CONGENITAL SYNDROMES

DESCRIBE THE DYSMORPHIC FEATURES

WHAT’S YOUR DIAGNOSIS ?
LIST THE OTHER ASSOCIATED DYSMORPHIC FEATURES
WHAT OTHER SYSTEMIC DISORDERS ARE LIKELY TO BE PRESENT ?
DOWN SYNDROME
WHAT IS THIS ?
WHAT ELSE WOULD YOU EXAMINE FOR ?
CLUE: 2 VESSEL CORD
 VATER / VACTERL ASSOCIATION
• Association: (anomalies that
occur more often together than
by chance alone)
• 1/5,000
Failure of rupture
V = VERTEBRAL
of cloacal
A = ANORECTAL (ATRESIA)
diaphragm
C = CARDIAC (VSD)
(imperforate anus)
TE = TEF
R = RENAL
Horseshoe
Ectopic
L = LIMB
Polydactyly, forearm
defects, absent thumbs
Need 3 for Dx
T6 & T10 HEMIVERTEBRAE
DESCRIBE WHAT YOU SEE
WHAT’S YOUR DIAGNOSIS ?
WHAT OTHER ANOMALIES MIGHT BE PRESENT ?
EDWARD SYNDROME

MICROCEPHALY
SMALL JAW & MOUTH
SHORT NECK
HYPERTHELORISM
LOW UPTURNED NOSE
LOW SET EARS
OVERLAPING FINGERS
ROCKER BOTTOM FOOT
SUBLUXATION OF KNEES
EDWARD
SYNDROME
EDWARD SYNDROME
FEMALE

DESCRIBE WHAT YOU SEE

DIAGNOSIS ? MALE
 NONAN SYNDROME

WEBBED NECK
LARGE HEAD: FACE
HYPERTHELORISM
WEBBED NECK DOWN-SLANTING EYES
SCOLIOSIS LOW SET EARS
SHORT BROAD NOSE
NONAN SYNDROME
NONAN SYNDROME
• AD congenital disorder
• A RASopathy:
NONAN SYNDROME
• Developmental syndrome
caused by germline
mutations in genes that alter
the Ras subfamily and
Mitogen-activated protein
kinases that control signal
transduction
• Both male and female
• Referred to as the male version
of Turner's
• Principal features:
• congenital heart defect
• short stature
• learning problems
• pectus excavatum
• impaired blood clotting
• characteristic configuration
of facial features:
• webbed neck
• flat nose bridge.
WHAT DO YOU SEE ?
WHAT IS YOUR DIAGNOSIS ?
WHAT OTHER SYSTEMIC PROBLEMS MIGHT BE PRESENT ?
MICROCPHALY
HYPOTELORISM
PROBOSIS
CYCLOPIA
MICROPTHALMIA
SMALL MOUTH
BROAD FLAT NOSE
LOW SET EARS
CLEFT LIP & PALATE
POST AXIAL POLYDACTYLY
ROCKER BOTTOM FOOT
MENTAL RETARDATION
UMBILICAL HERNIA
HEART DEFECTS
RENAL ANOMALIES *
PATAU SYNDROME
PATAU SYNDROME
DESCRIBE
WHAT’S THE DIAGNOSIS ?
WHAT SYSTEMIC PROBLEM
WOULD YOU BE CONCERNED
ABOUT ?
TURNER SYNDROME

45X0
 KLIPPEL-FEIL SYNDROME
• Rare
• Initially reported in 1912 by Maurice
Klippel and André Feil (France)
• Fusion of any 2 or more cervical
C3 & C4 vertebrae
VERTEBRAL
BODIES
• Heterogeneous group of patients
• Sporadic; AD; AR
• Some cases associated with
mutations of the GDF6 gene on
chromosome 8
• Isolated or part of a syndrome
• Identified by shortness of the neck
• Associated very low hairline
• Limited neck movement
KLINEFELTER’S SYNDROME

