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154 Cards in this Set
- Front
- Back
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Tuberous Sclerosis
TSC1, TSC2 genes |
AD, 2/3 de novo
tumor supressor loss of function prenatal - childhood onset skin - hypomelanotic macules, facial angiofibromas, shagreen patch, ungula fibroma CNS - astrocytoma, cortical tubers renal - angiomyolipomas heart - rhabdomyoma eye - retinal hamartomas and achromic patches |
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Von Hippel Lindau
VHL (3p25) |
AD, 20% de novo
null, truncated, missense mtns tumor suppressor LoF childhood onset renal cell ca (40%) - greatest source mortality and morbidity hemangioblastomas (cerebellum, retina, spinal cord) pheo (ass'd with missense mutations, not with null mutations) |
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Hereditary paraganglioma-pheochromoctyoma
SDHD, SDHC, SDHB |
new syndrome!
AD, de novo, parent of origin effects missense, deletions paragangliomas pheochromocytomas tests: epinephrine, norepinephrine, dopamine |
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Bloom syndrome
BLM |
AR
AJ founder mtn - 2281del6ins7 - 1/100 chromosomal instability, hyper-recombination pre, postnatal growth retardation microcephaly skin - photosensitive, butterfly rash ca predisposition - multiple, esp colon normal IQ, some learning disab? tx - BMT, avoid UV, x-ray |
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Ataxia-telangectasia
ATM (11q22.3) |
AR/incomplete dominant (hets have breast and lung ca risk)
Amish founder mtn mostly null mtns onset - childhood ataxia - cerebellar, progressive, 1-4yo onset ocular apraxia after 3yo (difficulty moving eyes side-to-side, may turn head instead) conjunctival telangectasia (also - vitiligo, premature greying, cafe-au-lait) ca predisposition - mostly blood ca tests: serum AFP, radiation sensitivity, 7;14 translocation, MRI - dystrophic cerebellum tx - avoid radiation |
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Fanconi Anemia
13 complementation groups |
FancA - 65% of cases
FancC - AJ mtn - IVS4+4A>T (1/89 carrier frequencey) FancD1 - BRCA2! AR, except FancB - XLR childhood onset congenital anomalies - radial ray, short stature, renal anomalies, skin hypo/hyperpigmentation Bone marrow failure (90%) Ca - AML, other blood ca, head and neck, GU, skin, GI tests: increased sensitivity (chromosome breakage) to crosslinking agents tx - avoid x-rays, BMT or stem cell transplant |
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Xeroderma pigmentosum
XPA (25%), XPC (25%), ERCC2 (15%), POLH (21%) |
AR
defect in nucleotide excision repair of UV-induced DNA lesions (thymine dimers) extreme sun sensitivity - sunburn, erythema, freckling, photophobia ca - 1000x risk of skin and eye cancers; internal neoplasms neuro (30%) - progressive degeneration - microcephaly, SNHL, cognitive impairment tests - cellular UV hypersensitivity |
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Cowden (PTEN hamartoma tumor syndrome)
PTEN (10q23) (85% yield) |
AD, de novo
tumor suppressor LoF allelic - bannayan-riley-ruvalcaba, proteus macrocephaly trichilemmomas*, papilomatous papules ca - breast (25-50%), thyroid (usually follicular*, 10%), endometrial colon - hamartomatous polyps (40-50%) |
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Peutz-Jeghers syndrome
STK11 (19p13) (aka LKB1) (50% of cases) |
AD, 20-50% de novo
40% have deletions (higher than other tumor supressor syndromes) distinct polyps - "branching tree," through GI tract, esp. small bowl pigmented spots on lips, buccal mucosa (dark blue to brown) ca - breast (54%), colon (39%), pancreas (36%), stomach (29%), uterus, testes, |
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Lynch (aka HNPCC)
MSH2 and MLH1 (80% of cases), MSH6 (7-10%), PMS1, PMS2 (both rare) |
AD
missense, deletions (MLH1, MSH2) ca - colon (80%), endometrium (20-60%), stomach (11-19%), ovary (9-12%) dx'c criteria - amsterdam (3 fam members, 2 generations, 1 ca <50yo) tests - MSI in 90% of lynch tumors (but also 15% of sporadic), IHC identifies which protein/gene better prognosis than other CRC 2/3 of tumors occur in proximal colon |
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familial adenomatous polyposis (FAP)
APC 5q21-22 |
AD, 20-30% de novo
tumor suppressor LoF (gatekeeper) most mtn truncating (LoF); 10% deletions (so sequencing isn't enough) dx'c criteria: >100 polyps or 10-100 and +FHx CRC ca - 100% penetrant, mostly affect recto-sigmoid region rare other ca - upper GI (5-10%), pancreatic (2%), papillary thyroid (2%), hepatoblastoma (<2%), brain (medulloblastoma) rare benign - desmoid tumors of abndomen (painful, recur), osteomas of jaw and skull, epidermoid cysts, CHRPE 100% penetrant tx - colectomy, upper GI screening |
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Gardner syndrome
APC 5q21-22 |
AD
FAP + osteomas soft tissue tumors desmoid tumors of abdominal wall epidermoid cysts |
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Turcot syndrome
APC 5q21-22, Lynch genes |
FAP +
CNS tumors - medulloblastomas |
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aFAP
APC 5q21-22, especially 3' and 5' |
FAP -
fewer polyps (avg 35 vs >100) older onset |
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MYH associated polyposis (MAP)
MYH |
AR (vs. related AD syndrome)
Y165C, G382D - 85% of northern european mutations polyposis, but few polyps (<100) later onset (20-50yo) hets have increased colon ca risk |
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BRCA1
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17q21
AJ mtn - 185delAG (1%), 5382insC (0.4%) Dutch - 3 large del 5-10% (?) del/dup/rearrangement ca - breast (40-87 ), ovarian (16-63), prostate (25) 90% of hereditary ovarian cancers are due to BRCA1 mutations breast ca path - triple negative |
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BRCA2
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13q12.3
ovarian ca cluster (exon 11) AJ mtn - 617delT (1.2%) iceland mtn - 999del5 5-10% (?) del/dup/rearrangement path - nothing unique (?) ca - breast (28-84), ovarian (27), male breast (6-14), prosate (20), melanoma, pancreas, other rare ca |
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NF1
NF1 (17q11.2) |
AD, 50% de novo (v. high mtn rate)
80% of mtn - truncating tumor suppressor LoF (gatekeeper) onset - prenatal to childhood dx'c criteria: >=2 of 6+ CAL, 2+ neurofibromas, 1 plexiform neurofibroma, axilary or inguinal freckling, optic glioma, 2+ lisch nodules, osseous phenotype, affected FDR up to 50% have MR or LD optic glioma (50%) (benign) 100% penetrant but highly variable |
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Li-Fraumeni
p53 (17p13) (70% of cases) |
AD, de novo (?%)
tumor suppressor LoF (DNA repair and cell cycle regulation) dx'c criteria: proband with sarcoma <45yo & FDR w ca <45yo & FDR or SDR w ca <45 or sarcoma at any age ca (50% by 35yo, 90% lifetime for women, 70% lifetime for men) - SBLA - sarcoma, breast (v. early onset, avg age dx 32yo), brain, leukemia, adrenocortical ca in childhood |
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retinoblastoma
RB1 (13q14) |
AD, 80% de novo (?)
