Dysmorphic Syndromes

Dysmorphic syndromes
Professor Dr Thong Meow Keong

Senior Consultant & Clinical Geneticist
Head, Genetic Medicine Unit
University of Malaya Medical Centre
Head, Genetics & Metabolism Unit

Faculty of Medicine
University of Malaya
Malaysia
Overview
 What are birth defects (congenital malformations)?
 Major and minor birth defects
 Multiple birth defects and dysmorphic syndromes
 Types of dysmorphic syndromes – selected cases
 Approach to dysmorphic syndromes
 Curative and preventive aspects of birth defects
and dysmorphic syndromes
Prof Thong Meow Keong Head, Genetic Medicine Unit University of Malaya Medical Centre
Birth defects
 Birth defects or structural abnormalities present at
birth has been recognised since the early ages e.g.
rock drawings and art from past civilisations. Records
of birth defects was described in cuneiform, and
documented in the writings of Babylonian astrologists
4000 years ago.
 Other examples include: achondroplasia and clubfoot
were depicted in Egyptian tomb paintings; Hippocrates
(460-377 BC) was familiar with the condition of
hydrocephalus.
Birth defects - history
Modern era:
 1941 – rubella virus was recognised as a human
teratogen
 1959 – abnormalities of human chromosomes
visualised (person with Down syndrome)
 1962 – thalidomide embryopathy
 1970 – Minimata Bay mercury poisoning
 1980 onwards – more teratogens recognised eg.

alcohol, anticonvulsants, isotretinoin
Terminology
 Major birth defect – abnormalities of prenatal origin that if
uncorrected or uncorrectable, significantly impair normal physical
or social function or reduce normal life expectancy.
 Minor birth defect – abnormalities of prenatal origin that are

present at birth, occurring in fewer that 4% of infants and do not
have surgical, medical or cosmetic importance at the time of
examination during the newborn period. However 3 or more
minor birth defects in an individual may suggest the possibility of
a syndromic diagnosis.
 Normal phenotypic variant – minor birth defects that occur in

more that 4% of infants and are considered as features that lie at
the end of the spectrum of normal configuration. Example:
Mongolian blue spot
Incidence of birth defects
 Spontaneous miscarriages Incidence (%)
 First trimester 80-85
 Second trimester 25
 All babies
 Major birth defect apparent at birth 2-3
 Major birth defect apparent later 2
 Minor birth defect 10-15
Multiple birth defects 1%
Birth defects and dysmorphic syndromes:
introduction
 Multiple birth defects are found in 1% of all newborns and majority
are associated with dysmorphic features.
 Of these, about 30-40% are diagnosed as having a specific or
recognizable syndrome; the remainder have unknown entities that
will require more time and further tests
 A definitive diagnosis of a dysmorphic syndrome requires a detailed
history and family tree, careful physical examination and
investigations
 There are 300 well described syndromes in Smith’s Recognizable
Patterns of Human Malformation and close to 2000 unique
syndromes in dysmorphology databases such as POSSUM and
Baraitser-Winter databases
Cause of death in Malaysian children
(< 5 years)
 A Study on Under Five Deaths in Malaysia 2006, Ministry of Health Malaysia

Birth defects and dymorphic
syndromes - impact
 Physical suffering and psychological trauma
 Family breakdown, marital discord and depression are common
 Increased risk of sudden infant deaths, non-accidental injuries
 Poor self esteem, school failure and anxiety amongst siblings
 Social stigmatisation
 Community loss – loss of productivity and income (parents) as a

result of patient’s frequent hospitalisations
 Assistance needed for the care of the affected child at home or in
an institution
 Increased need for specialized expertise and services, resources
for rehabilitation and maintenance of care
 Need for support groups, respite care and palliative care services
Minor birth defects (isolated)
 Pre-auricular pit / tag
 Single palmar crease
 Fifth finger clinodactyly (in-curved little finger)
 Syndactyly between second and third toes
 Umbilical hernia
 Sacral pit / dimple
Usually aetiology unknown