47XXY
• PARTIAL CHROMOSOME 5 DELETION [SHORT ARM (P)] CRI DU CHAT
• 10-20% OF CASES INHERITED SYNDROME
• HIGH-PITCHED CAT-LIKE CRY
• MICROCEPHALY
• HYPERTELORISM
• SIMIAN CREASE
• LBW
• HYPOTONIA
• DELAYED DEVELOPMENT
• MR
• 90% DIE BEFORE ONE YEAR
 •
WILLIAMS SYNDROME •
AD
Microdeletion 7q (elastin)
• 1/15,000
• Cocktail personality (cheerful demeanor )
• Distinctive elfin facies
• Long philtrum
• Broad mouth
• Stellate irises
• Short nose (low nasal bridge) with
bulbous nasal tip
• Cardiac:
• Supravalvular aortic stenosis (80%)
• Peripheral pulmonic stenosis
• Pulmonary valvular stenosis
• Mental retardation (often strong language
skills)
• Transient idiopathic hypercalcemia
• Renal function abnormalities
• Constipation
 WILLIAMS SYNDROME
• Monitoring (AAP):
• Cardiology exam at birth and puberty,
yearly BP
• Serum Calcium
• Serum Creatinine q 4yrs
• Urinalysis – annually, unless normal
then q 2yrs
• Urine Ca/Cr ratio – q 4 yrs
• Baseline US of bladder and kidneys at
birth
• Thyroid function q2yrs until 5 yrs then
q4yrs
• Hearing and ophthalmology assessment
before 3yrs
CLUE: HE HAD HYPOGLYCAEMIA AT BIRTH
 SOTO SYNDROME
• Mutation in the NSD1 gene on chromosome 5
• NSD1 is a transcription coregulator protein
• Cerebral Gigantism (large head)
• Extraordinary physical growth in first 2-3 yrs
• AD
• 1/25,000
• LGA
• Macrocephaly, frontal prominence
• Hypotonia
• Seizures
• Developmental delay
• Behavioral difficulties
BECKWITH WIEDEMANN SYNDROME
• AD
BECKWITH-WIEDEMANN SYNDROME
• 11p15 problem
• Overactivity of the IGF-2 gene (growth factor)
and/or no active copy of CDKN1C (inhibitor of cell proliferation).
• Macrosomia
• Microcephaly
• Hemihypertrophy
• Macroglossia
• Hypoglycemia
• Pancreatic islet hyperplasia
• Abdominal wall defects
• Omphalocele
• Pits and ear creases
• Increased incidence of paediatric tumors
• Wilms
• Hepatoblastoma
• Suggested screening:
• Abdominal US q 3mo until 8yrs
• Alpha-Fetoprotein until 4yrs
• Normal IQ
 CROUZON’S SYNDROME
• mutations in the
fibroblast growth
factor receptor-2
(FGFR2) gene
located on
chromosome 10.
APERT SYNDROME
WHAT’S HIS DIAGNOSIS ?
WHAT IS A MAJOR RISK IN HIS CONDITION
 MARFAN SYNDROME
• AD, FBN1, fibrillin
• 1/15,000
• Major criteria in 2 systems and another
system
• Ocular
• Upward lens subluxation
• CV
• Dilatation of ascending aorta + AR
• Dissection of ascending aorta
• Minor: MVP

ECTOPIA LENTIS
 MARFAN SYNDROME
• Major Skeletal (4/8) • Pulmonary
• Pectus carinatum • No major criteria
• Pectus excavatum nee • Minor:
• Wrist & thumb sign • Pneumothorax
• Decreased U:L ratio • Skin
• Span:hgt ratio > 1.05 • Lumbosacral dural ectasia on CT or
• Scoliosis > 20° MRI
• Decreased elbow extension < 170° • FHx
• Major: positive
 MARFAN SYNDROME
• B-blockers may decrease aortic
dilatation
• SBE prophylaxis
• No competitive sports if mild aortic
dilatation
• Glaucoma due to dislocated lens
 HOMOCYSTEINURIA
• Marfanoid appearance
• Myopia
• Downward dislocation of lens
• Arterial thromboembolism
FAS

