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ABGC Boards Exam > Multi-Systemic and microdeletion syndromes > Flashcards

Multi-Systemic and microdeletion syndromes Flashcards

1
Q

Williams syndrome genetics

A
  • del 7q11.23
  • submicroscopic and requires FISH detection
  • deletion includes elastin (ELN) gene, LMPK1
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2
Q

Williams syndrome features

A

-outgoing, “cocktail party” personality in younger age
-cardiac defects (75% cases)-SVAS near pathognomonic, also PVS, ASD, VSD, aortic hypoplasia and arterial anomalies
-joint hypermobility and lordosis, scoliosis, short stature
-dysmorphic features
+elfin-like facies-smooth philtrum, thin upper lip, puffiness around eyes/periorbital fullness and cheek fullness, medial eyebrow hair
+stellate irides
+micrognathia and teeth abnormalities
-DD, ID, SD
-hypercalcemia
-FTT and feeding difficulties with GI problems
-voice hoarseness, premature graying

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3
Q

VCFS/DiGeorge genetics

A

-deletion of 22q11.2
+includes TBX1
-relatively common-incidence of 1 in ~2000
-10% inherited
-mutation effects migration of neural crest cells to 3rd and 4th pharyngeal pouches, causes structural defects of cardiac outflow tract, and hypoplasia of the thymus and parathyroid glands

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4
Q

22q11.2 deletion syndrome features

A

-dysmorphic features
+Hooded eyelids
+prominent nose with squared nasal root, bulbous tip
+ear anomalies
+sometimes asymmetric crying face
+malar hypoplasia/underdeveloped cheek bones
-clefting, hypernasal speech and nasal regurgitation related to velopharyngeal incompetence, SD
-LD, ID, DD, psychiatric issues
-cardiac anomalies and CHDs
-hypocalcemia due to hypoparathyroidsim and T-cell/immuno deficiency due to thymic hypo/aplasia
-GU and GI anomalies

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5
Q

Miller-Dieker genetics

A
  • 17p13.3 deletion
  • requires FISH or molecular dx, but 50% patients have visible deletions on karyotype; varying size
  • loss of LIS1 associated with Lissencephaly and failed neuronal migration
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6
Q

Miller-Dieker features

A

-dysmorphic features
+micrognathia and thin vermillion border with protuberant upper lip
+tall, prominent forehead with bitemoporal hollowing, vertical ridging or furrowing of forehead
+upslanting palpebral fissures
+short, upturned nose with anteverted nares
-type 1 lissencephaly (smooth brain) leading to microcephaly, ID, seizures, spasticity
-hypotonia, feeding difficulties
-breathing difficulties
-leads to early death without ability to meet milestones

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7
Q

Smith-Magenis genetics

A

17p11.2 deletion

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8
Q

Smith-Magenis features

A

-dysmorphic features
+brachycephaly, midface hypoplasia with prognathism
-ID, behavioral problems (self-destructive, sleep disturbance)
-GR
-peripheral neuropathy
-voice hoarseness

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9
Q

1p36 deletion genetics

A

-contiguous gene deletion of 1p36 region
+can have variable breakpoints unlike most other CGD syndromes-terminal or interstitial
-0.5-1.2% of all idiopathic ID, prevalence of 1 in ~5000
-detection
+can be seen on karyo, but sometimes missed with G-bands
+FISH-telomere studies and 1p36 probe
+easily identified by MCA

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10
Q

1p36 features

A 
-microbrachycephaly and structural brain anomalies
\+moderate to severe ID
\+seizures (>50%)
\+behavioral probs-self-injurous behaviors, biting, tantrums
-hypotonia
-hearing problems
-skeletal anomalies
-CNS, GI and GU anomalies
-facies
\+straight eyebrows with deep-set eyes
\+midface hypoplasia
\+long philtrum
\+pointed chin
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11
Q

McDermid-Phelan Syndrome genetics

A
  • 22q13 deletion sydrome
  • deletion of SHANK3 gene
  • detected by FISH
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12
Q

McDermid-Phelan features

A
  • widely variable
  • ID and severe speech delay
  • hypotonia
  • mild facial dysmorphism
  • sometimes ASD, behavioral probs, seizures
  • GI, renal, heart problems
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13
Q