No or minimal medical consequences by themselves
Sacral dimple / pit
Umbilical hernia
Transverse palmar crease
Polydactyly
Post axial polydactyly Pre axial polydactyly
Preauricular pit and tag
Major birth defect(s)
 May be single or isolated
 May be multiple
 Aetiology:
 Chromosomal (abnormalities from non-disjunction,
translocations etc)
 Genetic (mutations in genes – point mutations, deletions)
 Environmental (biological, chemical, physical agents)
 Multifactorial (genetic and environmental factors)
 Unknown
Birthmarks (> 4cm )
2
Low set ear
Occipital
protuberance
Inner canthus
Pinna must be
inserted at or
above the line
Hypertelorism
and hypotelorism
Hypotelorism
Hypertelorism
Skull and scalp abnormalities
Overhanging occiput
Microcephaly and macrocephaly
Occipital-frontal circumference
measurements:
Microcephaly – OFC below the 3rd
percentile or more than 2 SD below the
appropriate mean
Macrocephaly – OFC above 95th
percentile or more than 2 SD above the
appropriate mean
Congenital cytomegalovirus
infection
Hydrocephalus
Palpebral fissures
Upslanting
Downslanting
Nose abnormalities
Anteverted nostrils
Flat nasal bridge

Cleft lip / palate
Cleft palate
Bilateral cleft lip and palate

Genitalia abnormalities
Bifid scrotum
Undescended / ectopic testes
Hydrocoele
Talipes (clubbed feet)
Nearly 95% are talipes equinovarus
(foot turns inward and downward) ;
the others are talipes
calcaneovalgus
Incidence: 1-3 per 1,000
May be isolated or associated with
other syndromes or neuromuscular
disorders
Left uncorrected: feet deformities
and awkward gait
Recurrence risk: 3%
Screening: Ultrasound. Marker for
other syndromes
Syndactyly
Webbing between fingers / digits
Congenital contractures (arthrogryposis)
Syndrome
 Consistent and recognisable pattern of multiple
birth defects whose unique combination of
features set it apart from all other patterns.
[Greek “syndro” = things that run together]
 Often, there will be a known underlying cause.
 Example: Down syndrome (trisomy 21), fetal
valproate syndrome, Edward syndrome, Patau
syndrome, Turner syndrome
Major birth defect(s):
chromosomal disorders
Down syndrome
Down syndrome (DS)
Frequency: 1 in every 660 babies born with DS; estimated 800 newborns in
Malaysia are affected with DS each year.
External features:
•Flat nasal bridge
•Eyes may have an upward and outward slant
•Protruding tongue
•Small and low set ears
•Small and stubby hands with single crease across the palm; in-curved little
finger (clinodactyly)
•Wide gap between the toes
•Low muscle tone (hypotonia)
DS is associated with an extra chromosome 21 in each body cell
1. Standard trisomy (95%)
2. Translocation (3%)
3. Mosaicsm (2%) Prof Thong Meow Keong Head, Genetic Medicine Unit University of Malaya Medical Centre
Medical complications
Delay in achieving milestones and moderate to severe learning
difficulties in majority of DS individuals
Cardiac malformations (40%)- atrio-ventricular septal defect & others
Gastrointestinal malformations (2-15%) e.g. duodenal stenosis,
Hirschsprung disease; imperforate anus
Due to secretory otitis
Visual Deficits (40-80%) – myopia, cataract, strabismus media - the eustachian
Auditory Deficits (10 - 50%) – conductive deafness tube is not formed
properly, defect in
Epilepsy (5-10%) drainage of middle ear
Congenital (1%) and infantile/childhood hypothyroidismeffusion
(20%)
Leukaemia (about 10-15x increase compared to general population)
Atlanto-axial instability (20%) which results in spinal cord injury (1%)
Alzheimer’s disease (early onset usually age 30-40) (15%)
Edward syndrome Extra chromosome 18 (non-
disjunction, translocation, mosaic)
Incidence: 1 in 4,000 – 7,000
Features: severe growth and
developmental retardation,
micrognathia, overhanging occiput,
camptodactyly, contractures,
congenital heart diseases, short
sternum, rocker-bottom feet
High mortality: 90% death by 1 year
of age
Screening: Ultrasound; prenatal
diagnosis via CVS, amniocentesis
Confirm prenatal and postnatal by
karyotype
Patau syndrome
Extra chromosome 13 Camptodactyly= bent fingers
Incidence: 1 in 10,000
Features: Microcephaly, cleft lip
and palate, micro-ophthalmia,
polydactyly and camptodactyly,
congenital heart diseases,
umbilical hernia, undescended
testes, renal defects, brain
abnormalities
Survival: 95% mortality by 1
year of age
Screening: Ultrasound, CVS,
amniocentesis; confirm on
chromosome study
Turner syndrome (TS)
TS affects development in females.
About 50% of TS - monosomy X (45, X); the others
have change in only some of their cells (mosaicism).
Incidence:1 in 2,500 newborn females. Underdiagnosis likely as
some fetuses with TS do not survive to term (miscarriages).
Two presentations: Newborns (30% of TS) have extra folds of skin
on the neck (webbed neck), low posterior hairline, puffiness
(lymphedema) of dorsum hands and feet, skeletal abnormalities,
or kidney problems. The other presentation is female with short
stature (usually by 5 years old) or adolescent girls with delayed
puberty and short stature.
30-50% - congenital cardiac lesions e.g. coarctation of aorta
Early loss of ovarian function (premature ovarian failure)
Most have normal intelligence - minority has nonverbal learning
disabilities.
genetic disorders
Barts hydrops fetalis
Parents who are carriers for alpha
thalassaemia trait (South-east Asia [S.E.A.]
deletion in alpha globin gene) has 1 in 4
(25%) of Barts hydrops in each pregnancy
Features: Severe hydrops fetalis, majority
in-utero death. May be associated with
severe maternal pre-eclampsia. Hydrops fetalis (fetal hydrops) is a serious fetal condition defined as
abnormal accumulation of fluid in 2 or more fetal compartments,
Inheritance: Autosomal recessive including ascites, pleural effusion, pericardial effusion, and skin
edema
Screening: All parents for alpha
thalassaemia trait (low MCV, MCH) and
DNA studies for S.E.A deletion.
Prenatal diagnosis: Chorionic villus
Hydrops fetalis (fetal hydrops) is a serious fetal condition defined as abnormal accumulation of fluid in 2 or more fetal
sampling including
compartments, for S.E.A deletion
ascites, pleural effusion, pericardial effusion, and skin edema
Osteogenesis imperfecta
(O.I. type II)
Severe deformities - small chest cage leading to

