Multiple Congenital Anomaly Syndromes Flashcards
Rubenstein- Taybi syndrome
1/100,000 to 1/125,000 AD mutations in CREBBP (most de novo) seen in ~40%, microdeletion of 16p13.3 in ~10% and mutations in EP300 seen in 3% -broad thumbs and toes, possibly with deviation, postnatal growth deficiency -typical facies: downslanted palpebral fissures, prominent or beaked nose with septum extending below alae nasi, maxillary hypoplasia. Hirsuitism, heavy arched eyebrows, long eyelashes Cardiac defects (PDA, VSD, ASD) in 1/3 Intellectual disability (moderate)
Treacher Collins syndrome
1/50,000
AD with mutations in TCOF1, also AD mutations in POLR1C, POLR1D
Craniofacial disorder with malar hypoplasia sometimes with zygomatic bone cleft
-lower lid coloboma, absent eyelashes medial to the defect, downslanted palpebral fissures, projection of scalp hair onto lateral cheek
Malformation of auricles or microtia, external ear defect, conductive hearing loss, micrognathia
Normal intelligence
Cornelia de Lange
1/50,000
AD mutations in NIPBL (~60%); other rare genes AD or XL
-prenatal growth deficiency, microcephaly, hoarse voice
-bushy eyebrows,synophrys, long curly eyelashes, depressed nasal bridge, anteverted nares, thin upper lip, hirsuitism, cutis marmarota
-Micromelia, oligodactyly, 5th finger clinodactyly, flexion contracture of elbow, syndactyly of 2 and 3 toes.
GI and GU anomalies
Intellectual disability (mild to severe)
Stickler syndrome
1/10 000
AD mutations in COL2A1, COL11A1, or COL11A2
-mutations in COL2A1 also cause achondrogenesis II, SED congenita, Kneist dysplasia, hypochondrogenesis
-flat face with prominent eyes, depressed nasal bridge.
High myopia, cataracts, retinal detachment
Hearing loss
Cleft palate, Pierre robin sequence
Joint hypermobility, early onset arthritis
Kabuki syndrome
1/32,000 to 1/68,000
AD mutations in MLL2 (in ~80%)
Postnatal growth deficiency (significant)
Long palpebral fissures, eversion of lateral portion of lower eyelid, arched eyebrows with sparse lateral third
Prominent, abnormal ears, short nose
CHD in half (coartc, BAV, MVP, others)
Persistence of Fetal fingertip pads, short 5th fingers, joint hypermobility
ID (moderate)
Neurofibromatosis type I
1/3000
AD mutations in NF1
Dx criteria: >5 Cafe au L macules, inguinal/axillary freckling, 2 or more neurofibromas or 1 plexiform neurofibroma, lisch nodules, optic gliomas, tibial pseudoarthrosis or sphenoid wing dysplasia, 1st degree relative with NF1
Relative macrocephaly, learning disability, mild ID, ADHD, scoliosis, CNS tumours (childhood), malignant peripheral nerve sheath tumours in <10%
Noonan syndrome
1/1,000 to 1/2,500
AD mutations in 1 of several genes: PTPN11, SOS1, RAF1, KRAS, etc. Some gen phen correlation
Short stature, CHDs (pulmonary valve stenosis, ASD, TOF), hypertrophic cardiomyopathy, variable DD
-Facies: hypertelorism, downslanted palpebral fissures, thick eyelids, ptosis, posteriorly rotated ears with fleshy helices
Broad or webbed neck, low posterior hairline
Pectus deformity (excavatum and/or carinatum), shield chest
Cryptorchidism in males, bleeding diathesis (due to coag or bleeding defects)
CHARGE syndrome
1/10,000
AD mutations in CHD7
C: coloboma (unit or bi)
H: heart defects (TOF, VSD, DORV, TA)
A: choanal atresia (unit or bi, or stenosis)
R: restrictions in growth/development
G: GU anomalies (hypogonadism, cryptorchidism)
E: ear anomalies ( abnormal outer ears, ossicular anomalies, Mondini defect of cochlea, hypoplastic semicircular canal (with hearing loss)
- square face w/ broad forehead, prominent nasal bridge and columella, flat midface