1q21.1 abnormalities

A

-can have dups and dels
+del with variable phenotype (mild-moderate ID, microcephaly, cataracts, neuropsychiatric disorders, cardiac anomalies
+dup with variable phenotype (ID, ASD, neuropsychiatric conditions, macrocephaly, dysmorphic features)
-parents with aberrations may also have phenotype

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14
Q

15q13.3 deletion syndrome

A

-normally 1.5 Mb del
+often inherited
+low CNR-non-allelic homologous recombination
+can involve CHRNA7, which lesser defines phenotype if this is the only gene deleted
-variable phenotype
+mild ID (50%)
+neuropsychiatric conditions, behavioral problems
+seizures

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15
Q

16p11.2 anomalies

A
  • both dels and dups (low CNRs)
  • may be inherited from a parent without phenotype
  • affected child could have ASD, minor facial anomalies, speech delay
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16
Q

16p13.11 aberrations

A

-both dels and dups (low CNRs)
+deletion phenotype better established
-inherited from parents with zero or mild features
-variable phenotype with neuropsychiatric disorders, dysmorphic features and CHDs

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17
Q

17q12 deletion syndrome

A 
-~1.5Mb deletion
\+mostly related to low CNRs and NAHR
\+TCF2 and LHX genes involved
-presents like MODY-"MODY5"
-renal cystic dysplasia, renal hypoplasia, abnormal renal function, cryptorchidism, elevated renal enzymes
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18
Q

17q12 microduplication syndrome

A

-~1.5Mb duplication
+mostly related to low CNRs and NAHR
-can be de novo or inherited from non/mildly affected parents
-can cause cognitive impairment, epilepsy, dysmorphic features, renal anomalies

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19
Q

15q24 deletion syndrome

A

-min of 1.7Mb deletion
+low CNRs & NAHR
+P450sec involved
-all reported de novo in literature
-delayed bone age with elevated serum triglycerides
-hypospadius, cryptorchidism, joint laxity, bowel atresia, scoliosis, growth hormone deficiency

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20
Q

P450sec

A

mitochondrial cholesterol cleavage enzyme

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21
Q

1q41-1q42 deletion syndrome

A

-~1.17Mb deletion
+DISP1 involvement
-mechanism unknown, all cases de novo
-presents like Fryn’s syndrome
+gyral malformations, small cerebellum, enlarged ventricles
+cleft palate, talipes, diaphragmatic hernia

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22
Q

2p15-2p16.1 deletion syndrome

A

-min of 200kb deletion
+VRK2 involvment
-unknown mechanism, all cases de novo
-pachygyria, fourth ventricle enlargement, brain stem and cerebellar hypoplasia
-optic nerve hypoplasia, renal anomalies, leg spasticity, high-arched palate, calcaneovalgus

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23
Q

prenatal microarray limitations

A

cannot find balanced rearrangements and triploidy by SNP

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24
Q

prenatal microarray detection

A
  • 6.0% cases with ultrasound finding had a clinically relevant del/dup not detectable by karyo
  • 1.7% of cases referred for AMA or positive serum screen had a finding
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25
Q

Rubinstein-Taybi Genetics

A

-incidence of 1 in 100000-1 in 125000
-most commonly see de novo mutations in CREBBP, though microdeletion of 16p13.3 (includes gene) can be seen in 10% cases
+3% due to EP300

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26
Q

Rubinstein-Taybi phenotype

A

-broad thumbs and great toes, possible with deviation
-postnatal growth deficiency
-facies
+downslanting palpebral fissures
+prominent or beaked nose longer septum than nostril wings with maxillary hypoplasia
+hirsuitism-heavy arched eyebrows, long eyelashes
+cardiac defects in 1/3-PDA, VSD, ASD
-moderate ID

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27
Q

Treacher Collins genetics

A

-incidence of 1 in 50000
-most commonly due to AD mutation of TCOF1
+failure of treacle protein to allow neural crest migration in 1st and 2nd pharyngeal pouches
+POLR1C, POLR1D can also be implicated

