Smith's Syndromes I

CBP or EP300 mutations, 16p13.3 deletions

Short stature, ID, speech difficulties, gait anomalies, broad thumbs and toes with radial angulation, slanted palpebral fissures, hypoplastic maxilla, beaked nose

hypomethylation of paternal H19 on 11p15 (50%), maternal UPD 7 (10-15%), mat UPD11, pat 7q32 deletions

Short stature (prenatal onset), skeletal asymmetry, mild global DD, speech delay, small triangular face, clinodactyly

• AR; BLM gene (RecQ helicase) on 15q26.1
• increased chromosome breakage and SCE

short stature (prenatal onset), malar hypoplasia, telangiectatic erythema of the face, predisposition to all types of cancer (leading cause of mortality)

AR; 7-dehydrocholesterol reductase (DHCR7) deficiency-->v. low plasma cholesterol

moderately small at birth/FTT, ID, broad nasal tip with anteverted nares, ptosis, syndactyly of 2nd and 3rd toes, hypospadias & cryptorchidism in males

AD; mixed lineage leukemia 2 (MLL2) mutation (60%), Xp11.3 microdeletion including KDM6A

postnatal growth retardation, ID, long palpebral fissures, eversion of lower lateral eyelids, large protuberbant ears, persistent fingertip pads

7q11.23 microdeletion; haploinsufficiency for ELN and LIMK1 attributed to heart defect and visuospatial construction defects respectively

prenatal growth deficiency, ID, "cocktail party" personality, prominent lips, hoarse voice, supravalvular aortic stenosis

AD; PTPN11 (GOF), SOS1, RAF1, KRAS, BRAF, MEK1, NRAS

typical and atypical facies that change with age, webbing of neck, pectus excavatum, cryptorchidism, pulmonic stenosis

AD; HRAS mutations

macrocephaly, coarse face, thin deep-set nails. loose skin over hands and feet, large for dates (50%), ID, CHD (52%), increased cancer risk

AD; BRAF, MEK1, MEK2 mutations in majority of cases

CHD, ectodermal anomalies (sparse curly hair, absent eyebrows/lashes, atopic dermatitis, etc), relative macrocephaly with frontal bossing and bitemporal narrowing,

X-linked recessive; FGD1 (Xp11.21)

mild short stature, round face with hypertelorism and downslanting palpebral fissures, brachydactyly, shawl scrotum

• AD; de novo; laminin A (LNMA) mutation
• classic mutation c.182C>T-->use of cryptic splice site->truncated protein

senile-like appearance, alopecia, atrophy of subcutaneous fat, skeletal hypoplasia and dysplasia

AR; ERCC6 (65%) and ERCC8 (35%); functions in nucleotide excision repair

senile-changes in infancy (loss of adipose tissue), retinal degeneration, impaired hearing, ID, gait anomalies, relative microcephaly

X-linked CGG repeat expansion >200 repeats within FMR1; premutation range=54-200

• ID, mild connective tissue dysplasia, macro-orchidism, ASD, characteristic facies (prominent forehead, elongated face, prognathism, large ears)
• female premutation carrier: incr. POF
• female & male premutation carriers: risk of atypical parkinsonism with ataxia and tremor (FXTAS)

AD; mutation/deletion in nuclear receptor SET domain containing protein (NSD1)

overgrowth (prenatal onset), large hands and feet, variable ID, dolicocephaly, prominent jaw, abnormalities of cerebral ventricles

AD; *loss of KvDMR methylation, pat UPD 11, incr. methylation of imprinting center 1, 11p15 microdeletions

overgrowth (prenatal onset), macroglossia, omphalocele, macrosomia, ear creases

17p13.3 deletion (PAFAH1B1, YWHAE, CRK?)

lissencephaly, high forehead with vertical soft tissue ridging , small anteverted nose

17p11.2 deletion (RAI1)

ID, brachycephaly, brachydactyly, broad flat midface, speech delay, brain anomalies, facial coarsening with age, disrupted circadian rhythms, behavioral anomalies

17p11.2 duplication

hypotonia, FTT, ID, ASD, apnea, cardiovascular anomalies, dysmorphic features

X-linked recessive; ATP7A (copper-transporting ATPase) at Xq13.3

sparse, twisted and fractured hair, progressive cerebral deterioration with seizures, wormian bones, metaphyseal widening with formation of lateral spurs that often fracture

deletion of maternal UBE3 (70-75%), paternal UPD 15, imprinting defect

severe ID and DD, ataxic gait, paroxysm of laughter, characteristic facies (microbrachydactyly, maxillary hypoplasia, deep set eyes, large mouth with protruding tongue, prognathia)

paternal deletion 15q11.3 (70%), maternal UPD (25-30%), imprinting center mutations

hypotonia, obesity, small hands and feet, mild ID, genital anomalies

tetrasomy 12p

sparse anterior scalp hair & prominent forehead, long philtrum with thin upper lip, streaks of hypo- and hyperpigmentation, profound ID

