Smith's Syndromes I

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  1.   Rubenstein-Taybi
    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
  2. Russell-Silver
    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
  3.     Bloom Syndrome 
    • 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)
  4.   Smith-Lemli-Opitz
    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
  5.   Kabuki Syndrome
    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
  6.  Williams Syndrome
    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
  7.   Noonan Syndrome

    typical and atypical facies that change with age, webbing of neck, pectus excavatum, cryptorchidism, pulmonic stenosis
  8.   Costello
    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
  9. Cardio-Facio-Cutaneous (CFC)
    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,
  10.   Aarskog
    X-linked recessive; FGD1 (Xp11.21)

    mild short stature, round face with hypertelorism and downslanting palpebral fissures, brachydactyly, shawl scrotum
  11.   Hutchinson-Gilford Progeria
    • 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
  12. Cockayne
    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
  13.   Fragile X
    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)
  14.   Sotos
    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
  15. Beckwith-Wiedemann
    AD; *loss of KvDMR methylation, pat UPD 11, incr. methylation of imprinting center 1, 11p15 microdeletions

    overgrowth (prenatal onset), macroglossia, omphalocele, macrosomia, ear creases
  16.   Miller Dieker
    17p13.3 deletion (PAFAH1B1, YWHAE, CRK?)

    lissencephaly, high forehead with vertical soft tissue ridging , small anteverted nose
  17. Smith Magenis
    17p11.2 deletion (RAI1)

    ID, brachycephaly, brachydactyly, broad flat midface, speech delay, brain anomalies, facial coarsening with age, disrupted circadian rhythms, behavioral anomalies
  18. Potocki-Lupski
    17p11.2 duplication

    hypotonia, FTT, ID, ASD, apnea, cardiovascular anomalies, dysmorphic features
  19.   Menkes
    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
  20.   Angelman
    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)
  21.   Prader-Willi
    paternal deletion 15q11.3 (70%), maternal UPD (25-30%), imprinting center mutations

    hypotonia, obesity, small hands and feet, mild ID, genital anomalies
  22.   Pallister-Killian
    tetrasomy 12p

    sparse anterior scalp hair & prominent forehead, long philtrum with thin upper lip, streaks of hypo- and hyperpigmentation, profound ID
  23.   Zellweger
    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
  24. Myotonic Dystrophy type I
    AD; CTG expansion in DM1 gene on 19q13.3

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

    variable age of onset
    Moebius Sequence
    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

  26. Blepharophimosis-Ptosis-Epicanthus inversus syndrome (BPES)
    AD, forkhead TF 2 (FOXL2) mutations on 3q22.3-q23

    inner canthal fold, lateral displacement of inner canthi, ptosis, infertility in some females
  27.   Robin sequence
    primary defect=early mandibular hypoplasia-->micrognathia, glossoptosis, cleft soft palate
  28.   Van der Woude
    AD, mutations in interferon regulatory factor 6 (IRF6), microdeletions within 1q32-q41

    lower lip pits +/- cleft lip, +/- absent 2nd premolars
  29.   CHARGE
    chromodomain helicase DNA-binding (CHD7) mutations

    coloboma, heart defects, anal atresia, retarded growth, genital anomalies, ear anomalies (& hearling loss)
  30.   Waardenburg
    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
  31.   Treacher Collins
    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
  32.   Miller Syndrome
    AR; dihydroorotate dehydrogenase (DHODH) deficiency

    treacher-collins like facies, limb deficiency (often missing 5th digit of hands and feet)
  33.   DiGeorge/VCFS
    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)
  34.   Langer-Giedion
    microdeletion 8q21.11-q24.13 encompassing TRPS1 & EXT1

    multiple exostoses, bulbous nose with peculiar facies, loose redundant skin in infancy, ID, cone-shaped epiphyses
  35.   Roberts
    AR; mutations in cohesion 1 homolog (ESCO2) on 8p21.1

    hypomelia/tetraphocomelia, midfacial defect, severe growth deficiency, ID
  36. Popliteal pteryguim
    • AD; IRF6
    • allelic to van der woude

    popliteal web, cleft palate, lower lip pits
  37. Holt Oram
    • 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
  38.   Fanconi Pancytopenia
    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
  39.   TAR
    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
  40. AASE/Diamond-blackfan anemia
    AD; mutation in one of nine ribosomal protein (RP) genes

    triphalangeal thumbs, congenital anemia that improves with age
  41.   Achondroplasia
    AD; FGFR3 mutation

    short limbs, low nasal bridge, megalocephaly, lumbar lordosis,
  42.   Cantu
    AD; ABCC9/SUR2 mutations

    congenital hypertrichosis, cardiomegaly, osteochondrodysplasia, macrocephlay, coarse facies (improves with age)
  43. I cell disease/mucolipidosis II
    AR; GNPTAB deficiency

    early alveolar ridge hypertrophy, joint limitation, thick tight skil in early infancy, coarse face, dystosis multiplex
  44. MPS I (hurler-scheie)
    AR, α-L-iduronidase deficiency (IDUA) on 4p16.3

    coarse facies, skeletal anomalies, ID, hepatosplenomegaly, cloudy corneas, hernia
  45. Hunter/MPS II
    X-linked; iduronate sulfatase (IDS) deficiency

    coarse facies, skeletal anomalies, heart defects, hepatosplenomegaly, hernias, clear corneas, no affected females
  46. Sanfilippo (MPS III)
    X-linked; iduronate sulfatase (IDS) deficiency

    coarse facies, skeletal anomalies, heart defects, hepatosplenomegaly, hernias, clear corneas, no affected females
  47. Sanfillipo (MPS III)
    AR; sulfamidase deficiency (SGSH) at 17q25.3

    mild coarse facies, mild skeletal anomalies, ID, hepatosplenomegaly,
  48.   Morquio (MPS IV)
    AR; N-acetylgalactosamine6-sulfatase (GALNS), β-galactosidase (GLB1) deficiency

    mild coarse faces, severe kyphosis and knock-knees, cloudy cornea
  49. Sly (MPS VII)
    AR; β-glucuronidase deficiency (GUSB)

    ID, coarse facies, corneal clouding, skeletal anomalies, hepatosplenomegaly
  50. Saethre-Chotzen
    AD; TWIST haploinsufficiency

    craniosynostosis, brachycephaly with maxillary hypoplasia; prominent ear crus, syndactyly, hypertelorism
  51.   Apert
    AD; FGFR2 (majority p.Ser252Trp)

    irregular craniosynostosis, midfacial hypoplasia, syndactly (partial or full fusion)
  52.   Crouzon
    AD; FGFR2

    shallow orbits, premature craniosynostosis, maxillary hypoplasia

Card Set Information

Smith's Syndromes I
2015-05-10 22:01:14
Genetic Syndromes
genetic syndromes and disease genes
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