A number sign (#) is used with this entry because Apert syndrome is caused by

heterozygous mutation in the FGFR2 gene (176943) on chromosome 10q26.

Crouzon syndrome (123500) and Pfeiffer syndrome (101600) are allelic disorders
with overlapping features.

▼Description

Apert syndrome is a congenital disorder characterized primarily by

craniosynostosis, midface hypoplasia, and syndactyly of the hands and feet with a
tendency to fusion of bony structures. Most cases are sporadic, but autosomal
dominant inheritance has been reported (Mantilla-Capacho et al., 2005).
Cohen (1973) provided a review of all the 'craniosynostosis syndromes.'

▼Clinical Features
Apert (1906) defined a syndrome comprising skull malformation characterized by
acrocephaly of brachysphenocephalic type and syndactyly of the hands and feet
with complete distal fusion with a tendency to fusion of bony structures. The hand,
when all the fingers are webbed, has been compared to a spoon and, when the
thumb is free, to an obstetric hand.
Blank (1960) assembled case material on 54 patients with Apert syndrome born in
Great Britain. Two clinical categories were distinguished: (1) 'typical'
acrocephalosyndactyly, to which Apert's name is appropriately applied; and (2)
other forms lumped together as 'atypical' acrocephalosyndactyly. The feature
distinguishing the 2 types is a middigital hand mass with a single nail common to
digits 2-4, found in Apert syndrome and lacking in the others. Thirty-nine of the 54
were of Apert type. Six of 12 autopsies showed visceral anomalies, but in none were
these identical. Schauerte and St-Aubin (1966) pointed out that progressive
synostosis in Apert syndrome occurs in the feet, hands, carpus, tarsus, cervical
vertebrae, and skull, and proposed 'progressive synosteosis with syndactyly' as a
more appropriate designation.
In a report on Crouzon disease, Dodge et al. (1959) described 2 sporadic cases of
Crouzon-type craniofacial changes with syndactyly of both hands and feet. Most
conclude that this disorder is actually Apert syndrome with unusually marked facial
features (Temtamy and McKusick, 1978).
Kreiborg et al. (1992) found fusion of cervical vertebrae in 68% of patients with
Apert syndrome: single fusions in 37% and multiple fusions in 31%. C5-C6 fusion
was most common. In contrast, cervical fusion occurs in 25% of patients with
Crouzon disease and most commonly involves C2-C3 only. Kreiborg et al.
(1992) concluded that when fusions are present, C5-C6 involvement in the Apert
syndrome and C2-C3 involvement in Crouzon disease can be used to distinguish the
2 conditions. Radiographic study of the cervical spine is imperative before
undertaking anesthesia for surgery in these patients.
Wilkie et al. (1995) scored the severity of the syndactyly in Apert syndrome
according to a modified version of the classification of Upton (1991). In the Apert
hand, the central 3 digits are always syndactylous; in the least severe instance, type
1, the thumb and part of the fifth finger are separate from the syndactylous mass; in
type 2, the little finger is not separate; and in type 3, the thumb and all fingers are
included. Similarly, syndactyly in the foot may involve mainly the 3 lateral digits
(type 1) or digits 2-5 with a separate big toe (type 2), or be continuous (type 3).
Cohen and Kreiborg (1995) studied 44 pairs of hands and 37 pairs of feet in Apert
syndrome, using clinical, dermatoglyphic, and radiographic methods. They also
studied histologic sections of the hand from a 31-week stillborn fetus. They noted
that in general the upper limb is more severely affected than the lower limb.
Coalition of distal phalanges and synonychia found in the hands was never present
in the feet.