allelic het - missense, deltions, insertions, hypermethylation of promoter 40% of all cases are due to mutation hereditary cases - more likely to be bilateral (but not always), younger dx (<1y vs. 1-2y) risk for other ca later in life (70%) - sarcomas, radiation therapy increases ca risk incomplete penetrance (esp. if residual activity) |
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Men2a
RET (10q11.2) |
AD, <5% de novo
exon 10 & 11 (95%) - allelic - hirschprung (LoF) GoF proto-oncogene ca - medullary thyroid (60%) in early *adulthood* (vs. 2B) -pheochromocytoma (50%) -*parathyroid adenoma/hyperplasia* (20%) (vs. 2B) represents 20-50% of medullary thyroid cancer screening: prophylactic thyroidectomy by 6yo, pheo and PTH screening annually after 6yo |
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Men2b
RET (10q11.2) |
AD, *50% de novo
exon 15 (95%) - one mtn v. common, so low genetic heterogeneity allelic - hirschprung (LoF) GoF proto-oncogene ca - medullary thyroid (60%) in *childhood* (bilateral, multicentric) -pheochromocytoma *muccosal neuromas of tongue and lips *marfanoid habitus, big lips *ganglioneuromas of GI tract *NO parathyroid hyperplasia (vs. 2A) accounts for <2% of MTC tx/screening: prophylactic thyroidetomy by 1yo, pheo screening annually after 3yo |
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congenital adrenal hyperplasia
12-hydroxylase deficiency CYP1A2 (6p21.3) |
AR
1% of mutation are de novo missense mutations, common dels most common form of this disorder 1/300 in Yupik Eskimos of Alaska ~1/50 carrier rate in US defect in biosynth of glucocorticoids and mineralcorticoids, leads to over production of androgens classic - null alleles, severe, 3/4 salt wasting nonclassic - one not null allele sex-dependent pheno females - most comon cause of pseudohermaph. males - early virilization salt wasting -> neonatal death if not treated tests: on NBS panels |
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hereditary hemochromatosis
HFE (6p21.3) |
AR
Cys282Tyr/Cys282Tyr (90%), Cys282Tyr/His63Asp (10%) v. high carrier rate in whites (38%) His63Asp - lower penetrance incomplete penetrance, variable expressivity, sex-dependent penetrance GI mucosa absorbs too much iron bronzing of skin, diabetes, cirrhosis, cardiomyopathy, fatigue (most frequent complaint) tests: ferritin (want <300ng/ml), liver function |
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Factor V Leiden thrombophilia
F5 |
AD, incomplete dominant
Arg506Gln, GoF b/c resistant to deactivation by protein C incomplete penetrance, genetic & environmental modifiers 2-15% of Europeans |
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Genetic factors in venous thrombosis
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Factor V Leiden (12-14%)
Prothrombin mutations (6-18%) Antithrombin III or protein C or S (5-15%) |
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Hemophilia B
F9 (Xq27.1-q27.2) |
XLR, but 10% of female carriers affected
hemarthrosis, intracranial bleed deep muscle hematomas excessive bruising severity inversely correlates with activity "Leyden" - variant - mtn in promoter - severe in childhood but resolves tets: prolonged PTT (pro-thrombin time) tx: replace missing factor |
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Hemophilia A
F8 (Xq28) |
XLR, some carriers manifest
allelic hetero - deletions, insertions, inversion, point common mtn - (50%) intron 22 inversion del of C term due to aberrant homologus recomb - test with PCR or southern hemarthrosis, intracranial bleed deep muscle hematomas prolonged, renewed bleeding after trauma excessive bruising severity inversely correlates with activity (<30% is lower limit of nml) tx: IV replacement of missing factor |
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Beta-Thalassemia
HBB (11p15.5) |
AR
genetic heterogeneity (15 mtn - 90%) trait - het, asymptomatic, mild anemia major - homoz, hemolytic anemia postnatally tests (carriers) - reduced MCV, Hb electrophoresis - elevated Hb A2, Hb F carrier rates: mediteran'n 1/25, SE asian 1/30 tx - transfusion |
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Alpha-Thalassemia
HBA1, HBA2 (16pter-p13.3) |
AR
90% deletions, 10% point mutations HB Bart: --/--, hydrops fetalis, perinatal death (SE asia only) HB H: --/a-, moderate anemia, etc. trait: --/aa or -a/-a, low MCV, low MCH, mild anemia carrier: -a/aa - no phenotype tets (carriers): MCV, MCH - both reduced; HB eletrophoresis - normal tx: Hb H - transfusion during hemolytic crisis carrier rates: SE asian, asian 1/20 cis; medit'n, african-am'n, carribean, west african 1/30 trans |
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Beckwith Wiedeman syndrome
11p15 |
AD (15% familial, 85% sporadic)
DMR2 (KCNQOT1) loss of meth'n (50%) paternal UPD 11p15 (10-20%) DMR1 (H19) gain of meth'n (2-7%) CDKN1C mtns (40% of familial, 5010% of sporadic) cytogenetic abnl @ 11p15 (<1%) 11p15 - growth factors, tumor suppressors 9x increase in risk with ART (also for Angelman syn but not for PWS) key features - omphalocele, macroglossia, macrosomia, embryonal tumor (wilms, hepatoblastoma), neonatal hypoglycemia, ear creases/pits |
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Pallister-Killian syndrome
tetrasomy 12p, mosaic isochromosome 12p 47,XY i(12)(p10) |
tissue-limited mosaicism - NOT in blood, only in fibroblasts (on karyotype. recently detected by aCGH on interphase cells from blood sample -- culturing causes selection bias?)
profound MR seizures hypo- or hyper-pigmented streaks dysmorph: prominent forehead, sparse anterior scalp hair (localized alopecia), flat occiput, short nose, flat nasal bridge, short neck, coarse facies congenital diaphragmatic hernia |
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Gaucher
GBA (1q21) |
AR
AJ mtn N370S 1/18 carrier (type 1) LSD distinct cells named for the disease (macrophages filled with glucosylcerbroside) hepatosplenomegaly nose bleeds, reduced platelets (easy bruising, slow clotting) bone pain ("crises"), bone deterioration, bone infarcts type 1: most common, bone, organ, blood, lung, no CNS involvement type 2: + progressive CNS disesase type 3: + slower progressive CNS disease also perinatal-lethal and cardiovascular type - clinically dx'd tests: enzyme activity tx: ERT, substrate reduction, BMT for type 3 |
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CHARGE
CHD7 (8q12.1) (60%) |
AD (nearly all de novo, germline mosaicism reported, empiric 1-2% recurrence risk)
coloboma (80-90%) heart defect choanal atresia (50-60%) growth and mental retardation GU malformations characteristic ear (90-100%) cranial nerve anomalies (SNHL, swallowing, palsy) (70-90%) |
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branciootorenal syndrome (BOR)
EYA1 (8q13.3)(40%), SIX1 (14q23)(rare) |
AD
point mtn, dup/del (10%) ear malformations - outer, middle, inner deafness - conductive, SNHL, mixed preauricular pits, tags banchial fistulae, cysts facial asymmetry renal malformations - hypoplasia, agenesis |
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Bardet-Biedl syndrome
12+ genes, M390R in BBS1 (18-32%), 91fsX95 in BBS10 (10%), BBS (8%), BBS6 (6%) |
AR, "triallelic" inheritance
cilia-opathy truncal obesity, normal prenatal growth cone-rod dystrophy -- blindness postaxial polydactyly hypogonadism, complex GU malformations renal dysfunction |
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Antley-Bixler syndrome
(aka POR deficiency?) POR (7q11.2) |
AR
highly variable range of allelic disorders of steroidogenesis ambiguous genitalia in both sexes maternal virilization during pregnancy w affected fetus craniosynostosis, frontal bossing, midface hypoplasia, hydrocephalus choanal stenosis or atresia stenotic auditory canals neonatal fractures, bowing of long bones, joint contracture renal malforamtions tests: NBS, low uE3 on mat'l serum screen |
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Aarskog syndrome
FGD1 (Xp11.2) (7-20%) |
XLR (some AR, AD reported)
shawl scrotum cryptorchidism hypertelorism brachydactyly, cervical verterbral abnormalities, pectus excavatum single simian crease short stature MR (30%) hyperextensibility |
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Leber hereditary optic neuropathy (LHON)
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1178A>G in ND4 subunit of complex 1 of eletron transport chain
largely homoplasic (unlike most mtDNA diseaes) maternal inheritance rapid onset blindness - young adult sex bias - penetrance 50% in males vs. 10% in females (so can appear x-linked) may also have dystonia |
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NARP