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28
Q

Treacher Collins phenotype

A

craniofacial disorder with malar hypoplasia and zygomatic bone cleft
-lower eyelid coloboma with absent eyelashes in the area of defect and down slanting palpebral fissures
-projection of scalp hair onto lateral cheek
-microtia and external ear malformation with CHL
-micrognathia
+obstructive apnea is main concern in newborns

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29
Q

Cornelia de Lange genetics

A
  • incidence of 1 in 50000
  • mostly due to AD mutation of NIPBL; rarer gene mutations inherited in AD and XL (SMC1A) manner
  • usually sporadic
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30
Q

Cornelia de Lange phenotype

A
  • IUGR, LBW, FTT
  • microcephaly with mild to severe ID
  • voice hoarseness
  • hirsuitism with bushy eyebrows, synophrys (unibrow), long curly eyelashes
  • depressed nasal bridge, anteverted nares
  • thin upper lip
  • cutis marmorata-mottled red-purple rash
  • micromelia, oligodactly or 5th finger clinodactly, flexion contracture of elbow, syndactly of 2nd-3rd toes
  • GI and GU anomalies
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31
Q

Stickler syndrome genetics

A

-1 in 10000
-caused by AD mutation of COL2A1, COL11A1 or COL11A2
+note mutations in COL2A1 can also cause achondrogenesis II, Kneist dysplasia, SED congenita and hypochondrogenesis
+rare AR mutations in COL9A1 can also occur

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32
Q

Stickler syndrome phenotype

A

-flattened face/profile with depressed nasal bridge and prominent eyes
-eye anomalies including high myopia/nearsightedness, cataracts and retinal detachment or vitreoretinal degeneration
-Pierre Robin sequence or isolated palatal hard or soft palate cleating, with or without bifid uvula
-hearing loss
-joint hyper mobility, widening of joints (epiphyseal dysplasia) with early arthritis onset
+marfanoid body habitus

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33
Q

Kabuki syndrome genetics

A

-incidence of ~1 in 30000-1 in 70000
-caused by AD mutation of MLL2
+first found by WES

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34
Q

Kabuki phenotype

A
  • significant postnatal growth deficiency
  • eversion (out-turning) of lateral portion of lower eyelid, long palpebral fissures
  • arched eyebrows with a sparse lateral third
  • prominent abnormal ears
  • short nose that gives appearance of long philtrum
  • 50% with CHD (coarctation, MVP, BAV)
  • moderate ID
  • persistance of fetal fingertip pads, shortened 5th finger, joint hyper mobility
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35
Q

NF1 genetics

A
  • incidence 1 in 3000

- AD mutation of NF1 gene

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36
Q

NF1 features

A
  • CaLMs and other abnormal skin findings
  • eye findings
  • predisposition to CNS tumors (optic glioma, neurofibroadenomas, rarely peripheral nerve sheath tumors)
  • relative macrocephaly with ID, DD, LD, ASD, ADHD
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37
Q

NF1 diagnostic criteria

A

-6 or greater CaLMs (often seen before 1y)
+at least 5mm before puberty, 15mm after
+typically rounded with smooth borders
-inguinal or axillary freckling
-2 or more neurofibromas or 1 plexiform (usually by 10-20y)
-2 or more Lisch nodules/iris hamartoma (usually seen by 10y)
-optic glioma
-tibial pseudoarthritis or sphenoid wing dysplasia (osseous lesion)
-1st degree relative with NF1

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38
Q

Noonan syndrome genetics

A

-incidence of 1 in 1000-1 in 2500
-due to AD mutations of PTPN11, SOS1, KRAS, RAF1, etc
+effecting the MAPK pathways
-some genotype phenotype correlations
-known and overlap with other conditions
+cardiofaciocutaneous syndrome, Costello

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39
Q

Noonan phenotype

A

-short stature
-CHDs: pulmonic valve stenosis most commonly, ToF, ASD
+HCM also common (especially with RAF1, RIT1)
-variability of DD
-eye abnormalities: hypertelorism of light colored eyes, down slanting PFs, thick eyelids, ptosis, strabismus, nystagmus, refractive errors
-triangular face shape
-posteriorly rotated ears with fleshy helices
-pectus or shield chest, broadened and webbed neck
-low posterior hairline, curly hair (sparse, wispy hair in LAH subtype, curly hair especially in Costello)
-cryptorchidism in males
-bleeding diathesis due to premature apoptosis and lymphatic dysplasia
-skin anomalies such as freckling, lentigines, CaLMs

