School of Medicine, 2001 Marcus Avenue, Lake Success,
New York 11042, USA
E-mail address: drsachs@nycoms.com
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 111122
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.06.002
to the use of bisphosphonates that inhibit osteoclast formation. However, it is becoming apparent that there are clusters
of patients with genetic sequences that increase susceptibility
to this class of drugs, rendering the patient increasingly susceptible to MRONJ. That being said, there are classic syndromes that affect bone and are associated with other physical
abnormalities that are genetically transmitted. These are
illustrated in this article.
Osteopetrosis
Genetics
Osteopetrosis is autosomal recessive in its neonatal form and is
often called marble bone disease. The autosomal dominant
form, often called late onset, is more benign in its clinical
nature and is divided into a Type 1 and Type 2 expression. The
prevalence is about 1 in 250,000 births. There is a higher
incidence of this condition in Costa Rica, Saudi Arabia, and
Denmark (1/20,000).
Clinical features
Osteopetrosis is a generalized disease of bone in which there is
failure of normal bone remodeling by resorption or an overproduction of bone. Various defects in osteoclast or osteoblast
function have been implicated. As a consequence, the bone
becomes dense and radiopaque with a radiographic homogeneity between the cortical and medullary bone (Fig. 1). There
are various clinical forms of this disease. The worst outcomes
nberg disease.
are seen with the neonatal form, Albers-Scho
This entity is generally fatal, although early bone marrow
transplantation can slow the progression of the disease process. Most patients do not live beyond adolescence.
The progressive density of affected bones without a
resorptive phase promotes early fracture and encroachment on
the cranial nerve foramina resulting in diminished vision,
hearing, and fifth nerve function. Extramedullary hematopoiesis may result in hepatosplenomegaly and pancytopenia.
oralmaxsurgeryatlas.theclinics.com
112
Sachs
Fig. 1 Montage of patient with sclerotic bones associated with osteopetrosis. (A) Bowed femur. (B) Dense vertebra with lack of normal
spine. (C) Sclerotic mandible with multiple unerupted molars. (DeF) Enlarged calvarium. (G, H) Sclerotic and thickened zygoma and
mandible. (I) Diffuse ostesclerosis noted on chest x ray. (JeL) Radiodense feet, hands, and pelvis. (From Xue Y, Wang W, Mao T, et al.
Report of two Chinese patients suffering from CLCN7-related osteopetrosis and root dysplasia. J Craniomaxillofac Surg 2012;40:416e20;
with permission.)
Differential diagnosis
Although the infantile neonatal form presents with a unique
clinical presentation, the benign form of the disease, which
can affect the mandible, cranium, and cervical spines with a
sclerotic process, needs to be differentiated from other forms
of osteosclerosis, such as Van Buchens disease, osteopathia
straita, and sclerosteosis.
Fig. 2 Draining cutaneous fistulae secondary to chronic osteomyelitis, a common finding when the osteopetrotic jaws are
subject to trauma, including dental extractions. (Courtesy of
D. Sarasin, DDS, Cedar Rapids, IA.)
Clinical features
Osteopathia straita is a bone disease that is characterized by
enlarged sclerotic craniofacial bones. The facial appearance is
square and broad. Although dense and enlarged, the midface
lacks projection (Fig. 3A). The encroachment on the cranial
foramina results in cranial nerve dysfunction (Fig. 3B). More
than 50% of patients have hearing loss. Along with characteristic craniofacial changes, the long bones demonstrate a
peculiar linear striation giving a combed-through appearance
(Fig. 3C). Other craniomaxillofacial features include frontal
bossing, hypertelorism, hearing loss, cleft palate, bifid uvula,
and a dense cranial base (Fig. 3D). Temporomandibular joint
ankylosis has been described.
Other systemic findings include ventricular septal defect,
atrial septal defect, laryngeal tracheal malacia, polydactyly,
and syndactyly. This condition is a frequent feature of focal
dermal hypoplasia.
113
However, the unusual linear striations of the long bones are
almost pathognomonic, but can be seen in benign forms of
osteopetrosis.
Clinical features
Differential diagnosis
The craniofacial presentation needs to be differentiated from
osteopetrosis as well as other craniosclerotic syndromes.
Fig. 3 (A) Patient with osteopathia striata; note the pseudo prognathism secondary to maxillary hypoplasia. (B) This 3-dimensional (3D)
cone-beam computed tomography (CT) image demonstrates diffuse sclerosis of the facial bones, orbits, and mandible. As time progresses,
the foramina may close around existing nerves, causing hypoesthesia or dysfunction. (C) Long bone of a patient with osteopathia striata.
Note longitudinal linear striations, as well as fracture of distal fibula. (D) Lateral cephalogram in patient with osteopathia striata. Note
markedly thickened skull base, obliteration of maxillary sinus with sclerotic bone and density to skull, mandible, and cervical spines. ([C]
Courtesy of E. Winn, MD, Long Island, NY.)
114
age. This disease is characterized by painful burning and
swelling over the face and jaws (Fig. 4A). This swelling might
also involve the thorax and extremities (Fig. 4B). This is an
inflammatory process accompanied by fever, with elevated
white blood cell count and increased sedimentation rate.
According to Eversole, The histology is one of elevated
periosteal new bone formation. This may be related to
congenital anomalies of the vessels supplying the periosteum
and causing the involved bones to be hypoxic, become
necrotic, and create overlying soft tissue inflammation and
eventually new bone formation in the periosteum (Fig. 4C).
Sachs
Clinical features
SOD is characterized by unilateral expansion of the posterior
maxilla, gingival hyperplasia, lack of one or both premolars,
delayed eruption of teeth, and hypoplastic or ghost teeth. The
affected bone exhibits a course radiopaque appearance not
unlike the ground-glass look of fibrous dysplasia; however, the
trabeculation appears vertical in orientation (Fig. 5A). This
condition usually presents in childhood and affects boys more
frequently than girls. Another unusual feature of this syndrome
is the associated facial cutaneous lesions characterized by
hypertrichosis and hyperpigmentation, which may be considered a Becker nevus (Fig. 5B, C).
Differential diagnosis
Fibrous dysplasia
Ossifying fibroma
Hemimaxillofacial dysplasia
Regional odontodysplasia
Genetics
Fig. 4 (A) Infantile cortical hyperostosis: note bilateral tender swelling of the face and erythema of overlying skin. (B) Lower extremity
swelling in patient with Caffey Silverman syndrome. (C) Periosteal new bone formation (arrow) seen in infantile cortical hyperostosis. In
time this will resolve and return to normal form. ([A, C] From Wong YK, Cheng JC. Infantile cortical hyperostosis of the mandible. Br J Oral
Maxillofac Surg 2008;46:498; with permission; and [B] Courtesy of Department of Radiology, Childrens Hospital of Pittsburgh, Pittsburgh,
PA.)
115
Fig. 5 (A) Cross sections through maxillary bone in a patient with SOD. Note homogeneous radiopacity and missing premolars. As this
process evolves, vertical linear striations may be seen. (B) A 9-year-old with SOD: faint, pigmented hypertrichotic lesion on the right face
associated with a focal osteosclerotic process in the underlying maxilla. (C) Same patient at age 17: note increase in pigmentation and
presence of hair. This is often referred to as Becker nevus.
Cherubism
Genetics
This is an autosomal dominant disease with multiple spontaneously occurring cases. A mutation of gene SH3BT2 is known
to cause cherubism.
Clinical features
Cherubism is a bilateral progressive enlargement of the maxilla
and mandible. First called familial fibrous dysplasia by Jones in
1933, the name was modified to cherubism because of the
angelic or cherubic look of the affected children who appeared
to be looking up to heaven (Fig. 6A). The onset is between ages
2 and 5 years. The swelling of jaws is progressive and can be
extensive. Lesions tend to stop expanding at puberty and
regress during adulthood.
The radiographic picture is characteristically expansile
multilocular soap-bubbleetype radiolucencies. They create
116
Sachs
Fig. 6 (A) A 9-year-old boy with cherubism. Note bilateral facial enlargement with upward pointing pupils and inferior scleral show.
(B) Sagittal section of patient with cherubism. Note orbital extension that created diplopia. The multilocular radiolucencies are typical
of cherubism. Biopsy revealed a multinucleated giant cell lesion consistent with cherubism. (C) The same patient as in (A) seen 20 years
later, showing significant recontouring of the previous expansile process. (D) Radiolucent, soap-bubble appearance of lesion involving
the bilateral mandible and the right maxilla in a patient with cherubism. Note orthodontic therapy aligning the dentition in the
presence of this disease process. (E) The previous expansile multilocular radiolucency seen in (D) has become more sclerotic and
corticated.
Differential diagnosis
Genetics
Includes fibrous dysplasia, giant cell lesions of the jaws, brown
tumor of hyperparathyroidism.
Typically cherubism does not cause elevation in serum calcium, alkaline phosphatase, or acid phosphatase.
Clinical features
Although most fibrous dysplasias are solitary lesions and are
nonsyndromic, when multiple bones are involved (polyostotic),
one must consider McCune Albright syndrome (Fig. 7). The
hallmarks of this entity are the following:
1. Polyostotic fibrous dysplasia
au lait (coast of California)
2. Cafe
3. Abnormal function of one or more endocrine glands
causing hyperthyroidism, hyperparathyroidism, pituitary
adenomas, acromegaly, precocious puberty, and diabetes
mellitus
The abnormal facial growth pattern is usually unilateral
and often involves the craniofacial bones. Only 3% of patients
with polyostotic fibrous dysplasia have McCune-Albright syndrome. The long bones are most commonly affected, producing a bowing of the femur in what has been termed
shepherds crook or hockey stick abnormality. The facial
bones show expansion and increased radiodensities, including
at the sphenooccipital base of the skull. The orbit, cranium,
skull base, and mandible can be involved with this very typical
ground-glass appearance.
117
Differential diagnosis
Polyostotic fibrous dysplasia.
Osteogenesis imperfecta
Genetics
This is an autosomal dominant disease that is caused by
mutation of 2 genes that encode type I collagen, specifically
COL1A1 and COL1A2. The prevalence of this condition is 1 in
20,000 births.
Clinical features
Osteogenesis imperfecta are a group of inherited connective
tissue disorders that affect type I collagen and result in bone
abnormalities characterized by easy fracture (Fig. 8). It is
often called brittle bone disease. In all, there are 9 types. Type
1 is the most common by far and type 2 is always lethal. The
Fig. 7 (A) Expanded maxilla in a patient with McCune-Albright syndrome. This patient went on to have multiple endocrine neoplastic
au lait (coast of California) seen in a
diseases and continued craniofacial bone enlargement over 3 decades. (B) Regular-border cafe
patient with McCune-Albright syndrome. (C) At age 16, despite several contouring procedures, the disease produced a canted and enlarged
right maxilla that was eventually corrected with a LeFort I osteotomy. (D) Radiograph demonstrating an asymmetric maxilla with
opacification of the sinus.
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Sachs
Fig. 8 (A) A 14-year-old with type 1 osteogenesis imperfecta. Note the class III malocclusion secondary to maxillary hypoplasia. (B) A
14-year-old patient with osteogenesis imperfecta. Note marked mandibular prognathism and abnormal cervical spines. (C) Dentinogenesis
imperfecta in the same patient. This condition, which is generally autosomal dominant, is recessive in patients with osteogenesis
imperfecta. (D) Blue sclera as seen in various forms of osteogenesis imperfecta. This finding results from a thin and translucent scleral
layer, which allows the bluish choroid layer to become more apparent. (E) A patient with osteogenesis imperfecta demonstrating short
stature with bowing of the extremities. The bones in these patients fracture easily and often. Treatment with antiosteoclast medications,
such as bisphosphonates, or with pro-osteoblastic agents has shown some promise in treating these patients. ([E] From Horton WA, Hall JG,
Hecht JT. Achondroplasia. Lancet 2007; 370:162e72; with permission.)
Marfan syndrome
Genetics
This is an autosomal dominant trait with a wide variation in
expression. It involves a mutation of the fibrillin gene FBN1,
which is located on the 15q15-21.3 chromosome.
Clinical features
Marfan syndrome is a genetic connective tissue disorder
affecting the formation of fibrillin type-I. This protein is a
major component of microfibrils, which interact with elastin
119
deficiency. Once identified, these patients should be evaluated
for aortic aneurysm and may require antibiotic prophylaxis
before oral surgical care. Two important studies in working up
patients with Marfan syndrome are echocardiography, which is
positive in 90% of the cases, and slit lamp examination of the eye.
These patients are often on long-term beta-blocker therapy.
Clinical features
This syndrome presents with aplasia or hypoplasia of one or
both clavicles, associated with delayed closure of the fontanelles, exaggerated transverse foramen of the cranium, and
multiple impacted and nonerupted teeth (Fig. 10). Patients
with cleidocranial dysplasia have short stature with a brachycephalic skull. They demonstrate frontal bossing. The maxilla
and zygoma are hypoplastic, creating a skeletal class III relationship. The patients have a broad nasal base and hypertelorism. The paranasal sinuses are underdeveloped or absent.
The absence of clavicular continuity creates a wide range of
shoulder movements. Spina bifida occulta occur throughout the
spine and cone-shaped epiphyses are present in the distal
phalanges. The oral findings include a high arched palate,
submucous or complete clefting of the hard and soft palate,
and delayed union of the mandibular symphysis. These patients
present with multiple impacted and supernumerary teeth, the
Fig. 9 (A) A 12-year-old female with Marfan syndrome presenting with a typical long face, incompetent lips, hypertelorism, and downslanting palpebral fissure. (B) The long fingers in Marfan patients have been described as spiderlike (arachnodactyly). The index finger may
wrap around the wrist with a phalanx to spare (positive wrist sign). The fingers can often be bent backwards and are extremely flexible due
to the defective connective tissue. (C) Mandibular prognathism may be the primary reason for a patient with Marfan syndrome to consult
with an oral and maxillofacial surgeon.
120
Sachs
Fig. 10 (A) A patient with cleidocranial dysplasia demonstrating maxillary hypoplasia, hypertelorism, and frontal bossing. (B) The same
patient with cleidocranial dysplasia (CCD) demonstrating multiple unerupted teeth and class III malocclusion. (C) Panoramic and 3D CT image
demonstrating multiple impacted teeth. Selective extractions and surgical exposures in combination with orthodontics can result in a
functional dentition for these patients. (D) This patient demonstrates easy midline rotation of shoulders due to congenitally absent clavicles.
Differential diagnosis
The combination of short stature, absent clavicles, and multiple impacted teeth is pathognomonic of this condition.
Clinical features
Genetics
121
Fig. 11 (A) A patient with thalassemia demonstrating a displaced maxilla secondary to extramedullary hematopoiesis filling the
maxillary sinuses. Note the grossly incompetent lips and skin pallor. (B) Lateral cephalogram demonstrating vertical maxillary excess,
obliterated maxillary sinuses, and hair-on-end pattern of the skull. This is secondary to marrow proliferation in the diploe and loss of the
outer skull cortex. (C) Intraoperative photograph showing the excision of a section of the maxilla for treatment of maxillary hyperplasia in
a patient with thalassemia major. (D) Postoperative photograph of the patient in (A) after posterior and superior repositioning of the
maxilla.
Suggested readings
Cassidy and Allanson. The Management of Genetic Syndromes.
Hennekam R, Allanson J, Krantz I. Gorlin Syndromes of the Head and
Neck. 6th edition.
Jones KL. Smiths Recognizable Patterns of Human Malformation.
Osteopetrosis
Gorlin Syndromes of the Head and Neck. p. 245.
Jones; Smiths recognizable Patterns of Human Malformation. p. 453e5.
Makarem, et al. Osteopetrosis: oral and maxillofacial manifestations.
Int J Head Neck Surg 2012;3(2):115e7.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:356e65.
122
hemimaxillofacial dysplasia. Oral Surg Oral Med Oral Pathol 1990;
70(1):81e5.
Gorlin Syndromes of the Head and Neck. p. 1169.
Kuklani RM, Nair MK. Segmental odontomaxillary dysplasia: review of
the literature and case report. Int J Dent 2010;2010:837283.
Welsch MJ, Stein SL. A syndrome of hemimaxillary enlargement,
asymmetry of the face, tooth abnormalities, and skin findings
(HATS). Pediatr Dermatol 2004;21(4):448e51.
Cherubism
Carvalho SE, Carvalho Silva GC, Vieira TC. Cherubism: clinicoradiographic features, treatment, and long-term follow-up of 8 cases.
J Oral Maxillofac Surg 2007;65(3):517e22.
Gorlin Syndromes of the Head and Neck. p. 1218.
Osteogenesis imperfecta
Gorlin Syndromes of the Head and Neck. p. 219.
Jones; Smiths Recognizable Patterns of Human Malformation.
p. 562.
Sachs
Kindelan J, Tobin M, Roberts-Harry D, et al. Orthodontic and orthognathic management of a patient with osteogenesis imperfecta and
dentinogenesis imperfecta: a case report. J Orthod 2003;30(4):
291e6.
Marfan syndrome
Becker A, Lustmann J, Shteyer A. Cleidocranial dysplasia:
Part 1eGeneral principles of the orthodontic and surgical
treatment modality. Am J Orthod Dentofacial Orthop 1997;
111(1):28e33.
Beighton, et al. International nosology of heritable disorders of
connective tissue. Am J Med Genet 1988;29(3):581e94.
De Paepe A, Devereux RB, Dietz HC, et al. Revised diagnostic
criteria for the Marfan syndrome. Am J Med Genet 1996;62(4):
417e26.
Gorlin Syndromes of the Head and Neck. p. 1283e9.
Jones; Smiths Recognizable Patterns of Human Malformation, chapter
546.
Marfan AB. Un Cas de Deformation Congenitales Desquatre, 1986-Paris.
Pyeritz RE. The Marfan syndrome. Annu Rev Med 2000;51:481.
Fabry disease
Key points
Fabry disease, also known as Anderson-Fabry disease, is
an inherited X-linked recessive disorder of lysosomal
storage.1e3
Fabry disease is the second most prevalent lipid storage
disease after Gaucher disease and occurs from a deficient activity of lysosome hydrolase, alpha-galactosidase A.1e4
Genetics
The alpha-galactosidase A gene has been mapped to the region
q22.1 of the X chromosome.5e8 When mutated, a progressive
accumulation of a glycolipid called globotriaosylceramide
(Gb3) affects mainly endothelial and vascular smooth muscle
cells and causes damage to many major organs1 including renal
and cardiac insufficiency,2 and central nervous system disorders including cerebral infarction and skin and pulmonary
symptoms.1e4,9e11 It is mostly a male disease with the reported
incidence varying from 1 in 17,000 to 1 in 117,000 men in white
populations.12e14 However, this disease is probably unreported
because many of the manifestations are nonspecific, the disease is rare, and often the initial diagnosis is not accurate.4
Women can have the disease but usually have milder symptoms
that occur later in life.15e17 There are rare reports of women
being asymptomatic early in life, but then showing symptoms
as severe as those of men with the classic phenotype.15,16
The author has nothing to disclose.
a
Private Practice, Long Island Oral and Maxillofacial Surgery, P.C.,
134 Mineola Boulevard, Mineola, New York 11501, USA
b
Division of Oral and Maxillofacial Surgery, Nassau University Medical
Center, 2201 Hempstead Turnpike, East Meadow, New York 11554, USA
* Division of Oral and Maxillofacial Surgery, Nassau University Medical Center, 134 Mineola Boulevard, Mineola, NY 11590.
E-mail address: vnannini@hotmail.com
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 123134
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.05.005
Clinical features
Clinical manifestations of the disease often occur early in life,
caused by the increase in glycolipids, which causes inflammation and fibrosis.3 Therefore, severe neurologic pain in the
limbs, especially during times of stress, begins around the age
of 10 years.4 Renal dysfunction with proteinuria and polyuria,
often leading to renal failure, is one of the serious complications of the disease.3 Skin lesions are often present, including
hypohidrosis and angiokeratomas.4 The labial mucosa is often
involved with a maculopapular eruption (Fig. 1). Corneal
changes are usually an early sign with a whorl-like keratopathy
seen on a slit lamp examination (Fig. 2).11,18,19 As these patients age, central nervous system involvement often leads to
increased incidence of stroke.20,21 Cardiovascular effects
include hypertension and cardiomyopathy with eventual heart
failure.4,22 Oral and maxillofacial findings include increased
prevalence of maxillary cysts and maxillary prognathism.23
Thickening of the lips and a bulbous nose have been described
in many cases.4 Perioral linear telangiectases24 and cases of
granulomatous cheilitis and granulomatous gingivitis25e27 are
noted. Tinnitus is reported in approximately 40% of patients
with this disorder.4 Because of the severe major organ
dysfunction, most of these patients die at an early age secondary to stroke, end-stage renal failure, or cardiovascular
complications.
Differential diagnosis
Because this disorder is rare, it is often misdiagnosed because
of early nonspecific manifestations, including neurologic and
skin disorders. These disorders can include rheumatoid
arthritis, fibromyalgia, multiple sclerosis, and Meniere disease.4 The disorder is often discovered following more
serious complications such as stroke, cardiac insufficiency,
and renal failure.20e22,28e30 Because treatment with enzyme
replacement therapy has been shown to have positive results,
early diagnosis of Fabry disease is important. When suspected, serum assays of leukocyte alpha-galactosidase A
activity are effective in men; however, genetic testing
in women is recommended because of inclusive serum
results.4
oralmaxsurgeryatlas.theclinics.com
124
Nannini
Fig. 2 Faint but extensive vortex keratopathy seen on retroillumination. (From Kanski J. Clinical diagnosis in ophthalmology.
Cornea. 1st edition. Philadelphia: Mosby, an imprint of Elsevier;
2006. Fig. 6.232; with permission; and Courtesy of W. Lisch, MD,
Hanau, Germany.)
Clinical features
Oral surgeons should be suspicious that any patient displaying
angiokeratomas of the face, cheilitis granulomatosa, or granulomatous gingivitis may have the potential for Fabry disease,
especially young men. With late-stage disease and renal, cardiac, and neurologic complications, treatment must be carefully administered with close consultation with the appropriate
specialists.
Williams syndrome
Key points
Williams syndrome, also known as Williams-Beuren
syndrome, is a rare autosomal dominant neurodevelopmental disorder affecting men and women
equally.1e3
Williams syndrome was first discovered in 1961 by J.C.P.