respiratory failure;bent limbs (fractures)
Other types of ‘milder’ O.I.- Blue sclerae; severe
osteoporosis; limb deformities; dental problems –
dentinogenesis imperfecta; deafness
Inheritance: autosomal dominant; mutation in
COL1A1 gene and others Prof Thong Meow Keong Head, Genetic Medicine Unit University of Malaya Medical Centre
multifactorial disorder
(environmental and genetic
predisposition)
Neural tube defects Spina bifida
Anencephaly
Neural tube defects
 Defects of the spine or skull resulting from the failure of the neural
tube to close completely, usually by 4th week of gestation.
 Anencephaly: failure of the cranium and brain to form
 Encephalocele: protrusion of the brain through the skull
 Spina bifida: failure of the spinal cord to close
 Majority are isolated NTDs, minority are due to syndromic causes.
Results in early death, paralysis and neurogenic bladder.
 Polygenic with environmental factors
 Incidence 1 per 1000; may be reduced by periconceptional folic
acid supplementation or fortification 400 ug daily one month before
conception till 3 months of gestation by 60-70%
 Recurrence risk after one child with NTD: 3-4%
 Prenatal diagnosis:
 Maternal serum screening (raised alpha fetoprotein)
 Ultrasound
Birth defects and dysmorphic
syndromes - history taking
 Family history, consanguinity
 Pedigree drawing, non-paternity
 Past obstetric history
 Teratogenic exposure
 Diagnostic procedure done
 Antenatal and perinatal complications
 Delivery and neonatal status
 Growth and development
 Current medical problems
Understanding family tree
 Can be used to record medical conditions
 Concisely record family relationships
 Can assist in identifying people at risk of a genetic

condition
Pedigree drawing:
 Use standard symbols and nomenclature
 At least a 3-generation family tree
 Identify significant relationships eg polygamous marriage;
consanguinity; inherited disease in the family
 Identify proband (index case) and at-risk individuals
A picture paints a 1000 words
Sarina is married with two girls. She has 3 brothers and 2
sisters. One of her brothers has 3 boys. The youngest sister
has achondroplasia. Another brother has schizophrenia.
Sarina is a alpha thalassaemia carrier. Another sister just
married and expecting her first child. Sarina’s mother died 3
years ago of breast cancer, her father is still alive but has
stomach cancer.
I:1 I:2
Breast Ca 1997
Stomach Ca
II:1 II:2 II:3 II:4 II:5 II:6 II:7 II:8