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ATPase subunit 6 gene - point mtns
heteroplamic maternal inheritance neuropathy, ataxia, RP, dev'l delay, MR, lactic acidemia |
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Leigh syndrome (aka subacute necrotizing encephalopathy)
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ATPase subunit 6 gene - point mtns
heteroplasmic; diverse etiologies - can be mtDNA or nuclear (AR) maternal inheritance early-onset progressive neurodeg'n - hypotonia, dev'l delay, optic atrophy, respiratory abnormalities cranial nerve abnormalities, respiratory dysfunction, ataxia, hyperintense signals on T2-weighed images of head onset - infancy to early childhood progressive, lethal |
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MERRF
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tRNAlys point mtns
8344A>G - common mtn heteroplasmic maternal inheritance onset late childhood to adulthood progressive myoclonic epilepsy with ragged-red muscle fibers, myopathy, ataxia, SNHL, dementia some pt have symmetrical lipomatosis (large subcutaneous fat masses, usually around neck) |
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MELAS
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tRNAleu(UUR) point mtn
most commonly 3243A>G heteroplasmic maternal inheritance myopathy, mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes variable expressivity - may present as only diabetes and deafness |
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deafness - mtDNA
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progressive SNHL, often induced by aminoglycoside antibiotics
12S rRNA gene - two mtns - 1555A>G, 7445A>G homoplasmic maternal inheritance |
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chronic progressive external ophthalmoplegia (CPEO)
mtDNA |
the commone MELAS point mtn in tRNAleu(uur) - 3243A>G
large deletions similar to KSS heteroplasmic deletions - sporadic point mutations - maternal inheritance progressive atrophy of extracoular muscles, ptosis |
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pearson syndrome
mtDNA |
large deletions
heteroplasmic usually sporadic, somatic mutations pancreatic insufficiency, pancytopenia, lactic acidosis, KSS in second decade |
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Kearns-Sayre syndrome (KSS)
mtDNA |
~5db large deletion (most cases), heteroplasmic
generally sporadic, due to somatic mutations other rare causes - mtDNA point mtn, nuclear genes (AR and AD) progressive myopathy, progressive external ophthalmoplegia of early onset, cardiomyopathy, heart block, ptosis, atypical retinitis pigmentosa, ataxia, diabetes, elevated protein in CSF, cerebellar ataxia |
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achondroplasia
FGFR3 @ 4p16.3 |
~100% of cases due to Gly280Arg (98% 1138G>A, 2% 1138G>C), one of the most mutable nucleotides in genome
AD, 80% de novo - only from father, ass'd with APA GoF constitutive activation --> inhibits chondrocyte proliferation at growth plate most common form of dwarfism rhizomelic, macrocephaly, frontal bossing, midface hypoplasia, trident hand, limited elbow extension onset: prenatal, only detectable by u/s after 24 wks; detectable by x-ray sooner normal lifespan except 3-7% die in infancy b/c of central or obstructive sleep apnea normal intelligence except delayted motor dev't b/c macrocephaly, hypotonia |
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Alzheimer disease
Early-onset mendelian forms |
PSEN1 - 20-70% of early onset familial, fully penetrant
APP - 1-2% of early onset familial, fully penetrant PSEN2 - <5% of early onset familial, reduced penetrance early onset: <60yo dementia, confusion, poor judgement, language disturbance, agitation, withdrawal, hallucinations beta-amyloid plaques, neurofibrillary tangles, amyloid angiopathy diagnosis can only be definitively made on autopsy, clinical diagnosis has 80-90% sensitivity, APOE e4 homozygote increases clinical dx sensitivity to 97% |
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charcot-marie-tooth - most common form
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PMP22 duplications or GoF mutations
accounts for 70-80% of all CMT 17p11.2, unequal crossing over of flanking repeats allelic disorder: HNPP due to deletions, LoF AD, 1/4-1/3 de novo abnormal peripneral myelination onset: <30yo nearly fully penetrant, but variable expressivity slowly progressive weakness, atrophy of distal leg muscles, mild sensory impairment distal weaknes -> foot drop, gait abnormalities, foot deformities (pes cavus, hammer toes) tests: slow nerve conduction (by 5yo, even if asymptomatic), nerve biopsy, genetic test to confirm dx |
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Cystic fibrosis
CFTR @ 7q31.2 |
AR
1/29 carrier rate in caucasians, 1/3200 incidence deltaF508 (80% of caucasian mutations) 5T - in intron 8, variably penetrant, ass'd with abnl phenotype when cis with R117H, more often when cis with 13TG carrier panel - 23-25 mtn present in >1/1000 patients, doesn't include polyT, only reflux to that if find R177H progressive lung disease - chronic infection, progress to end-stage disease exocrine pancreatic insufficiency (85-95%) CBAVD, azoospermia (95% of males) meconium ileus (15-20%) -20% have rectal prolapse dx'c criteria: =>1 phenotypic feature AND (2 CFTR mtn OR 2 abnl sweat chloride (>60) OR transepithelial nasal potential difference) |
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46,XY females
DAX1 |
duplication of part of Xp that includes DAX1 (Xp21.3)
DAX1 has dosage dependent effect on SRY, excess DAX1 b/c of duplication suppresses normal male-determining function of SRY |
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DFNB1 - most common AR nonsyndromic prelingual SNHL
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GJB2 (connexin26) -98% of cases
common mtn - 35delG (whites), 235delC (asians), 167delT and del35G (AJ) 2% of cases - double het for mtn and GJB6 (connexin30) del tests: audiometry, dysmorph exam, CT scan to eval for temporal bone abnormalities genetic test: GJB2 seq'g, including common splice site mtn, test for 2 GJB6 dels empiric risks - if isolated case to hearing parents and GJB2/6 testing is normal - 14% recurrence risk |
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Jervell and Lange-Nielson synd
KCNQ1 @11p15.5, KCNE1 @ 21q22.1-q22.2 |
AR, hets at risk for long QT syndrome (without HL)
congenital bilateral severe-profound SNHL long QT syndrome |
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Pendred syndrome
SLC26A4 @ 7q31 (50%) FOX1I (1%) |
AR
bilateral severe SNHL, usually congenital, progressive temporal bone abnormalities - dilated vestibular aqueducts with or without cochlear hypoplasia (Mondini) goiter (75%), onset late childhood to early adulthood, normal thyroid allelic - DFNB4 - no thyroid defects tests: hearing testing, CT/MRI of temporal bone genetic testings: SLC26A4 common mtn, sequencing |
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usher syndrome
11 genes - most common and testing available? |
Type I - MY07A (50%), several others
Type II - USH2A (80%), others AR Type I - congenital profound bilateral SNHL, congenital balance problems, RP onset pre-puberty Type II - cogenital mild-severe bilateral SNHL, normal balance, RP onset teens-20s Type III - progressive later onset HL, progressive balance problems, variable onset RP tests: hearing tests, electroretinography (ERG), eye exam for pigment changes |
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Waardenburg synd
PAX 3 @ 2q35 |
AD, de novo are rare
point mtn (90%), deletions (6%) highly variable (all features) type 1 - congenital SNHL, pigmentary abnl (heterochormic irides, white forelock, premature gray, leukoderma), telecanthus, NTD type 2 - same, no telecanthus type 3 - 1 + skeletal abnlts (limb hypoplasia or contracture, carpal bone fusion, syndactyly) type 4 - 1 + hirschprung dis |
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Jervell and Lange-Nielson synd
KCNQ1 @11p15.5, KCNE1 @ 21q22.1-q22.2 |
AR, hets at risk for long QT syndrome (without HL)
congenital bilateral severe-profound SNHL long QT syndrome |
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Pendred syndrome
SLC26A4 @ 7q31 (50%) FOX1I (1%) |
AR
bilateral severe SNHL, usually congenital, progressive temporal bone abnormalities - dilated vestibular aqueducts with or without cochlear hypoplasia (Mondini) goiter (75%), onset late childhood to early adulthood, normal thyroid allelic - DFNB4 - no thyroid defects tests: hearing testing, CT/MRI of temporal bone genetic testings: SLC26A4 common mtn, sequencing |
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usher syndrome