(VERMILLION BORDER )
 TREACHER COLLINGS
SYNDROME
• Rare (1:50,000)
• AD
• Mutation of TCOF1 (codes for a
relatively simple, nucleolar protein
called treacle)
• Symmetric downslanting eyes
• Malformed ears
• Lower eyelid colobomas
• Zygomatic hypoplasia
• Micrognathia
• Lateral lower eyelid drooping
DESCRIBE
HYPERTELORISM
 HYPERTELORISM
• Abnormally increased distance between two organs or bodily parts, usually
referring to an increased distance between the eyes (orbital hypertelorism)
• Seen:
• Basal Cell Nevus syndrome
• DiGeorge syndrome
• Loeys-Dietz syndrome
• Apert syndrome
• Waardenburg syndrome
• Noonan syndrome
• LEOPARD syndrome
• Crouzon syndrome
• Wolf-Hirschhorn syndrome
• Cri du chat syndrome
A RARE GENETIC EATING DISORDER
 • Hypotonic infants
PRADER WILLI SYNDROME • Often breech delivery
• Rare genetic eating disorder
• Poor feeding
• Causes:
• Paternal deletion: • Insatiable appetite later
• 15q11 – 13 (75%) • Cognitive impairment
• Maternal UPD (20%): • Often fair complexion
• MOSAIC TRISOMY 20
• Almond-shaped eyes
• Small hands and feet
• Infertile (hypoplastic testes and penis)
• Diabetes mellitus as adults:
• Unresponsive to oral hypoglycemics
• Pickwickian Syndrome (Obesity
hypoventilation syndrome)
• Treatment
• Intensive behavioural modification
• GH replacement improves body
composition (decreased fat)
• Testosterone replacement for boys
 RUSSELL SYLVER SYNDROME
• GROWTH DISORDER (FORM OF DWARFISM)
• Maternal duplication of 11p15 associated
• 1/50,000 to 1/100,000
• One type of dwarfism
• Often SGA
• Feeding problems (uninterested in feeding; takes only small
amounts with difficulty)
• Hypoglycemia
• Excessive sweating as a baby, especially at night, and a greyness or
pallor of the skin (may be due to hypoglycemia)
• Triangular shaped face with a small jaw and a pointed chin that
tends to lessen slightly with age: mouth tends to curve down
• Blue tinge to eyes in younger children • Continued poor growth with no "catch up"
• OFC may be of normal size and disproportionate to a small body size • Precocious puberty (occasionally)
• Wide and late-closing fontanelle • Low muscle tone
• Clinodactyly
• GERD
• Body asymmetry (one side grows more slowly than the other)
• A striking lack of subcutaneous fat
• Constipation (sometimes severe)
 BLOOM SYNDROME
• Defect in BLM gene (15q26.1)
• Needed for replication, repair,
recombination
• Small size
• Narrow chin, prominent ears & nose
• Facial rash
• Often become diabetics
• Neurological,lung, immune system
deficiency
• Chromosomal instability resulting in
many chromosomal breaks and
sister chromatid exchanges
• High incidence of a wide range of
cancer
 ANGLEMAN SYNDROME

• Causes:
• Large maternal deletion (75%)
• Paternal UPD (mosaicism) (2%)
• Imprinting center mutation (2%)
• Mutation in associated gene UBE3A BIG SMILE
(5 – 10%)
 ANGLEMAN SYNDROME
• Severe mental retardation
• Paroxysms of laughter
• Absent speech
• Ataxia and jerky arm movements:
• Puppet gait
• Hypopigmentation
• Microbrachycephaly
• Wide mouth
• Tongue protrusion
• Seizures
 PIERRE ROBIN SYNDROME