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40
Q

CHARGE syndrome genetics

A
  • incidence of 1 in 10000

- AD mutation of CDH7

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41
Q

CHARGE defects

A

-coloboma-of iris, retina, optic disc
-CHDs-ToF, VSD, DORV, tricuspid atresia
-choanal atresia
+u/l or b/l and can be just stenosis
+CN dysfunction can cause hypo or anosmia
-restricted growth and development
-GU anomalies-hypotrophic hypogonadism, cryptorchidism
+GI and TE fistula may also occur
-ear anomalies and hearing loss
+Mondini defect of cochlea is characteristic
+can see outer ear deformity, ossicular defects and hypoplastic semi-circular canal

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42
Q

CHARGE facies

A

-square face shape with mid face hypoplasia, broad prominent forehead, prominent nasal bridge
+CNS problems can cause facial palsy
+sometimes clefting
-ear anomalies-low set cup shape visible to outside
-nose anomalies

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43
Q

SLOS genetics

A

-incidence of 1 in 20000-1 in 60000
-AR mutation of DHR7
+deficiency of 7-dehydrocholesterol reductase causes low cholesterol levels with high 7-dehydrocholesterol
+cholesterol deficiency causes problems for cell membrane development, myelination, steroid synthesis, vitamin D and bile acid production

44
Q

SLOS phenotype

A
  • severe ID
  • microcephaly with frontal-temporal narrowing and GR
  • ptosis and epicanthal folds, abnormal ears and anteverted nares
  • CHD: HLHS, ASD, PDA, VSD
  • GU anomalies: hypospadias
  • Y-shaped 2-3 toe syndactly, post-axial polydactyly
45
Q

Oculocutaneous Albinism genetics

A
  • incidence of 1 in 20000
  • caused by AR mutation of TYR or OCA2 most commonly (Types I and II), TYRP1 and SLC45A2 mutation may also occur (Types III and IV)
  • affect melanin production, lightening skin, hair and eyes
46
Q

oculocutaneous albinism phenotype

A
  • Type I: white hair, very pale skin, light irides
  • Type II & IV: less severe with creamy white skin, light blond/yellow/light brown hair
  • Type III: occurs more frequently in individuals with naturally darker skin, so they tend to have reddish-brown skin, red/ginger hair and hazel or brown irides
47
Q

otopalatal-digital syndrome genetics

A

-XL mutation of FLNA gene
+gene mutations can also cause frontometaphyseal dysplasia, FG syndrome type II, cardiac valvular dysplasia, periventricular heterotopia, etc
-two types with Type II being more severe
-disorder of skeletal development

48
Q

otopalatal-digital syndrome phenotype

A
  • hearing loss-CHL, SNHL or a mix and ossicular abnormalities
  • mild ID, frontal and occipital prominence, mid face hypoplasia
  • hypertelorism with down slanting PFs
  • small nose
  • small mouth with soft palate clefts and absent or impacted teeth
  • skeletal: small trunk with pectus excavatum and small iliac crest, limited elbow extension, tibial bowing
  • short broad distal phalanges, widely spaced toes, short 3-5 metacarpals (“tree frog” digits)
49
Q

L-1 or XL hydrocephalus genetics

A
  • incidence of 1 in 25000-1 in 60000 males

- mutation of L1CAM gene on X chromosome

50
Q

L1 phenotype

A

-hydrocephalus due to aqueductal stenosis
+leads to macrocephaly, ID, spasticity
-can see agenesis of the corpus callous
-adduction/inward bending of thumb

51
Q

hypohidrotic ED phenotype

A

-hypo or anhidrosis related to failed sweat gland formation
+can lead to hyperthermia
-hypotrichosis of scalp, eyebrows and eyelashes gives sparse, fine, hypochromic hair
-conical teeth or oligodontia
-skin anomalies: thin, hypo-pigmented skin, papular changes on face, periorbital hyper pigmentation and wrinkling