11 genes - most common and testing available? |
Type I - MY07A (50%), several others
Type II - USH2A (80%), others AR Type I - congenital profound bilateral SNHL, congenital balance problems, RP onset pre-puberty Type II - cogenital mild-severe bilateral SNHL, normal balance, RP onset teens-20s Type III - progressive later onset HL, progressive balance problems, variable onset RP tests: hearing tests, electroretinography (ERG), eye exam for pigment changes |
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Waardenburg synd
PAX 3 @ 2q35 |
AD, de novo are rare
point mtn (90%), deletions (6%) highly variable (all features) type 1 - congenital SNHL, pigmentary abnl (heterochormic irides, white forelock, premature gray, leukoderma), telecanthus, NTD type 2 - same, no telecanthus type 3 - 1 + skeletal abnlts (limb hypoplasia or contracture, carpal bone fusion, syndactyly) type 4 - 1 + hirschprung dis |
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Duchenne muscular dystrophy (DMD)
DMD at Xp21.2 |
XLR
null mtns - large dels (65%), large dups (5-10%), small dels, insertions, substitutions (25-30%) - nearly all identifiable by molecular testing (multiplex PCR, (formerly southern), MLPA, sequencing) XLR onset 3-5yo, proximal weakness then distal, gower maneuver, wheelchair by 12yo, DCM in 100% cognitive impairment - MR in 1/3 manifesting carrier females isolated cases - 2/3 from carrier mother, 1/3 de novo (equally from males and females) germline mosaicism - so if mom not a carrier, 7% recurrence risk (i.e. 14% rate of germline mosaicism) high mtn rate (10^-4) carrier testing: for known mtn or linkage (but huge gene so recombination may occur) or by CK (50% penetrant, decreases with age) -dystrophin recombination rate: 10-12% (v. high, important for linkage) |
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Becker muscular dystrophy (BMD)
DMD at Xp21.2 |
XLR, 10% de novo, manifesting carriers (esp DCM)
mtns retain reading frame - large dels (85%), dups (6-10%), point or small mtn (5-10%), unknown (5-10%) muscle biopsy - some protein present ambulatory unto 20s, DCM, activity-induced cramping, flexion contractures of elbows, preservation of neck flexor (vs. more severe allelic disorder). |
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Familial hypercholesterolemia
LDLR @ 19p13.2 |
AD, incomplete dominant
private mtn, some found mtn 1/500 environmental modifiers - esp. diet hypercholesterolemia (onset at birth), xanthomas, arcus corneae, atherosclerosis, CAD homoz - onset in childhood, chol > 600mg/dL hets - CAD onset in 30s+, chol > 300mg/dL |
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Fragile X
FMR1 @ Xq27.3 |
XL, expansion only from mother, expansion risk increases with size and decreases with AGG
nl - 5-40, grey - 41-58, pre - 59-200, full - >200 pre - POF (20%) and FXTAS (?%, <100%) MR, autistic spectrum, hyperactivity post-puberty: long face, big ears, prominent chin and forehead, macro-orchidism connective tissue pheno: hyperflexible, flat feet, MVP, soft velvety skin testing: PCR (misses full) and/or southern blot (imprecise), methylation testing |
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Apert synd
FGFR2 @ 10q26 |
only two mtn - P253R (syndactyly more common), S252W (cleft palate more common)
AD, de novo (APA ass'n) coronal synostosis, midface hypoplasia distinct features: bony and soft tissue foot and hand syndactyly (mitten hand), DD/MR (50%) |
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Crouzon synd
FGFR2 @ 10q26 |
AD, de novo (APA ass'n)
coronal synostosis, distinct features: significant proptosis, normal hands, parrot beak nose, mandibular prognathism, progressive hydrocephalus (30%) variant with acanthosis nigrans Ala391Glu in FGFR3 (not 2!) |
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Pfeiffer synd
FGFR2 @ 10q26 (most) FGFR1 (5% of type 1) |
AD, de novo (APA assn)
coronal synostosis, proptosis, midface hypoplasia distinct features: broad, short, medially devaited thumbs and big toes; mild syndactyly, vision and hearing problems type 1 - rare, less severe, normal IQ type 2, 3 - more common, more severe - DD/MR, exorbitism, hydrocephalus, seizures, choanal atresia |
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Thanatophoric dysplasia
FGFR3 @ 4p16.3 |
de novo, (APA ass'n), germline mosaicism not reported
GoF mtn Arg248Cys (50% of cases of type I) Lys650Glu (type II) micromelia, macrocephaly, perintatal lethal, short ribs and narrow thorax, redundant skin folds along arms, cloverleaf skull (type II, not type I), bowed limbs (type I, not type II), detectable on u/s (as early as 12-14wk) |
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Hypochondroplasia
FGFR3 @ 4p16.3 |
AD, de novo
N540K (70%; C1620A 50%, C1620G 21%), other mtn (10%). i.e. identifiable mtn in 80% difficult to diagnose postnatal short stature - childhood presentation (vs. prenatal presentation in allelic disorders) rhizo- or mesomelic shortening stocky build, limited elbow extension, brachydactyly, mild joint laxity, macrocephaly, normal facies mild-mod. MR (rare) tests: x-ray features |
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Diastrophic dysplasia
SLC25A2 (DTDST) @ 5q32-q33.1 |
AR (unlike other similar diseases!)
5 mtn represent 65% of alleles, rare mtn id'd by sequencing get yield up to >90% sulfate transporter mtn - biochemical analysis esp. useful if not mtn found x-rays limb shortening, normal-sized skull, hitchhiker thumbs, spinal deformities, contractures of large joints, early onset osteoarthritis, clubfoot, normal IQ, ear cysts ("cauliflower ears") |
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Osteogenesis imperfecta
COL1A1 (17q21.33), COL1A2 (17q21.33) |
type 1: null mtn, milder phenotype b/c less normal protein (vs. abnormal protein), blue sclarae, brittle bones, no bone deformity, genetic testing 100% sensitive, hearing loss in 50%
type2: abnl protein/dominant negative, perinatal lethal, severe skeletal abnormalities, fractures, dark sclerae, dentinogenesis imperfecta, de novo mtn, genetic testing 98% sensitive type 3: abnl protein/dominant negative, progressive deforming, fractures, limited growth, blue sclerae, hearing loss frequent, genetic testing 60-70% sensitive type4: abnl protein/dominant, moderate severity, normal to grey sclerae, deforming, genetic testing 70-80% sensitive type 7: AR (vs. others - AD, de novo) |
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EDS classic type (I and II)
COL5A1 @ 9q34.2, COL5A2 @ 2q31 (50%) ? |
AD
skin - strongest skin phenotype of all subtypes - hyperextensible, abnl (slow) wound healing, wide atrophic scars, smooth velvety, easy bruising, molluscoid pseudotumors, subcutaneous spheroids joints - hypermobile, dislocations, subluxations hypotonia, hernia, chronic pain, aortic dilatation (rare) biochem testing - not helpful genetic testing - 50% sensitivty |
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EDS hypermobility type (III)
? TNXB (rare) |
AD
least severe subtype joint hypermobility - primary manifestation - dislocations, subluxations, chronic pain, degenerative joint disease skin - may be mildly affected (soft, velvety, slightly increased elasticity, easy brusing), but only mildly and no fragility no testing available |
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EDS vascular type (IV)
COL3A1 @ 2q31 (~100%) |
AD (50%), de novo (50%)
major criteria: arterial rupture, intestinal rupture, uterine rupture during pregnancy, family history of vascular EDS minor criteria: thin, translucent skin, easy bruising, facies (thin lips and philtrum, small chin, thin nose, large eyes), acrogeria (aged hands), hypermobility of small joints... testing - collagen III biochem (95%) genetic tesing - COL3A1 sequencing (98-99%) |
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EDS kyphoscoliotic type (VI)
PLOD1 (?%) |
AR (vs. other subtypes)
enzyme defect - crosslinking skin - friable, hyperextensible, thin scars, easy bruising progressive scoliosis, often present at birth joint laxity, generalized severe hypotonia at birth scleral fragility, rupture of globe rupture of medium-size arteries tests - urinalysis for cross-linking or enzyme analysis in fibroblasts |
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Stickler syn.
COL2A1, COL11A1, COL11A2 |
AD, highly variable
ocular - myopia, cataract, retinal detachment hearing loss, hypermobile ear systems craniofacial - cleft palate, bifid uvula, micrognathia, robin sequence joint - mild spondyloepiphiseal dysplasia, precocious arthritis, hypermobility genetic testing - <100% |
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Congenital contractural arachnodactyly (beals synd.)