Williams, who found patients with supravalvar aortic
stenosis, facial anomalies, and mental retardation.4
Independently in 1962, A.J. Beuren found similar phenomena in his patients but also certain dental characteristics and pulmonary artery stenosis.5
Genetics
Williams syndrome and its manifestations seem to result from a
1.5-Mb deletion on the number 7 chromosome pair at 7q11.23,
which includes 26 to 28 genes.6e11 This deletion significantly
affects the production of elastin, which leads to supravalvar
aortic stenosis and other cardiovascular disorders such as peripheral artery stenosis.6,12e14 The other characteristics of this
disease arise because adjacent genes responsible for facial and
neural development are located in the deletion.12,15 The
Williams syndrome is characterized by its elfin facial appearance,17,18 growth delays with low body weight,19,20 mental
retardation,16,17 cardiovascular disorders,1,4,5,21e28 sleep disorders,29 and transient hypercalcemia, usually as infants. These
patients tend to have intelligence quotients in the 50 to 60 range
and are overly friendly, extremely talkative, with severe bouts
of anxiety.12,16,17 The facial abnormalities (Fig. 3) include periorbital fullness, full upper and lower lips, long philtrum, flat
nasal bridge, micrognathia, and abnormal dentition (Fig. 4)
including hypocalcification of the enamel, short and narrow
primary teeth, and crowded permanent teeth.12,18,19,30e35
Hyperacusis has been noted to be present in most patients.36
Although it is been reported that there is an increase in gingival
height and width of these patients, there was no increase in loss
of attachment.31,32,37e39 There have been reports in the literature of keratoconus,40 multiple sclerosis,41 Crohns disease,42
and Burkitts lymphoma,43 but these are rare.
Differential diagnosis
Some of the symptoms of Williams syndrome are also found in
other disorders. Patients with Noonan syndrome have similar
facial appearances, including micrognathia, flat nasal
bridge,1,44 and leprechaunism (an endocrine disorder that
produces elfin facial features and growth retardation).45 Idiopathic infantile hypercalcemia not related to Williams syndrome has been reported.46 The definitive diagnostic test for
Williams syndrome is the fluorescence in-situ hybridization
test, which conclusively shows the gene deletion.16,47,48
125
Hurler syndrome
Key points
Hurler syndrome is a rare autosomal recessive disease
that is classified in a group of disorders called mucopolysaccharidosis. It is also known as mucopolysaccharidosis type 1-H.
First described by Dr Gertrud Hurler in 1919, Hurler
syndrome was discovered in 2 unrelated boys with
similar characteristics including mental impairment,
distortion of facial features, respiratory and cardiac
disease, hepatosplenomegaly, and corneal opacities.1e4
It is the most severe form of mucopolysaccharidosis
and, without treatment, leads to early death before the
second decade of life.5
Genetics
these patients can be difficult because of their mental disorders, which often require sedation or general anesthesia for
treatment.46 As patients age, cardiovascular concerns along
with hypertension require close consultation with the appropriate medical practitioners.
Clinical features
Children with Hurler syndrome initially appear nearly normal at
birth but, because of accumulation of glycosaminoglycans,
progressive cell and tissue malfunction occurs, leading to
mental retardation, hepatosplenomegaly, corneal clouding,
with eventual cardiopulmonary failure.5,8,9 Clear cells (Hurler
cells) have been identified in infants within the myocardium.10
Affected individuals have short long bones and short and broad
digits consistent with dwarfism.5,11 Carpal tunnel syndrome
and limited mobility are common.12,13 Facial deformities
(Figs. 5 and 6) are prevalent, including an enlarged deformed
head with frontal bossing, a flattened nasal bridge, and
hypertelorism.11 The patients have thickened patulous lips
with a flattened philtrum.11,14e16 They have significant macroglossia that, over time, leads to an anterior open bite11 and,
combined with a short neck, leads to sleep apnea and significant complications from anesthesia.17,18 There are dental
anomalies, including short conical teeth, widely spaced
dentition, and supernumerary teeth in the mandibular
rami.19,20 There have been reports of increased dentigerous
cyst formation in the mandible.11
Differential diagnosis
Fig. 4 Williams syndrome: typical dental abnormality characterized by small, malformed, widely spaced teeth with malocclusion. (From Perloff JK. Congenital heart disease in adults. 3rd
edition. Philadelphia: Saunders, an imprint of Elsevier; 2008.
Fig. 20-14; with permission.)
126
Nannini
Hunter syndrome
Key points
Fig. 5 Hurler syndrome. Coarse facial features, macrocephaly,
scaphocephalic skull, flattened nasal bridge, hypertelorism, short
neck, chest deformity, and protuberant abdomen in a girl with
Hurler syndrome (mucopolysaccharidosis I). (From Paller A,
Mancini AJ. Hurwitz clinical pediatric dermatology: a textbook of
skin disorders of childhood and adolescence. 4th edition. Philadelphia: Saunders, an imprint of Elsevier; 2011. Fig. 24.13; with
permission.)
Genetics
The incidence of mucopolysaccharidosis II (MPS II) ranges from 1
in 110,000 to 1 in 135,500 live births.10 Because it is an X-linked
disease, most patients are male. There are some female cases
reported, which require either 2 pathologic alleles or a normal
inactivated allele.1,6,10 However, the female cases tend to have
attenuated symptoms.1,9 The gene that produces iduronate-2sulphatase is located on chromosome Xq28 with the exonic point
mutations G374sp comprising half of the mutations.11 Significant variability in the mutations is evident.12 It is thought that
this variance explains much of the difference between phenotypes and also the difficulty in treating patients with MPS II.11
Clinical features
127
Differential diagnosis
Because there are significant differences in the expression of
this disorder, it can be difficult to distinguish this from other
forms of mucopolysaccharidosis. In the severe expression of
MPS II, there are many similar characteristics to Hurler syndrome, except without the corneal clouding.9,11,17 Other
lysosomal storage disorders that share similar features include
MPS VI (Maroteux-Lamy syndrome) and MPS VII (Sly syndrome).6
A preliminary test to confirm mucopolysaccharidosis is an increase in urinary glycosaminoglycans.6,25 Although this is not
specific to Hunter syndrome, further blood testing for deficiency of iduronate-2-sulfatase in leukocytes, serum, or
plasma will secure the diagnosis.1,6 A mnemonic screening tool
has been developed and has correctly identified 95% of patients
with no family history of Hunter syndrome.26
Heerfordt syndrome
Key points
Heerfordt syndrome is a rare manifestation of systemic
sarcoidosis that includes fever, parotid swelling, uveitis, and facial nerve paralysis.1e5
It was described by Danish ophthalmologist Christian
Heerfordt, who reported these traits without the
connection to sarcoidosis.6 That direct link was reported in 1937 by Dr Jan Waldenstrom.7
The histology is classic for multiple noncaseating granulomas found in the parotid or salivary glands and
lacrimal glands.1
Treatment of Heerfordt syndrome with long-term corticosteroids seems to have a good prognosis.2e4
Genetics
Fig. 8 Ivory-colored papules on the upper back in Hunter syndrome. (From Kliegman RM, Stanton BF, St Geme JW III, et al.
Nelson textbook of pediatrics. 19th edition. Philadelphia: Saunders, an imprint of Elsevier; 2011. Fig. 651-13; with permission.)
128
Nannini
Clinical features
In patients with sarcoidosis, usually fever, followed by uveitis,
parotid gland swelling, and then facial nerve palsy are classic
for Heerfordt syndrome (Figs. 9 and 10).1e5 The parotid glands
usually enlarge bilaterally and are firm to the touch.14e21
Bilateral lacrimal gland enlargement is often seen with either
anterior or posterior uveitis, accompanied by blurred
vision.9,14,16 Although the facial nerve palsy is usually unilateral, bilateral deficits have been reported.22e24 Neurosensory
deficits of other cranial nerves, including the palate,18 have
been reported.
Differential diagnosis
The differential diagnosis for each of the components for
Heerfordt syndrome can be extensive. For example, bilateral
gren syndrome,
parotid swelling can be attributed to Sjo
tuberculosis, mumps, sialadenitis, and Mikulicz disease; however, none of these have uveitis. The definitive diagnosis is
made by histologic confirmation of sarcoidosis, which presents
as noncaseating granulomas.2,3 In cases in which tissue biopsy
is difficult, increased angiotensin converting enzyme levels in
combination with a positive 67 gallium scintigraphy have been
shown to have 99% accuracy.2
Sj
ogren syndrome
Key points
Fig. 9 Parotid enlargement typically occurs in Heerfordt syndrome, which also manifests fever and acute anterior uveitis.
(From Kanski J. Clinical diagnosis in ophthalmology. 1st edition.
Philadelphia: Mosby, an imprint of Elsevier; 2006. Fig. 10.75; with
permission.)
129
Fig. 11 (A) Bilateral parotid and submandibular gland hypertrophy in a patient with Sjogren syndrome. (B) Bilateral sublingual gland
hypertrophy in a patient with Sjogren syndrome. (Courtesy of D DeLuke, DDS, MBA, Richmond, VA.)
Genetics
gren syndrome affects about 0.2% to 3% (200e3000 per
Sjo
100,000) of the population and has a significant female/male
ratio of 9:1.3,6 The important role of genetics in this disorder is
emphasized when siblings and relatives of patients with prigren syndrome have a significantly higher risk of also
mary Sjo
gren and other autoimmune dishaving the disease.7 With Sjo
orders, genetic factors are varied and complex.6 Variations
in human leucocyte antigen on chromosome 6 subunit DR
(HLA-DR) and human leucocyte anitgen on chromosome 6
subunit DQ (HLA-DQ), which are located within the major
histocompatibility complex class II genes, determine basic
gren synimmune response and have been implicated in Sjo
drome.1,6 Genes that affect production and proliferation of
T and B cells have also been studied.6,8,9 Multifactorial genetic
and immunologic events are involved in the expression of this
disorder.9e14
occurs along with hyaline deposits often described as epimyoepithelial sialoadenitis (Fig. 12).2
Differential diagnosis
Sarcoidosis with or without Heerfordt syndrome, multiple
sclerosis, and other neurologic disorders has been reported to
gren syndrome.25e27 Because exocrine dysfunction is
mimic Sjo
gren syndrome is often difficult to
the primary symptom, Sjo
diagnose. The American European consensus group established
gren syndrome.28 The patient
criteria for the diagnosis of Sjo
must have subjective symptoms of dry eyes and dry mouth,
objective ocular and salivary gland tests, histopathology
Clinical features
gren syndrome is classified primarily by lymphocytic infilSjo
tration of multiple exocrine glands, specifically the lacrimal
and salivary glands, resulting in keratoconjunctivitis sicca and
xerostomia. Because of lack of lacrimal secretions, corneal
abrasions, visual discomfort and impairment are possible.5
Xerostomia results in susceptibility to dental caries, periodontal disease, and difficulty in chewing and swallowing.15e19
There is often swelling of the parotid glands bilaterally
gren syndrome, extra(Fig. 11A and B).20 In secondary Sjo
glandular systemic involvement occurs (most likely rheumatoid arthritis or systemic lupus erythematous).1,2 Other clinical
features include fatigue21 and thyroid, liver, and kidney disease.22,23 There are reports of immune-mediated anemia and
gren syndrome.24 The most
thrombocytopenia secondary to Sjo
serious complication related to this disorder is the development of lymphoma; these patients have a 10 to 50 times higher
risk than normal individuals.2 On biopsy of the affected
glandular tissue, periductal infiltration with lymphocytes
130
usually by minor salivary gland biopsy, and the presence of
serum
autoantibodies
of
anti-Ro
and/or
anti-La
specificity.2,28e30
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Oral Cir Bucal 2014;19(1):e20e3.
30. Lida Santiago M, Seisdedos MR, Garca Salinas RN, et al. Frequency
of complications and usefulness of the minor salivary gland biopsy.
Reumatol Clin 2012;8(5):255e8.
Ehlers-Danlos syndromes
Clinical manifestations
oralmaxsurgeryatlas.theclinics.com
136
Koutlas
Fig. 1 Extreme joint hypermobility in a patient with EDS. (Courtesy of the collection of Robert J. Gorlin, DDS.)
touch their nose with the tongue (Gorlin sign; only seen in
the 8%e10% of the general population) (Fig. 5)
5. Dental abnormalities including hypoplastic enamel and
dentin, high cusps with deep occlusal fissures, and deformed
roots with pulp stones. Multiple keratocysts have been described in a patient with EDS II
6. Epicanthic folds, myopia, strabismus, eversion of the upper
eyelids, and, less often, blue sclera
137
EDS type VIII
EDS VIII is characterized by early-onset periodontal disease and
pretibial skin ecchymoses.
Differential diagnosis
The different types of EDS should be distinguished from
other inherited disorders that can present with hyperelastic
skin (cutis laxa syndromes), gerodermia osteodysplastica,
vascular fragility syndromes, and familial generalized articular hypermobility.
Parry-Romberg syndrome
Parry-Romberg (or Romberg) syndrome (PRS) is, in most cases,
a sporadic disorder characterized by slow progressive atrophy
or shrinkage of facial tissues including skeletal muscle, skin,
eyes, hair, and frequently bone of, in most instances, half of
the face (Fig. 7). It is accompanied very often by contralateral
Jacksonian epilepsy and trigeminal neuralgia. Bilateral manifestations occur in 5% to 10% of cases, and ipsilateral
138
Koutlas
involvement of the rest of the body is rare. The cause is unknown; however, alterations in the peripheral trophic sympathetic system, cerebral disturbance of fat metabolism, trauma,
autoimmunity, and, recently, Borrelia spp infection have been
considered as possible causes. It is more common in females,
and in many studies the left side of the face seems to be more
frequently affected.
Clinical manifestations
PRS appears usually during the first decade, with the overlying
skin of the affected side becoming darkly pigmented. When the
facial bones are affected the disease starts earlier. The progression of the disease can be as long as 9 to 10 years, and it
becomes stationary for life. Hair involvement precedes that of
skin, with the affected side of the scalp characterized by focal
areas of complete alopecia, loss of eyelashes, and the median
portion of eyebrows. Some patients have a scar-like demarcation on the forehead near the midline known as linea
scleroderma or en coup de sabre (strike of the sword). Histopathologically there is atrophy of the epidermis, dermis, and
adnexal elements and vessels, in addition to inflammation.
These characteristics are also present in patients with linear
scleroderma.
Oral manifestations
Hemiatrophy of the tongue can be an early finding (Fig. 8).
Atrophy of half of the upper lip and tongue may lead to
exposure of maxillary teeth of the affected side. Delayed
eruption, root dilaceration, root hypoplasia (Fig. 9), and resorption are rarely described. Alteration in the development of
the mandible, which leads to malocclusion, is also reported
(Fig. 10).
Differential diagnosis
Neurologic manifestations
Epileptic seizures are the most common neurologic manifestation, often of the Jacksonian type (motor cortexerelated
Ophthalmologic manifestations
The most common manifestation is enophthalmos resulting
from loss of periorbital fat (Fig. 11). Loss of the underlying
bone may cause the outer canthus to be displaced downward.
Other ocular stigmata include atrophy of the eyelid, uveitis,
retinal vasculitis, glaucoma, and retinal pigmentations. The
contralateral eye may be also affected.
139
Oral manifestations
There is hypodontia (Fig. 12), less often oligondontia, and in
rare extreme cases anodontia. The most frequently missing
teeth are the maxillary incisors, second molars, maxillary canines, and, less often, the premolars. The permanent dentition
is usually more severely affected. Moreover the tooth shape
varies, with teeth being conical and having narrow crowns.
Nail manifestations
Hypoplastic fingernails (Fig. 13) and/or toenails occur early in
life. Toenails are usually more severely affected than fingernails. Nails grow slowly, are spoon-shaped, and are prone to
fracture. The nail condition improves with age.
Differential diagnosis
similar to those of PRS. Congenital facial hypoplasia is diagnosed at birth, and there is diminution of the teeth of the
affected side. The oculo-auriculo-vertebral spectrum of malformations should also be included in the differential diagnosis. However, this group of conditions is related to anomalies
of the first and second branchial arches.
The differential diagnosis of WS includes X-linked and autosomal recessive hypohidrotic ED. However, patients with such
forms of ED have typical facies and decreased sweating, and
their nails are usually not dysplastic. Among those included are
Fried syndrome, DOOR (Deafness and OnychoOsteodystrophy
with Retardation) syndrome, and Curry-Hall syndrome. Of
these conditions, Fried syndrome closely resembles WS; however, it is autosomal recessive, and features sparseness and
thinness of hair and eyebrows as well as an everted lower lip.
Nails are not so severely affected. Curry-Hall syndrome also
features polydactyly.
Witkop syndrome
Witkop syndrome (WS), also known as tooth-nail or nail dysgenesisehypodontia syndrome, is an autosomal dominant type
of ectodermal dysplasia (ED) with an estimated incidence of 1
to 2 in 10,000. It affects 2 ectodermal derivatives, namely
teeth and nails. It is caused by nonsense mutations of the MSX1
at 4p16.1. Isolated cases, without family history, have been
described.
Clinical manifestations
Teeth and nails are affected without involvement of sweat
glands and the characteristic facies seen in EDs. Most patients
report normal heat tolerance and normal sweating. Occasionally, hair may be thin and slow growing but without microscopic abnormalities.
140
Koutlas
palatal and cranial base widths, small malar bones, and small
calvarial height.
Oral manifestations
Hemizygotes lack most deciduous and permanent teeth
(Fig. 16). The teeth that are rarely absent are central upper
incisors, upper and lower canines, and first molars. Upper incisors and canines have conical crowns. Taurodontism can also
be observed. The alveolar ridge is hypoplastic or undeveloped.
Clinical manifestations
The defining and major findings of the syndrome are hypohidrosis, hypotrichosis, and hypodontia.
Cutaneous manifestations
Hypohidrosis is the characteristic clinical presentation,
resulting from the severe reduction of sweat glands leading to
intolerance to heat (Fig. 14). Early in life and during the first
year, children with the disorder present with fever of unknown
etiology. Mild exertion can lead to hyperpyrexia. Sebaceous
glands are severely reduced to absent, causing severe dryness.
Patients can have hair, although it is usually fine and short.
Eyelashes and eyebrows are scant and occasionally missing.
Mammary glands are hypoplastic or absent. Nails are generally
normal.
Facial manifestations
In general, patients present with prominent frontal bossing and
a depressed nasal bridge (Fig. 15). There is loss of vertical
height owing to the absence of teeth. Cephalometric and
anthropometric studies feature smaller facial height, small
141
Table 1
(HHT)
Type
Gene
Locus
Protein
HHT1
ENG
9q34.1
Endoglin
HHT2
ACVRL1
12q11eq14
Activin A receptor
type IIelike 1
HHT3
Unknown
5q31
Unknown
HHT4
Unknown
7p14
Unknown
JPHT
MADH4
18q21.1
SMAD4
Fig. 16 Oligodontia and conical teeth. (Courtesy of the collection of Robert J. Gorlin, DDS.)
Clinical manifestations
In general, patients can present with epistaxis, hemoptysis,
hematemesis, and hematuria. Although all lesions can be seen
in patients with both HHT1 and HHT2 types, pulmonary and
possibly cerebral AVMs are more common in patients with ENG
mutations, and hepatic AVMs are more common in patients
with ACVRL1 mutations. However, pulmonary hypertension in
the absence of severe vascular shunting is almost exclusive to
ACVRL1 mutations.
Table 2 highlights the various clinical features of HHT. The
oral manifestations are described separately in more detail.
Oral manifestations
The lips and tongue dorsum and tip are more frequently
affected (Figs. 17 and 18) than the buccal mucosa, gingiva, and
palate. Recognition of oral lesions has led many times to the
establishment of the diagnosis, and this has been undoubtedly
the experience of this author. The clinician should differentiate
Fig. 17 Telangiectasias of hereditary hemorrhagic telangiectasia. Multiple telangiectasias on the nose and lips. (From Wilcox
CM. Atlas of clinical gastrointestinal endoscopy. Philadelphia: WB
Saunders; 1995. p. 123; with permission.)
142
Table 2
Koutlas
Clinical features of HHT
Clinical
presentation
Frequency Diagnostic
(%)
procedure
Potential
complications
Epistaxis
90
Evident
Anemia
Massive acute
hemorrhage
Telangiectasias
of the lip, oral
mucosa, nose,
fingertips,
other mucous
membranes
(bladder,
uterus, vagina)
80
Evident
Cosmetic
Hemorrhage
Gastrointestinal
telangiectasia
15e30
Endoscopy
Hemorrhage
Anemia
Pulmonary AVMs
50
CT scan
C-Echo
Asymptomatic
Hypoxemia
1. Stroke
2. Brain abscess
3. Migraine
Hemorrhage
1. Hemoptysis
2. Hemothorax
Cerebral vascular
malformations
10e20
MRI
Hemorrhage
Angiography Headache
Epilepsy
Cardiac failure
in children
Hepatic vascular
malformations
Spinal AVMs
30e70
Rare
Doppler
Asymptomatic
ultrasono- Pulmonary
graphy
hypertension
CT
Portal
hypertension
Biliary ischemia
MRI
Hemorrhage
Paraplegia
Pain
experience bleeding even with tooth brushing. Dental prophylaxis can cause bleeding from labial telangiectasias, and
scaling and root planing should be carried out with great care
and even avoided in some instances. To control epistaxis,
Sublingual
phlebectases
Cherry angiomas
Fabry syndrome
Maffuci syndrome
Hereditary benign
telangiectasia
CREST syndrome
Differential diagnosis
The telangiectasias seen in patients with HHT should be
differentiated from telangiectasias and other vascular lesions
seen in normal patients that generally develop after the age of
40 years. Conditions presenting with telangiectasias and
vascular anomalies in oral and perioral tissues are listed in
Table 3.
143
Ascher syndrome
Ascher syndrome (AS) is characterized by blepharochalasis,
double lip, and nontoxic thyroid enlargement. Thyroid enlargement is not necessary for the diagnosis. Most cases are
sporadic, although an autosomal dominant trait has been
established in some patients.
Clinical manifestations
Labial manifestations
There is tissue duplication (Fig. 19) occurring between the pars
glabrosa and the pars villosa that can exist from childhood,
which is not evident when the lips are closed but becomes
striking when patients smile. Hyperplastic salivary glands,
increased vascularity, and occasional inflammation are appreciated microscopically.
Ocular manifestations
There is prominent shagging of the eyelids (Fig. 20), most
frequently the upper, which is caused by relaxation of the
tarsal fold. The eyelid itself is atrophic. In many instances this
occurs after multiple episodes of angioedema-like episodes.