52
Q

hypohidrotic ED genetics

A

-incidence of 1 in 20000 for XL mutations in EDA1
+90% female carriers can have detectable problems by sweat test or dental exam
-can also have AR and AD mutations of EDAR or EDARADD, plus others

53
Q

orofacial digital syndrome genetics

A

-incidence between 1 in 50000-1 in 250000
-13+ identified types, some not well described and genetics unclear, but all with overlapping features
+type I caused by XL mutation of OFD1 gene
+most others AR

54
Q

OFD phenotype

A

-oral: tongue clefting, lobulated tongue, hamartomas of the tongue, hyper plastic frenulum
+absent, extra or dysplastic teeth
+palatal cleft
-poly, syn, brachy, and clinodactly can all occur in fingers and toes
-can see dandy walker malformation, genesis of the corpus callosum, ID
-hypertelorism
*PCKD in type I

55
Q

Alport syndrome genetics

A
  • incidence of 1 in 50000
  • most commonly due to XL mutation of COL4A5, but AR and AD mutations in COL4A3 and COL4A4 are also causative
  • all collagen 4 genes associated with basement membrane development in renal glomeruli
56
Q

Alport phenotype

A

-hematuria and proteinuria that leads to renal scarring and renal failure
+female carriers of XL and AR mutations may have microscopic hematuria on urinalysis
-hearing loss due to abnormal inner ear function
-misshapen lenses affect vision
+anterior lenticonus is a pathognomonic

57
Q

Fanconi anemia genetics

A

-incidence of 1 in 160000
+higher in AJ, black South Africans and Spanish Roma descent
-15 known genes, mostly AR, though one XL known
+80% due to mutation of FANCA, FANCC or FANCG
-mutations effect DNA repair pathway

58
Q

FA phenotype

A

-progressive bone marrow failure with pancytopenia (leukopenia, thrombocytopenia)
-short stature
-microcephaly, ID (25%)
-radial ray defect with thumb hypo or aplasia or supernumerary thumb
-hypoplastic or malformed kidneys, double ureter
+sometimes see additional GU or myelodysplastic syndrome
-increased risk for malignancy; namely hematologic (AML), also solid tumors (brain, oral cavity)

59
Q

cri du chat genetics

A
  • 5p deletion-del 5(14p;15p)

- incidence of 1 in 45000-1 in 50000

60
Q

WHS genetics

A

-4p del-del 4(p16)
+severity relates to size of deletion
-etiologies: generally de novo or caused in half cases by unbalanced translocation
-1 in 45000-1 in 50000

61
Q

cri-du-chat phenotype

A

-mewing cry (laryngealmalasia, stridor)
-microcephaly and micrognathia
+severe ID (IQ<20)
-moon-like round facies, hypertelorism, epicentral folds, low-set ears
-CHDs

62
Q

WHS phenotype

A

-pre and postnatal GR, microcephaly
+ID (IQ<20), seizures, hypotonia, DD, LD
-“Greek warrior helmet” facies and scalp closure defects
+dysplastic ears with pits and tags
+clefting, short philtrum, downturned mouth corners
+coloboma, hypertelorism, high arched brows
+broad nasal root that continues to forehead, short nose
-cardiac (50%), renal and skeletal defects
-genital abnormalities
-dry, mottled skin
-dental problems

63
Q

22q management

A

-endocrine and immunological management remain constant over time
+may require GR supplementation
+hypocalcemia can be intermittent and cause seizures that affect cognitive function-MUST monitor in times of stress (ex: during surgeries)
-cardiac management tends to be most prevalent early in life and in mid-childhood when a valve might need replaced or additional surgical repair is needed
-speech and language management initiate near school age
+feeding and palatal issues come up earlier though
-psychiatric and behavioral management increase with age
*most lifespan not impacted and if survive newborn period, people survive for their lifetime

64
Q

22q diagnosis

A

-can be diagnosed by FISH, but MLPA and MCA preferred because they size mutation
+LCRA-D usually whats found
+nested mutations missed by FISH and can be familial
-NBS identifies low T-cell, trying to pick up SCID-incidental
-NIPS can identify prenatally & polyhydramnios related to nasal regurgitation can be a sign, sometimes IUGR
-cardiac defects if bad enough diagnosed prenatally or in severe AEs