AR; peroxisome biogenesis disorder caused by mutation in one of the PEX genes (peroxins)

hypotonia, high forehead with flat facies, hepatomegaly, postnatal growth deficiency, severe ID and structural brain anomalies, congenital cataracts

AD; CTG expansion in DM1 gene on 19q13.3

myotonia with muscle atrophy, cataract, hypogonadism; premature hair recession in males

variable age of onset

6th and 7th nerve palsy

micrognathia with U-shaped palate, high nasal bridge, small mouth with downturned corners, associated anomalies: limb reduction defects, hypodontia, splenogonadal fusion

AD, forkhead TF 2 (FOXL2) mutations on 3q22.3-q23

inner canthal fold, lateral displacement of inner canthi, ptosis, infertility in some females

primary defect=early mandibular hypoplasia-->micrognathia, glossoptosis, cleft soft palate

AD, mutations in interferon regulatory factor 6 (IRF6), microdeletions within 1q32-q41

lower lip pits +/- cleft lip, +/- absent 2nd premolars

chromodomain helicase DNA-binding (CHD7) mutations

coloboma, heart defects, anal atresia, retarded growth, genital anomalies, ear anomalies (& hearling loss)

AD mutations in PAX3, MITF, SOX10, EDNRB, EDN3;

lateral displacement of medial canthi, partial albinism (white forelock and hypochromic iridis), hypopigmentation of skin (patches), deafness

AD; treacle (TCOF1) mutations on 5q32-q33.1 (93%); POLR1D & POLR1C (~9%)

malar hyoplasia with down-slanting palpebral fissures, defect of lower lid, malformation of external ear

AR; dihydroorotate dehydrogenase (DHODH) deficiency

treacher-collins like facies, limb deficiency (often missing 5th digit of hands and feet)

22q11.2 deletion; haploinsufficiency of TBX1

thymic hypoplasia, velopharyngeal insufficiency, conductive hearing loss secondary to cleft palate, prominent nose with squared nasal root, heart defects (VSD, TOF, etc)

microdeletion 8q21.11-q24.13 encompassing TRPS1 & EXT1

multiple exostoses, bulbous nose with peculiar facies, loose redundant skin in infancy, ID, cone-shaped epiphyses

AR; mutations in cohesion 1 homolog (ESCO2) on 8p21.1

hypomelia/tetraphocomelia, midfacial defect, severe growth deficiency, ID

• AD; IRF6
• allelic to van der woude

popliteal web, cleft palate, lower lip pits

• AD, TBX5 on 12q21.4
• variable expressivity, anticipation

upper limb defect exclusively (radial defects including forearm hypoplasia to absent or triphalangeal thumbs), cardiac anomaly, narrow shoulders

AR; 15 complementation groups

incr. chromosome breaks, radial hypoplasia (incl. hypoplastic or absent thumbs), hyperpigmentation, pancytopenia, incr. risk for AML or squamous cell carcinomas, bone marrow failure

AR; 1q21.1 microdeletion concurrent with RBM8 polymorphism SNP on undeleted chromosome

thrombocytopenia, bilateral absent radius (thumbs intact), leg abnormalities including hip dislocation, subluxation of knees

AD; mutation in one of nine ribosomal protein (RP) genes

triphalangeal thumbs, congenital anemia that improves with age

AD; FGFR3 mutation

short limbs, low nasal bridge, megalocephaly, lumbar lordosis,

AD; ABCC9/SUR2 mutations

congenital hypertrichosis, cardiomegaly, osteochondrodysplasia, macrocephlay, coarse facies (improves with age)

AR; GNPTAB deficiency

early alveolar ridge hypertrophy, joint limitation, thick tight skil in early infancy, coarse face, dystosis multiplex

AR, α-L-iduronidase deficiency (IDUA) on 4p16.3

coarse facies, skeletal anomalies, ID, hepatosplenomegaly, cloudy corneas, hernia

X-linked; iduronate sulfatase (IDS) deficiency

coarse facies, skeletal anomalies, heart defects, hepatosplenomegaly, hernias, clear corneas, no affected females

X-linked; iduronate sulfatase (IDS) deficiency

coarse facies, skeletal anomalies, heart defects, hepatosplenomegaly, hernias, clear corneas, no affected females

AR; sulfamidase deficiency (SGSH) at 17q25.3

mild coarse facies, mild skeletal anomalies, ID, hepatosplenomegaly,

AR; N-acetylgalactosamine6-sulfatase (GALNS), β-galactosidase (GLB1) deficiency

mild coarse faces, severe kyphosis and knock-knees, cloudy cornea

AR; β-glucuronidase deficiency (GUSB)

ID, coarse facies, corneal clouding, skeletal anomalies, hepatosplenomegaly

AD; TWIST haploinsufficiency

craniosynostosis, brachycephaly with maxillary hypoplasia; prominent ear crus, syndactyly, hypertelorism

AD; FGFR2 (majority p.Ser252Trp)

irregular craniosynostosis, midfacial hypoplasia, syndactly (partial or full fusion)

AD; FGFR2

shallow orbits, premature craniosynostosis, maxillary hypoplasia