▼Other Features
Varying degrees of mental deficiency have been associated with Apert syndrome;
however, individuals with normal intelligence have also been reported. Individuals
who have craniectomy early in life may have improved intelligence. Patton et al.
(1988) did a long-term follow-up on 29 patients of whom 14 (48%) had a normal or
borderline IQ, 9 had mild mental retardation (IQ, 50-70), 4 were moderately
retarded (IQ, 35-49), and 2 (7%) were severely retarded (IQ less than 35). Early
craniectomy did not appear to improve intellectual outcome. Six of 7 school drop-
outs with normal or borderline intelligence were in full-time employment or
vocational training. Contrary to early conclusions such as that of Park and Powers
(1920), Cohen and Kreiborg (1990) concluded that many patients with Apert
syndrome are mentally retarded. They had information on 30 patients with
malformations of the corpus callosum, the limbic structures, or both, and suggested
that these malformations may be responsible for mental retardation. Progressive
hydrocephalus seemed to be uncommon and was frequently confused with
nonprogressive ventriculomegaly.
Cinalli et al. (1995) found that only 4 of their series of 65 patients with Apert
syndrome required shunting for progressive hydrocephalus. Only 1.9% of their
patients had chronic herniation of the cerebellar tonsils, the finding present in 72.7%
of patients with Crouzon syndrome.
In reviewing their series of 70 children with Apert syndrome, Reiner et al.
(1996) found an IQ greater than 70 in 50% of the children who had a skull
decompression before 1 year of age versus only 7.1% in those operated on later in
life. Malformations of the corpus callosum and ventricular size did not correlate
with the final IQ, whereas anomalies of the septum pellucidum did. The third
significant factor in intellectual achievement was the setting in which the children
were raised. IQ was normal in 39.3% of patients living with their family, but in only
12.5% of those institutionalized.
Pelz et al. (1994) reported an 18-month-old girl who had distal esophageal stenosis
in addition to typical manifestations of Apert syndrome.
Cohen and Kreiborg (1995) commented on the cutaneous manifestations in a series
of 136 cases of Apert syndrome (Cohen and Kreiborg, 1993). Hyperhidrosis was
found in all patients. The skin became oily at adolescence and thereafter, with
acniform lesions on the face, chest, back, and upper arms. The authors commented
on and illustrated the phenomenon of 'interrupted eyebrows,' which may be due to
the underlying bony defect. The orbital plate of the frontal bone is very short,
resulting in early fusion of the sphenoparietal suture. This leads to marked retrusion
and elevation of the supraorbital wings, most pronounced laterally. Interruption of
the eyebrows corresponds to this defect. Several patients had excessive skin
wrinkling of the forehead.
Maroteaux and Fonfria (1987) reported a patient with seemingly typical Apert
syndrome except for the presence of postaxial polydactyly of the hands and preaxial
polydactyly of the feet. The authors could not discern whether the findings
represented a low frequency feature of Apert syndrome or a distinct
syndrome. Sidhu and Deshmukh (1988) reported a somewhat similar case in the
child of a first-cousin couple. However, Gorlin (1989) doubted the existence of a
separate recessive entity and stated that polysyndactyly in the feet, especially
replication of metatarsals, is not rare in Apert syndrome.
Lefort et al. (1992) reported a patient with Apert syndrome and partial preaxial
polydactyly characterized by duplication of the first metatarsal and presence of 6
phalanges.
Cohen and Kreiborg (1995) observed postaxial polydactyly of the hands in 3 (7%) of
44 patients with Apert syndrome, noting that while it is uncommon, it is not a rare
finding. The authors suggested that 'acrocephalosyndactyly' versus
'acrocephalopolysyndactyly' represents a pseudodistinction and that use of these
terms should be discontinued.
Mantilla-Capacho et al. (2005) reported a female child with typical features of Apert
syndrome and preaxial polydactyly of the hands and feet with distal bony fusion.
She did not have cleft palate. Genetic analysis revealed the common FGFR2
mutation (S252W; 176943.0010). The authors noted that only 8 patients with Apert
syndrome and polydactyly had been reported, and that their case was the first
confirmed by genetic analysis. Mantilla-Capacho et al. (2005) concluded that
polydactyly, although rare, should be considered part of the spectrum of
abnormalities found in Apert syndrome, and suggested that Apert syndrome be
considered part of the group of acrocephalopolysyndactylies.
In a review of cranial imaging in 30 patients with Apert syndrome, Quintero-Rivera
et al. (2006)reported ventriculomegaly (76% of patients), hydrocephalus (13%),
complete absence of the septum pellucidum (17%), partially absent septum
pellucidum (23%), and defects of the corpus callosum (23%). In addition, 21 patients
had abnormal semicircular canals, 28 had jugular foraminal stenosis, 5 patients had
Chiari I malformation, 5 had low-lying cerebellar tonsils, and 2 had posterior fossa
arachnoid cysts.
In a review of 63 patients with Apert syndrome prior to craniofacial surgery, Khong
et al. (2006)found that, at a mean age of 4 years, at least 14% had amblyopia, 60%
had strabismus, 19% had anisometropia, and 34% of eyes had ametropia. Exposure
keratopathy and corneal scarring occurred in at least 8% of patients and optic
atrophy in at least 8%.
Andreou et al. (2006) reported a 4-year-old girl with Apert syndrome associated
with a heterozygous mutation (P253R; 176943.0011) in the FGFR2 gene. She also
developed a low-grade papillary urothelial carcinoma of the bladder. No FGFR3
(134934) mutations were identified in the bladder tumor.