65
Q

22q psychiatric issues

A

-LD in 99% individuals
-psychiatric disorders
+25% kids-ADHD, OCD, ASD, anxiety
+60% adults-schizophrenia (1/4), depression, anxiety, OCD

66
Q

22q cardiac defects

A

-affects 40-50% of patients
1. ToF
2. VSDs
3. conotruncal defects
+R-sided aortic arch
+aberrant L-subclavian artery
-also truncus, vascular rings, ASDs

67
Q

22q immunodeficiency signs

A
  • impaired T-cell function with chronic infection
  • humoral defects lead to poor vaccine response
  • IgA deficiency
  • autoimmune disease (juvenile rheumatoid arthritis (JRT), idiopathic thrombocytopenia (ITP), hemolytic anemia, vitiligo, thyroid disease)
68
Q

rare 22q associations requiring intervention

A

-laryngeal web, esophageal atresia, TE fistula
-choanal atresia and other nasal anomalies or obstructive glossoptosis
-SNHL, CHL, ear formation anomalies
-cervical and thoracic spine anomalies, severe scoliosis with rapid onset
+some interventions can preclude use of MRI on individuals in future
-neurological and brain anomalies or craniosynostosis
-malignancies
-polydactly, radial ray defect, club foot
-eye anomalies

69
Q

Bernard-Souilier syndrome

A

-ex of 22q11 and AR dz co-occurence
+mutation of GP1BB
-causes thrombocytopenia, megakaryocytic

70
Q

CEDNIK syndrome

A

-ex of 22q11 and AR dz co-occurrence
+mutation of SNAP29
-seen with polymicrogyria, neuropathy, ichthyosis, keratodermata

71
Q

branchio-oto-renal syndrome (BOR)

A

-AD mutations of EYA1, SIX5, SIX1
+caused by 2nd branchial arch defects
-features include branchial cleft sinuses or cysts, pre-auricular pits or tags with malformed ears and hearing loss, and renal malformations

72
Q

Meckel-Gruber

A

-AR lethal condition
+incidence of about 1 in 14K-130K
+8 different known cilia genes affected
-diagnosable prenatally by targeted ultrasound or genetics
-no amniotic fluid production
-characteristic encephalocele, polydactyly, and enlarged polycystic kidneys
-can also see cardiac, skeletal and GU anomalies

73
Q

Kartagener

A

-AR DNAI1 and DNAH5 most common, but other genes known and many unknown causes
+causes defects of cilia and flagella
-incidence of 1 in 16K
-causes chronic respiratory and ear infections and infertility
-can also get situs inversus and heterotaxy

74
Q

Diastrophic dysplasia

A

-AR mutation of SLC26A2
-phenotype:
+proportionate short stature due to shortened limbs
+joint contractures, club foot, scoliosis, hitchhikers thumb
+osteoarthritis
+cleft palate and ear anomalies (cauliflower ear)
-management:
-therapies and surgeries for joint pain, scoliosis
-cystic ear swelling management

75
Q

FA management

A

autologous or donor hematopoietic stem cell transplant

76
Q

Pendred syndrome

A

-AR mutation of SLC26A4
-affected individuals develop SNHL and thyroid goiter
+enlarged vestibular aqueduct (EVA) is a key feature

77
Q

Holt-Oram syndrome

A

-AD mutation of TBX5
-presentation includes:
+hand anomalies-carpal abnormalities, missing thumb or thumb that looks like a finger
+arm bone deformities-deformed or absent distal arm bones
+clavicle or scapular anomalies
+CHDs-ASDs, VSDs, conduction defects

78
Q

WAGR

A
  • wilms tumor, aniridia, GU anomalies, ID
  • can sometimes see psychiatric implications, obesity, pancreatitis and kidney failure
  • caused by 11p mutations
79
Q

VACTERL association

A 
-multifactorial cluster of symptoms
\+some features may be subtle and not identifiable until later
-vertebral anomalies
-anal atresia or GU anomalies
-cardiac defects
-TE fistula
-missing or misshapen kidneys
-limb anomalies
80
Q