Schizophrenia Achondroplasia
III:1 III:2 III:3 III:4 III:5 III:6

syndrome - physical examination
 General inspection
 Growth centiles – weight, length, head circumference
 Body and limb proportions
 Dysmorphic features (describe)
Face
Head and neck
Skin
Trunk
Limbs
 Secondary malformations
examples: congenital heart disease, genitalia abnormalities
 Ophthalmology/Otorhinolaryngology (ENT) assessment
syndromes - investigations
 Investigations are based on clinical diagnosis or clinical
presentations
 Photography - past and present (if dysmorphic)
 Skeletal survey / babygram (if present with short stature or
skeletal abnormalities)
 Imaging studies eg echocardiogram, ultrasonogram, magnetic
resonance
 Biochemical or metabolic tests (enzyme studies)
 Cytogenetics (karyotype – chromosomal analysis)
 Molecular genetics (Mutation analysis of gene)
 Consultation with clinical geneticists
Dysmorphic syndromes: importance of a
correct diagnosis
 Delineation of a syndrome diagnosis is important because:
 natural history can be understood
 prognosis and the long term outcome can be provided
 treatment options can be planned
 screening for possible complications to be done
 inheritance pattern and risk of recurrence can be counselled
 reproductive options for the family can be provided during genetic
counselling.
 Not having a definitive syndromic diagnosis can be distressing for
some individuals or families and may result in constant searching
for information or specialists to ‘confirm’ the diagnosis
(“Diagnostic odyssey”)
syndromes - management
 Management of immediate medical/ surgical problems
 Confirm diagnosis. Definitive diagnosis may not be made in
majority of patients during first visit.
 Genetic counselling
Determine mode of inheritance
Recurrence risks estimation
Burden of disease
Reproductive options provided
 Grief and bereavement support
 Provide social support and rehabilitation. Review regularly
for new changes. Support Groups essential.
 Long-term surveillance and prevention
Prevention and control of some birth
defects and dysmorphic syndromes
 Genetic counselling for at-risk families
 Family history and genogram (pedigree) analysis
 Public health policies
 Avoidance of teratogens in pregnancy
 Rubella vaccination
 Population screening and pre-marital screening
 Thalassaemia carriers
 Sexually transmitted diseases
 Pre-pregnancy and antenatal care
 Peri-conceptional folic acid
 Control of maternal illnesses e.g diabetes mellitus
 Maternal and neonatal screening programmes
 Maternal serum screening and prenatal diagnosis
 Newborn screening: Birth defects; Inborn errors of metabolism
An approach in
the genetics clinic
for a child with
suspected
dysmorphic
syndrome
Summary
 Birth defects, dysmorphic syndromes and congenital
malformations are common causes of mortality and morbidity in
neonates and children.
 It is the most important cause of ‘under-5’ mortality in Malaysia.
 There is a 2-3% risk of birth defects in the livebirth population
 These conditions have a significant impact on the individual,
family, community and country
 There is a need to be familiar with terminology used to describe
minor, major birth defects and specific dysmorphic syndromes
 Clinical approach to dysmorphic syndromes include careful
history taking, pedigree drawing, physical examination,
investigations and planning short and long term management
 There are curative and preventive strategies available
Thank you
Prepared by Prof Thong Meow Keong

Head, Genetic Medicine Unit
University of Malaya Medical Centre

Dysmorphic Syndromes - Thong Meow Keong

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Professor Dr Thong Meow Keong

Head, Genetics & Metabolism Unit

 1970 – Minimata Bay mercury poisoning

 1980 onwards – more teratogens recognised eg.

 Minor birth defect – abnormalities of prenatal origin that are

 Normal phenotypic variant – minor birth defects that occur in

Multiple birth defects 1%

 A Study on Under Five Deaths in Malaysia 2006, Ministry of Health Malaysia

 Community loss – loss of productivity and income (parents) as a

Usually aetiology unknown

Post axial polydactyly Pre axial polydactyly

 Environmental (biological, chemical, physical agents)

 Multifactorial (genetic and environmental factors)

Flat nasal bridge

Bilateral cleft lip and palate

Undescended / ectopic testes

Webbing between fingers / digits

Severe deformities - small chest cage leading to

 Concisely record family relationships

 Can assist in identifying people at risk of a genetic

II:1 II:2 II:3 II:4 II:5 II:6 II:7 II:8

III:1 III:2 III:3 III:4 III:5 III:6

 Consultation with clinical geneticists

Prepared by Prof Thong Meow Keong

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