▼Inheritance
Although most cases of Apert syndrome are sporadic, it also follows autosomal
dominant inheritance. Roberts and Hall (1971) observed affected mother and
daughter. Van den Bosch (quoted by Blank, 1960) observed the typical deformity in
mother and son, and Weech (1927) reported mother and daughter. The evidence
strongly suggests autosomal dominant inheritance. Paternal age effect is
demonstrable.
Allanson (1986) described 2 sisters with Apert syndrome, born to normal, unrelated
parents. Germinal mosaicism was proposed.
Rollnick (1988) described what is purportedly the first example of male transmission
of Apert syndrome in affected father and daughter.

▼Diagnosis

Prenatal Diagnosis
Leonard et al. (1982) made the prenatal diagnosis of Apert syndrome by fetoscopy.
Chang et al. (1998) excluded the diagnosis of Apert syndrome in the fetus of an
affected woman with a mutation in the FGFR2 gene (P253R; 176943.0011).

▼Pathogenesis

Lomri et al. (1998) analyzed proliferation and differentiation of calvaria cells derived
from Apert syndrome infants and fetuses with FGFR2 mutations. Histologic analysis
revealed premature ossification, increased extent of subperiosteal bone formation,
and alkaline phosphatase-positive preosteoblastic cells in Apert fetal calvaria
compared with age-matched controls. Preosteoblastic calvaria cells isolated from
Apert syndrome infants and fetuses showed normal cell growth in basal conditions
or in response to exogenous FGF2. In contrast, the number of alkaline phosphatase-
positive calvaria cells was 4-fold higher than normal in mutant fetal calvaria cells
with the most frequent Apert mutation, S252W (176943.0010), suggesting increased
maturation rate of cells in the osteoblastic lineage. These and other results showed
that Apert FGFR2 mutations lead to an increase in the number of precursor cells that
enter the osteogenic pathway, leading ultimately to increased subperiosteal bone
matrix formation and premature calvaria ossification during fetal development;
thus, a connection was established between the altered genotype and the cellular
phenotype in craniosynostosis of Apert syndrome.
Miraoui et al. (2010) used microarray analysis to investigate the signaling pathways
that are activated by FGFR2 mutation in Apert craniosynostosis. Transcriptomic
analysis revealed that EGFR (131550) and PDGFR-alpha (173490) expression was
abnormally increased in human Apert calvaria osteoblasts compared with wildtype
cells. Pharmacologic inhibition of EGFR and PDGFR reduced the pathologic
upregulation of phenotypic osteoblast genes and in vitro matrix mineralization in
Apert osteoblasts. Activated FGFR2 enhanced EGFR and PDGFR-alpha mRNA
expression via activation of PKC-alpha (176960)-dependent AP1 (see JUN, 165160)
transcriptional activity. The increased EGFR protein expression in Apert osteoblasts
resulted in part from a posttranscriptional mechanism involving increased Sprouty2
(602466)-Cbl (165360) interaction, leading to Cbl sequestration and reduced EGFR
ubiquitination.