Optiz/GBBB

A

-XL MID1 mutations or AD SPECP1L mutations
-causes ocular hypertelorism, ID, DD, midline defects
+laryngeal cleft
+genital anomalies in males
+CHDs, imperforate anus and corpus callous anomalies are rarer features

81
Q

EB

A
  • AD keratin 5 or 14 mutations
  • blistering, skin fragility, hyperkeratosis
  • splitting within/above the basal layer
82
Q

lamellar ichthyosis

A
  • AR mutations in TGM1, ALOXE3, ALOX12B, ABCA12
  • causes 90% kids to be born as collodion babies
  • CIE over time becomes a thick brown, plaque-like scale
  • most severe can have have snowflake sign prenatally with thick hardened scales
83
Q

albinism

A

-AR mutations of TYR, OCA2, OCA3, OCA4, HPS
+reduction of melanin synthesis
-white hair, white skin, blue irises

84
Q

McCune Albright

A

-GNAS mutations
-polyostotic fibrous tissue of bones
+can lead to fractures, deformity and unevenness
-coast of Maine CALMs
-endocrine anomalies such as thyroid goiters or hyperthyroidism
+can sometimes see Cushing disease before age 2y
-acromegaly and weight gain possible
-coarse facial features

85
Q

Sturge-Weber Syndrome

A
  • due to somatic mosaicism of GNAQ
  • see port-wine birthmark, facial angiomas, nevus flameus due to blood vessel dilation
  • formation of leptomeningeal angioma affects blood flow to brain and can lead to atrophy and calcifications, or even stroke-like episodes
  • enlarged globe eye and the early development of glaucoma within 1y
86
Q

Usher syndrome

A

-AR mutations cause 3 types
+Type 1: MY07A, CDH23
+Type 2: USH2
+Type 3: CLRN1
-SNHL due to inner ear anomalies, starts at birth
+can also see balance problems related to vestibular anomalies
-vision worsens over time related to retinitis pigmentosa, sometimes leads to tunnel vision and cataracts
-50% of deaf-blind individuals have this

87
Q

Connexin and non-syndromic DFNB1 mutations

A

-congenital, non-progressive, non-syndromic SNHL
-genetics
+B-AR
+A-AD
+no letter-XL
-98% kids with 2 GJB2/Conn26 muts
+carrier frequency 1 in 22
+2% double hets for GJB2/GJB6 (but GJB6-connexin 30 is rare)

88
Q

Alagille syndrome

A

-AD JAG1 deletions or point mutations and NOTCH2 mutations
+sometimes inherited from mildly affected parent
-cardiac defects, esp PA and branching stenosis
-jaundice due to neonatal choleastasis caused by paucity of the intrahepatic bile ducts
-butterfly vertebral anomalies
-posterior embryotoxon-corneal anomaly that appears as a border thickening on slit-lamp
-renal anomalies
-dysmorphic features-broad forehead, deep set eyes, pointed chin

89
Q

Kallman syndrome

A
  • XLR mutations of ANOS1, plus other AR versions
  • anosmia and delayed puberty
  • can also sometimes have CL+or-palate
90
Q

Premature aging syndromes

A

-Hutchinson-Gilford Progeria
+AD mutations of LMNA, can also have heart problems
-Cockayne syndrome
+AR mutations of ERCC8, have ID
-Werner syndrome
+AR mutations of WNR, have normal development until puberty

91
Q

Townes-Brockes

A 
-AD mutations of SALL1
\+can have variable expressivity
-imperforate or stenotic anus
-hand abnormalities: polydactly, broad great thumbs, triphalyngeal dysplasia
-ear abnormalities and hearing loss
-cardiac anomalies and renal defects
92
Q

Aicardi syndrome

A

-XLD mutations of Xp22
+male lethal
-seizures, agenesis of the corpus callous
-little or no speech
-retinal lacunae (punches in retina where brain shows through)
-vertebral defects, rib anomalies and polydactyly

93
Q

LEOPARD or NSML

A
  • AD PTPN11 mutations most common
  • milder noonan facies and loose thickened nuchal skin
  • skin: many dispersed flat lentigines/macules often don’t appear until 4-5y, CALMs earlier
  • ECG anomalies and pulmonic stenosis
  • genitalia anomalies including of ovaries in females
  • growth retardation
  • SNHL deafness in ~20% cases
94
Q