Patients initially experience swollen lids, and the initiation of
this swelling coincides with enlargement of the lip. Histologically there may be enlargement of the lacrimal glands.
Thyroid
Euthyroid goiter develops in some patients with AS. However,
rare examples of hypothyroidism and myxedema are reported.
Differential diagnosis
Blepharochalasis and double lip can be encountered as isolated
anomalies. Specifically, acquired double lip is frequently the
result of habitual trauma. Congenital double lower lip has been
described in association with blepharochalasis, broad nose
with broad tip, highly arched palate, and bilateral third finger
clinodactyly.
Behcet syndrome
Initially described as the combination of ocular inflammation
and orogenital ulcerations, Behcet syndrome (BeS), or Behcet
disease, is a multisystem immunodysregulation disorder, of
unknown etiology, possibly triggered by environmental antigens, including bacteria and viruses, and characterized by
vasculitis of small and large arteries and veins. Although not
hereditary, an autosomal recessive mode of inheritance is
proposed in pediatric patients who present, less frequently,
with genital and eye disease. Interleukin-10 (anti-inflammatory
cytokine) gene mutations have also been described.
Clinical manifestations
BeS affects men and women approximately equally, usually in
their third decade. Men can present with a more severe course.
BeS is more frequent in countries along the Silk Road where
the prevalence of the HLA-B51 is also relatively high in comparison with the rest of the world. The highest rate of BeS is
observed in Turkey, with 1 in 250 people affected. Other
countries with a high incidence include Iran, Israel, North
Africa, Japan, and China. In the United States a rate of 5.2 per
100,000 population was calculated in Olmsted County, Minnesota. BeS is very infrequent in the United Kingdom.
The International Society for BeS (ISBD) has established
criteria for the diagnosis, which have 91% sensitivity and 96%
specificity. Oral ulcers are a cardinal finding. Two other findings among a list of signs must additionally be present. The list
includes genital ulcers, eye disease, skin lesions, and a positive
pathergy test, which refers to development of papules and
pustules 48 hours after inserting 20-gauge needles in a vertical
144
or oblique way through the superficial aspect of the skin. The
area to be tested for the pathergy test is the hairless area of
the forearm, which should be cleaned with alcohol (but not
with a surgical cleaning solution) before insertion. The ISBD
criteria do not include intestinal, central nervous system,
or pulmonary vascular disease occasionally seen in patients
with BeS.
Oral manifestations
Recurrent aphthous stomatitis (RAS) occurs in 97% to 100% of
patients (Fig. 21). Recurrent oral ulcerations with 3 episodes in
1 year are a mandatory criterion for the diagnosis of BeS. All
types of RAS can occur, namely minor, major, and herpetiform,
with minor aphthae more commonly seen in men and major
aphthae more frequently seen in women. Ulcers affect predominantly the nonmasticatory mucosa, covered by white to
yellowish pseudomembrane and surrounded by a red halo.
Deeper lesions last longer. In one study a positive intraoral
pathergy test was seen in 85% of participating patients. Low
frequency in RAS has been observed in smokers with BeS.
Genital manifestations
Genital ulcers are also a cardinal finding in BeS (Fig. 22). These
ulcers are painful and, similarly to RAS, are covered by pseudomembrane, feature swelling in the periphery, and, if larger
than 1 cm, frequently heal with scarring. Male patients develop
ulcers usually in the scrotum and the inguinal area. Penile
lesions are rare (Fig. 23) and urethritis is not observed. The
ulcers in women affect the labia majora and femoral/inguinal
regions. These ulcers can cause scar formation, which does not
occur in the labia minora and vestibule. Vaginal and cervical
ulcers are rare.
Cutaneous manifestations
Erythema nodosum characterized by red painful nodules
is observed in approximately 50% of patients, more commonly females, and affects primarily the lower extremities in the areas of the pretibial surface in a symmetric
pattern. The lesions heal with pigmentation. Arms and
thighs can also be involved.
Superficial thrombophlebitis is appreciated more frequently in males. It presents as red nodules in the area of
the tibia and follows the course of the great saphenous
vein. As older lesions heal, new ones appear with areas of
hyperpigmentation. There is increased risk for deep vein
thrombosis.
Acneiform papulopustular lesions can develop on the
back, chest, shoulders, and, less frequently, the face,
Koutlas
which is the area of predilection for acne vulgaris.
Acneiform lesions in postadolescent patients not on systemic steroids should be interpreted as a sign of BeS.
Ocular manifestations
Eye involvement is observed in half of the patients. Chronic
and relapsing bilateral uveitis is usually observed, with hypopyon uveitis seen in approximately 20% of the patients, signifying severe retinal disease. Patients also develop keratitis,
conjunctivitis (Fig. 24), corneal ulcerations, and papilledema.
Musculoskeletal manifestations
Approximately half of the patients develop nondeforming
monoarthritis or oligoarthritis, usually in the knees, followed in
frequency by ankles, wrists, and elbows.
Vascular and cardiac manifestations
Approximately 30% of patients develop thrombophlebitis.
Thromboses of the superior and inferior vena cava are also
seen. Budd-Chiari syndrome is rare but carries high mortality.
Arterial involvement is less frequent, but when it occurs
can cause death. Myocarditis, pericarditis, and intracardial
thrombus formation have been infrequently reported.
Central nervous system manifestations
Parenchymal and, less often, nonparenchymal brain disease
can develop in approximately 10% of the patients, who
present with pyramidal, cerebellar, and sensory manifestations, and intracranial hypertension caused by dural
sinus thrombosis. Parenchymal disease has a more serious
prognosis.
Other manifestations
Gastrointestinal involvement occurs in about 30% of Japanese patients, but is less common in patients from the
Mediterranean. Pleural pericardial effusions, mediastinal
lymphadenopathy, glomerulonephritis, secondary amyloidosis, epididymitis, and bladder involvement have been
described in the literature.
Differential diagnosis
The differential diagnosis includes inflammatory bowel disease
(IBD), reactive arthritis and autoimmune bullous disorders.
Aphthous-like lesions, erythema nodosum, and nonerosive
arthropathy can accompany IBD. However, genital ulcers and a
positive pathergy confirm the diagnosis of BeS as they are not
seen in IBD.
Fig. 21 Bechet syndrome: (A) Deep crater-like ulcers consistent with recurrent aphthous stomatitis (RAS) major type. (B) Shallow ulcers
consistent with RAS minor type. Courtesy of the collection of Robert J. Gorlin, DDS.)
145
Oral manifestations
Nonspecific ulcers, candidiasis, and periodontal disease may
develop in some patients.
Differential diagnosis
Felty syndrome
Clinical manifestations
Because of leukopenia/neutropenia, patients have an
increased risk of serious infections, and often present with
persistent ulcers of the lower extremities caused by rheumatoid vasculitis. Moreover, 30% of patients can develop large
granular lymphocytic leukemia.
Reactive arthritis
Disclaimer: Hans Conrad Julius Reiter (1881e1969) was the
fourth person to describe what has been known in the literature as Reiter syndrome. His patient, a soldier, presented with
large joint oligoarthritis, urogenital tract infection, and uveitis. Reiter was a Nazi criminal. For these 2 reasons the
designation Reiter syndrome is avoided in the following
paragraphs. Readers are encouraged to avoid such designation. The condition has been renamed as reactive arthritis.
Reiter syndrome is only a clinical subtype of this disease. Also,
some consider the condition as a syndrome of psoriasis
because, histopathologically, it features psoriasiform dermatitis and mucositis.
Reactive arthritis (ReA) is a form of seronegative spondyloarthritis characterized by inflammatory back pain, additive
or migratory oligoarthritis, and extra-articular symptoms that
typically follow a gastrointestinal (most frequently Yersinia,
146
Koutlas
Salmonella, Shigella, Campylobacter) or urogenital (most frequently Chlamydia trachomatis, Neisseria gonorrhoeae,
Mycoplasma genitalium) infection by a minimum of 1 to a
maximum of 3 to 6 weeks. It commonly affects young Caucasian adults carrying the HLA-B27 allele. Ocular, skin, and heart
involvement are not uncommon and can vary in severity. ReA
affects males and females equally. However, when related to
Chlamydia trachomatis, males are more frequently affected.
The arthritis is not caused by the microbial agent itself but by a
CD4 T-cell response to the invading bacteria that triggers
articular inflammation, along with a CD8 response. The altered
immune response leads to the unbalanced production of
T-helper 2 cytokines, and this further helps the poor elimination
of the antigen by the host. The HLA-B27 haplotype perpetuates
the chronicity of the process. The average duration of acute
ReA is 3 to 5 months. If the arthritis lasts more than 6 months it
is regarded as a sign of development of chronicity.
Clinical manifestations
The patients initially present with history of gastrointestinal or
genitourinary infection. The typical patient with ReA features:
Asymmetric oligoarthritis of the lower extremities and,
less frequently, the upper extremities including small
joints (dactylitis)
Enthesitis (Achilles tendon) or bursitis
Acute inflammatory back pain that worsens in the night,
radiating to the buttocks
Ocular manifestations
Conjunctivitis and anterior uveitis leading to redness,
pain, irritation, and blurred vision (Fig. 25)
Skin manifestations
Balanitis circinata (Fig. 26) characterized by well-circumscribed erythematous erosions on the glans penis that
frequently resemble the lesions of migratory stomatitis.
These lesions are seen in 20% to 39% of patients
Keratoderma blennorrhagicum on the soles and, less
frequently, palms
Oral manifestations
Occasional transient painless ulcerative lesions similar to
migratory stomatitis (Fig. 27) present in less than 20% of
patients
Differential diagnosis
Other forms of arthritis may be considered in the differential
diagnosis of patients with similar symptoms and signs. Obtaining
a good medical history can point toward the correct diagnosis.
147
Table 4
Clinical manifestations
An acute and a late phase are recognized. The initial symptoms
of the acute phase include fever, stinging eyes, and discomfort
in swallowing. These symptoms precede mucocutaneous lesions by a few days.
Acute phase: mucocutaneous manifestations
Erythematous to livid confluent purpuric macules develop
initially in the presternal region of the trunk, face, palms, and
soles, which expand throughout the body in a matter of days
(Fig. 28). There is concomitant development of erythematous
lesions, erosions, and ulcers in the mucous membranes that
include the mouth (see later discussion), genitals (balanitis and
colpitis), eyes (severe conjunctivitis and blepharitis), and the
upper aerodigestive tract (Fig. 29). There is a positive Nikolsky
sign on the skin. Skin detachment when limited defines SJS.
However, expansion of the detachment, depending on the
percentage of the body surface affected, signifies progression
toward SJS/TEN overlap and TEN (Fig. 30).
Oral manifestations
Typical hemorrhagic erosions covered by crusts (Fig. 31) are
observed on the lips while the erythematous and ulcerative
lesions are distributed throughout the oral mucosa (Fig. 32),
sometimes including the masticatory mucosa.
Late phase and sequelae
Hyperpigmentation and hypopigmentation, pruritus, hyperhidrosis, xeroderma, nail dystrophies, atrophic or hypertrophic
scars, conjunctival keratinization, keratoconjunctivitis sicca,
depapillation of the tongue, lack of sensation, and loss of taste
are observed.
Differential diagnosis
The differential diagnosis may vary based on the skin detachment. In early stages of the disease, maculopapular drug or
viral eruptions should be considered. However, such processes
do not present with the hemorrhagic and erosive lesions seen in
SJS. Typical target lesions are a feature of EMM, so the
distinction can be made. In later stages of SJS/TEN, when
blisters and skin detachment are prevalent, a Tzanck test or
cryostat histology are necessary to exclude the diagnosis of
staphylococcal scalded-skin syndrome. Targetoid lesions are
not present in staphylococcal scalded-skin syndrome, and
Clinical manifestations of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
SJS
SJS/TEN overlap
TEN
Primary lesions
Erythematous lesions
Atypical targetoid lesions
Erythematous lesions
Atypical targetoid lesions
Erythematous lesions
Epidermal detachment, spontaneous
or by friction
Atypical targetoid lesions
Distribution
Isolated lesions
Confluence on face and trunk
Isolated lesions
More confluence on face and trunk
Mucosal
involvement
Yes
Yes
Yes
Systemic
symptoms
Usually
Always
Always
Detachment (%)
<10
10e30
>30
148
Koutlas
Moderate risk
Allopurinol
Cephalosporins
Carbamazepine
Macrolides
Cotrimoxazole: sulfonamides
and sulfasalazine
Quinolones
Lamotrigine
Tetracyclines
Phenobarbital
Phenytoin
Abbreviation: NSAID, nonsteroidal anti-inflammatory drug.
Progeria
There is a range of diseases characterized by accelerating
aging, such as Hutchinson-Gilford progeria syndrome (HGPS),
Werner syndrome, Cockayne syndrome, trichothiodystrophy,
and ataxia-telangiectasia, of which HGPS stands out. HGPS is
characterized by premature signs of aging at a very early age
and death before the age of 20 years caused by cardiovascular
or cerebrovascular disease. The incidence is 1 in 4 million, with
approximately 100 patients known to be alive in the world
according to the Progeria Research Foundation. Although it is
very rare, the disease has stirred a tremendous interest in the
pathobiology of aging. Initially the disorder was thought to be
autosomal recessive, but recent evidence suggests a single
nucleotide mutation with autosomal dominant expression
affecting the lamin A gene (LMNA), which is located in chromosome 1q. The mutated LMNA is called progerin, and in patients with HGPS there is production of normal lamin A as well
as progerin.
149
Clinical manifestations
Growth
Growth is normal for the first 9 to 12 months, when it plateaus
until about 10 years of age. At this age patients have the size of
a normal 3-year-old child, rarely exceeding 110 cm in height
and 15 kg in weight, and the appearance is that of a diminutive, wasted-looking older person. There is no sexual maturation and the voice is high-pitched and squeaky. Intelligence is
normal.
Craniofacial manifestations
The face is small in comparison with the cranial vault (Fig. 33).
Alopecia starts developing around age 2 years, with eyebrows
and eyelashes also generally lost. Frontal and parietal bossing
is evident early, and scalp veins become prominent. Ears are
small without ear lobes and the nose is beak-like. There is
mandibular hypoplasia leading to micrognathia and increased
mandibular angle.
Oral manifestations
Circumoral cyanosis is noted. Dental manifestations vary, with
most patients featuring hypodontia, microdontia, and teeth
with variations in shape. There is delay in eruption. Only a few
patients have normal teeth; however, there is crowding caused
by micrognathia.
Skin manifestations
There is significant loss of subcutaneous fat that results in thin,
tight skin. Scleroderma-like changes are also seen in some
patients. The veins over the thighs and scalp become prominent (Fig. 34).
Musculoskeletal manifestations
The chest is narrow and the abdomen protuberant. Although
bone maturation is normal, bones are osteoporotic, and joints
feature limited extension and degenerative changes including
hip dislocation. A horse-riding stance is observed early.
Osteolytic changes are seen radiographically, and are most
prominent in the terminal phalanges and clavicles. The
calvaria is thin and the anterior fontanel open. Frontal sinuses
are frequently absent.
Cardiovascular manifestations
Accelerated cardiovascular and cerebrovascular diseases result
in death between the ages of 7 and 20 years. Major events are
preceded by severe atherosclerosis leading to congestive heart
failure, ischemic attacks, and diastolic hypertension. Multiple
other organs seem to be unaffected by this disease, including
the liver, kidney, lung, gastrointestinal tract, bone marrow,
and brain.
Differential diagnosis
150
Koutlas
Memarpour M, Shafiei F. Witkop tooth and nail syndrome: a report of
three cases in a family. Pediatr Dermatol 2011;28:281e5.
Ascher syndrome
graying hair, and early hair loss and scleroderma-like
changes. Patients also present with osteoporosis, diabetes,
atherosclerosis, and neoplasms. The median age of death is
54 years.
Recommended readings
Ehlers-Danlos syndromes
Ehlers-Danlos syndromes. In: Hennekam RC, Krantz ID, Allanson JE,
editors. Gorlins syndromes of the head and neck. 5th edition.
New York: Oxford University Press; 2010. p. 594e610.
Jensen JL, Storhaug K. Dental implants in patients with Ehlers-Danlos
syndrome: a case series study. Int J Prosthodont 2012;25:60e2.
Jerjes W, Upile T, Shah P, et al. TMJ arthroscopy in patients with
Ehlers-Danlos syndrome: case series. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 2010;110:e12e20.
Ali K. Ascher syndrome: a case report and review of the literature. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:e26e8.
do AA, de Pochat VD, Barreto TF, et al. Management of an
de Figuere
unusual presentation of Ascher syndrome. J Craniofac Surg 2012;23:
e570e1.
Gomez-Duaso AJ, Seoane J, Vazquez-Garcia J, et al. Ascher syndrome:
report of two cases. J Oral Maxillofac Surg 1997;55:88e90.
Behcet syndrome
Hatemi G, Yazici Y, Yazici H. Behcets syndrome. Rheum Dis Clin North
Am 2013;39:245e61.
Mat C, Yurdacul S, Devim A, et al. Behcets syndrome: facts and controversies. Clin Dermatol 2013;31:352e61.
Felty syndrome
Feltys syndrome. In: Kasper DL, Braunwald E, Fauci AS, et al, editors.
Harrisons principles of internal medicine. 16th edition. New York:
McGraw Hill; 2005. p. 1972.
Feltys syndrome. In: Hoffbrand AV, Pettit JE, Vyas P, editors. Color
atlas of clinical hematology. 4th edition. Philadelphia: Mosby
Elsevier; 2010. p. 485.
Parry-Romberg syndrome
Reactive arthritis
Witkop syndrome
Altug-Atac AT, Iseri H. Witkop tooth and nail syndrome and orthodontics. Angle Orthod 2008;78:370e80.
Cao ZH, Wei ZY, Zhu QY, et al. HLA-B*58:01 allele is associated with
augmented risk for both mild and severe cutaneous adverse
151
Progeria
Burtner CR, Kennedy BK. Progeria syndromes and ageing: what is the
connection? Nat Rev Mol Cell Biol 2010;11:567e78.
Kieran MW, Gordon L, Kleinman M. New approaches to progeria.
Pediatrics 2007;120:834e41.
Progeria (Hutchinson-Gilforn syndrome). In: Hennekam RC, Krantz ID,
Allanson JE, editors. Gorlins syndromes of the head and neck.
5th edition. New York: Oxford University Press; 2010. p. 447e51.
Hamartoneoplastic Syndromes
David M. Shafer, DMD*, Lisa Marie Di Pasquale, DDS
KEYWORDS
Hamartoma Gorlin-Goltz Peutz-Jeghers Gardner syndrome Multiple endocrine neoplasia Sturge-Weber
Neurofibromatosis Tuberous sclerosis
KEY POINTS
Hamartomas are benign malformations presenting as an excess of normal tissue within the tissue of origin.
Although some syndromes show a clear genetic transmission, the underlying reasons for many of these abnormalities are
not fully understood.
The hamartomatous syndromes are usually associated with other neural, cutaneous, skeletal, or developmental
malformations.
The orofacial signs and symptoms often precede systemic displays of the syndromes. Thus, oral and maxillofacial surgeons
are in a unique position to identify and aid in diagnosing many of the hamartoneoplastic syndromes.
oralmaxsurgeryatlas.theclinics.com
154
rarely, the orthokeratinized type. Also typically displayed are a well-defined basal epithelial layer, palisaded nuclei, no rete ridges, and prominent epithelial
rests. Inflammatory cells are commonly found in the
underlying connective tissue. Syndromic OKCs have a
higher rate of satellite cysts. Ameloblastoma and squamous cell carcinomas of the jaw can, rarely, arise from
OKCs.2,4
Differential diagnosis
Diffuse osteoma cutis, basaloid follicular hamartomas
(associated with myasthenia gravis), Bazex syndrome,
Rombo syndrome, multiple seborrheic keratoses in patients with adenocarcinoma. Multiple jaw cysts may be
mistaken for dentigerous cysts or isolated OKCs. Severe
calcifications of many organs may also suggest
pseudohypoparathyroidism.1
Treatment considerations for the oral and maxillofacial
surgeon
OKCs are typically the first presenting feature of the
syndrome so radiographic examination of skull and
jaws is indicated. Biopsy of the skin lesions confirms
clinical presentation of nevoid basal cell carcinomas,
whereas OKCs may be distinguished histologically.
OKCs associated with NBCCS tend to develop multiple
new cysts and may be confused with recurrence of
previous lesions. Because syndromic OKCs present at
an earlier age than sporadic cysts, with the multiplicity of lesions and potential for recurrence, management by the maxillofacial surgeon continues into
adulthood because lifelong follow-up is anticipated
(Figs. 1 and 2).2e4
Gardner syndrome
Genetics
Gardner syndrome (GS) has been found to be associated
with the extracolonic manifestations of adenomatous
Hamartoneoplastic Syndromes
polyps are at high risk for malignant transformation. By
30 years of age, 50% of patients show malignancy of a
polyp, and as age advances the likelihood of malignancy
is expected to reach 100%.1
Beside multiple osteomas, other dental-osseous abnormalities occur in w17% of patients and include supernumerary teeth and impacted teeth, hypercementosis,
root resorption, dentigerous cysts, and multiple complex odontomas. Odontomas tend to be in both the
mandible and the maxilla, most frequently in the incisalpremolar area.9
Differential diagnosis:
Multiple polyps of the colon can raise suspicion for juvenile polyposis of the colon, Turcot syndrome, PeutzJeghers syndrome (PJS), Cronkite-Canada syndrome,
Torre-Muir syndrome, Cowden syndrome (CS), and
Bannayan-Riley-Ruvalcaba syndrome.1
Treatment considerations for the oral and maxillofacial
surgeon
The role of the oral and maxillofacial surgeon is for
early detection of GS. Extraintestinal manifestations
are common, and 70% of all affected individuals have
significant abnormalities detectable on a dental
panoramic radiograph.8 Because intestinal lesion
polyposis is often a late sequela, multiple facial bone
and dental abnormalities should prompt further
investigation for predictive testing of at-risk individuals to predict and identify children who may
have inherited the GS or APC gene.7 Computed tomography images provide the necessary details of the
osteomas, and are the preferred radiologic examination for the assessment of bone abnormalities. Osteomas that restrict mandibular function or affect
cosmesis may require resection with risk for recurrence. Necessary exodontia should be approached
with care because increased density of alveolar bone
and possible loss of the periodontal space caused by
hypercementosis may complicate the procedure
(Fig. 3).9
155
Klippel-Tr
enaunay-Weber syndrome
Genetics
naunay
First reported in France in 1900, Klippel-Tre
syndrome (KTS) is a rare congenital disorder characterized by multiple large venous varicosities and malformations, capillary malformations, and cutaneous
nevi and lymphatic abnormalities with hard and soft
tissue hypertrophy. The diagnosis can be made by
identification of two of the fundamental features of
varicose veins, capillary malformation and hypertrophy
of the affected limb.11 Although a genetic basis is suggested because of cases being reported occurring
within particular families, the cause of this syndrome
remains unknown. There are no direct hereditary factors, suggesting an inheritance on a multifactorial
basis.11 One hypothesis states that the syndrome could
result from a lethal gene that survives by mosaicism.12
The presumed disorder suggested is a developmental
derangement of mesoderm, lending to arteriovenous
malformations, intrauterine injury to the sympathetic
ganglia and intermediolateral tract, and resultant
dilation of microscopic arteriovenous anastomoses.12
Clinical features
The classic presentation of KTS is a triad of abnormalities that includes varicose veins, capillary malformations, and hypertrophy of affected limbs. In addition,
malformations of the venous valves may be seen.11 The
vascular irregularities typically occur in the lower extremities because gravity assists venous drainage from
the head and neck. These deep vein abnormalities can
result in obstruction of normal venous flow and can lead
to venous hypertension, development of varices, and
hypertrophy of the limb.12
Capillary malformations typically present as port-wine
stains (PWSs). They are usually purple, macular, endothelium-lined vascular channels located in the superficial dermis. These lesions are nonproliferative, do not
blanch, and typically do not resolve.12
Fig. 3 (A) Panoramic radiograph of multiple odontomas of the jaws. (B) Large bilateral osteomas in a patient with Garner syndrome. (C)
Dense, compact bone from an osteoma of the mandible in a patient with Garner syndrome. (Courtesy of [A] O. Erdo
gan, DDS, PhD, Adana,
Turkey; and [B] L. Eisenbud, DDS.)