FBN2 @ 5q23-q31 |
AD
Marfanoid + major joint contracture, camptodactyly (finger contracture), crumpled ears, muscle hypoplasia, kyphosis/scoliosis (severe), aortic dilatation (rare) rare severe infantile form genetic testing - 75% |
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hereditary multiple osteochondromas (aka multiple exostoses syndrome)
EXT1, EXT2 |
AD, 10% de novo
96% penetrant onset-childhood benign cartilage-capped bone growths/tumors at growth plate of long bones, surface of flat bones small risk of malignant transformation short metacarpals, leg length inequity, bowed long bones, compression of nerves or blood vessels genetic testing - sequencing 70%, deletion analysis 20% |
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Glucose-6-phosphate dehydrogenase deficiency
G6PD @ Xq28 |
XL(R) - manifesting female carriers with mild disease
heterozygote advantage - malaria (so prevalent in mediteranean basin, africa, asia - 5-25%) allelic heterogeneity african variants milder than medit'n variants neonatal jaundice hemolytic anemia triggers: oxidative stress (b/c leads to glutathione deficiency) - infections, oxidative drugs, toxins, fava beans testing - enzyme activity in erythrocytes |
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Hirschsprung disease
RET (isolated - 50% familial, 25% sporadic), EDNRB, EDN3, GDNF, NRTN |
genetic heterog. - allelic and locus
AR, AD, multigenic variable expressivity - intra and interfamilial, isolated vs. syndromic, short vs. long segment reduced and sex dependent penetrance (males>females, incidence - 4:1 m:f) empiric recurrence risks dependent on proband's sex and phenotype congenital intestinal aganglionosis neurocristopathy (neural crest cell dis.) constipation, obstruction, failure to pass meconium, abdominal distension, enterocolitis dx based on histopathology |
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Holoprosencephaly
chromosomal (50%) syndromic nonsyndromic - SHH (30-40% familial AD, 5% overall), TGIF, PTCH, TMEM1, HPE6 (all rare) |
diverse etiologies - chromosomal (50%), syndromic, nonsyndromic monogenic, teratogenic (maternal diabetes)
recurrence risk depends on etiology AD familial nonsyndromic -variable expressivity -reduced penetrance (70%) onset: prental ventral forebrain maldev't, developmental delay dysmorphisms - cyclopia, hypotelorism, an/microphthalmia, absent frenulum, single incisor, males: female (1:2) (vs. most birth defects) syndromes - SLO, meckel-gruber tests - MRI/CT, karyotype, prenatal u/s (dx at 16-18wk) sequencing |
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Huntington disease
HD @ 4p16.3 CAG repeats - polyglutamine - in exon 1 |
AD
anticipation - expansion in spermatogensis only nml 10-26; premutation 27-35 (3-10% chance expansion and transmission from a male); reduced penetrant mtn 36-39; fully penetrant mtn >40; juvenile >60 toxic gain of novel property mvmnt abnormalities (voluntary and involuntary) cognitive abnormalities (all aspects of cognition) psychiatric abnormatlities (personality changes, affective psychosis, schizophrenia) bhvr disturbances (social disinhibition, aggression, outbursts, apathy, sexual deviation, increased apetite) mean dx: 35-44yo mean death: 54-55yo brain atrophy, neuronal dysfunction tests: PCR-based (<115 repeats), southern only for rare >115 or homozygous juvenile (5-10% of cases) - more severe presentation, rapid decline, seizures (<10yo) |
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Miller-Dieker syndrome
17p13.3 deletion |
70% cytogenetically detectable, others need FISH or CGH
lissencephaly type 1 or 2 death by 2yo hypotonia, little-no development, seizures, FTT microcephaly dysmorphic - bitemporal narrowing, prominent forehead, vertical furrows in forehead, short nose, upturned nares, protuberant upper lip, thin vermillion border, small jaw diff'l: isolated lissencephaly due to LIS1 del (35%) or mtn (15%) |
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SBMA (Kennedy's disease)
AR @ Xq11-12 |
XLR
CAG (poly-gln) repeats in exon 1 normal <34; (no premutation); reduced penetrance 36-37; full penetrance >=38 progressive neuromuscluar disease - proximal muscle weakness and atrophy, fasciculations difficulty with swallowing, speaking ('bulbar') gynecomastia, testicular atrophy, reduced fertility (mild androgen insensitivity) |
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Myotonic dystrophy (1)
DMPK @ 19q13.2 |
AD, anticipation - with biggest increases in oogenesis
CTG repeats in 3'UTR normal: 5-34; premutation: 35-49; full mutation >50 mRNA toxic gain of function mild (50-150) - mild myotonia, cataract classic (100-1000) - distal muscle weakness and wasting, myotonia, cataract, balding, arrhythmia congenital (>1000, ?>2000) - infantile hypotonia, congenital severe generalized weakness, respiratory insufficiency and early death, MR is common mitotic instability -> variability tests: EMG, serum CK, muscle biopsy, slit lamp exam genetic test: PCR for up to 100, then southern for larger |
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Friedrech's ataxia
FXN @ 9q13 |
GAA repeat expansion in intron 1
interferes with transcription (LoF) AR 5% are compound hets for a point mtn and repeat expansion nomral: 5-33; premutation: 34-65; borderline/reduced penetrance: 44-66; full mtn: 66-1700 involved in iron metabolism and protecting against oxidative stress in mitochondria onset: 10-15yo progressive ataxia, depressed tendon reflexes, spasticity of lower limbs, dysarthria, scoliosis, pes cavus, optic nerve atrophy, loss of position and vibration senses, HCM, diabetes |
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Limb-girdle muscular dystrophy (LGMD)
CAPN3, DKRP, LMNA, SGCA, SGCB, SGCG, DYSF |
most AR, some AD
heterogeneous group, phenotype depends on genetic subtype must distinguish from dystrophinopathies muscle biopsy - IHC to identify subtype and then targeted genetic testing progressive, loss of ambulation (20-30y?) weakness and wasting in limb musculature, proximal > distal heart and bulbar spared in most subtypes |
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SMA (spinal muscular atrophy)
SMN1 (aka telSMN), SMN2 @ 5q12.2-13.3 |
AR, 2% have one de novo mtn
95-98% homozygous del of exons 7 and 8 in gene 1 2-5% compound hets for 7/8 del and a point mtn in gene 1 multiple copies of gene 2 can make phenotype milder variable spectrum, no definitive genotype-phenotype corr'n arthrogryposis, progressive muscle weakness (degneration and loss of anterior horn cells), peripheral nerve hypomyelination type O - prenatal onset, type I - <6mo onset, type II - onset >6mo, type III - onset 2-3yo, type IV - adult onset carrier testing: recommended by ACMG, PCR dosage assay, complicated by extra copies of gene 1 and point mtns |
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SCA (spinocerebellar ataxias)
many genes |
AD, AR, XL
group of disorders, each characterized by causative gene and mode of inheritance slowly progressive incoordination of gait, wide-based gait/stance poor coordination of hands, speech, eye mvmt atrophy of cerebellum CAG/polyQ - 1, 2, 3, 6, 7 (expand in spermatogenesis) CAG CTG - 8 (expands in oogenesis) CAA/CAG - 17 others caused by point mtn, del, etc. must rule out non-genetic cause of ataxia |
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cri du chat
5p- (5p15.2 and distal?) |
contiguous gene syndrome/partial aneusomy
most dels are visible on karyotype 85% de novo deletions (most paternal in origin) 12% due to parental translocation or inversion distinct cry, decreases with age slow growth mental retardation microcephaly hypotonia dysmorphisms - round face, hyperterlorism, micrognathia, epichanthal folds, low-set ears |
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wolf-hirschhorn
4p- |
partial aneusomy/microdeletion/contiguous gene syndrome