-other features: CN dysfunction with hyposmia or anosmia, facial palsy, facial clefts, TE fistula
22q11.2 deletion syndrome
DiGeorge syndrome, velocardiofacial syndrome
1/4,000 (about 10% inherited)
CHD in 85% diagnosed in childhood (VSD, R-sided aortic arch, TOF, aberrant L subclavian artery) (~40% of all ages)
Craniofacial: cleft palate, velopharyngeal insufficiency
Facies: hooded eyelids, prominent nose w/ squared nasal root, malar hypoplasia, ear anomalies, asymmetric crying face
Hypocalcemia
Absent thymus, immunodeficiency
Mild to moderate learning problems (esp. math/spatial learning)
Psychiatric disease in adults (schizophrenia)
Williams syndrome
1/15,000-1/20,000
Microdeletion of 7q11.23 (elastin gene responsible for SVAS, vascular stenosis, joint laxity, LIMK1 gene responsible for visuospatial, cognitive differences
CHD: supravalvular aortic stenosis, pulmonic valve stenosis, VSD, ASD
Renal artery stenosis, aortic hypoplasia, other arterial anomalies
Facies: medial eyebrow flare, periorbital fullness, stellar iris, full lips, widely spaced teeth
Hoarse voice, prematurely grey hair, joint hypermobility, contracture, scoliosis, lordosis, short stature, hypercalcemia
Feeding difficulties early with vomiting, constipation
DD. outgoing, friendly, easily approach strangers
Miller-Dieker syndrome
Incidence: unknown (rare)
Microdeletion of 17p13.3, size varies. Loss of LIS1 critical for lissencephaly, involved in neuronal migration
-lissencephaly (loss of gyral pattern): ID, microcephaly, seizures, feeding difficulties, spasticity, hypotonia
Facies: high forehead, vertical ridging and furrowing of forehead, small nose, anteverted nostrils, upslanted palpebral fissures, protruberant upper lip with thin vermillion border
Breathing difficulties, achieve almost no developmental milestones and death in early childhood
Smith lemli opitz
1/20,000 to 1/60,000 AR mutations in DHCR7 -deficiency of 7-dehydrocholesterol reductase. Defect in cholesterol biosynthesis with low cholesterol and elevated 7-dehydrocholesterol ID often severe, microcephaly with frontal narrowing and growth restriction Ptosis, abnormal ears, anteverted nares CHD: HLHS, ASD, PDA, VSD GU anomalies (common hypospadias) Y shaped 2-3 toe syndactyly
Zellweger syndrome
Aka cerebro-hepato-renal syndrome
1/25,000 to 1/100,000
AR defect in peroxisomal biogenesis due to PEX genes ( required for peroxisomal biosynthesis and import of proteins)
Also associated with abnormal VLCFAs
Severe Neonatal hypotonia and growth restriction
Enlarged anterior fontanelle, tall forehead, flat face, upslanted and narrow palpebral fissures
Hepatomegaly, limb contractures, club feet
Epiphyseal stippling
Often fatal in 1st year of life, survivors have seizures, severe ID
Oculocutaneous albinism
1/20,000
AR mutations in 1 of 4 genes
Type 1: TYR. White hair, very pale skin, light eyes
Type 2: OCA2 less severe, white skin, blond yellow or light brown hair
Type 3: TYRP1 (typically affects dark-skinner people) with reddish-brown skin, ginger or red hair, hazel or light brown irises
Type 4: SCL45A2. Less severe, same pheno as 2
Mutations affect ability of cells to make melanin, affecting pigmentation of skin, hair and eyes
Rett syndrome
~1/10,000 females
Mutations in MECP2 (X linked)
(Initially thought lethal in males, now know to cause neonatal encephalopathy and ID in males (some with unaffected carrier mothers))
-plateau of development between 6-18 months of age followed by developmental regression
Postnatal deceleration of head growth leading to microcephaly
Stereotypical hand wringing
Seizures, spasticity, breathing disturbances, sleep abnormalities
Autism, absent speech