156
Limb hypertrophy in KTS is always associated with
limb elongation leading to limb discrepancy. Excessive
limb growth is both in length and girth, with hard
tissue and soft tissue hypertrophy, and the growth rate
is unpredictable, without regular rate or form. The
soft tissues include increases in vascular tissue, muscle, and skin.11 Associated with the soft tissue hypertrophy is vascular hyperplasia and arteriovenous
malformations.13
Approximately 5% of KTS anomalies affect the head and
neck14 and appear as orofacial anomalies with hard and
soft tissue hypertrophy. As with the hypertrophy of the
extremities, the tissues appear to be increased unilaterally and may spread throughout the maxilla,
mandible, tongue, lips, cheek, and palate.13
The excessively large varicosities seen in KTS are
congenital lesions, and appear earlier than usual varicose veins, typically being seen when patients begin to
ambulate. These abnormalities may be painful and
tender, and can lead to fatigue, heaviness, and ulcerations. Aneurysms of deep veins may occur as a result of
high pressure or vessel wall fragility.12 Other vascular
deformities such as aplasia, phlebitis, and valvular
incompetence can manifest.
Patients may have lymphatic abnormalities such as
aplasia, hypoplasia, and extremity edema from congestion of the lymphatic system. Associated additional
findings such as abdominal hemangioma, heart defects,
syndactyly, polydactyly, oligodactyly, and macrodactyly have been reported in the literature.13 Complications from KTS can include cellulitis, thrombosis,
emboli, disseminated intravascular coagulation, and
neurologic disease.15
Differential diagnosis
KTS should be distinguished from other congenital
vascular anomalies like Parkes Weber syndrome, which
is limb enlargement with a malformation and arteriovenous fistula.
Sturge-Weber syndrome (SWS) commonly presents with
facial hemangiomas along with focal seizures, sensory
and motor paralysis, calcifications of vessel walls, and
visual field defects. Also included are neurofibromatosis, Beckwith-Wiedemann syndrome, and Maffucci
syndrome.1
Treatment considerations for the oral and maxillofacial
surgeon
Addressing the facial asymmetry and esthetics is the
main goal for the oral and maxillofacial surgeon. Lesions associated with KTS are associated with capillary
fragility and tend to bleed easily.13 Prolonged
bleeding may be expected, and significant preoperative hematological testing should be performed in
patients with KTS to avoid possible postoperative
bleeding problems.16 Lesions of KTS occur in the head
and neck as unilateral enlargement, and may disrupt
the dentoalveolar segment presenting as displaced
teeth with malocclusion. Beyond the abnormal blood
vessels, the literature also suggests defects in platelets, coagulation factors, and fibrin degradation
products (FDP) contributing as systemic causes of
bleeding.13 Thus, the preoperative tests requested
should include FDP, antithrombin III, and specific
factor XIII assay before performing any oral surgical
procedures (Figs. 4 and 5).13
Sturge-Weber syndrome
Genetics (including inheritance patterns and frequency)
Sturge-Weber Syndrome (SWS) is a neurocutaneous
syndrome characterized by port-wine staining (PWS) in
the skin of the face and leptomeningeal angiomatosis.17
SWS is generally proposed to be a result of genetic
mosaicism; therefore, it arises spontaneously without
family history. Precise population-based data do not
exist for the prevalence or incidence of SWS, but the
Hamartoneoplastic Syndromes
incidence of a PWS is estimated to be 0.3% in newborns,
without evidence of a sex predilection. SWS is an
embryologic anomaly and arises in utero when a
vascular plexus fails to regress from the portion of
neural tube that is destined to become facial skin,
thereby causing angiomatosis of the leptomeninges.1
Clinical features (including histology if relevant)
Dermal capillarovenous malformations, called PWSs,
are made up of postcapillary venules within the dermis.
They appear at birth on the face in 90% of patients, but
may spread to neck, chest, and back. They start out as
pink macules, but tend to darken and increase in
thickness with age.18 As a disruption in the development of cephalic neuroectoderm, a distribution among
the trigeminal nerve is seen, particularly the ophthalmic (V1) division. These cutaneous abnormalities
never regress spontaneously.
Congenital glaucoma is the most common presentation in
a patient with a PWS with V1 division involvement.19 Other
ocular abnormalities include strabismus and choroidal
vascular lesions.20 They show angiomatosis vascular hyperplasia, blanch with pressure, and can present in the
oral cavity affecting the buccal mucosa, lips, and even
the alveolar process, which can result in changes to the
eruption pattern of teeth and malocclusion.
The characteristic angioma of the leptomeninges
generally affects the temporal, parietal, or occipital
areas and even possible involvement of the cerebral
vascular system.1 If cutaneous lesions are lacking, the
diagnosis of SWS is made from radiologic findings,
including intracranial calcifications, which are likely to
be caused by decreased blood flow in areas of pial
angiomatosis.21
Progressive neurologic deficits are present in 40% of
patients. The presence of calcifications, atrophy, or
seizures may suggest cognitive decline and need for
surgical intervention.21 Other symptoms associated
with SWS include hemiparesis, hemiplegia, cerebral
atrophy, and angiomatosis of various other organs.19
Differential diagnosis
KTS often occurs with SWS, suggesting a similar underlying disorder.1
Coats disease involves telangiectasias of the retinal
blood vessels and may involve other areas of the face.
Congenital hemangiomas typically do not present as
large as the PWS. A rare, hereditary form of vascular
157
malformation presenting intraorally is the Osler-WeberRendu syndrome.22 Neurofibromatosis, Bannayan-RileyRuvalcaba syndrome, and Beckwith-Wiedemann
syndrome should also be considered in a differential
diagnosis.
Treatment considerations for the oral and maxillofacial
surgeon
The most commonly accepted treatment of PWS is
accomplished with the use of a pulsed dye laser using
wavelengths of 577 nm and 585 nm. The lesions typically do not cause functional problems with bleeding
and treatment is directed toward improving cosmesis.
Before initiating treatment it is important to distinguish
PWS lesions from other lesions that may have a greater
blood flow and therefore an increased risk of bleeding.
Hemangiomas may not become clinically evident until
the patient is older, whereas vascular malformations
are almost always noticed at birth and continue to grow
with the patient.22 If the lesion is purely dermal or
submucosal, and the underlying bone is not affected,
bony surgery including osteotomies for orthognathic
surgery can be performed without fear of excessive
bleeding.22
Spontaneous expansion of a vascular malformation or
bleeding secondary to trauma or infection may cause
the patient to present with acute painful swelling.16
Pyogenic granulomas frequently develop within PWSs,
particularly in the mouth.1 These patients should be
evaluated hematologically, including prothrombin
time, partial thromboplastin time, fibrin split products,
and fibrinogen and platelet levels. Surgical intervention
can then be planned in the absence of coagulopathy
(Fig. 6).21
Peutz-Jeghers syndrome
Genetics
Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder that typically manifests in childhood and
early adulthood and is characterized by orofacial
melanosis and intestinal polyposis with an increased
risk of gastrointestinal and other cancers.23
The inheritance pattern is autosomal dominant, and PJS
is the most common hereditary hamartomatous
gastrointestinal polyposis syndrome.24 The mutated
Fig. 6 (A) Capillary malformation with cobblestone appearance in an adult with SWS. (B) Angiomatous lesion of the left mandible in a
patient with SWS. (Courtesy of [B] D. DeLuke, DDS, MBA, Richmond, VA.)
158
gene on chromosome 19 seems to serve as a tumor
suppressor gene that encodes for serine threonine kinase (STK11).23 A truncation in the protein and loss of
its expression causes a reduced kinase activity and loss
of function to control growth in intestinal cells.24 With a
high degree of penetrance, the estimated incidence of
PJS is between 1 in 50,000 and 1 in 200,000 with no
evident gender or racial predilection.1
Clinical features
Gastrointestinal manifestations are the most important
component of this syndrome. The intestinal polyps are
usually found in the small bowel and the colon,1 but
they may be found anywhere along the gastrointestinal
tract and at even extraintestinal sites.25 Presenting
signs and symptoms, such as abdominal pain, anemia
secondary to bleeding, and intestinal obstruction
caused by intussusception occur early in life, with more
than 30% of patients presenting with symptoms in the
first decade, and 60% by age 20 years.26
The correlation between PJS and cancer remains
controversial. Many sources suggest that the intestinal
polyps found in PJS are at an increased risk of
cancer through the hamartomas-adenoma-carcinoma
pathway.26 Other malignancies have been shown to be
related to PJS, including cancers of the breast, lung,
ovary, uterus, cervix, testicle, and pancreas. Ovarian
malignancies in particular occur in 10% to 14% of female
patients with PJS. In addition, gynecomastia can
develop in men by hormonal imbalance caused by
calcified Sertoli cell testicular tumors.26
Mucocutaneous hyperpigmentation is an early manifestation of PJS and occurs in 95% of patients.23 Characteristic bluish-black spots appear at birth, and are
concentrated around the vermillion of the lips, palate,
buccal mucosa, and tongue, as well as the anus, genitals, and periorbital region.24 Variable in intensity,
these lesions tend to fade after puberty but remain on
the palate and buccal mucosa, thus being helpful in
diagnosis.1 On histology, the macules appear as
increased melanin in basal cells, and an increased
number of melanocytes at the dermoepidermal
junction.24
Differential diagnosis
Familial juvenile polyposis, hereditary mixed polyposis,
CS, Cronkhite-Canada syndrome, familial adenomatous
polyposis syndrome, Bannayan-Ruvalcaba-Riley syndrome, and basal cell nevus syndrome should all be
considered in the differential diagnosis. The pigmented
lesions differential includes Leopard syndrome, Laugier-Hunziker syndrome, and Carney complex.24 Toxins
such as lead, arsenic, and bismuth are known to cause
diffuse pigmentation of the gingiva. Other metabolic
disorders associated with hyperpigmentation are
chronic nutritional deficiencies, including pellagra,
celiac sprue, and anorexia nervosa.27
Treatment considerations for the oral and maxillofacial
surgeon
The diagnosis of PJS remains primarily a clinical process. Because the oral lesions present before the onset
of gastrointestinal disease, oral health care providers
have a unique role for surveillance of the oral cavity
with frequent recall for presenting signs and symptoms.24 Any mucocutaneous features and family history
should direct the clinician toward the diagnosis and the
Cowden syndrome
Genetics
Cowden syndrome (CS), also known as multiple
hamartomas syndrome, is a dermatosis characterized
by multiple hamartomatous papules and nodules of the
face, oral cavity, and skin.29 CS has an autosomal
dominant inheritance and complete penetrance of
equal frequency in both sexes. CS is rare, with prevalence of 1 in 200,000, often manifesting in the second
or third decade with the obvious signs being lesions of
the skin and oral mucosa.30 However, a variable penetrance does exist among patients.31 CS shows a race
predilection and tends to be more common in white
people.32
The causative genetic abnormality is reported to be a
germline mutation in chromosome 10q23. A mutated
tumor suppressor gene PTEN (phosphatase and tensin
homolog) has a loss of function in regulating cell growth
with an inability to check the protein tyrosine kinase.31
Clinical features
The distinguishing lesions of CS are mucocutaneous
hamartomas. The hamartomas arise as alterations of
ectodermal, endodermal, and mesenchymal origin and
can affect multiple organs systems.32
The facial lesions generally arise first, and the papules
or nodules can be found over facial skin, mucosal
Hamartoneoplastic Syndromes
surfaces, lips, and neck, as well as hyperkeratosis on
extremities and palmoplantar surfaces.1
Lesions appear as papillomatous formations with features of hair follicles, thus giving the histology of tricholemmomas, composed of epithelial cells with
abundant glycogen surrounded by smaller palisading
cells.1 Oral fibromas and papillomas can also be seen.33
Lesions may coalesce to form a cobblestone
appearance.
These hamartomatous lesions may progress to cancer,
specifically tumors of the breast, thyroid, polyposis of
the gastrointestinal tract, and malignancy of the female reproductive tract. Although breast cancer is the
most serious complication of CS, the female reproductive tract may show symptoms such as irregular menses,
ovarian cysts, and uterine leiomyomas.30 Other benign
lesions may develop, such as thyroglossal duct cysts,
fibrocystic breast disease, and multinodular thyroid
goiter.1
Multiple gastrointestinal polyps are also common. They
may be seen throughout the gastrointestinal tract,
although the incidence of malignant transformation of
the gastrointestinal polyps is unknown.30
Skeletal abnormalities such as scoliosis have been
documented and progressive macrocephaly seems to be
an important early marker of CS in young children.1 A
hypoplastic mandible and maxilla, microstomia, higharched palate, and malocclusion may accompany the
large head circumference.29
Differential diagnosis
Byars-Jurkiewicz syndrome presents with fibroadenomas of the breast, scoliosis, and gingival fibromatosis.
The cutaneous lesions may resemble epidermodysplasia, Darier disease, Torre-Muir syndrome, and the
multiple oral fibromas in tuberous sclerosis.
Similarities exist between the intraoral lesions and
polyposis of the intestines in CS, multiple endocrine
neoplasia (MEN) type 2B, and neurofibromatosis.1
Multiple traumatic fibromas, multiple verruca vulgaris,
and Sipple syndrome.33
Treatment considerations for the oral and maxillofacial
surgeon
Extensive papules, papillomas, and oral lesions should
suggest CS and are often the first presenting sign. Early
recognition of this syndrome is important in view of the
high risk for the development of such malignant tumors.
In patients with CS, follow-up at 6-month intervals has
been recommended.34
The oral lesions may interfere with function and prosthetic treatment plans and their surgical removal is
then indicated using electrocautery.
At extreme risk for caries, the patients should also
maintain strict oral hygiene (Figs. 8 and 9).32
159
160
mutations to the RET proto-oncogene on chromosome
10 are thought to be responsible, because RET transduces the growth and differentiation of developing
tissues including those derived from the neural crest.37
Although nearly 100% of patients with MEN 2A have familial genetic abnormalities, patients with MEN 2B
often do not have a family history of the disease and
50% of cases are caused by spontaneous germline mutations.38 The overall frequency of MEN 2 in the United
States is 1 in 50,000 cases. MEN 2A is slightly more
common than MEN 2B.39
Clinical features
MEN 2B is the rarest of the 3 MEN syndromes, clinically
presenting as neoplastic changes to the endocrine
glands with a cluster of phenotypic changes.
General appearance is often a marfanoid habitus with
other musculoskeletal anomalies occurring in at least
75% of cases.35 These anomalies include pes cavus,
slipped capital femoral epiphysis, kyphosis, scoliosis,
lordosis, increased joint laxity, and extremity
weakness.30
The distinctive orofacial features of MEN 2B are often
the first features to be expressed and are considered
reliable markers of the disease.36 Multiple mucosal
neuromas are present, which are hamartomatous proliferations of nerve cells presenting as nodules on the
face, gingiva, palate, anterior portion of the tongue,
and the buccal mucosa.35,36 Skeletal facial features
such as a broadened nasal bridge, a high-arched palate,
and a prognathic mandible contribute to an overall
dolichofacial profile.35 Lip enlargement is classically
seen and is caused by diffuse angioneuromatosis. The
oral lesions are generally asymptomatic and benign.36
Ocular signs include dry eyes present in childhood with
children unable to cry tears. Prominent corneal nerves
are observed in all cases, as well as neuromas of the
tarsal plate with characteristic lid margin thickening.40
Childhood onset of chronic constipation is a common
complaint. Diffuse intestinal ganglioneuromatosis is
present in approximately 40% of cases and can occur
anywhere along the gastrointestinal tract.37 Chronic
diarrhea may also occur and may be related to the
medullary thyroid carcinoma.35
Differential diagnosis
Pheochromocytoma can also occur with neurofibromatosis, or as an isolated tumor, or in von Hippel-Lindau
syndrome presenting with certain brain tumors.
Pheochromocytoma with medullary thyroid carcinoma
occurs in MEN IIA and Sipple syndrome. Hyperparathyroidism may have genetic inheritance or be secondary
to hyperplasia or adenomas of the parathyroids.
Duodenal carcinoid or Hirschsprung disease may also be
confused with the intestinal ganglioneuromatosis of
MEN 2B.1
Treatment considerations for the oral and maxillofacial
surgeon
Oral health care providers are likely to encounter patients with this syndrome for evaluation of orofacial
lesions, malocclusion, generalized spacing between
teeth, anterior open bite, and facial asymmetry.36 MEN
2B, with distinctive oral characteristics, should be
considered by the oral and maxillofacial surgeon who
may be the first practitioner to diagnose the syndrome
and refer for appropriate treatment35
Proteus syndrome
Genetics
Proteus syndrome (PS) is a rare hamartomatous disorder
affecting multiple tissues including bone, soft tissue,
vascular structures, and skin.42,43 The term PS was suggested by Wiedemann and colleagues42 after the Greek
god Proteus who was able to change his shape at will.
The cause and genetic basis of PS is not yet known, and
no sex predilection is associated.44 A postzygotic mutation has been postulated because of clinical discordance in identical twins, the mosaic distribution of the
lesions, and because all cases have been sporadic.42
The frequency of PS is also difficult to determine,
because fewer than 200 published cases fulfilling diagnostic criteria worldwide.43 The PTEN gene has been
implicated because of its role in other hamartomatous
syndromes.45 However, there is no clear phenotypic
distinction between PS with and without PTEN mutations, and both may fulfill the diagnostic criteria.42 The
clinical features of PS probably represent a second hit
in specific tissues or at a specific stage of embryologic
development in patients with inherited PTEN mutation.
Thus, PS is a phenotypic diagnosis and can result from
mutations in several different genes.45
Clinical features
Wiedemann and colleagues42 proposed diagnostic
criteria: gigantism of the hands and/or feet, pigmented
Hamartoneoplastic Syndromes
161
PS may develop unusual tumors such as testicular,
ovarian, and central nervous system tumors.42
Differential diagnosis
PS is thought to be part of a spectrum of hamartomatous
neurocutaneous syndromes.48 CS, Bannayan-RileyRuvalcaba syndrome, and proteuslike syndrome have
germline PTEN mutations, as does a VATER-like disorder
with hydrocephalus and macrocephaly with autism.42 PS
must also be differentiated from neurofibromatosis,
naunay-Weber syndrome, enchondromatosis,
Klippel-Tre
and Maffucci syndrome.49
Treatment considerations for the oral and maxillofacial
surgeon
In roughly 30% of the cases reported, facial anomalies
occur, including malformed ears, high-arched palate,
malocclusion, mandibular prognathism, and depressed
nasal bridge.50 There is also an increased risk of
development of a malignancy, deep venous thrombosis,
and pulmonary embolism. Although vascular malformations and epidermal nevi may be among patients
cosmetic concerns, surgical removal of the vascular
tumors is discouraged because of the formation of unsightly scars, keloids, and tissue overgrowth.48 However,
when undertaken, excisions of subcutaneous tumors is
difficult because abnormal tissue may be left and the
planes of dissection are vascular. Many stages are usually required and postoperative morbidity is increased
and complex, because leakage from residual lymphatic
channels is expected. It is frequently necessary to
anticipate secondary deformities. Families should be
made aware that, with patience and multiple procedures, a satisfactory outcome might be expected
(Fig. 12).50
Neurofibromatosis
Genetics
Neurofibromatosis type 1 (NF1), also known as von
Recklinghausen disease, is an autosomal dominant,
multisystem disorder affecting approximately 1 in 3500
people.1 The NF1 gene, located on chromosome
17q11.2, encodes for the tumor suppressor neurofibromin, expressed in neural and glial cells, Schwann
cells, and melanocytes.51 NF1 has one of the highest
rates of spontaneous mutations, and loss of function
leads to unregulated cell growth in these tissues.
Penetrance is 100%, thus patients with the mutation
manifest tumors clinically, although expressivity is
highly variable.51 NF2 results from a mutation in the
NF2 gene and is characterized by bilateral vestibular
schwannomas and various other tumors.52
Clinical features
The diagnosis of NF1 is based on clinical findings. There
are definite diagnostic criteria for NF1 that satisfy any 2
-au-lait macules, 2 or
of the following: 6 or more cafe
more neurofibromas or 1 plexiform neurofibroma, axillary or groin freckling, optic glioma, 2 or more Lisch
nodules, a distinctive bony lesion, dysplasia of the
sphenoid bone or of long bone cortex, and a first-degree
relative with NF1.53
-au-lait macules has smooth
The classic lesion of cafe
borders (coast of California) and homogeneous color
-au-lait. NF1 becomes evident in
close to that of cafe
162
Fig. 12 (A) Connective tissue nevi on feet of patient with PS who also has overgrowth of the right foot. (B) Supraorbital osseous protuberances, more pronounced on the left side, and dolichocephaly in a patient with PS. (From [A] Twede JV, Turner JT, Biesecker LG,
et al. Evolution of skin lesions in Proteus syndrome. J Am Acad Dermatol 2005;52(5):834e8; and [B] Raboudi T, Bouchoucha S, Hamdi B,
et al. Soft-tissue necrosis complicating tibial osteotomy in a child with Proteus syndrome. Orthop Traumatol Surg Res 2014;100(2):247e50;
with permission.)