deletions vary in size, 156kb critical region, interstitial usualy p12-16 75% have de novo del (mostly from father) 13% have imbalance from parent's balanced rearrangement 12% have unusual cytogenetic abnormality (ex. ring 4) distinct facies - 'greek warrior helmet' - broad nasal bridge that continues up to forehead, hypertelorism, epicanthus, high arched eyebrows, short philtrum, downturned mouth,micrognathia, ptosis pre and postnatal growth deficiency hypotonia MR in all (variable degree) seizures, structural brain abnlty (33%) skeletal anomalies (60-70%) cleft lip/palate, heart defect (50%), hearing loss (>40%), urinary malformation (25%) tests: karyotype detects 60-70% of deletions, FISH/array CGH detects >95% |
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Williams syndrome
7q11.23 deletions |
contiguous gene del/microdel syndrome - submicroscopic, requires FISH or array
one gene (ELN) can cause the cardiac phenotype AD, but most de novo heart - aortic and other artery stenosis, MVP connective tissue - joint limitation or laxity, hoarse voice hypotonia MR - mostly mild distinct facies - broad brow, bitemporal narrowness, periorbital fullness, stellate/lacy iris pattern, strabismus, short nose, full nasal tip, malar hypoplasia, long philltrum, full lips, wide mouth, prominent ear lobes kids - epicanthal folds, full cheeks, widely spaced teeth adults - long face and neck, sloping shoulder, appear 'gaunt' endocrine disorders - hypercalcemia/uria, hypothyroidism FTT in infancy hernia, rectal prolapse bhvr/perosnality - overly friendly, highly empathic, anxiety, ADD |
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Rubinstein-Taybi
CREBBP (del 10%, mtn 40-60%) @ 16p13.3 EP300 (mtn 3%) |
AD, mostly de novo
MR postnatal growth delay (prenatal usually normal) microcephaly, short statur dysmorphism - beaked nose, ptosis, downslanting palpebral fissures, columella extending below the nares, highly arched palate, 'grimicing' smile, talon cusps (on teeth) broad thumbs, toes, often angulated |
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Noonan syndrome
PTPN11 @ 12q24.1 (50%) SOS1 @ 2p22-p21 (13%) KRAS @ 12p12.1 (<5%) RAF1 @ (3-17%) |
AD, 25-70% de novo
cardiac - HCM (20-30%), pulmonic valve stenosis (20-50%), other feeding problems short stature, scoliosis, pectus learning disabilities (25%), mild MR (33%) bleeding problems facies - short, broad/webbed neck, tall forehead, hypertelorism with downslanting palpebral fissures, deeply grooved philtrum, low posterior hairline, thickened or ptotic eye lids, myopathic facies in childhood, triangular face as teenager, nasolabial folds as adult sequencing of known genes - ~75% yield |
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Phenylketonuria
PAH BH4 |
AR, significant allelic heterogeneity (and sort of locus heterogeneity)
first step of PHE metabolism: PHE-> TYR severe MR, microcephaly, seizures psych-autistic, hyperactive, anger, anxiety, depression hypopigment'n (hair, skin) odor (esp. ear wax) - musty, sweet maternal: aim for <300umol/L during pregancy; pheno: microcephaly, MR, CHD, IUGR, postnatal growth retard'n normal: 30-90umol/L; benign hyper: 120-600: hyper: 600-100; abnormal >1000 NBS: ~100% sensitive, also picks up benign hyper, need to confirm ASAP to start tx by 4 wk, assay substrate to product ratio and substrate levels tx: nearly curative (executive fxn defects, hyperactivity, depression, anxiety), low protein, special food w/o that AA, large neutral AA to compete across blood brain barrier, cofoactor, aim for 40-350umol/L must distinguish between cofactor and enzyme etiology b/c treatment differes |
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Tyrosinemia type I
FAH |
AR
AA disorder, in TYR/PHE pathway fumarylacetoacetase deficiency presents in infancy, death by 10yo if untreated liver - liver failure, cirrhosis, ascites, coagulopathy, fasting intolerance, hepatocellula carcinoma renal - enlargement, dysfunction, renal fanconi/renal tubular acidosis (AA in urine) skeletal - rickets (secondary to renal disease) growth failure odor - boiled cabbage NBS - tyrosine (other causes of elevated tyrosine: liver disease, transiently elevated in newborns, prematurity....?) tests: plasma - high tyr, met, phe; serum - high AFP urine - high tyr metabolites, succinylacetate genetic testing: 4 common mtn, sequencing - total yield 95% tx - phe and tyr free formula, low protein diet, NTBC - inhibits upstream enzyme, converts phenotype to tyrosinemia II (better growth, improved liver fxn, kidney fxn, add skin and eye pheno of II) tests: |
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Homocystinuria
CBS cystationine beta-synthase deficiency |
AR
AA disorder myopia, ectopia lentis (early, by 8yo) (downward vs. upward in Marfan) marfanoid habitus, scoliosis, pectus osteoperosis (vs. Marfan) thromboemoblism (vs. Marfan) MR (vs. Marfan) high arches (vs. marfan) no aortic dissection (vs. Marfan) Plasma AA: high homocysteine, methionine tx: low protein diet, Met-free formula, cofactor supplementation - B6 (30% responsive), cofactor to augment alternative pathway (B12/folate) |
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glycine encephalopathy
GLDC (80%), AMT (10-15%), GCSH |
AR
AA disorder usually immediate and devastating neonatal presentation lethargy, hypotonia (right after birth) myoclonic jerks, seizures, pathoneumonic EEG pattern (burst suppression) decreased respiration MR tests: urina AA: high glycine, CSF: high glycine, high CSF:plasma glycine ratio, enzyme activity on liver biopsy genetic testing (90-95%) tx: sodium benzoate (binds gly, forms hippurate, excreted), destromethorphan (NMDA antagonist), not very treatable |
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glutaric aciduria type 1
glutaryl-CoA dehydrogenase deficiency |
AR
OA disorder macrocephaly (unlike other metabolics) normal and then trigger event (catabolic) -> encephalopathy/metabolic stroke -> hypotonia, profound dystonia and or choreoathetosis motor >> cognitive dysfunction MRI abnormalities tests: metabolic acidosis, hyperammonemia during episodes, UOA - glutaric acid, MRI - fluid and atorphy of frontal lobes, basal ganglia changes tx: fluids, glucose, carnitine in episode; riboflavin trial, lysin-restricted diet |
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isovaleric acidemia
isovaleryl CoA dehydrogenase |
AR
OA disorder, defect in leucine degradation pt normal and then sick/not eating for some reason -> catabolic -> excess leucine -> metabolic acidosis, respiratory alkalosis, ketosis, hyperammonemia lethargy, vomiting, dehydration thrombocytopenia, neutropenia encephalopathy, seizures, coma, death odor: sweaty feet tests: metabolic acidosis, high anion gap, hyperammonemia UOA: isovaleric and OH isovaleric acid, isovaleric-glycine, ketones prognosis better than PA, MMA, and good if treatment started early tx - low protein diet, Leu free formula carnitine and glycine to help clear excesses emergency attn in crises |
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methylmalonic acidemia
MUT, MMAA, MMAB |
AR
cbl C - combined MMA, homocystinuria (relatively common) OA disorder final step in breakdown of multiple AA (isoleu, val) and some FA, right before kreb cycle methylmalonate builds up more severe than isovaleric acidemia acute: severe metabolic acidosis, ketosis, hyperammonemia (secondary), lethargy, vomiting, dehydration, hypotonia, encephalopathy hepatomegaly (vs. IVA), thrombocytopenia, neutropenia, coma, death other: cardiomyopathy, basal ganglia infarcts/metabolic stroke, pancreatitis, bone marrow suppression, progressive renal disease tests: metabolic acidosis, high anion gap, high ammonia paa - high gly uoa - methylmalonate, ketones tx: sodium benzoate for hyperammonemia, carnitine (metabolic sponge), vit b12 b/c cofactor (some responsive, others not), metronidazole b/c gut flora produce a lot of proprionate, kidney liver transplant (not curative), restrict protein and precursors (VOMIT), emergency attn when sick NBS: B12 deficiency can cause false positive |
