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
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
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
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
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
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
7
Q
Smith-Magenis genetics
A
17p11.2 deletion
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
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
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
11
Q
McDermid-Phelan Syndrome genetics
A
- 22q13 deletion sydrome
- deletion of SHANK3 gene
- detected by FISH
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
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
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
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
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
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
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
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
20
Q
P450sec
A
mitochondrial cholesterol cleavage enzyme
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
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
23
Q
prenatal microarray limitations
A
cannot find balanced rearrangements and triploidy by SNP
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
25
Rubinstein-Taybi Genetics
-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
26
Rubinstein-Taybi phenotype
-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
27
Treacher Collins genetics
-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
28
Treacher Collins phenotype
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
29
Cornelia de Lange genetics
- incidence of 1 in 50000
- mostly due to AD mutation of NIPBL; rarer gene mutations inherited in AD and XL (SMC1A) manner
- usually sporadic
30
Cornelia de Lange phenotype
- 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
31
Stickler syndrome genetics
-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
32
Stickler syndrome phenotype
-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
33
Kabuki syndrome genetics
-incidence of ~1 in 30000-1 in 70000
-caused by AD mutation of MLL2
+first found by WES
34
Kabuki phenotype
- 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
35
NF1 genetics
- incidence 1 in 3000
| - AD mutation of NF1 gene
36
NF1 features
- 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
37
NF1 diagnostic criteria
-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
38
Noonan syndrome genetics
-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
39
Noonan phenotype
-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
40
CHARGE syndrome genetics
- incidence of 1 in 10000
| - AD mutation of CDH7
41
CHARGE defects
-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
42
CHARGE facies
-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
43
SLOS genetics
-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
SLOS phenotype
- 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
Oculocutaneous Albinism genetics
- 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
oculocutaneous albinism phenotype
- 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
otopalatal-digital syndrome genetics
-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
otopalatal-digital syndrome phenotype
- 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
L-1 or XL hydrocephalus genetics
- incidence of 1 in 25000-1 in 60000 males
| - mutation of L1CAM gene on X chromosome
50
L1 phenotype
-hydrocephalus due to aqueductal stenosis
+leads to macrocephaly, ID, spasticity
-can see agenesis of the corpus callous
-adduction/inward bending of thumb
51
hypohidrotic ED phenotype
-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
hypohidrotic ED genetics
-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
orofacial digital syndrome genetics
-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
OFD phenotype
-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
Alport syndrome genetics
- 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
Alport phenotype
-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
Fanconi anemia genetics
-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
FA phenotype
-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
cri du chat genetics
- 5p deletion-del 5(14p;15p)
| - incidence of 1 in 45000-1 in 50000
60
WHS genetics
-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
cri-du-chat phenotype
-mewing cry (laryngealmalasia, stridor)
-microcephaly and micrognathia
+severe ID (IQ<20)
-moon-like round facies, hypertelorism, epicentral folds, low-set ears
-CHDs
62
WHS phenotype
-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
22q management
-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
22q diagnosis
-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
22q psychiatric issues
-LD in 99% individuals
-psychiatric disorders
+25% kids-ADHD, OCD, ASD, anxiety
+60% adults-schizophrenia (1/4), depression, anxiety, OCD
66
22q cardiac defects
-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
22q immunodeficiency signs
- 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
rare 22q associations requiring intervention
-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
Bernard-Souilier syndrome
-ex of 22q11 and AR dz co-occurence
+mutation of GP1BB
-causes thrombocytopenia, megakaryocytic
70
CEDNIK syndrome
-ex of 22q11 and AR dz co-occurrence
+mutation of SNAP29
-seen with polymicrogyria, neuropathy, ichthyosis, keratodermata
71
branchio-oto-renal syndrome (BOR)
-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
Meckel-Gruber
-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
Kartagener
-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
Diastrophic dysplasia
-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
FA management
autologous or donor hematopoietic stem cell transplant
76
Pendred syndrome
-AR mutation of SLC26A4
-affected individuals develop SNHL and thyroid goiter
+enlarged vestibular aqueduct (EVA) is a key feature
77
Holt-Oram syndrome
-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
WAGR
- wilms tumor, aniridia, GU anomalies, ID
- can sometimes see psychiatric implications, obesity, pancreatitis and kidney failure
- caused by 11p mutations
79
VACTERL association
```
-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
Optiz/GBBB
-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
EB
- AD keratin 5 or 14 mutations
- blistering, skin fragility, hyperkeratosis
- splitting within/above the basal layer
82
lamellar ichthyosis
- 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
albinism
-AR mutations of TYR, OCA2, OCA3, OCA4, HPS
+reduction of melanin synthesis
-white hair, white skin, blue irises
84
McCune Albright
-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
Sturge-Weber Syndrome
- 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
Usher syndrome
-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
Connexin and non-syndromic DFNB1 mutations
-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
Alagille syndrome
-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
Kallman syndrome
- XLR mutations of ANOS1, plus other AR versions
- anosmia and delayed puberty
- can also sometimes have CL+or-palate
90
Premature aging syndromes
-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
Townes-Brockes
```
-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
Aicardi syndrome
-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
LEOPARD or NSML
- 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
NSLAH
-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
CFC
- 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
Costello
- 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
hemophilia testing
- 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
hemophilia A genetics
- 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
hemophilia B genetics
- 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
hemophilia phenotype
-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
VWF
- 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
hereditary hemochromatosis
-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
Denys Drash and Frasier syndromes
-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
SOX9 mutations
-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
Androgen Insensitivity syndrome
-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
5-alpha-reductase
-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