• Congenital facial abnormalities

• PRS: a chain of certain developmental malformations
entailing the next
• 3 main features are cleft palate, retrognathia and
glossoptosis
• PRS may be caused by genetic anomalies at chromosomes 2,
11, or 17
 BARDET-BIEDL SYNDROME
• Previously Laurence-Moon-Bardet-Biedl
• AR
• Obesity
• Postaxial polydactyly
• Hypogonadism
• Mental deficiency
• Pigmentary retinopathy
• Problems with night
• vision, color, visual acuity
• Myopia
• Kidney – concentrating problems and RTA
 PRUNE BELLY SYNDROME
• Eagle-Barrett Syndrome
• Absence of abdominal musculature
• Cryptorchidism
• Renal anomalies:
• Dysplastic kidneys
• PUV
• VUR
• Hydronephrosis
 STICKLER SYNDROME
• AD
• Flat face
• Scooped out nasal bridge
• U-Shaped cleft palate
• Pierre Robin sequence
• Myopia
• Risk of retinal detachment
• Hyperextensible joints
• Beware Difficult Airway!
 WAARDENBURG SYNDROME
• AD
• PAX-3 mutation
• 1/15,000 – 1/25,000
• Heterochromia
• White forelock
• SNHL 15 - 25%
• Dystropia canthorum
• Wide nasal bridge
• Short palpebral fissures
• DEAFNESS
 CHARGE SYNDROME
• AD
• 1/1000
• Coloboma
• Heart:
• Tetralogy
• aortic arch
• conotruncal defects
• Choanal Atresia
• Retardation:
• Growth and development
• Genitourinary
• Ear / deafness
• Need 4 features for Dx
• CHROMOSOME 7 MUTATION
 CORNELIA DE LANGE SYNDROME
• AD (most cases sporadic)
• 1/25,000
• Hirsutism
• Bushy and arched eyebrows
• Long curly eyelashes
• Low hairline
• Upturned nose and cupid’s
• bow lips
• Microcephaly, LGA and postnatal FTT
• Ulnar dysplasia
• Mental retardation
• MULTIPLE GENES ASSOCIATED
 RUBENSTEIN-TAYBI SYNDROME
• AD
• Microdeletion 16q
• 1/25,000
• Microcephaly
• Growth retardation (SHORT)
• Down-turned upper lip
• Beaked nose
• Mental retardation
• Broad thumbs and great toes
• Increased spinal cord tethering
 DiGeorge / VELOCARDIOFACIAL (VCF) SYNDROMES
• 1/5,000
• AD
• C – Cardiac:
• VSD
• Conotruncal abn:
• Tetralogy
• Truncus
• Interrupted aortic arch
• A – Abnormal facies
• T – Thymic hypoplasia:
• T cell abnormalities
• C – Cleft palate
• H – Hypocalcemia:
• 1st year of life
• Parathyroid aplasia or hypoplasia
• 22 - 22q11 deletion
LISCH NODULES

AXILLARY FRECKLING
 NEUROFIBROMATOSIS
• NF-1
• AD
• 1/3,000; 30 % new mutations in NF-1
• NF-1 on chromosome 17q11
• Von Recklinghausen’s Dz or VRNF
• NF-2
• AD
• 1/33,000; 50% new mutations in NF-2
• NF-2 on chromosome 22q1
 NEUROFIBROMATOSIS 1
• Dx: • Health Supervision:
• > 6 CALM
• Eye exam for 1st degree relatives
• > 5 mm pre-pub (Lisch nodules)
• > 15 mm post-pub
• Optho exams q 1 yr
• > 2 NF / 1 plexiform
• Axillary/groin freckling • Hearing before school-entry
• > 2 Lisch nodules:
• pigmented hamartomatous nodular
aggregate of dendritic melanocytes
affecting the iris
• Optic gliomas
• Skeletal abnormalities
• Cortical thinning of long bones +
pseudoarthrosis, sphenoid dysplasia
• First degree relative
 NEUROFIBROMATOSIS 2
• Dx:
• Bilateral acoustic neuromas (VIII tumors)
• First degree relative with NF-2 and 2 of:
• Neurofibroma
• Meningioma
• Schwannoma:
• CN V111 tumour
• Juvenile posterior subcapsular lenticular opacities
 OTHER SYNDROMES WITH CALM
• Tuberous sclerosis:
• TSC 1: chromosome p long arm:
• Protein hamartin
• TSC 2: chromosome 16 short arm:
• Protein tuberin
• Multisystemic abnormal tissue growth

• McCune Albright:
• Hyperfunctioning endocrine
• Fibrous dysplasia
• CALM
• Mutation long arm chromosome 20
 ACHONDROPLASIA
• AD
• Defect in FGFR-3
• Associated with advanced paternal age
• 1/10,000
• Short limb dwarfism
• Megalocephaly
• Midface hypoplassia
• Trident hand
• Square pelvis
• Small sacroiliac notch
• Narrowed interpeduncular distances
• Shortened proximal long bones
• Narrow foramen magnum
• Hydrocephalus
 ACHONDROPLASIA
• Risks • Health supervision:
• UAO • Document OFC & growth
• Sudden infant death parameters
• OSA • Neuroimaging
• Hydrocephalus • C-spine imaging
• Cord compression due to kyphosis • Hearing assessments annually
• GERD • Polysomnography
• Obesity
 THANATOPHORIC DYSPLASIA
• Another type of rhizometric (rhizomelic) skeletal dysplasia
• Lethal
• Disproportionately Small chest (rib cage):
• Respiratory distress
• Typical findings:
• No sciatic notch
• French-telephone femurs
• H-shaped vertebrae