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propionic acidemia
PCCA, PCCB propionylCoA carboxylase deficiency |
AR
OA disorder second last step in breakdown of isoleucine and valine (and others) similar phenotype to MMA PFVLCSz - vomiting prominent severe metabolic acidosis, ketosis, hyperammonemia FTT lethargy, vomiting, dehydration hypotonia, encephalopathy hepatomegaly (vs. IVA) thrombocytopenia, neutropenia coma, death other: MR, basal ganglia infarct, CM, pancreatitis tests: metabolic acidosis, high anion gap, high ammonia paa: high glycine uoa: propionate metabolites and ketones tx: sodium benzoate for hyperammonemia, carnitine, biotin (enzyme cofactor), metronidazole b/c gut flora produce a lot of proprionate, restrict precursors (VOMIT), emergency attn when sick, kidney/liver transplant (not curative) poor prognosis, even with tx |
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galactosemia
GALT |
AR
classic - <5% activity, Q188R common mtn, G allele on isoelectric focusing duarte - 5-20%, N314D, D allele, treat?? individuals who are compound hets for duarte/gal alleles can appear normal hypoglycemia, feeding problems, FTT, vomit'g, diarrhea catracts**, e coli sepsis** jaundice**, hepatomegaly, hepatocellular damage, bleeding language delays**, POF** tests: NBS detects ~100%, high substrate and reduced enzyme activity confirmation: enzyme activity, then molecular testing tx: lactose-restriced diet, start within first 10 days, calcium supplementation; residual phenotype: cataracts, speech delay, DD, poor growth, cognitive deficits (exec fxn), POF |
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glycogen storage disease type I
G6PC (80%) - G6Pase SLC37A4 (20%) - G6Pase translocase |
AR
defect in glycogen metabolism, glycogen builds up in liver, kidneys, muscles doll like faces**, thin extremities, short stature, protuberant abdomen hepatomegaly, hepatocellular ca renomegaly, renal dysfxn hypoglycemia (3-4hr post feed), lactic acidosis, neutropenia osteoperosis, delayed puberty, polycystic ovaries tests: no response to glucagons, metabolic acidosis, high lactate, high uric acid, high chol, TG dx by enzyme activity on liver sample or by genetic testing tx - avoid fasting (frequent feeds, glucose drip at night, cornstarch), kidney/liver transplant |
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VLCAD
ACADVL |
AR
FAO disorder - most severe form can't breakdown fatty acids C14-20 LCHAD and TFP have similar phenotypes HCM/DCM (vs. MCAD, SCAD; reversible with tx), sudden death, DD, seizures, hepatomegaly, fatty infiltration of liver, hypoketotic hypoglycemia severe early-onset multiorgan form - present in infancy w HCM/DCM, preicardial effusion, arrhythmias, hypotonia, hepatomegaly, intermittent hypoglycemia hepatic or hypoketotic hypoglycemic form - present early chidlhood w hypoketotic hypoglycemia and hepatomegaly, no CM later onset episodic myopathic form - intermittent rhabdomyolysis, muscle cramps and/or pain, and/or exercise intolerance, usually w/o hypoglycemia tests: acylcarnitine analysis of plasma during crisis/stress, enzyme activity, analysis of FAO in fibroblasts, molecular testing tx - avoid fasting, very low fat diet, supplement MCFA, emergency attn if sick, not eating |
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MCAD
ACADM |
AR, 50% homozygous for K304E, 40% K304E/another allele
FAO disorder, can't break down C8, C10, C12 sudden death, ~5% of SIDS present 3-24months, sometimes later fatal in 40% of cases hypoketotic hypoglycemia lethargy, vomiting DD, seizures hepatomegaly, fatty infiltration of liver muscle and heart normal (vs. L, VL) tests: plasma acylcarnitines (elevated C8), plasma fatty acid profile, UOA, urine acylglycines, octenoic acid (C8:1) is isgnature metabolite, enzyme activity in fibroblasts, molecular testing for common mtn (A985G) and sequencing -treatable w early diagnosis tx: avoid fasting (good prognosis), don't need to overly restrict fats ('heart healthy diet'), carnitine, emergency attn if sick, lethargic, not eating |
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SCAD
ACADS |
AR
FAOD - mildest form (some think shoudln't be on NBS) can't breakdown C4 hypoketotic hypoglycemia DD, seizures FTT muscle weakness (vs. M) NBS tx - avoid fasting, emergency attn if sick, not eating |
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OTC - ornithine transcarbamylase deficiency
OTC @ Xp21.1 |
XL**
90% from carrier mother, 10% de novo (vs. usually 2/3 carrier mother for genetic lethal XL - difference b/c mutation rate high in spermatogenesis so many moms carry mtn de novo from MGF) -- important to determine mother's carrier status most common UCD v. high ammonia (>2000), high glutamine (with ammonia), high orotic acid** (only UCD with this) low - citrulline, arginine; normal UOA (vs. UOA disorders) usually neonatal and severe presentation - first 48-72 hours - vomiting, lethargy, coma late (esp. girls) - FTT, DD/MR, episodic ataxia, vomiting, protein avoidance, neuropsych, postpartum hyperammonemia acute tx - 10% dextrose, eliminate protein intake, IV ammonul (sodium benzoate and sodium phenylacetate), hemodialysis if resistent to tx chronic tx - protein restriction, avoid catabolism, oral phenylbuterate, close monitoring, liver tx prenatal testing must be done by molecular testing b/c enzme not expressed in chorionic vili or amniotic cells |
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CPSI, NAGS deficiency
CPSI, NAGS |
AR
UCD disorder - most severe (similar severity to OTC) classical neonatal presentation, milder later onset forms high - ammonia, glutamine low - orototic acid* (vs. OTC), citrulline, arginine tx - protein restriction, arginine supplementation, augment alternate pathways |
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Arginase deficiency
ARG1 |
AR
UCD, last step in UC distinct from other UCDs - chronic not acute, later presentation, ammonia not elevated high - arginine normal until 1-3yo -- growth retardation, spasticity, seizures, DD or regression, loss of ambulation, bowel, bladder control, severe MR tx - low protein diet, avoid fasting, urgent care if sick, ammonia scavenging agents, liver transplant |
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Tay-Sachs
HEXA @ 15q23-24 |
AR
AJ - 1/30 carrier - 1278insTATC (82%), two others LSD - GM2 gangliosides accumulate in lysosomes enzyme activity inversely correlates iwth severity (infantile vs. juvenile vs. adult) infantile form: normal until ~6mo - slowing dev't then regression (loss of motor skills) by 8-10mo hyperacusis*, apathy, cherry red macula/spot* progresses to seizures, blindess, spasticity death by 2-5yo no hepatosplenomegaly* (vs. other storage disorders) juvenile - muscle coordination problems, seizures, vision problems (start 1st year), survival into late childhood, adolescence juvenile form - onset 2-4y w neuro deterior'n, ataxia, incoordination --> seizures, spasticity, +/- cherry red spot chronic adult form - rare, slower progression, bipolar psychosis, progressive dystonia, spinocerebellar degeneration, motor neuron disease, muscle weakness and fasiculations, quite variable enzyme testing: dx based on absent HEXA activity with normal HEXB activity; false positives due to pseudodeficiency alleles (f/u with DNA testing) (2% of AJ with abnl activity have pseudodef., 35% of non-AJ do) genetic testing: 6 common mutations - 98% yield in AJ, 59% yield in non-jews |
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Sandhoff
HEXB activator protein |
LSD disease, similar toTay-Sachs - distinguish with enzyme testing, AR, deficiency in HEXA activity and HEXB activity b/c of mutations in HEXB or in activator protein.