▼Molecular Genetics
In all 40 unrelated patients with Apert syndrome, Wilkie et al. (1995) identified
heterozygosity for 1 of 2 mutations in exon 7 of the FGFR2 gene: S252W
(176943.0010) or P253R (176943.0011). The findings confirmed that Apert syndrome
is allelic to Crouzon syndrome.
In a patient with Apert syndrome, Oldridge et al. (1997) identified a noncanonical
mutation in exon 7 of the FGFR2 gene (S252F; 176943.0017).
In a series of 260 cases of Apert syndrome, Oldridge et al. (1999) found that 172
carried the S252W mutation and 85 had the P253R mutation, indicating that the
molecular mechanism of Apert syndrome is exquisitely specific. Two patients had
an Alu-element insertion in or near exon 9 (176943.0025).
Lajeunie et al. (1999) identified the S252W and P253R mutations in 23 (64%) and 12
(33%) of 36 Apert syndrome patients, respectively. One affected fetus had the S252F
mutation.
Moloney et al. (1996) found that 74 of 118 patients with Apert syndrome had the
FGFR2 S252W mutation and 44 had the P253R mutation. Using sequence analysis of
the neighboring introns flanking the mutation-prone exon and a novel PCR-based
assay, ARMS (amplification refractory mutation system), to determine the phase of
the mutant allele and nearby polymorphisms in 57 informative families, Moloney et
al. (1996) determined that the mutant allele was paternal in origin in all cases. The
authors noted that a paternal bias for point mutations is evident in a number of
disorders, but that the extreme skewing in favor of paternal mutations observed in
Apert syndrome is unusual. A paternal age effect was noted. The data suggested a
stronger paternal age effect for the S252W mutation, which involves a CpG
dinucleotide, than for the P253R mutation, which does not.
Glaser et al. (2003) used allele-specific peptide nucleic acid PCR assays to determine
FGFR2 mutation frequency in the sperm of 148 men aged 21 to 80 years. The number
of sperm with FGFR2 mutations increased in the oldest age groups among men who
did not have a child with Apert syndrome. These older men were also more likely to
have both mutations in their sperm. However, this age-related increase in mutation
frequency was not sufficient to explain the Apert syndrome birth frequency. In
contrast, the mutation frequency observed in men who were younger and had
children with Apert syndrome was significantly greater, suggesting selection for
sperm with specific mutations. Glaser et al. (2003) concluded that contributing
factors to the paternal age effect may include selection and a higher number of
mutant sperm in a subset of men ascertained because they had a child with Apert
syndrome. No age-related increase in the frequency of these mutations was
observed in leukocytes. Selection and/or quality control mechanisms, including
DNA repair and apoptosis, may contribute to the cell type differences in mutation
frequency.

▼Genotype/Phenotype Correlations
Park et al. (1995) reported 36 patients with Apert syndrome, 35 of whom were found
to carry either the S252W or P253R mutation in the FGFR2 gene, with a frequency of
71% and 26% for these 2 mutations, respectively. A study of 29 different clinical
features demonstrated no statistically significant differences between the 2
subgroups defined by the 2 major mutations.
Slaney et al. (1996) found differential effects of the 2 FGFR2 mutations on syndactyly
and cleft palate in Apert syndrome. Among 70 unrelated patients with Apert
syndrome, 45 had the S252W mutation and 25 had the P253R mutation. The
syndactyly in both the hands and the feet was more severe in patients with the
P253R mutation. In contrast, cleft palate was significantly more common in patients
with the S252W mutation. No convincing differences were found in the prevalence
of other malformations associated with Apert syndrome.
Lajeunie et al. (1999) found considerable clinical variability among 36 patients with
Apert syndrome confirmed by genetic analysis. Two patients had no clinical or
radiologic evidence of craniosynostosis. In 2 other patients with atypical forms of
syndactyly and cranial abnormalities, the detection of a specific mutation was
helpful in making the diagnosis.
Among 21 Apert syndrome patients who underwent craniofacial surgery, von
Gernet et al. (2000)found that the postsurgical craniofacial appearance was better in
patients with the P253R mutation, whereas these patients showed a more
pronounced severity of the syndactyly. Six patients had the P253R mutation and 15
had the S252W mutation.