-au-lait spots
the first few years of life when cafe
develop.53,54
The hallmark neurofibroma is a benign peripheral nerve
sheath tumor. In the maxillofacial region, severe facial
disfigurement is almost always caused by a plexiform
neurofibroma of the trigeminal nerve and may invade
both the cheek and oral cavity.52 Cutaneous neurofibromas usually do not become apparent until puberty,
and then may continue to increase in size and number
throughout adulthood.55 Although these neurofibromas
do not progress to malignant neoplasms, studies have
shown that 1% to 2% of patients with NF1 develop malignant peripheral nerve sheath tumors.54,56
Skin fold freckling (Crowe sign) is the most specific of
the cardinal criteria for NF1, and is considered nearly
pathognomonic. It generally occurs around 5 years of
age in either the axillae, groin, neck, circumoral area,
or the trunk area.53
Bony abnormalities are variable and include scoliosis,
sphenoid wing or long bone dysplasia, and osteopenia.
Primary defects may include scalloping of vertebrae,
congenital bowing of long bones, and osteolytic lesions,
and secondary erosive defects caused by invasive
tumors.54
Lisch nodules are small, hyperpigmented macules of
the iris. They occur in about 20% of children by 6 years
of age and 95% of adults with NF.54 The slow-growing
optic glioma is a tumor of the optic nerve and is present
in approximately 20% of patients. It presents as eye
proptosis and decreased visual acuity associated with
precocious puberty.53
Neurologic complications have been observed in 55% of
patients. These complications may include neurophysiologic disorders, and 1 in 200 present with cognitive
defects and learning difficulties.54
Patients with NF2 may present with acoustic neuromas,
tumors of Schwann cell origin, and multiple neurofi-au-lait
bromas in the absence of Lisch nodules and cafe
spots.52
Differential diagnosis
An important disorder to distinguish from NF1 is NF1-au-lait
like syndrome. This syndrome consists of cafe
macules, axillary freckling, and macrocephaly, and is
negative for an NF1 gene mutation.51
Syndromes associated with multiple mucosal neuroma
are MEN IIb, KTS, Jaffe-Campanacci syndrome, and
McCune-Albright syndrome.1
Treatment considerations for the oral and maxillofacial
surgeon
Abnormalities of dentition might be the first clinical
sign to allow correct diagnosis of NF1. Impacted, displaced, or missing teeth with enlargement of the
alveolar ridge are oral manifestations of NF1. Radiological findings include widening of mandibular canal
and mental foramen.52,57
Management often involves multiple specialties because there is no specific medical management available.54 Pigmented lesions are generally not treated and
darken in response to sunlight, and tend to fade with
time to become less noticeable. Symptomatic neurofibromas that compromise function are candidates for
surgical removal; however, multiple lesions and plexiform neurofibromas may be tangled with normal tissue,
causing difficulty in removal while preventing neurologic deficits.52,54 Despite the solitary nature of the
tumor, the vascularization is dense and vascular
malformations are common. Intraosseous neurofibromas often require large resections of the mandible
(Figs. 13 and 14).52,55
Tuberous sclerosis
Genetics
Tuberous sclerosis complex (TSC) is an autosomal
dominant, systemic disorder characterized by the formation of hamartomas in multiple organ systems, most
commonly the brain, skin, kidney, and eye. Eighty
Hamartoneoplastic Syndromes
Fig. 13
163
retardation.62 Cognitive impairment in TSC is thought to
result directly from cortical tubers, seizures, or both.
The most common brain lesions include abnormal
neuronal and glial elements, cortical and white matter
tubers, and giant cell astrocytomas. Other findings such
as cerebral atrophy, cerebral infarct, cerebral aneurysm, and arachnoid cysts may be present.59
Hypomelanotic macules may be the first cutaneous
manifestation and are reliably detected in patients
with tuberous sclerosis during infancy.63 Lesions may
appear as ash leaf spots, confection macules, thumbprint macules, or angiofibromas. Facial angiofibromas
occur in up to 90% of patients, typically presenting in
preschool years and occurring as bilateral and symmetric, small, telangiectatic papules on the cheeks,
chin, and nose.59,63 Approximately 50% of patient have
eye problems, including retinal hamartomas.62 Nontraumatic ungual fibromas are among the major diagnostic criteria for the diagnosis of TSC and a major
concern to patients because of pain and distortion of
the nail; they have a frequency of 15% to 52%.64
Oral lesions have been reported in about 11% of patients.58 These lesions consist mainly of fibrous growths
affecting the oral mucosa of the anterior gingiva, lips,
tongue, and palate. Pitted enamel hypoplasia is
another characteristic oral manifestation of the disease
found in 58% of patients.60
Between 50% and 80% of patients with TSC have renal
lesions like angiomyolipomas, renal cysts, nephrolithiasis, and renal tumors.61
Diagnosis of tuberous sclerosis is difficult because no
single symptom is present in all patients, and none are
absolutely pathognomonic.64
Differential diagnosis
Several familial tumor syndromes can present with
multiple facial and oral papules, including TSC, CS, BirtHogg-Dube syndrome, and MEN type I. Moreover, facial
angiofibromas have also been reported to occur in patients with MEN type 1 and neurofibromatosis.1
-au-lait spots (arrow). (B) Nonencapsulated neural elements typical of neuroFig. 14 (A) Patient with typical neurofibromas and cafe
fibroma are seen in this palatal excision in a patient with neurofibromatosis. ([A] From Reynolds RM, Browning GG, Nawroz I, et al. Von
Recklinghausens neurofibromatosis: neurofibromatosis type 1. Lancet 2003;361(9368):1552e4, with permission; and [B] Courtesy of
D. DeLuke, DDS, MBA, Richmond, VA.)
164
Fig. 15 Clinical and histologic features of oral lesions in one patient with tuberous sclerosis complex. Biopsy specimen of dome-shaped
fibroma on hard palate (A) revealed haphazard array of collagen with several thin-walled vascular channels underlying thickened
epithelium (B). Biopsy specimen of fibroma at angular commissure (C) revealed vessels and fibrous bands of collagen (D). (B and D, Hematoxylin-eosin stain; bar Z 65 _m; original magnification 3100.) (From Sparling JD, Hong CH, Brahim JS, et al. Oral findings in 58 adults
with tuberous sclerosis complex. J Am Acad Dermatol 2007;56(5):786e90; with permission.)
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Clinical features
The clinical features of Treacher Collin syndrome (TCS) consist
of bilaterally symmetric, abnormal development of the structures arising from the first and second branchial arches. This
abnormal development contributes to deficient generation of
the lower two-thirds of the face (Fig. 1).
The first branchial arch is involved with the growth of the
mandible and the zygomaticomaxillary complex and the second arch or hyoid arch is involved with development of the
middle ear. The classically presented patient accordingly has a
convex facial profile with gross hypoplasia or incomplete formation of the zygoma, maxilla, and mandible in all 3 dimensions. These individuals also have normal intelligence.
These facial features are summarized in Table 1.
The authors have nothing to disclose.
Department of Oral & Maxillofacial Surgery, Houston Methodist
Specialty Physician Group, Weill Medical College Cornell University,
New York, 6560 Fannin Suite 1280, Houston, TX 77030, USA
b
Oral and Maxillofacial Surgery, Virginia Commonwealth University,
Richmond, VA, USA
* Corresponding author.
E-mail address: dmalfi@houstonmethodist.org
a
Differential diagnosis:
Craniofacial microsomia: features are asymmetric and
usually unilateral
Pierre Robin sequence: children born with severe hypoplasia of the mandible, high arching cleft palate, and a
relative macroglossia
Stickler syndrome comprises a group of hereditary conditions involving eye, ear, and joint deformities plus
Pierre Robin sequence
Nager syndrome includes malformed upper limbs as well
as cleft palate and severe palatal hypoplasia
oralmaxsurgeryatlas.theclinics.com
168
Alfi et al.
Fig. 1 A 6-year-old girl with TCS. Note the facial features of TCS: colobomata, lower lid hypoplasia, downward slanting of palpebral
fissures, prominent nasal dorsum, malar and zygomatic hypoplasia, mandibular hypoplasia, microgenia, Angle class 2 open bite. (Courtesy
of Dr. Sidney Eisig.)
structures are hypoplastic or missing the corneas are unprotected, which may necessitate earlier reconstruction of the
orbital and zygomatic structures.
Table 1
Eyes
Ears
Nose
Mouth
Musculoskeletal
Skeleton
Muscles
Joint
Mandibular hypoplasia
Microgenia
Hypoplastic glenoid fossa
Maxillary hypoplasia
Muscular hypoplasia (muscles of
mastication)
Absent, hypoplastic, or deformed
TMJ
Speech
Correction of a cleft palate should follow the standard cleft
treatment recommendations.
Secondary treatment strategy should take place at the end
of skeletal maturity and include orthognathic surgery and
zygomatic-orbital reconstruction.
Malar and orbital reconstruction uses a full-thickness
calvarium bone graft through a coronal incision and exposure.
It is recommended that this procedure be performed after the
age of 6 years, for skeletal maturity of the midface, as well as
the ability to reconstruct the donor calvarium site with a local
split-thickness calvarium graft.
Maxillomandibular reconstruction is best approached with
traditional orthognathic surgery at 13 to 15 years of age, at the
time of early skeletal maturity. Le Fort I and rami osteotomies
with sliding genioplasty are usually indicated.
When the deformity results in absent ramus, condyle, or
glenoid fossa, then reconstruction may be performed at the
time of malar and orbital reconstruction. The use of costochondral bone graft to reconstruct the ramus-condyle is advocated. A second reconstruction with conventional osteotomies
is almost certain to be warranted after skeletal maturity.
As with conventional orthognathic surgery, nasal reconstruction should be performed as the final reconstructive procedure when indicated.
Goldenhar syndrome
Hemifacial microsomia (HFM), Goldenhar syndrome, and oculoauriculovertebral dysplasia have been used interchangeably.
169
Fig. 2 A patient before (A) and after (B) mandibular distraction. (From Gateno J, Teichgraeber FJ, Aguilar E. Computer planning for
distraction osteogenesis. Plast Reconstr Surg 2000;105(3):873e82; with permission.)
Table 2
Skin
Eyes
Ears
Nose
Mouth
Musculoskeletal
Skeleton
Clinical features
Goldenhar syndrome shares phenotypic manifestations of first
and second branchial arch derivative malformations. The
findings can be viewed as similar to those of TCS, but usually
these findings are unilateral, causing gross facial asymmetry.
Hallmark features include microtia, hemifacial microsomia, epibulbar dermoids, and preauricular skin tags. A
constellation of other findings may be present and are listed in
the following table (Table 2). The OMENS classification system
was developed to indicate the 5 major manifestations of HFM
(Table 3).
Muscles
Joint
Mandibular hypoplasia
Microgenia
Hypoplastic glenoid fossa
Maxillary hypoplasia
Malar hypoplasia
Orbital hypoplasia
Muscular hypoplasia (muscles of
mastication)
Absent, hypoplastic, or deformed
TMJ
Neurologic
Other
170
Table 3
Alfi et al.
OMENS
Orbit
Mandible
Ear
Facial
nerve
Soft tissue
Differential diagnosis:
VACTERL is an acronym for vertebral anomalies, anal
atresia, cardiac malformations, tracheoesophageal fistula, renal anomalies, and limb anomalies.
Nager syndrome: downward palpebral fissures, midface
hypoplasia, micrognathia, and upper limb (radial) deformities. Features are usually bilateral.
TCS: bilateral midface and mandibular hypoplasia,
microtia, and coloboma.
Fig. 3
A patient followed from infancy to teenage years shows a stable left hemifacial deformity.
171
Fig. 4 The patient from Fig. 3 with three-dimensional reconstruction and computer-simulated surgery. It was decided in this case that
early mandibular surgery, at age 12 years, would allow for alveolar growth of the left posterior mandible. This allows for a more predictable and symmetric final orthognathic surgery after skeletal maturity with use of Le Fort 1, bilateral sagittal split osteotomy, and
genioplasty.
Table 4
Eyes
M
obius syndrome
Ears
Nose
Mouth
Maxillary constriction
Cleft palate
Bifid uvula
Malocclusion (excessive overjet, anterior
open bite)
Lip incompetence and open mouth posture
Dental abnormalities (dental agenesis,
oligodontia)
Musculoskeletal
Skeleton
Micrognathia
Retrognathia
Muscles
Muscular hypoplasia
(associated with affected
nerves)
Neurologic
Other
Limb deformities
172
Alfi et al.
bius syndrome, before surgery. Note the thin upper lip. (B) After surgery, with bilateral reduced latissimus dorsi muscle
Fig. 5 (A) Mo
powered by the masseteric branch of the seventh nerve. Upper lip augmented with lipodermal graft. (From Harrison DH. The treatment of
unilateral and bilateral facial palsy using free muscle transfers. Clin Plastic Surg 2002;29:539e49; with permission)
Clinical features
bius syndrome are described as having maskPatients with Mo
like faces. The facial weakness associated with cranial nerve
VII and VI palsies leaves children with expressionless faces with
the inability to abduct the eye. The expressivity is variable and
patients may also have additional cranial nerve palsies, limb
deformities, and other manifestations.
Commonly associated clinical features are listed in Table 4.
Differential diagnosis:
Hereditary congenital facial paralysis: shares similar
findings; however, this syndrome is limited to palsy of the
facial nerve only.
Further readings
Behrents RG, McNamara JA, Avery JK. Prenatal mandibulofacial
dysostosis (Treacher Collins syndrome). Cleft Palate J 1977;
14:13.
Bergmann C, Zerres K, Peschgens T, et al. Overlap between VACTERL
and hemifacial microsomia illustrating a spectrum of malformations
seen in axial mesodermal dysplasia complex (AMDC). Am J Med
Genet A 2003;121:151e5. http://dx.doi.org/10.1002/ajmg.a.20167.
Bianchi B, Copelli C, Ferrari A, et al. Facial animation in children with
Moebius and Moebius like syndromes. J Pediatr Surg 2009;44:
2236e42.
Bianchi B, Ferri A, Brevi B, et al. Orthognathic surgery for the complete
rehabilitation of Moebius patients: principles, timing and our
experience. J Craniomaxillofac Surg 2013;41(1):e1e4.
Gateno J, Teichgraeber JF, Xia JJ. Three-dimensional surgical planning
for maxillary and midface distraction osteogenesis. J Craniofac Surg
2003;14:833e9.
Gateno J, Xia J, Teichgraeber JF, et al. The precision of computergenerated surgical splints. J Oral Maxillofac Surg 2003;61:
814e7.
Gateno J, Xia JJ, Teichgraber JF. Three-dimensional computer-aided
surgical simulation for maxillofacial surgery. Atlas Oral Maxillofac Surg
Clin North Am 2005;13(1):25e39. http://dx.doi.org/10.1016/j.cxom.
2004.10.004.
Gateno J, Xia JJ, Teichgraber JF, et al. Clinical feasibility of computeraided surgical simulation (CASS) in the treatment of complex
173
Posnick JC, Ruiz R, Tiwana P. Treacher Collins syndrome: comprehensive evaluation and treatment. Oral Maxillofac Surg Clin North Am
2004;16:503e23.
Posnick JC. Treacher Collins syndrome: evaluation and treatment.
Orthognathc surgery principles and practice. Elsevier. 2014, Ch 27:
1059e1094.
Posnick JC. Hemifacial microsomia: evaluation and treatment.
Orthognathc surgery principles and practice. Elsevier. 2014, Ch 27:
1095e1158.
Poswillo D. The pathogenesis of the Treacher Collins syndrome (mandibulofacial dysostosis). Br J Oral Surg 1975;13:1e26.
Poswillo DE. The pathogenesis of the first and second branchial arch
syndrome. Oral Surg Oral Med Oral Pathol 1973;35:302e28.
Rune B, Selvik G, Sarnas KV, et al. Growth in hemifacial microsomia
studied with the aid of roentgen stereophotogrammetry and
metallic implants. Cleft Palate J 1981;18:128.
Terzis JK, Noah EM. Mobius and Mobius like patients: etiology, diagnosis, and treatment options. Clin Plast Surg 2002;29:497e514.
Venramini-Pittoli S, Kokitsu-Nakatya NM. Oculoauriculovertebral spectrum: report of nine familial cases with evidence of autosomal
dominant inheritance and review of the literature. Clin Dysmorphol
2009;18:67e77.
Clefting Syndromes
Stephanie J. Drew, DMD
KEYWORDS
Clefting syndromes Clefting disorders Pierre-Robin Velocardiofacial syndrome
Van der Woude syndrome Stickler syndrome CHARGE syndrome
KEY POINTS
There are over 500 syndromes with clefting as part of the phenotype.
An understanding of sequence is needed to effectively manage patients with clefting disorders.
Various treatments are available for the wide variety of clefting disorders.
Introduction
The process of lip and palate morphogenesis depends on
complex molecular signaling pathways to enable cellular proliferation, differentiation, and apoptosis. Both genetic and
environmental factors may be responsible for dysregulating
these pathways, leading to development of cleft lip or palate.
Cleft lip with or without cleft palate is a distinct entity from cleft
palate only. Palate closure occurs between weeks 8 and 12 in
utero, and lip formation is concluded by week 7. During these
periods of development, dysregulation of different pathways
leads to cleft of the lip, palate, or both (Figs. 1 and 2).
Cleft lip and palate, when it occurs as the only malformation (anomaly), is considered nonsyndromic. Seventy percent
of all cases of cleft lip and palate are nonsyndromic. Cases of
cleft palate only are different in that they are nonsyndromic
50% of the time.
However, when cleft lip and palate or cleft palate alone is
associated with other clinical features (anomalies), it is
considered syndromic. Thus, cleft lip and palate occurs as
syndromic 30% of the time. Cleft palate only occurs as syndromic 50% of the time. The diagnosis of a syndrome is made
from the overall pattern of anomalies present. The more
anomalies noted, the easier it is to diagnose. However, sometimes, some of these features may not be fully expressed and
are more difficult to diagnose.
More than 500 syndromes are identified with cleft lip and
palate as part of the phenotype. The most common mechanisms related to syndromic cleft lip and palate are either single
gene mutations or chromosome abnormalities. Of note are the
findings in some syndromes of trisomy chromosomes (13, 18,
and 21), partial deletions, and duplications. Therefore, several
genomic regions containing loci either excessive or insufficient
can lead to cleft lip and palate. There are both autosomal
dominant inheritance patterns and autosomal-recessive
The author has nothing to disclose.
Hofstra School of Medicine, Hempstead, New York, USA
Stony Brook University Medical Center, 101 Nicolls Road, Stony
Brook, NY 11794, USA
Private Practice, The New York Center for Orthognathic and Maxillofacial Surgery, 474 Montauk Highway, West Islip, NY 11795, USA
E-mail address: DrDrew@nycoms.com
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 175181
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.05.001
FGFR1
Kallmann syndrome
COL2A1, COL11A1,
COL11A2
SOX9
Pierre Robin
TBX1
DiGeorge/velocardiofacial
syndromes: 22q11 deletion
oralmaxsurgeryatlas.theclinics.com
176
Drew
Fig. 1
Treatment considerations
For the oral and maxillofacial surgeon, understanding the
significance of syndrome-related clefting is necessary to plan
surgery throughout the patients lifetime as well as manage
associated potential complications of the syndrome-related
anomalies. Some of these anomalies may include major organ
issues from deformations, to malformations, disruptions, and
dysplasias. Of course, these anomalies may affect anesthesia
management, behavior and compliance, wound healing,
and the overall treatment planning and long-term predictability of the surgical procedures. Some of the more common
syndromes are discussed in the following sections. However,
in general, treatment follows a practical protocol based on
developmental, functional, and social/aesthetic goals of
treatment.
Fig. 3
Chromosome.
Palate closure
The soft palate is typically closed before the hard palate during
the first 2 years. However, there are several teams who close
both the hard and soft palate simultaneously at this time.
Closure of the hard palate depends on team protocols: some
perform this procedure at around 2 years, whereas others
delay and place pinned prostheses during infancy to let soft
tissues hypertrophy to make closure easier and also so that
skeletal growth is less restricted. The hard palate is then
closed at around age 5 years before the child starts school
(Figs. 5 and 6).
Myringotomy
This surgery is usually combined with palatal surgery once
hearing deficits are confirmed.
Fig. 2
Clefting Syndromes
177
Rhinoplasty
Bone grafting
Fig. 5
Pharyngeal flap
Orthodontic care
Orthodontic intervention is needed for several reasons. First, if
there is maxillary hypoplasia in a transverse dimension, the
Orthognathic surgery
This surgery is performed at the cessation of growth, if
needed. Many children with cleft palate have maxillary skeletal deficiency and subsequent functional malocclusions.
Often, these skeletal problems are masked with both cosmetic
surgical procedures and orthodontic compensation. Studies
vary as to the frequency of need for corrective jaw surgery in
patients with cleft palate; frequencies from 25% to 75% have
been reported in the literature.
Special consideration when planning for these children is
given to the amount of movement needed and scar tissue
resistance. Vascular anomalies may also be present in some
syndromic children.
Distraction
In the child with cleft palate who needs corrective jaw surgery,
if the maxillary skeletal deficiency is greater than 12 mm, it is
often difficult to achieve a stable result with standard
orthognathic surgery, because of the enormous strain placed at
the scarred regions of the palatal tissues. Distraction should be
178
considered in these cases to slowly advance the maxilla and
stretch these tissues.
Distraction surgery has also been used in infants with
mandibular hypoplasia and cleft palate who are in airway
distress, in order to open the airway and to either prevent tracheostomy or to allow for decannulation. Conservative therapy
is first attempted with these children. The palatal tissues need
to be closed in these hypoplastic patients. The airway is further
compromised if the mandible is the cause of the obstruction.