NSLAH

A

-SHOC2+other rasgenes
-classic noonan facies and features
+heart defects more likely to include MV dysplasia too though
-easily pluckable, wispy, sparse hair
-darkly pigmented skin with eczema

95
Q

CFC

A
  • mostly BRAF mutations + other ras genes, almost all de novo
  • macrocephaly with high forehead, ptosis, epicanthal folds, hypertelorism with down slanting palpebral fissures
  • low posteriorly rotated ears
  • deep philtrum, cupid’s bow lip, high palate and retrognathia
  • cardiac: HCM most common, but also PVS, ASD/VSD, MV/TVD, BAV
  • sparse curly, wooly/brittle hair
  • dry skin, severe eczema, hyperkeratosis, flat broad nails and CALMs
96
Q

Costello

A
  • almost all HRAS (p.Gly12Ser) de novo
  • FTT, short stature
  • ID, friendly sociable personality, relative macrocephaly sometimes with postnatal Chiari I malformation development
  • cardiac: mostly HCM, some PVS, SVT arrhythmia or multifocal/ectopic atrial tachycardia
  • deep palmar and plantar creases with severely dry skin
  • premature aging
  • risk for malignant solid tumors (rhabdomyos and neuroblastoma, transitional cell bladder ca)
97
Q

hemophilia testing

A
  • prolonged PTT, normal PT
  • should see correction with addition of normal plasma in mixing study
  • normal PFA-100 or platelet aggregation
  • normal VWF factor, abnormal FVIII or FIX activity
98
Q

hemophilia A genetics

A
  • most often due to a FVIII intronic inversion
  • other missense or nonsense muts next common (less severe cases)
  • followed by small, then large dels
99
Q

hemophilia B genetics

A
  • absence of dominant mutations
  • gross gene alterations most common (2500+ described), then frameshift or splicing and nonsense or missense
  • better gene therapy target because gene is smaller
100
Q

hemophilia phenotype

A

-A and B clinically indistinguishable
-bleeding at circumcision can be first sign
-easy bruising leads to hematoma, spontaneous truncal bruising and venipuncture (can see central clearing)
+easily confused with abuse
-subdural and intramuscular hemorrhaging and hemoarthrosis
-tx includes factor concentrate administration as early as possible, but risk of inhibition buildup, A has targeted drug therapy

101
Q

VWF

A
  • name sake gene mutated
  • normal platelets and PT, possible prolonged PTT, low antigen, possible ristocetin cofactor issues
  • bruising, mucocutaneous bleeds, prolonged bleeding after trauma, menorrhagia
102
Q

hereditary hemochromatosis

A

-AR mutations of HFE
-Inappropriately high iron absorption by the GI mucosa leads to excessive iron storage in the liver, skin, pancreas, heart, joints, testes
-first symptom often fatigue
+abdominal pain, weakness, lethargy, weight loss to follow
-treat with phlebotomy

103
Q

Denys Drash and Frasier syndromes

A

-related to WT1 mutations
-causes glomerulosclerosis of the kidneys and ambiguous genitalia in 46, XY karyotypic males
+females tend to only have kidney features
-increased risk for Wilm’s tumor

104
Q

SOX9 mutations

A

-AD mutations, usually de novo
-isolated Pierre-Robin
-campomelic dysplasia
+often perinatal lethal due to skeletal anomalies, especially bowed legs, rib anomalies, dislocations and long bone problems; see ambiguous genitalia
-46, XX testicular DSD
-Swyer syndrome (DSD with feminization)

105
Q

Androgen Insensitivity syndrome

A

-XLR mutations of AR
+body produces androgens, yet cannot respond to them due to failed receptor formation
-46, XY males with female external genitalia and ectopic internal male genitalia
-require removal of undescended testes to avoid cancer risk and HRT
-infertility

106
Q

5-alpha-reductase

A

-AR mutations of SRD5A2
+causes failed conversion of testosterone to DHT
-46, XY karyotypic males born with female or ambiguous genitalia
-at puberty male sex hormones increase so may see some further virilization, but still less hair production and infertility

ABGC Boards Exam (22 decks)

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