▼Cytogenetics

Dodson et al. (1970) described deletion-translocation of the short arm of a

chromosome 2 to the long arm of a chromosome 11 or 12 in a patient with Apert
syndrome. They found reports of chromosomal abnormalities in 3 other cases of
Apert syndrome.

▼Population Genetics
Blank (1960) estimated the frequency of Apert syndrome to be 1 in 160,000 births.
Cohen et al. (1992) studied the birth prevalence of Apert syndrome in Denmark,
Italy, Spain, and 4 areas of the United States. A total of 57 cases gave a birth
prevalence calculated to be approximately 15.5 per million births, which is twice the
rate determined in earlier studies. The mutation rate was calculated to be 7.8 x 10(-6)
per gene per generation. Apert syndrome accounted for about 4.5% of all cases of
craniosynostosis. Czeizel et al. (1993) reported a validated birth prevalence of Apert
syndrome in Hungary to be 9.9 per million live births. The mutation rate was
calculated to be 4.6 x 10(-5) per gene per generation. Data on 14 other 'sentinel'
anomalies observed between 1980 and 1989 were given.
Tolarova et al. (1997) reported that the California Birth Defects Monitoring Program,
from 1983 through 1993, identified 33 infants with Apert syndrome. The sample was
enlarged with an additional 22 cases from the Center for Craniofacial Anomalies at
the University of California, San Francisco. Birth prevalence calculated from the 31
cases was 12.4 per million live births. The calculated mutation rate was 6.2 x 10(-6)
per gene per generation. Asians had the highest prevalence (22.3 per million live
births) and Hispanics the lowest (7.6 per million). In a population-based subsample
of 31 affected infants, there was an almost equal number of affected males and
females, but in the San Francisco sample there were more affected females (sex ratio
0.79). For all cases, the mean age of mothers was 28.9 years, and of fathers 34.1 years.
Almost half of the fathers were older than 35 years when the child was born; for
more than 20% of cases, both parents were older than 35 years.

▼Animal Model
Hill et al. (2013) used 2- and 3-dimensional imaging to evaluate postnatal brain and
skull development between days P0 and P2 in mice carrying the P253R FGFR2
mutation (176943.0011). Postnatal day 2 roughly corresponds to 10 months of age in
human infants. At P0, the mutant brain was 1% larger and the mutant skull was 2%
smaller compared to unaffected littermates. At P2, heterozygous mutant mice had
9% smaller skulls than controls, although the size reduction was not uniformly
distributed. The facial skeleton, including the palate, was reduced by 11%, whereas
the neurocranium was reduced by 3%, and the skull showed increased height in the
posterior neurocranium compared to controls. The brain size in mutant mice at P2
was not different from control mice overall, but there was shortening of the corpus
callosum as well as increased mediolateral and decreased rostrocaudal growth of
the cerebrum. The findings were similar to those observed in human infants with
Apert syndrome. The results suggested that size and form of the brain and skull
show different patterns of growth in mutant and control mice during the postnatal
period. However, the change in the skull-brain relationship from P0 to P2 implies
that each tissue affected by the mutation retains a degree of independence, rather
than one tissue directing the development of the other.

▼Nomenclature

Vogt (1933) described cases presenting the hand and foot malformations
characteristic of Apert disease together with the facial characteristics of Crouzon
disease, caused by a very hypoplastic maxilla. The syndactyly was less severe than
in Apert disease and the thumbs and little fingers were usually free. Nager and de
Reynier (1948) gave this deformity the name of Vogt cephalodactyly, while other
authors called it Apert-Crouzon disease, indicating the similarity to both
abnormalities. Temtamy and McKusick (1969) called it ACS II in an earlier
classification. There were no reported instances of hereditary transmission of this
specific phenotype, but this could be due simply to low reproductive fitness.

▼History
Wheaton (1894) may have provided the first description of Apert syndrome
(Mantilla-Capacho et al., 2005).

▼ See Also:
Cohen (1977); Erickson (1974); Hoover et al. (1970); Solomon et al. (1970)

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