Tooth replacement
A missing lateral incisor is the most common tooth that needs
replacement in the cleft site. There are several syndromic
clefting disorders that have multiple missing teeth as part of
the syndrome. The same basic guidelines for tooth replacement
in children are used for children with cleft palate. Prosthetic
rehabilitation should be geared toward the most aesthetic
outcome. It is often difficult to adequately reconstruct both
bone and soft tissue for dental implants; for some patients,
conventional crown and bridge work may be a reasonable option. Working hand in hand with the patient, restoring dentist,
and orthodontist is essential to achieve realistic goals.
Anesthesia
Oral anomalies challenge the anesthesia team, with possible
issues related to airway malformation, previous surgery
(especially pharyngeal flap surgery), and possible range of
motion issues associated with other syndromic clefting disorders that have concurrent temporomandibular joint anomalies.
Cardiac issues in some syndromic clefting disorders may also
need to be addressed as part of the anesthesia management.
Compliance
Younger patients may not be compliant after surgery, which
can lead to wound breakdown and poor wound healing.
If distraction is considered, the child needs to allow you to
turn the distractors to achieve the needed results. The parents
are often challenged with this task and may not be able to
accomplish it, and thus, the patient may need to see the surgeon daily during the distraction period.
Drew
have primary pulmonary dysgenesis. Other anomalies reported
are inguinal hernia or umbilical hernias. These patients often
have mental retardation and learning disabilities, as well as
behavioral issues. Metabolic issues include hypocalcemia in
infancy. These children may also be at increased risk for infections as a result of T-lymphocyte dysfunction.
Genetics
There is a defect in chromosome 22 with a microdeletion
(1.5e3.0 Mb) on the long arm of chromosome 22 (del22q11
syndrome).
Inheritance pattern
The inheritance pattern is autosomal dominant.
Frequency
This syndrome occurs in 1 in 2000 to 7000 live births.
Differential diagnosis
About 10% of patients with velocardiofacial syndrome (Fig. 8)
have DiGeorge syndrome, which consists of at least 2 of the
following features:
Conotruncal cardiac anomaly
Hypoparathyroidism, hypocalcemia
Thymic aplasia, immune deficiency
Fig. 8 Patient with typical phenotype features of velocardiofacial syndrome. Note long face, broad nasal bridge, and
epicanthal folds.
Clefting Syndromes
indicate a need for antibiotic coverage and/or specialized
anesthesia management during surgery. Also, any anomalous
carotid vessels may need to be documented preoperatively,
prior to any surgical dissection in the palatopharyngeal
region.
179
opening. There is high penetrance with this genetic mutation,
and families should be counseled.
Genetics
Genetics
Most reported cases of Van Der Woude syndrome (VWS) have
been linked to chromosome 1q32-q41 (VWS1) and are caused
by mutation in the IRF6 gene.
VWS2 has been mapped to chromosome 1p34 and a mutation
identified in the WDR65 gene.
This condition can be monogenic, chromosomal, or teratogenically induced. There are also several cases with unknown
genesis.
Inheritance pattern
Inheritance pattern
The inheritance pattern is autosomal dominant.
Frequency
Frequency
This syndrome is the most frequent form of syndromic clefting,
accounting for 2% of all cases of cleft lip and palate. The
prevalence ranges from 1:100,000 to 1:40,000 stillborn or live
births.
Differential diagnosis
Lip pitting may also be present in Popliteal Pterygium Syndrome, a closely related inherited syndrome.These patients
have unilateral cleft lip and palate, ankyloblepharon,
paramedian lip pits, unilateral renal aplasia, and coronal
hypospadias.
Fig. 9
Differential diagnosis
The differential diagnosis includes Stickler syndrome (Fig. 11)
and fetal alcohol syndrome.
(A) Patient with VWS after revision of animation of lip pits. (B) Unrepaired lip pits in a patient with VWS.
180
Drew
Fig. 10 (A) Child with Pierre Robin sequence and normal condyles. Micrognathia and microgenia evident. (B) This patient with PierreRobin sequence has agenesis of both mandibular condyles.
Fig. 11
(A, B) Stickler syndrome. Note long philtrum, prominent eyes, and small chin.
Clefting Syndromes
181
Stickler syndrome
Internet resources
Recommended resources
Texts
Benum of anesthesia and uncommon diseases. 6th edition. Philadelphia: Saunders; 2012.
Gorlin syndromes of the head and neck. 5th edition. New York: Oxford
Publisher; 2010.
Lesch-Nyhan syndrome
Genetics
Extremely rare, present in only 1 in 380,000 live births.1
Lesch-Nyhan syndrome (LNS) is an X-linked recessive
disorder of purine metabolism; however, up to 30% of
patients carry de novo mutations.2,3 It is caused by the
deficiency of hypoxanthine guanine phosphoribosyl
transferase (HPRT), which is a purine salvage enzyme
responsible for recycling purine bases into purine
nucelotides.4 Specifically, it converts hypoxanthine and
guanine into their respective 50 -mononucleotides.5
The gene for HPRT (HPRT1) is encoded on the long arm
of the X chromosome at Xq26-Xq27.2 This enzyme is
present in all tissues with the highest levels in the basal
ganglia, which accounts for the extrapyramidal effects
seen in this syndrome.4
Because it is an X-linked disorder, male patients are almost
exclusively affected. Female patients may be carriers.5
A phenotypic spectrum exists, which is thought to be
based on variability in HPRT levels and activity.4,5
Classic LNS is correlated with severe or complete HPRT
deficiency. Patients with partial HPRT deficiency may
present with hyperuricemia with or without neurologic
and/or behavioral symptoms.4,5
Funding Sources: None.
Conflict of Interest: None.
a
Department of Oral and Maxillofacial Surgery, Virginia Commonwealth University School of Dentistry, 521 North 11th Street, Room 311,
Richmond, VA 23298-0566, USA
b
Division of Oral and Maxillofacial Surgery, Department of Surgery,
Medical College of Virginia Medical Center, 521 North 11th Street,
Room 311, Richmond, VA 23298-0566, USA
* Corresponding author. Department of Oral and Maxillofacial
Surgery, Virginia Commonwealth University School of Dentistry, 521
North 11th Street, Room 311, Richmond, VA 23298-0566.
E-mail address: dlui@vcu.edu
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 183195
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.05.002
Clinical features
Often, children have a normal prenatal and perinatal
course with development of symptoms within the first 3
to 6 months.1
LNS has a spectrum of phenotypic presentations. However, classic LNS is characterized by aggressive and
self-mutilating behavior (most commonly persistent lip,
tongue, and finger biting resulting in severe avulsion
injury to perioral tissues and amputation of digits),
hyperuricemia, and involuntary movements with severe
dystonia (Fig. 1A, B).2,6,7
Other features that may be present include developmental delay, megaloblastic anemia, nephropathy, and
gout or tophi.2,4
The first sign is the appearance of an orange or reddish
sandy material in the diapers of newborns due to uric
acid crystalluria and microhematuria.2,3 Additional
early findings, within the first year of life, include
episodic opisthotonus and the inability of a child to sit
in a chair unless secured with chest or waist restraints
(see Fig. 1C).1,2,7
Differential diagnosis
Diagnosis is made based on phenotypic presentation,
elevated serum uric acid levels (greater than 4e5 mg/dL
in children), and HPRT enzyme assays.2,4
A wide array of disorders of purine metabolism exist
that exhibit features of LNS such as gout, Arts syndrome, ribosephosphate diphosphokinase, hyperactivity, and adenylosuccinate lyase deficiency.1
From a cognitive and neurobehavioral standpoint, LNS
may mimic dyskinetic or athetoid type cerebral palsy,
autism, Rett syndrome, Cornelia de Lange syndrome, or
Down syndrome.8
Treatment considerations for the oral and maxillofacial
surgeon
Treatment has largely been aimed at controlling the
presenting symptoms and prevention of severe injury
from self-mutilation.
oralmaxsurgeryatlas.theclinics.com
184
Lui et al.
Fig. 1 Self-injury in Lesch-Nyhan syndrome. (A) Injury from persistent lip biting. (B) Finger amputation from self-mutilating behavior. (C)
r PR, Jinnah HA. Lesch-Nyhan disease and the basal
Patient in protective physical restraints and wheelchair device. (From Visser JE, Ba
ganglia. Brain Res Brain Res Rev 2000;32(2e3):467; with permission.)
Allopurinol has been used to decrease the overproduction of uric acid.4 This, in turn, delays the
development of renal failure.6 Allopurinol, however,
has no effect on behavioral, neurologic, and cerebral
manifestations of the syndrome.4,6 Dystonia and spasticity have been managed with GABA agonists (eg,
benzodiazepines and baclofen), dopamine replacement
therapy (eg, L-dopa), and deep brain stimulation to the
globus pallidus.4,6 Control of self-injurious behavior has
been sought with benzodiazepines, neuroleptics, antiepileptics, and chloral hydrate.6 Recent studies have
demonstrated that the limitation of self-mutilating
behavior includes a combined approach using physical
restraints, behavioral treatment, and pharmacologic
therapy.6
In the event that self-mutilating behavior is refractory
to medical management, alternative therapies have
been proposed. Some have advocated extraction of
front teeth or all remaining teeth.6 To avoid this invasive treatment, other investigators have advocated oral
protective devices such as lip bumpers or shields,
tongue shields, and occlusal bite plates or splints,
which have shown some success.6
A recent study by Chen and colleagues4 demonstrated
regression in aggressive and self-injurious behavior and
to a lesser extent dystonia with oral supplementation of
S-adenosylmethionine based on its therapeutic potential to replenish the nucleotide pool in the brain.
185
Fig. 2 (A) Child with Marcus Gunn jaw-winking phenomenon demonstrating unilateral left upper eyelid ptosis. (B) Ptosis is resolved by
ska-Pawelec G, et al. Marcus Gunn
synkinetic upper eyelid elevation with concomitant jaw opening. (From Bartkowski SB, Zapala J, Wyszyn
jaw-winking phenomenon: management and results of treatment in 19 patients. J Craniomaxillofac Surg 1999;27(1):26; with permission.)
excision on the affected side.16e18 Other surgical procedures exist; however, it is beyond the scope of this
article to describe all methods.
Differential diagnosis
The differential diagnosis for cavernous sinus syndrome
includes superior orbital fissure syndrome, orbital apex
syndrome, Horner syndrome, carotid canal syndrome,
and Tolosa-Hunt syndrome.20,21
Treatment considerations for the oral and maxillofacial
surgeon
Treatment of this syndrome is aimed at identifying and
managing the underlying condition.
Broad categories of diseases resulting in the clinical
presentation of cavernous sinus syndrome include bacterial and fungal infection, noninfectious inflammation,
vascular lesions, and neoplasms.21
Several infectious processes may result in the development of cavernous sinus thrombosis. Infections of the
midface (ie, nasal furuncles) can enter the facial vein
and pterygoid plexus and be carried to the cavernous
sinus.23 Staphylococcus aureus is the most common
microbe in this setting.23 Acute or chronic sphenoid and
ethmoid sinusitis may result in cavernous sinus thrombosis. Common pathogens include Staphylococcus
aureus and Streptococcus pneumoniae, as well as other
186
Lui et al.
Fig. 4 (A) Patient presented with a left intracavernous internal carotid aneurysm (ICICA) occupying the posterior third of the cavernous
sinus, demonstrating left-globe proptosis, abducens nerve palsy, and sympathetic nerve impairment with partial Horner syndrome. (B)
Patient presented with a right ICICA occupying the anterior third of the cavernous sinus, demonstrating partial right eyelid ptosis and
restricted upward gaze of right globe significant for isolated right oculomotor superior division palsy. (From Silva MN, Saeki N, Hirai S, et al.
Unusual cranial nerve palsy caused by cavernous sinus aneurysms: clinical and anatomic considerations reviewed. Surg Neurol
1999;52(2):144e5; with permission.)
187
Treatment considerations for the oral and maxillofacial
surgeon
Appropriate imaging should include CT scan with angiography and/or magnetic resonance angiography if a
carotid-cavernous sinus fistula is suspected. If a carotid-cavernous sinus fistula is diagnosed, prompt
embolization is recommended.36,37
Obtain ophthalmologic consultation for patients with
associated globe injuries.
Treatment modalities in the literature have been
controversial. There are advocates for high-dose steroid therapy and surgical decompression, as well as for
no intervention.36,38
In the event of facial fractures requiring repair, open
reduction and internal fixation may generally be performed without fear of causing a worsening of associated cranial nerve palsies.30
Early repair of orbital blow-in fractures had a favorable
outcome in subjects with associated superior orbital
fissure syndrome.31
Trotter syndrome
Genetics
Although Trotter syndrome itself has no genetic basis, it
is based on a constellation of clinical symptoms secondary to the uncontrolled growth of nasopharyngeal
carcinoma (NPC). There is, however, an identifiable
genetic pattern for NPC.
NPC is a rare epithelial malignancy with only 25 to 30
cases per 100,000 person-years reported.39 It is most
commonly seen in Southeast Asia and the Mediterranean Basin.39 NPC is a multifactorial condition.
Infection with Epstein-Barr virus has been associated
with NPC, after numerous studies demonstrated the
presence of its DNA in nasopharyngeal tumors.39,40
Human leukocyte antigen (HLA), which are responsible
for presentation of viral antigens to the immune system,
are located within the major histocompatibility complex on chromosome 6p21.3.39 Furthermore, genomewide association studies of NPC have consistently
identified single nucleotide polymorphisms within the
HLA coding region, suggesting strong evidence for association between these mutations and NPC.39,41
An association between diets high in preservatives
(salted fish, eggs, and vegetables) and NPC has also
been found.42
Clinical features
The syndrome was first described by Trotter in 1911 as a
neoplastic lesion deep to the lateral nasopharyngeal
wall.43 A classic triad of presenting symptoms (ie,
deafness, neuralgia along the mandibular division of the
trigeminal nerve, and soft palatal paralysis or immobility) was originally described (see Fig. 1).43 Symptoms
corresponded to the lateral and anterior spread of the
neoplasm submucosally and, in late stages, included
other symptoms.43,44
The first symptom of decreased hearing or frank deafness
is due to involvement of the eustachian tube.44,45 As the
lesion progresses, involvement of the third division of
the trigeminal nerve leads to neuralgias of the side of the
head, ear, and lower jaw, as well as paresthesia of the
tongue.44,45 As the levator veli palatini muscle becomes
188
Lui et al.
Fig. 6 Superior orbital fissure syndrome demonstrates ptosis, pupillary dilation, and ophthalmoplegia. (A) Right lid ptosis. (B) Radiograph showing a fracture (red arrows) causing compression of superior orbital fissure. (C) Right pupillary dilation. (DeF) Right
ophthalmoplegia. (From Turvey TA, Golden BA. Orbital Anatomy for the Surgeon. Oral Maxillofac Surg Clin North Am 2012;24(4):528; with
permission.)
Horner syndrome
Genetics
Because Horner syndrome is a sequela of an underlying
disease process, it is not associated with a specific
genetic trait or inheritance pattern.
The most common identifiable cause of Horner syndrome is postganglionic lesions followed by preganglionic lesions, whereas the central lesions were the least
common.48
189
Fig. 7 (A) NPC with extension into mandibular division of trigeminal nerve in the masticator space (white arrow); Meckel cave and
sphenoid sinus (black arrows). (B) NPC extension into sphenoid sinus, cavernous sinus, and maxillary division of trigeminal nerve (black
arrows). (C) Encasement of internal carotid artery by NPC (black arrows). (From Moonis G, Cunnane MB, Emerick K, et al. Patterns of
perineural tumor spread in head and neck cancer. Magn Reson Imaging Clin N Am 2012;20:445; with permission.)
Clinical features
Horner syndrome or oculosympathoparesis is caused by
an interruption of sympathetic innervation along a
three-neuron pathway to the eye and its adnexa. It is
classically characterized as unilateral miosis, ptosis,
apparent enophthalmos, and anhidrosis of the affected
side (Fig. 8).49,50
Ptosis is a result of interruption of the sympathetic
ller muscle, which accounts for
innervation of the Mu
approximately 2 mm of upper eyelid elevation. Miosis is
caused by unopposed parasympathetic innervation to
the iris constrictor muscle. The facial anhidrosis occurs
because of lack of sympathetic innervation to the sweat
glands of the face.51 The apparent enophthalmos is due
190
Lui et al.
underlying causes of Horner syndrome may be beyond
the scope of an oral and maxillofacial surgeon and may
warrant referral.
Frey syndrome
tumors, cerebrovascular accident, multiple sclerosis, intrapontine hemorrhage, neck trauma, pituitary tumor, and syringomyelia.54
- Diseases associated with second-order neurons
include Pancoast tumor; birth trauma with injury to
lower brachial plexus; aneurysm or dissection of
aorta; subclavian or common carotid artery; iatrogenic complications from surgical intervention such
as radical neck dissection, thyroidectomy, carotid
angiography, coronary artery bypass graft, chest tube
insertion, or central venous catheterization; Hodgkin
disease; leukemia; tuberculosis; mediastinal tumor;
odontogenic abscess; acute otitis media; neuroblastoma; and lumbar epidural anesthesia.54,55
- Diseases associated with third-order neurons include
internal carotid artery dissection, migraines, cluster
headaches, carotid artery thrombosis, carotidcavernous fistula, herpes zoster, orbital apex tumor,
or idiopathic conditions.54
Treatment considerations for the oral and maxillofacial
surgeon
The presence of Horner syndrome is a sign for a potential underlying disease. Treatment of the underlying
condition often resolves the symptoms. However, many
Genetics
There are no known inheritance patterns because Frey
syndrome is an acquired disease.
Gustatory sweating is most commonly seen secondary
to parotid surgery; however, it also can occur after
radical neck dissection or blunt and penetrating trauma
to the region overlying the parotid gland.56,57 There is
no age or sex predilection.58
The incidence of Frey syndrome after parotid surgery
varies with reports ranging from 2% to 80%.59 Interestingly, if tested using a Minors starch-iodine test, more
than 90% of patients after parotid surgery will exhibit
some evidence of Frey syndrome.60 Symptoms are
perceived in only about 25% to 50% of patients, and they
are severe enough to warrant treatment in only 6% to
15% of cases.60,61
Frey syndrome usually has a latency of 6 to 18 months.
It can, however, occur in less than 6 months or more
than 36 months.58
In the pediatric population, case reports of auriculotemporal syndrome following trauma after forceps
delivery have been published in the literature.62
Clinical features
The classic appearance of Frey syndrome is sweating,
flushing, and sensation of warmth in the preauricular
and temporal areas during mastication.59
The Minor iodine-starch test can be used to delineate
the extent of the lesion. The test is administered by
applying an alcohol-iodine-oil solution to the affected
side of the face. The solution is allowed to dry and
lightly covered with starch powder. The patients are
then given a lemon candy for a gustatory stimulus for
10 minutes. Blue discoloration of the starch iodine
mixture is interpreted as a positive finding (Fig. 10).63e65
The condition occurs from the severing of postganglionic parasympathetic cholinergic secretomotor
fibers from the otic ganglion. These fibers, which are
carried by the auriculotemporal nerve, become misdirected during axonal regeneration and feed the
sympathetic fibers to the sweat glands of the skin,
causing gustatory sweating. This phenomenon explains
the delay in appearance of clinical symptoms.56,66
Differential diagnosis
Food allergy can be misdiagnosed in cases with facial
flushing without hyperhidrosis, especially among the
pediatric population.67
CNS tumors, although extremely rare, should be suspected in cases without evidence of localized trauma.68
Treatment considerations for the oral and maxillofacial
surgeon
Patients with Frey syndrome who have mild signs with
no symptoms can be observed. Those patients who
show symptoms and whose quality of life is affected
should be counseled. All risks and benefits should be
discussed before starting therapy.
Medical therapy includes topical anticholinergics such
as atropine, glycopyrrolate, scopolamine hydrobromide,
191
shown to be an effective, safe, and minimally invasive
treatment with long-lasting effect.70
Surgical treatment has been proposed, such as transection of the glossopharyngeal nerve, resection of
the auriculotemporal nerve, or tympanic neurectomy.
These modalities have variable success rates and are
not recommended.58
Ramsay-Hunt syndrome
Genetics
Ramsay Hunt syndrome (RHS) has an incidence of 5 per
100,000 per year. It is the second-most frequent cause
in nontraumatic peripheral facial palsy.71 The prevalence of RHS is more frequent in adults than in children
who have facial palsy.72
In the pediatric population, the incidence is also higher
in older children than in children younger than 6-yearsold. Children are also found to have milder symptoms
and a better prognosis for complete recovery of facial
animation and hearing when compared with adults.
Clinical features
RHS occurs because of the reactivation of the varicellazoster virus in the geniculate ganglion, involving the
seventh cranial nerve.
Clinically, it is characterized by acute peripheral
facial palsy with a painful herpetic eruption on the
ipsilateral auricle, external ear canal, anterior two-thirds of the tongue, or palate (Fig. 11).73,74 In addition to these classic symptoms, patients also
frequently have vestibulocochlear dysfunction due to
the close proximity of the eighth cranial nerve to
the geniculate ganglion.75 These patients frequently
reported tinnitus, hearing loss, nausea, vomiting,
vertigo, and nystagmus.76
In addition to the classic presentation, other cranial
nerves, such the glossopharyngeal, trigeminal, vagus,
abducens, and hypoglossal, have also been known to be
involved.77,78
Fig. 11 (A) A patient with vesicular lesions of the auricle and external auditory meatus. (B) Facial nerve palsy resulting in both weakness
of the lips (white arrows) and loss of nasolabial folds (black arrows) on the right face with facial animation. (From Taguchi T, Ueda S,
Kudo T, et al. Ramsay-Hunt syndrome. J Infect 2011;62(2):181; with permission.)
192
Differential diagnosis
Many conditions can produce isolated facial nerve palsy
similar to RHS; however, they can frequently be ruled
out by a thorough history and physical. Those conditions
syninclude Bells Palsy, sarcoidosis, Guillain-Barre
drome, Lyme disease, otitis media, multiple sclerosis,
cerebrovascular accident, as well as peripheral lesions
causing compression of the facial nerve.79
Treatment considerations for the oral and maxillofacial
surgeon
Treatment with prednisone and acyclovir has proven to
be effective, especially if started early after onset of
facial paralysis.80 Early administration of therapy 3 days
after onset of facial paralysis showed a significantly
higher recovery when compared with patients whose
therapy was started 7 days or more after onset of facial
paralysis.81
Lui et al.
Partial nerve degeneration was shown to be reduced
when early therapy was started with acyclovir-prednisone.82 Recovery from hearing loss was also shown to be
more successful when therapy was started earlier.
Melkersson-Rosenthal syndrome
Genetics
Melkersson-Rosenthal syndrome (MRS) is idiopathic.
However, evidence for an autosomal dominant inheritance pattern with a gene defect at chromosome 9p11,
which applied to patients with fissured tongue, has
been investigated.83
Clinical and histologic features:
MRS is an idiopathic granulomatous neuromucocutaneous disorder.84
Fig. 12 Patient with MRS displaying (A) left midfacial edema, (B) left facial nerve palsy, and (C) lingua plicata (fissured tongue). (From
Gerressen M, Ghassemi A, Stockbrink G, et al. Melkersson-Rosenthal syndrome: case report of a 30-year misdiagnosis. J Oral Maxillofac Surg
2005;63:1037; with permission.) (D) Photomicrograph ( 40) of an incisional biopsy taken from the labial mucosa of a patient with MRS,
exhibiting multiple focal, non-caseating granulomas. (Slide Courtesy of Dr Dean DeLuke.)
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Chromosomal Syndromes
Rita Shiang, PhD
KEYWORDS
Down syndrome Trisomy 21 Klinefelter syndrome Turner syndrome Aneuploidy Sex chromosomes
KEY POINTS
Chromosomal aneuploidies are caused by nondisjunction of chromosomes in meiosis or mitosis.
Down syndrome is caused by trisomy of chromosome 21.
Klinefelter and Turner syndromes are sex chromosome aneuploidies, with an extra X chromosome in the former and a
missing X in the latter.
Mosaicism is found in Down syndrome, Klinefelter syndrome, and Turner syndrome.
The risk of Down syndrome and Klinefelter syndrome increases with maternal age, but this phenomenon is not observed for
Turner syndrome.
The main features of Down syndrome are cognitive impairment, hypotonia, and characteristic facial features.
The 2 main features of Klinefelter syndrome are hypergonadotropic hypogonadism and small testicular volume, although
most individuals with Klinefelter syndrome remain undiagnosed.
The 2 main features of Turner syndrome are growth retardation, resulting in short stature throughout life, and infertility in
later years.
Down syndrome
Genetics
Down syndrome is the most frequently observed chromosomal
aneuploidy caused by trisomy 21 or partial trisomy 21.1,2 Most
(90%e95%) cases are caused by de novo chromosomal nondisjunction. About 2% to 6% of cases are caused by translocations
of 2 chromosome 21s or a Robertsonian translocation of chromosome 21 fused to another acrocentric chromosome. Another
2% to 3% of cases are mosaic for trisomy 21. The prevalence of
this disorder is 1/700 live births, but the risk of having a child
with Down syndrome greatly increases with the age of the
mother. The risk is 1/1000 at age 30 years and increases to 9/
1000 at age 40 years.3,4
Clinical features
The main features of Down syndrome include cognitive
impairment, hypotonia, and characteristic facial features. The
IQ of individuals with trisomy 21 is highly variable, and most
individuals fall between the moderate to severe range.5,6 IQ is
not stable and decreases with age.7 Specific cognitive weaknesses have been identified in expressive language, syntactic/
morphosyntactic processing, and verbal working memory.8
Craniofacial features include brachycephaly, midface hypoplasia, flat or depressed nasal bridge, micrognathia, and epicanthic folds (Fig. 1). In addition, there are outer (dysmorphic
Disclosures: No disclosures or conflicts of interests to report.
Department of Human and Molecular Genetics, Virginia Commonwealth University, PO Box 980033, Richmond, VA 23298-0033, USA
E-mail address: rshiang@vcu.edu
Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 197203
1061-3315/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cxom.2014.05.003
Differential diagnosis
Trisomy 18 is an aneuploidy that manifests in severe cognitive
delay and heart problems but may also have problems in the
digestive, reproductive, and urologic systems. The disorder is
often fatal in infancy or early childhood. Males with more than
1 X chromosome also have cognitive delay, distinct facies, and
skeletal problems. Individuals with isolated hypotonia have no
oralmaxsurgeryatlas.theclinics.com
198
Shiang
associated with cervical instability, with the need for surgical
intervention. To prevent any additional problems, radiologic
evaluation of the cervical spine should be performed before
any procedures requiring anesthesia. The neck should be
maintained in a neutral position to prevent any extreme
flexion, extension, or rotation.9,15,16 Tracheal stenosis can be
more common in children with Down syndrome, which can lead
to complications in anesthesia during surgery, such as complicated intubation or greater airway narrowing after intubation
or bronchoscopy.9 Comprehensive assessment, including cardiac assessment, should be performed before surgery. Residual
cardiac defects such as conduction disturbances and atrial
rhythm anomalies can persist throughout the life of the individual, even after successful cardiac repair.20 Complications
such as recurrent infections and a higher incidence of pulmonary hypertension, which contribute to increased mortality and
morbidity, can also arise.20
Fig. 1 A young child with Down syndrome showing midface hypoplasia, flat or depressed nasal bridge, and epicanthic folds.
Klinefelter syndrome
Genetics
Klinefelter syndrome is the most common sex chromosome
aneuploidy in males and is caused by having 1 extra X chromosome (47,XXY) (89.9%). Additional X chromosomes can also
be present (48,XXXY [1.1%]; 49,XXXXY [1.8%]), and mosaicism
can also exist (46,XY/47,XXY [6.6%]; 47,XXY/48,XXXY [0.2%]).
The prevalence was 1 in 660 men in a Danish population.21 The
risk increases with maternal age. The disorder is sporadic and
usually caused by meiotic or mitotic nondisjunction in germ
cells or in the fetus, respectively.
Clinical features
Treatment considerations for the oral and
maxillofacial surgeon
Atlantoaxial instability affects between 10% and 30% of individuals with Down syndrome, only 1.5% of whom need surgical intervention. Os odontoideum has been specifically
The 2 main features found in individuals with Klinefelter syndrome are hypergonadotropic hypogonadism with adults presenting with a high ratio of luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) levels when compared with
their testosterone levels and small testicular volume.22 Tall
Fig. 2 A 10-year-old girl noted to have C1-C2 instability on routine screening. (A) Flexion and (B) extension radiographs showing 7 mm of
motion. (From Dimar JR, Carreon LY. Spine deformity in Down syndrome. Spine Deform 2012;(Preview Issue):78; with permission.)
Chromosomal Syndromes
stature was believed to be a hallmark of the disorder, and
growth in childhood and adolescence is accelerated, but mean
adult height of affected men is 184.7 cm, which is not greatly
different from the mean adult height of unaffected men
(182.6 cm) in Denmark.22 Cryptorchidism (14%), gynecomastia
(44%), and behavioral and learning problems (36%) are also
observed, but not in all individuals.22 Verbal processing seems
to be specifically affected.23,24 Other variable features include
eunuchoid body habitus, long arms and legs, sparse body hair,
and mandibular prognathism (Fig. 3).25 This variable phenotype
is seen in Fig. 4, which shows an atypical phenotypic presentation.26 Individuals with Klinefelter syndrome are also at
increased risk for metabolic syndrome, osteopenia/osteoporosis, breast cancer, autoimmune disorders, and mortality.26e29 Individuals with more X chromosomes seem to have a
more severe phenotype, including additional congenital malformations and greater cognitive involvement.30
Klinefelter syndrome is the most common chromosomal
abnormality in azoospermic infertile men.31 Testicular histology through childhood remains normal but with fewer germ
cells (Fig. 5).22 By adulthood, there are few seminiferous tubules, with spermatogenesis and hyperplasia of Leydig cells.
Undifferentiated and differentiated Sertoli cells can be
observed.22
Most individuals with Klinefelter syndrome are undiagnosed.
Only 10% of the expected numbers are diagnosed before puberty and 25% in adults, mainly because of infertility or
hypogonadism.21 The major reasons for diagnosis of Kleinfelter
syndrome are maternal age prenatally, developmental delay
before puberty (<11 years old), and small testes in individuals
between 11 and 19 years old.30,32
Selective early initiation of testosterone supplementation
has been shown to restore the sex dimorphic changes in fat
deposition through puberty33 and may also prevent the
199
Differential diagnosis
Individuals with fragile X syndrome also present with intellectual disability and social anxiety, but their physical characteristics include an elongated face, large protruding ears, and
macroorchidism. Kallmann syndrome also presents with hypogonadism but is accompanied by a reduced sense of smell.
Kallmann syndrome and isolated hypogonadotropic hypogonadism are characterized by low levels of circulating sex
hormones. Marfan syndrome also presents with increased
height and long limbs but no hypogonadism. Klinefelter syndrome can be distinguished from these other disorders through
chromosomal analysis.
Fig. 3 Profile of a man with Klinefelter syndrome, showing
mandibular prognathism. The arrow points to the parotid region,
and in this rare case, parotid gland agenesis was observed. (From
Yilmaz YF, Titiz A, Yurur-Kutlay N, et al. Congenital bilateral parotid gland agenesis in Klinefelter syndrome. J Craniomaxillofac
Surg 2010;38:249; with permission.)
200
Shiang
Fig. 5 Comparisons of micrographs of testicular specimens from individuals with Klinefelter syndrome at various ages. (Left) Individuals
with normal testicular function and (right) affected individuals. Testicular architecture of specimens from unaffected and affected individuals is similar from fetal life until puberty, except that the number of germ cells is severely reduced in the prepubertal Klinefelter
syndrome sample. During puberty, gross morphologic changes appear. Normally, spermatogenesis is initiated, but the seminiferous tubules
in the affected individual show widespread degeneration and hyalinization. In an adult individual with Klinefelter syndrome, few
degenerated tubules may contain germ cells, but most of the testicular tissue is composed of clumps of Leydig cells. Arrows indicate
gonocytes. Bars represent 100 mm. GW, gestational week. (From Aksglaede L, Skakkebaek NE, Almstrup K, et al. Clinical and biological
parameters in 166 boys, adolescents and adults with nonmosaic Klinefelter syndrome: a Copenhagen experience. Acta Paediatr
2011;100:799; with permission.)
Klinefelter syndrome also manifest with an increase of taurodontism and caries when compared with a control population.35,36 Shovel-shaped incisors have also been reported in
patients with Klinefelter syndrome.
Turner syndrome
The 2 main features of Turner syndrome are growth retardation, resulting in short stature throughout life, and infertility in
later years.38 Growth failure begins prenatally and is observed
by 3 years of age. On average, adult height is 20 cm less than
typical height (Fig. 6).39e41 Although individuals with Turner
syndrome are not deficient in growth hormone, treatment with
growth hormone allows greater height attainment. It remains
to be determined if earlier growth hormone therapy increases
final height attainment.38 Infertility is caused by ovarian failure, the onset of which is variable but which can begin prenatally. A third of girls have onset of pubertal development,
but a smaller percentage have spontaneous menarche (16%).42
Most go on to show ovarian failure, although spontaneous
Genetics
Turner syndrome is mainly characterized by missing 1 or portions of an X chromosome in females. Many are missing an
entire X chromosome (45,X) (45%), and 15% are mosaic of 45,X/
46,XX. Individuals with Xq isochromosomes or mosaics of Xq
isochromosomes make up 11% of the population. The rest have
many different variants, including deletions and translocations
of the X chromosome, Xp isochromosomes, various combinations of mosaicism, and even karyotypes with Y chromosome
material. The prevalence of Turner syndrome was about 1 in
Clinical features
Chromosomal Syndromes
201
line, appearance of webbed neck, cubitus valgus, excessive
pigmented nevi, and horseshoe kidney, which occur with
varying frequency (Fig. 7).44
Heart anomalies are found in 50% of individuals with Turner
syndrome and are the main contributor to an increase in
mortality.45 Congenital structural abnormalities of the heart
include coarctation of the aorta (COA), bicuspid aortic valve
(BAV), and partial anomalous pulmonary venous return. The
presence of webbing of the neck, which indicates lymphedema, is significantly associated with BAV and COA.46,47 Aortic
dissection can develop in adults with Turner syndrome and is
found in 0.6% to 1.4% of individuals, which is a higher incidence
than found in the general population.48 Hypertension affects
up to 25% of adolescents and 50% of adults. It is mostly systolic
and is often nocturnal.49
Other morbidities associated with Turner syndrome include
increased rates of diabetes, metabolic syndrome, inflammatory
bowel disease, hypothyroidism, and celiac disease. These metabolic and autoimmune issues may be caused by a different body
composition in adult women. They weigh more and have greater
fat body mass and less lean body mass than women in the general
population.41 Scoliosis and kyphosis are identified in 10% to 20% of
girls with Turner syndrome. Also, decreased bone mineral density
is observed, which results in an increase in fractures, although
more fractures are also observed before puberty.50,51 HRT can
increase bone mineral density in adults.52,53
The standardized mortality is increased for all individuals
with Turner syndrome and is 4.08 for individuals with 45,X;
overall mortality is 2.86.37 Mortality is mainly caused by disorders associated with endocrine, nutritional, and metabolic
disorders, most likely associated with increased diabetes,
congenital anomalies, coronary disease, and cancer.37
Differential diagnosis
Noonan syndrome shares many features of Turner syndrome,
including short stature, webbed neck, and congenital heart
disease. Individuals with Noonan syndrome also present with
unusual facies, including hypertelorism and downward slanting
eyes, but have normal karyotypes.
Fig. 7 A young woman with Turner syndrome, showing excessive pigmented nevi, micrognathia, and prominent ears (left, profile) as well
as a wide short neck (right, frontal view). (From Russell KA. Orthodontic treatment for patients with Turner syndrome. Am J Orthod
Dentofacial Orthop 2001;120:316; with permission.)
202
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37. Stochholm K, Juul S, Juel K, et al. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol
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38. Gravholt CH. Clinical practice in Turner syndrome. Nat Clin Pract
Endocrinol Metab 2005;1:41e52.
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39. Ranke MB, Pflu
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40. Lyon AJ, Preece MA, Grant DB. Growth curve for girls with Turner
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41. Gravholt CH, Weis Naeraa R. Reference values for body proportions and body composition in adult women with Ullrich-Turner
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42. Pasquino AM, Passeri F, Pucarelli I, et al. Spontaneous pubertal
development in Turners syndrome. Italian Study Group for Turners Syndrome. J Clin Endocrinol Metab 1997;82:1810e3.
43. Mortensen KH, Rohde MD, Uldbjerg N, et al. Repeated spontaneous pregnancies in 45,X Turner syndrome. Obstet Gynecol 2010;
115:446e9.
44. Jones KL. Smiths recognizable patterns of human malformation.
6th edition. Philadelphia: Elsevier Saunders; 2006.
45. Price WH, Clayton JF, Collyer S, et al. Mortality ratios, life expectancy, and causes of death in patients with Turners syndrome. J Epidemiol Community Health 1986;40:97e102.
46. Clark EB. Neck web and congenital heart defects: a pathogenic
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49. Nathwani NC, Unwin R, Brook CG, et al. Blood pressure and Turner
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50. Gravholt CH, Juul S, Naeraa RW, et al. Morbidity in Turner syndrome. J Clin Epidemiol 1998;51:147e58.
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Anestesiol 2008;58:84e9 [in Portuguese].
Key points
Syndrome is a clinical diagnosis.
Many craniofacial abnormalities include synophrys, long
philtrum, and cleft palate.
Limb malformations are seen in these patients, along
with toe fusion.
Developmental delay is common.
Genetics
Multiple genes have been associated with this syndrome,
including nipped-B-like protein (NIPBL) on chromosome 5,
SMC1A, SMC3, and HDAC8 on the X chromosome. Most of these
cases are secondary to spontaneous genetic mutations.
Clinical features
Cornelia de Lange syndrome is a clinical diagnosis, based on
signs and symptoms. Certain features are noted, including low
birth weight, developmental delay, small stature, microcephaly, low hairline with synophrys, flat nasal bridge, long
philtrum, low-set ears, widely spaced teeth, cleft palate, limb
differences, excessive body hair, and partial fusion of the second and third toes. Children often have long eyelashes (Fig. 1).
Cardiac abnormalities may also be present at birth.
Gastrointestinal difficulties, including vomiting, diarrhea, and
constipation, are common.
Behavior issues may play a role in children as well, including
self-injury and aggression. Patients may display behaviors
similar to autism.
Differential diagnosis
Whistling face syndrome
Fetal alcohol syndrome
Prader-Willi syndrome
Key points
Most patients inherit disease from paternal chromosome 15.
Patients have severe hypotonia and feeding difficulties
in infancy.
Patients develop morbid obesity and diabetes.
Patients have hypogonadism with incomplete pubertal
development.
These patients show learning disabilities and behavioral
problems.
Genetics
Prader-Willi syndrome is sporadically inherited from deletion or impaired expression of chromosome 15, specifically
15q11-13. Diagnosis is confirmed using DNA methylation or
fluorescent in situ hybridization analysis. The incidence
ranges from 1 in 10,000 to 1 in 20,000. There is equal distribution in male and female patients, as well as along
differing ethnicities. In 70% of the cases, the abnormal gene
is from a paternal inheritance; however, uniparental
maternal disomy can lead to Prader-Willi syndrome in 25% of
cases, with purely abnormal gene expression comprising 1% to
5% of the cases.
oralmaxsurgeryatlas.theclinics.com
206
Clinical features
These patients typically show central infantile hypotonia with
a poor suck at birth. The hypotonia is universal and can also
lead to lethargy, a weak cry, and decreased movement. This
condition leads to infant feeding difficulty, which causes an
extreme drive to eat. Patients typically display morbid obesity,
with short stature. The inability to feel satiated is secondary to
hypothalamic abnormalities and causes patients to display
food-seeking behavior, hoarding food, and eating of inedible
objects. These patients develop sleep apnea and diabetes. It
is common to see psychological disturbances, including
207
Genetics
Alcohol passes the placental barrier, causing damage to the
developing central nervous system primarily but also causes
changes in the facial form, learning disabilities, functional
disabilities, and behavioral problems. At present, the pattern
develops in the offspring of expectant women who consume
large quantities of alcohol. The prevalence of fetal alcohol
syndrome is 2 per 1000 live births. The variability of expression
is thought to be related to the timing of alcohol ingestion
relative to fetal development, the amount consumed, and the
duration of alcohol use during pregnancy. Alcohol interferes
with neural migration in the first trimester and damage to the
hippocampus in the third trimester.
Clinical features
Fetal alcohol syndrome affects numerous systems. These patients frequently have growth deficiency, in which height and
weight are measured to be less than the tenth percentile.
There are 3 distinctive facial characteristics that must be
present to diagnose this syndrome: smooth philtrum, thin
vermilion, small palpebral fissures. Having all three changes
indicates abnormal brain development, although brain damage
may be present without these signs.
Alcohol can severely affect the central nervous system.
Changes include microcephaly and structural changes in the
brain. Neurologic symptoms include epilepsy, seizures, poor
gait, neurosensory hearing loss, and impaired fine motor skills.
Functional changes such as learning disabilities, poor academic
achievement, poor memory, inattention, and low performance
in an academic setting are all seen in this disease. Other
craniofacial changes include epicanthal folds, poor nasal
bridge support, and a short, upturned nose.
Cardiac and renal systems can be affected as well. Atrial
septal defects are rare, but have been seen. Hypoplastic,
dysplastic, and aplastic kidneys have also been described.
A multiteam approach is necessary to diagnose this syndrome. The following criteria are necessary to have a diagnosis
of fetal alcohol syndrome: growth deficiency, all three facial
features noted earlier, clinically significant central nervous
system damage, and a history of prenatal alcohol use (Fig. 3).
Fig. 3 This young girl was born with fetal alcohol syndrome. She
has a thin upper lip, with a smooth philtrum. She also has small
palpebral fissures. (From Turnpenny PD, Ellard S. Emerys elements of medical genetics. 14th edition. Philadelphia: Churchill
Livingstone; 2011. Fig. 16.6; with permission.)
Differential diagnosis
Noonan syndrome
Williams syndrome
Aarskog syndrome
Key points
Genetic disorder with recessive and dominant inheritance patterns.
Patients show craniofacial and orthopedic changes.
Syndrome defined as congenital myopathy.
208
Genetics
This syndrome is either autosomal dominant or autosomal
recessive, based on the type of expression of disease. The
phenotypic changes seen in this syndrome are caused by mutations in the embryonic myosin heavy chain (MYH3). There is
no sex or ethnic predilection. This disease has very few data,
because only 65 patients have been reported in literature.
Clinical features
This syndrome is considered a myopathy. There are several
clinical features associated with whistling face syndrome.
Patients have drooping upper eyelids, low-set ears, a long
philtrum, strabismus, and difficulty walking. Patients show
Fig. 4 (A) Whistling face syndrome: note the low-set ears and the neck contractures. (B) A patient with arthrogryposis of the hand with
contractures as seen in whistling face syndrome. (C) Patients with whistling face syndrome show an abnormally crowded dentition. (D)
Numerous signs of whistling face syndrome. Note the webbed neck, low-set ears, microstomia, downslanting eyes, and mask facies.
(Courtesy of D. DeLuke, DDS, MBA, Richmond, VA.)
Noonan syndrome
Key points
Autosomal dominant inheritance with mutation in the
RAS mitogen-activated protein kinase pathway.
Clinical examination for characteristic changes is
necessary for diagnosis.
Patients with disease are high risk for congenital cardiac disease.
This syndrome affects multiple physiologic systems,
including renal, cardiac, hematologic, and endocrine.
209
Genetics
Noonan syndrome has an autosomal dominant inheritance
pattern with an incidence of 1 in 1000 to 1 in 2500. Male and
female incidence is equal. Genetics of the disease are not well
understood, although the genes of the RAS mitogen-activated
protein kinase (MAPK) pathway have been found to cause
Noonan syndrome. More specifically, mutations in the protein
tyrosine phosphatase nonreceptor type 11 gene are now
identified. There have also been numerous other genes identified; however, the diagnosis still relies on a clinical
examination.
Clinical features
A clinical examination is essential for the diagnosis of Noonan
syndrome.
After birth, these patients show early feeding difficulties,
webbed neck, low posterior hairline, ptosis, hypertelorism,
low-set posteriorly rotated ears, and downslanting palpebral
fissures (Fig. 5). Learning disabilities are a concern for these
patients as well.
There are several different systems affected by the disease.
A solitary kidney, duplicate collecting system, and renal
pelvis dilatation are common findings in the renal system in
approximately 10% of the Noonan syndrome population. Eighty
percent of male patients have cryptorchidism. Male patients
also have delayed puberty and infertility, secondary to Leydig
and Sertoli cell dysfunction.
On hematology, these patients typically have thrombocytopenia, coagulation factor deficiencies, and platelet
dysfunction. Factor 11 deficiency is the most common.
Short stature is common, affecting from 50% to 70% of individuals. The cause is not clear. Growth hormone therapy has
been shown to be effective.
These patients have associated cardiac defects, including
pulmonary valve stenosis, and are at increased risk of developing hypertrophic cardiomyopathy. Echocardiography is
Fig. 5 Young boy with Noonan syndrome. The patient has hypertelorism with downslanting palpebral fissures. His ears are posteriorly
rotated and low set. (From Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin
Endocrinol Metab 2011;25(1):161e79; with permission.)
210
essential to monitor heart function and cardiac wall thickness
before any treatment or surgeries.
The RAS-MAPK pathway is associated with oncogenesis and,
as such, patients with Noonan syndrome are at higher risk
for leukemia and solid tumors compared with the general
population.
Differential diagnosis
Turner syndrome
Williams syndrome
Aarskog syndrome
Further readings
Astley SJ, Clarren SK. A case definition and photographic screening tool
for the facial phenotype of fetal alcohol syndrome. J Pediatr 1996;
129:33e41.
Benarroch F, Hirsch HJ, Genstil L, et al. Prader-Willi syndrome: medical
prevention and behavioral challenges. Child Adolesc Psychiatr Clin
N Am 2007;16:695e708.
CdLS Foundation Website. Cornelia de Lange syndrome Foundation.
Chacko E, Graber E, Regelmann MO, et al. Update on Turner and Noonan
syndromes. Endocrinol Metab Clin North Am 2012;41:713e34.
Chen H. Freeman-Sheldon Syndrome. In: Chen H, editor. Atlas of genetic diagnosis and counseling. US: Springer; 2012. p. 883e9.
Church MW, Abel EL. Fetal alcohol syndrome hearing, speech, language, and vestibular disorders. Obstet Gynecol Clin North Am
1998;25:85e97.
Clarren S, Alvord EC Jr, Sumi SM, et al. Brain malformations related to
prenatal exposure to ethanol. J Pediatr 1978;92:64e7.
Coles C, Brown RT, Smith IE, et al. Effects of prenatal alcohol exposure
at school age. Neurotoxicol Teratol 1991;13:357e67.
Driscoll D, Miller J, Schwartz S, et al. Prader-Willi syndrome. NCBI
Bookshelf; 2012.
Institute of Medicine, Stratton K, Howe C, Battaglia F, et al. Fetal
alcohol syndrome: diagnosis, epidemiology, prevention, and treatment. National Academy Press.
Landgraf M, Nothacker M, Kopp IB, et al. The diagnosis of fetal alcohol
syndrome. Dtsch Arztebl Int 2013;42:703e10.
Nargozian C. The difficult airway in the pediatric patient with craniofacial anomaly. Anesthesiol Clin North America 1998;16:839e52.
Streissguth A, Aase JM, Clarren SK, et al. Fetal alcohol syndrome in
adolescents and adults. JAMA 1991;265:1961e7.
Toriello H. Role of the dysmorphologic evaluation in the child with
developmental delay. Pediatr Clin North Am 2008;55:1085e98.
Papillon-Lefevre syndrome
Key points
Periodontal disease associated with Papillon-Lefevre
syndrome (PLS) affects the primary and permanent
dentition.
Keratosis of the palms and soles and the dorsal surfaces
and other skin sites are characteristic components of
the syndrome.
Cathepsin C gene mutations result in a gene product
that does not have functional cathepsin C (CTSC)
activity.
PLS and Haim-Munk syndrome (HMS) are allelic variants
of cathepsin C gene mutations.
Genetics
Papillon-Lefevre syndrome (PLS) is an autosomal-recessive
disorder caused by mutations on the cathepsin C gene. The
cathepsin C (CTSC) gene mutations have been mapped to
11q14.1-14.3. Heterozygous carriers of the mutation do not
have clinical manifestations of the disease. CTSC is a lysosomal protease and functions as an activator of neutrophil
serine proteases. Defective CTSC function likely impairs microbial degradation, cytokine pathways, neutrophil recruitment, and macrophage dysfunction. Also, impaired natural
killer cell cytotoxicity is noted in PLS. Haim-Munk syndrome
and perhaps aggressive prepubertal periodontitis are similar
to PLS in that they too demonstrate inactivation of CTSC. A
late onset variant of PLS without alteration of the CTSC gene
has been described, but this clinical situation is likely due to
another genetic cause.
Clinical features
The syndrome was first described by Papillon and Lefevre in
1924. The clinical findings associated with PLS include palmoplantar erythema and hyperkeratosis, and severe periodontitis
that affects both the primary and the permanent dentitions
(Figs. 1 and 2). Haim-Munk syndrome, described in 1965, has in
addition to the findings that characterize PLS, atrophic
changes to the nails, and finger findings of acro-osteolysis and
clawlike volar curves noted radiographically. Susceptibility to
infection has been described in these hereditary forms of
palmoplantar keratoses. Tooth loss is preceded by gingival
inflammation and subsequent periodontal bone loss and tooth
mobility; Aggregatibacter actinomycetemcomitans (AA) is an
identified pathogen in PLS. Tooth loss follows the pattern of
eruption, incisors lost first, and then the more posterior
dentition. Both primary and permanent dentition are affected.
The permanent dentition is often lost in the teenage or early
adult years. Upon tooth loss, the alveolar mucosa is normal in
appearance. Gorlin reported calcified falx and choroid plexus
in PLS.
Differential diagnosis
All forms of aggressive periodontitis should be included in the
differential. These forms of aggressive periodontitis include
syndromes associated with decreased number of neutrophils,
including the various types of severe congenital neutropenia
syndromes, cyclic neutropenia, bone marrow failure syndromes, as well as syndromes with abnormal neutrophil function, such as Chediak-Higashi syndrome, and leukocyte
adhesion deficiency types 1 and 2. In addition, syndromes of
metabolic or structural defects, such as Kindler syndrome,
Ehlers-Danlos syndrome type IV and VIII, hypophasphatasia,
and hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome should also be included in the differential.
Treatment considerations
Careful attention to oral hygiene and periodontal care are
essential; however, disease is progressive even with conventional approaches to periodontal disease. It has been recommended that compromised primary teeth should be
extracted 6 months before eruption of the permanent
oralmaxsurgeryatlas.theclinics.com
212
Fig. 1 Gingival manifestation of PLS. (Adapted from Dhanrajani P. Papillon-Lefevre syndrome: clinical presentation and a brief
review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2009;108:e1e7; with permission.)
Key points
Hereditary gingival fibromatosis type 1 (HGF1) is a
benign progressive fibrous gingival enlargement.
HGF1 is the result of a mutation in the SOS1 gene on
chromosome 2p21.
HGF1 severity is variable among affected individuals;
severe forms can impede tooth eruption.
Gingival fibromatosis is a feature of many syndromes.
Gingival hyperplasia related to medications (anticonvulsants, calcium channel blockers, and cyclosporine)
can clinically simulate HGF1.
HGF1 treatment consists of gingivectomy; timing of the
procedure is controversial.
Genetics
Hereditary gingival fibromatosis 1 (GINGF1) is an autosomaldominant form of gingival overgrowth caused by a heterozygous frameshift mutation in the SOS1 gene on chromosome
2p21. Additional forms of HGF (GINGF2, GINGF3, and GINGF4)
have been mapped to other chromosome loci. A less common
autosomal-recessive form and sporadic cases of HGF are
recognized. Mutation on the SOS1 gene has also been reported
in Noonan syndrome. The exact mechanism by which the SOS1
Fantasia
Fig. 2 Hyperkeratosis of the palms. (Adapted from Dhanrajani P. Papillon-Lefevre syndrome: clinical presentation and a brief
review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2009;108:e1e7; with permission.)
Clinical features
HGF1 is characterized by slowly progressive fibrous overgrowth
of the gingival tissues of the maxilla and mandible (Fig. 3).
Typically, the overgrowth is nonhemorrhagic and the affected
tissues are firm and of normal color, but secondary inflammatory changes can occur. The condition manifests at the time of
eruption of the primary or permanent dentition, and the degree of gingival overgrowth can be variable. Delayed tooth
eruption may occur. This phenomenon is referred to as variable
expressivity. Thus, members of an affected family may
demonstrate varying degrees of severity of the gingival overgrowth. Severe cases may completely cover the dentition. A
kindred with HGF and associated hypertrichosis has been
described. The clinical presentation of HGF1 may be indistinguishable from syndromes that may have gingival overgrowth
as a component of the disease and gingival overgrowth secondary to particular medications known to cause gingival hyperplasia. The histopathology of HGF1 is characterized by
abundant collagen with interspersed spindle-shaped fibroblasts, typically without an inflammatory component, but a
chronic inflammatory component consisting of plasma cells and
lymphocytes may be a secondary finding. The surface stratified
squamous epithelium often exhibits elongation of the rete
pegs into the underlying collagenous stroma. The histopathology is nonspecific and similar to the pathologic abnormality
noted in syndrome-related and medication-related gingival
overgrowths.
Differential diagnosis
A comprehensive review of syndromes that may have gingival
fibromatosis has been published by Hart and colleagues. These
syndromes include but are not limited to Jones syndrome
(gingival fibromatosis with progressive deafness), gingival
fibromatosis with hypertrichosis, gingival fibromatosis with
distinctive facies, Ramon syndrome, Zimmerman-Laband
213
Fig. 3 (A, B) Hereditary gingival fibromatosis. (Adapted from Kather J, Salgado MA, Salgado UF, et al. Clinical and histomorphometric
characteristics of three different families with hereditary gingival fibromatosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2008;105:348e52; with permission.)
Treatment considerations
Gingivectomy is the recommended treatment. It has been
suggested that this is best accomplished after the permanent
teeth have erupted. However, severe cases of HGF may require
gingivectomy to allow the dentition to erupt when the gingival
overgrowth is thought to be responsible for lack of anticipated
tooth eruption. Repeated debulking of the affected gingival
tissues may be necessary.
Klippel-Feil syndrome
Key points
Klippel-Feil syndrome (KFS) represents failure of the
process of vertebral segmentation and exhibits phenotypic variation and a spectrum of clinical severity.
Fused vertebrae results in limited range of motion, and
a short neck. A low posterior hairline completes the
triad. Often the complete triad is not observed.
Dangerous instability and neurologic symptoms can
occur in the more severe cases; osteoarthritis and
stenosis may develop over time.
Cleft palate has been noted in KFS.
Clinical features
KFS has variable clinical presentations but is characterized by
defective formation or segmentation of the cervical spine, short
webbed neck, limited range of motion of the neck with a
decrease in lateral bend and rotation, and low posterior hairline. Klippel and Feil, in 1912, first described this syndrome
reporting massive fusion of the cervical and thoracic vertebrae
in a 46-year-old man. Clarke in 1998 reported follow-up data of
a family with KFS, the new proband had separation of the C2-3
vertebrae at 10 weeks of age, but showed progressive ossification with complete fusion of C2-3 at 4 years of age. They
concluded that fusion is postnatal. Congenital scoliosis has been
reported in more than 50% of patients and rib abnormalities in
30% of patients. Cervical ribs have also been reported. Laryngeal cartilage malformations resulting in vocal impairment has
been described, as well as conductive, sensorineural, or mixedtype hearing loss. Sprengel deformity is identified in about 30%
of affected individuals. Sprengel deformity is related to limb
bud formation and characterized by upward displacement of
the scapula. The deformity may be minimal with no restriction
in motion to severe mobility restrictions. Thompson and colleagues reported on 6 family members with autosomal-dominant KFS; 4 of the 6 had cleft palate. Multiple jaw cysts in a
patient with KFS were reported by Eisenbud and colleagues.
Additional findings reported in KFS include facial asymmetry,
hemifacial microsomia, synkinesia, torticollis, renal anomalies,
cardiovascular abnormalities, upper extremity anomalies, cranial nerve abnormalities, and ear defects (Figs. 4 and 5).
Differential diagnosis
Genetics
Most cases of Klippel-Feil syndrome (KFS) occur sporadically.
KFS1 is autosomal-dominant, caused by a mutation in the GDF6
gene on chromosome 8q22; KFS2 is autosomal-recessive,
214
Fantasia
that characterizes KFS is of importance to the surgeon, anesthesiologist, and operating room, radiology, and emergency
medicine personnel caring for these patients. This special
attention to the cervical spine deformity is emphasized in the
context of radiology assessment protocols, craniofacial
trauma, or surgeries such as cleft, orthognathic, dentoalveolar,
neurosurgical, orthopedic, or other surgical or endoscopic
procedures that may affect the stabilization and positioning of
the cervical spine. Modified activities, bracing, or traction may
be used to treat symptoms related to KFS.
Key points
Oral-facial-digital syndrome type I (OFD1) is characterized at birth based on the identification of characteristic oral, facial, and digital findings.
Some cases of OFD1 are diagnosed only after the identification of polycystic kidney disease in late childhood
or adulthood.
Oral findings associated with the syndrome include
various clefts, bifid or lobed tongue with nodular
hamartomatous growths, hypodontia or supernumerary
teeth, and accessory hyperplastic frenula.
Facial findings include hypertelorism, broad nasal
bridge, and ala hypoplasia, with facial asymmetry and
micrognathia.
The most common finger findings are brachydactyly,
syndactyly, and clinodactyly; toe anomalies are less
common.
There are multiple OFD syndrome types often with
overlapping clinical features with different inheritance
patterns than OFD1.
Genetics
Oral-facial-digital syndrome I (OFD1) is characterized by an Xlinked dominant mode of inheritance with lethality in male
patients. Approximately 25% of female patients diagnosed with
the condition have an affected mother. The condition is highly
penetrant and exhibits variable clinical expressivity. The OFD1
gene, Cxof5 (Xp22.2022.3), is expressed in adult tissues.
Several different mutations in the gene have been defined. The
gene encodes OFD1 protein, is centrosomal, and localizes to
the basal body of primary cilia. OFD1 belongs to a group of
diseases characterized by cilia dysfunction and is classified as a
ciliopathy. The protein is widely expressed in the early stages
of development in all the tissues affected by the syndrome.
There are several other OFD syndromes that have overlapping
clinical features with OFD1.
Clinical features
Treatment considerations
Fusion of cervical vertebrae places these patients at risk for
cervical cord syndrome. Cord impairment can occur after even
mild trauma. Special attention to the cervical spine deformity
215
Fig. 5 Multiple views of a patient with Klippel-Feil Syndrome. Note the characteristic short, webbed neck and low posterior hairline.
(From Andro C, Pecquery R, De Vries P, et al. Split cervical spinal cord malformation and vertebral dysgenesis. Orthop Traumatol Surg Res
2009;95:549; with permission.)
or cleft uvula, hypodontia (especially the lower lateral incisors), or supernumerary teeth. Facial findings include
micrognathia, facial asymmetry, broad nasal bridge, hypertelorism, and nasal ala hypoplasia. Abnormalities of the
digits include brachydactyly, syndactyly, clinodactyly, and
less commonly, polydactyly. The fingers are more frequently
affected than the toes. Brain abnormalities include
agenesis of the corpus callosum, cerebellar abnormalities,
arachnoid cysts, and other central nervous system malformations. Fifty percent of individuals have some degree of
intellectual disability. Polycystic kidney disease is present in
50% of affected individuals, usually diagnosed no earlier
than late childhood. Some have cysts of the liver, pancreas,
and ovary. Milia of the skin are usually present at birth but
can undergo resolution with resultant pitting scars (Figs. 6
and 7).
Differential diagnosis
clinical features listed above can overlap with other OFD syndromes but the X-linked dominant inheritance pattern, male
lethality, and the presence of cystic kidney disease aid in
separating OFD1 from these other forms.
Treatment considerations
Surgical corrections of cleft lip or palate are indicated.
Removal of tongue nodules may be necessary because of the
size of these hamartomatous growths. Orthodontia and
correction of malocclusion is needed. Surgical intervention for
ankyloglossia, if severe, may be warranted, and referral to
speech pathology if indicated. Affected individuals should have
a hearing evaluation. Monitoring of the patient for polycystic
kidney disease is required.
Oligodontia
Key points
Oligodontia is defined as agenesis of 6 or more permanent teeth; the number does not include the absence of
third molars.
Hypodontia is defined as agenesis of less than 6 teeth;
the number does not include the absence of third molars.
Faulty use of the terms oligodontia and hypodontia is
problematic.
Oligodontia and hypodontia may be part of a genetic
syndrome or occur as a familial or sporadic nonsyndromic disorder.
There are numerous syndromes that have hypodontia or
oligodontia as an associated finding.
Genetics
Autosomal-dominant, autosomal-recessive, and X-linked inheritance occurs. Transcription factor gene mutations have
216
Fantasia
Fig. 7 Brachydactyly and clinodactyly of the fifth finger (A) and radiograph of both hands showing short metacarpals and phalanges (B).
(From Ozturk F, Doruk C. Orthodontic treatment of a patient with oral-facial-digital syndrome. Am J Orthod Dentofacial Orthop
2012;141:S110e8; with permission.)
Clinical features
Tooth agenesis (excluding third molars, typically bilateral and
symmetric such as the maxillary lateral incisors or premolar
dentition, or single tooth agenesis) has been estimated to occur
in up to 20% of the population. The absence of more than 6 teeth
(oligodontia) is less common. Tooth agenesis is associated with
numerous syndromes, and nonsyndromic forms that are either
familial or sporadic have been described. The gene involved in
cases of tooth agenesis often defines which teeth are missing.
For example, MSX1 associated tooth agenesis typically affects
the maxillary first premolars and PAX9-associated tooth agenesis is most frequently associated with the absence of the
maxillary and mandibular second molars. Alveolar bone hypotrophy is noted in the absence of teeth (Fig. 8).
Fig. 8 (AeD) Oligodontia. (From Qin H, Xu HZ, Xuan K. Clinical and genetic evaluation of a Chinese family with isolated oligodontia. Arch
Oral Biol 2013;58:1180e6; with permission.)
Differential diagnosis
The absence of teeth especially when multiple and symmetric
should prompt consideration for a familial occurrence and
possible association of syndromic features for which hypodontia and oligodontia may be a component. Other potential
causes of tooth agenesis include systemic or external influences that could adversely affect tooth formation, such as
infection, radiation, chemotherapeutics, and other environmental factors.
Treatment considerations
Radiographic imaging is needed to confirm the absence of
teeth. Prosthetic rehabilitation with partial dentures, full
dentures, overdentures, or implant placement is recommended. The adequacy of alveolar bone height may be problematic, and augmentation of the affected segments may be
required. Syndromic oligodontia may have additional considerations based on the specific syndrome.
Taurodontism
217
Say syndrome, Ackerman syndrome, X-chromosome aneuploidy
including Klinefelter syndrome, trisomy 21, and cleft lip and
palate subphenotypes. Autosomal-dominant, autosomalrecessive, and x-linked recessive inheritance patterns are
noted depending on the specific syndrome association.
Clinical features
Taurodontism is a condition affecting the teeth, usually the
molars, with pulp chambers enlarged in the vertical dimension
with resultant apical displacement of the bifurcation or
trifurcation of the tooth root. The condition is recognized on
dental radiographs or extracted teeth with root morphology,
suggesting the diagnosis and confirmed with radiographic
findings. There are varying degrees of severity of this defect
and the subclassification scheme of hypotaurodontism (mild),
mesotaurodontism (moderate), and hypertaurodontism (severe) has been suggested (Figs. 9 and 10). Diagnosis of taurodontism in the nonmolar dentition is difficult and
controversial; computed tomography may help with this diagnostic difficulty, but should be reserved for an affected tooth
needing endodontic management. It has been described as an
isolated finding, as a familial trait, as well as in geographic and
ethic groups including Eskimos and Aleuts, and fossil remains of
early man, and has been associated with syndromes.
Key points
Differential diagnosis
Treatment considerations
Taurodontism cannot be prevented and no treatment is
required. The identification of the condition mandates a need
for selected dental radiographs of family members to survey
Genetics
Taurodontism is rare, with prevalence in the primary dentition
of Japanese children reported to be 0.54%, and 5.6% in the
permanent dentition of Israeli adults. Other studies have
described a prevalence of 2.0% in Caucasian adults. The second
and third mandibular molars are the most commonly involved
teeth. Taurodontism has been described in several syndromes
including amelogenesis imperfecta type IV and type IC, distalless homeobox 3, simultaneously occurring taurdontism,
microdontia, and dens invaginatus, trichdentoosseous syndrome, oculodentodigital dysplasia, dentin dysplasia type I,
scanty hair-oligodontia-taurodontia syndrome, cranioectodermal dysplasia 4, hypohidrotic X-linked ectodermal dysplasia
1, otodental dysplasia, failure of primary tooth eruption, familial tumoral calcinosis hypophosphatemic syndrome, Barber-
218
Fantasia
Fig. 10 (AeC) Taurodontism of the mandibular molars. (From Metgud S, Metgud R, Rani K. Management of a patient with a taurodont,
single-rooted molars associated with multiple dental anomalies: a spiral computerized tomography evaluation. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 2009;108:e81e6; with permission.)
Recommended readings
Oligodontia
Available at: http://omim.org/oligodontia.
Bloch-Zupan A, Sedano H, Scully C. Dento/Oro/Craniofacial anomalies
and genetics. Chapter 2. Oxford (United Kingdom): Elsevier; 2012.
p. 9e74.
219
Frazier-Bowers SA, Guo DC, Cavender A, et al. A novel mutation in
human PAX9 molar oligodontia. J Dent Res 2002;81:129e33.
Kim JW, Simmer JP, Lin BPJ, et al. Novel MSX1 frameshift causes
autosomal dominant oligodontia. J Dent Res 2006;85:267e71.
Taurodontism
Casamassino PS, Nowak AJ, Ettinger RL, et al. An unusal triad: microdontia, taurodontism, and dens invaginatus. Oral Surg Oral Med Oral
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Daito M, Hieda T. Taurodont teeth in primary dentition. Jpn J Periodont
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Dong J, Amor D, Aldred MJ, et al. DLX3 mutation with autosomal
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Jaspers MT, Witkop CJ. Taurodontism, an isolated trait associated with
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Jorgenson RJ. The conditions manifesting taurodontism. Am J Med
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Kuchler EC, da Motta LG, Viera AR, et al. Side of dental anomalies and
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