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MPS I
alpha-L-iduronidase (aka Hurler, Hurler-Scheie, Scheie) |
AR
MPS, spectrum of phenotype - now called MPS I and attenuated MPS I severe - onset 6-12mo, die by 10yo coarse facies corneal clouding* hydrocephalus, macrocephaly skeletal dysplasia - dysostosis multiplex** (x-ray finding, bullet shape metacarsals) hepatomegaly umbilical or inguinal hernias short stature - linear growth stopes by 3yo) cardiomyopathy mitral and aortic valve regurg hearing loss, DD, MR, decreased ROM tx - BMT, ERT |
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MPS II - Hunter syndrome
iduronate sulfatase |
XLR*
LSD a lot like similar AR disorder but no corneal clouding** coarse facies, hydrocephalus, CM, heart failure, dysostosis multiplex, short stature, MR, decreased ROM in joints, carpal tunnel syndrome tx - ERT, BMT less successful than other similar disorder |
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Pompe disease/GSD II
GAA |
AR
GSD and LSD usually infantile onset (sometimes prenatal, sometimes childhood) hypotonia, muscle weakness**, HCM**, respiratory distress FTT, feeding difficulties hearing loss, fractures enzyme testing is diagnostic, DNA testing for GC'ing tx - ERT (die by 1-2yo without it) RT/OT/PT |
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Fabry
alpha galactosidase a deficiency GLA |
XL**, rarely de novo
LSD - GL-3 builds up - esp. in blood vessels, kidneys, heart onset - adolescence for males, adulthood for females vascular occlusion, ischemia, infract -> TIA, stroke corneal verticillata/whorls** angiokeratomas (groin, umbilicus, back) acroparasthesias (provoked by exercise, temp changes) hypohidrosis, anhydrosis renal disease CM, arrhythmia heat and cold intolerance vomiting, diarrhea, cramping depression, anxiety, fatigue proteinuria tests: enzyme activity (but not good for females) genetic testing: ~100% sensitive tx: ERT |
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MNGIE
thymidine phosphorylase gene |
AR
one of nuclear-encoded diseases affecting mtDNA - mtn in thymidine phosphorylase gene cause multiple mtDNA deletions manifestations: mitochondrial myopathy, peripheral neuropathy, GI and encephalopathy disease |
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mtDNA depletion syndrome
|
AR
mtn in nuclear-encoded genes needed for mtDNA replication (gamma polymerase), maintenance of nucleotide pools (TK2, dGK) heterogeneous group of disorders infantile onset myopathic, hepatic dx made in muscle (not blood) by compairing mtDNA: nDNA reations in patients vs. controls |
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MERRF - myoclonic epilepsy with ragged-red fibers
mtDNA tRNAlys |
maternal inheritance
heteroplasmic common mutations: 80% 8344G>A, 10% 8356T>C or 8363G>A highly variable (including ragged red fibers) - severity increases with somatic mtDNA mutation rate, i.e. with age complexes I and IV most severely affected b/c have most components transcribed in mitochon. onset: childhood through adulthood; slowly progressive or rapid decline myoclinic epilepsy myopathy (with or without ragged red fibers) other (variable) features: abnl brainstem provoked responses, SNHL, ataxia, renal dysfunction, diabetes, CM, dementia prenatal and predictive molecular testing are not useful b/c mtn load in blood/amnio/etc. doesn't reflect other tissues and b/c can't predict replicative segregation, tissue selection, somatic mtDNA accumulation |
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ADPKD (polcystic kidney disease)
PKD1 @ 16p13.1 (85%), PKD2 @ 4q21 (15%) |
AD, 10% de novo
common! 1/300-1/1000 variable expressivity (inter and intrafamilial), two-hit hypothesis for cyst formation, age-dep't penetrance renal - progressive failure, recurrent UTI, hematuria, nocturia, secondary htn intracranial saccular aneurysms, dilatation of aortic root, dissection of root, MVP sequencing - 85% yield also - deletions of PKD1 and TSC2 - tuberous sclerosis and PKD cysts - renal, hepatic, ovarian, pnacreat |
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Prader-Willi syndrome (PWS)
15q11-q13 |
etiology:
70% pat del (<1% recurrence risk) 15-25% mat UPD (<1% recurrence risk) 5% imprinting defect (50% recurrence risk) infancy: feeding difficulties, severe hypotonia, hypogonadism with cryptorchidism childhood: hyperhagia, obesity, delayed motor and language dev't, bhvr pheno (temper tantrums, stubbornness, manipulative, OCD), delayed puberty (b/c of hypogonadism) sterility, scoliosis, sleep apnea, short stature, osteoperosis dysmorphism: narrow bifrontal diametere, almond-shaped eyes, trangular mouth, small hands and feet, hypopigmentation of eyes, hair, skin testing: Meth-sensitive PCR or meth-sensitive restriction enzyme - 99% yield! then need further testing to determine etiology (for recurrence risk) tx: symptomatic, food management, growth hormone |
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Rett syndrome
MECP2 @ Xq28 (CDKL5 mtn in aytpical presentation w early onset seizures) |
XLD, almost exclusively females (rare males with mosaicism or XXY)
mtn (85%), del by MLPA, qPCR (15%) loss of fxn 99% de novo (70% from dad), rare unaffected carrier mother with skewed x inactivation germline mosaicism reported sex-dependnet phenotype males - lethal females - classic to atypical classic: normal dev't to 6-18 months, then develop'l slowing, stagnation, decelerating head growth (-> acquired microcephaly), neurodev'l regression (esp. speech and purposeful hand use, also motor skills), stereotyped repetitive hand movements (wringing); several years of stabilization, then progress to severe MR, progressive spasticity, rigidity, scoliosis ataxia, seizures, breathing irregularities, bruxism (teeth clenching) bhvr/psych - fits of screaming, inconsolable crying, autistic features, panic-like attacks long QT, reduced lifespan due to sudden death mtn in this gene show wide variability of phenotype with poor geno-pheno correlations dx confirmed by molecular testing, must rule-out angelman synd. |
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Sickle Cell disease
HBB |
AR
60-70% homozygous Hb S (Glu6Val), rest are compound hets - Hb S/Hb C, Hb S/beta-thal, etc. het advantage - malaria resistance - african-americans 1/14 carriers, non-hispanic caribbean w. indian 1/14, west african 1/6 Hb S reduced solubility when deoxygenated, form polymers, sickle shape of RBC, occlude capillaries (ischemia), get cleared --> hemoyltic anemia present first 2y of life - anemia, FTT, splenomegaly, repeat infections/sepsis, dactylitis (painful swelling of hands or feet) painful crises - bone vasoocclusions infarct --> organ damage - most significant - spleen, brain, lungs, kidneys NBS (to allow for antibiotic prophylaxis) test for Hb S - HPLC, IEF, or Hb electrophoresis DNA testing for Glu6Val tx - antibiotic prophylasix, vaccination, oral hydration, folate supplements, avoid hypoxia/exhaustion/temp extremes chronic RBC transfusions analgesics for pain crises |
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Turner syndrome
45,X |
sporadic - 80% of cases due to sex chromosome missing from father
1/2000-1/5000 births etiology: -50% 45,X -25% structural abnormality of X -25% mosaic 45,X second sex chromosome important for intrauterine survival? (1-2% of all conceptions are 45,X but only 1% of those survive, yet postnatal phenotype is mild) second X needed for maintenance (but not develop't) of oocytes and ovaries --> fibrous streak gonads --> 90% don't spontaneously enter puberty, hormones needed for secondary sex characteristics short stature (100%) (SHOX!) broad chest, wide spaced nipples, webbed neck, low nuchal hairline, cardiac anomalies, renal anomalies, SNHL, edema of hands and feet, dyspalstic nails shy, withdrawn osteoperotic fractures, thyroiditis, diabetes, IBD, heart disease tx - growth hormone for linear growth, progest./est. for secondary sex charact., echo, renal u/s, diabetes screening |
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Russel-Silver syndrome
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matUPD7 (10% of cases)
11p15.5 imprinting changes (?%) recurrence risk - low, most are sporadic pre and postnatal growth retardation - 2+ standard deviations below the mean; proportionate short stature with normal head circumfrence (so relative macrocephaly) traingular facies areas of hyper and hypopigmentation hemihypertrophy excessive sweating delayed bone maturation |
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NF2
NF2 @22q12.2 |
AD, 50% de novo
75% sequencing variants 15% deletions dx'c criteria: -bilateral vestibular schwanommas OR -a FDR with NF2 and -unilateral vestibular schwanomma -two of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity/juvenile cortical cataract some have cafe-au-lait ca - acoustic neuromas, meningiomas, gliomas, ependymomas, mesotheliomas |
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denys-drash
WT1 @ 11p13 |
AD, most de novo
-urogenital anomalies - XY males with ambiguous or female genitalia -wilms tumor (>90%) -mesangial sclerosis of kidneys |
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WAGR
11p13 contiguous gene deletion (including WT1 and PAX6) |
true contiguous gene syndrome
Wilms tumor (WT1) (40-50% risk) aniridia (PAX6) genital anomalies retardation testing: FISH detects 30% |
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Emery-Dreifuss muscular dystrophy
EMD @ Xq28, LMNA @ 1q21.2 |
XL - EMD - most female carriers unaffected, but can have cardiac or even full blown disease
AD, AR (rare) - LMNA (75% de novo) joint contracturs (early childhood onset) slowly progressive muscle weakenss and wasting (starts humero-peroneal, extends to scapular and pelvic girlde) cardiac involvemnt - palpitations, presyncope, syncope, CHF inter and intrafamilial variability dx based on muscle biopsy - path, emerin, lamins A/C and genetic testing (LMNA) |
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Acute intermittent porphyria
HMBS @ 11q23.3 |
AD
onset - after puberty reduced penetrance (10-50%), women>men potentially severe and debilitating intermittent acute attacks: abdominal pain(most common symptom), nausea, vomitting, constipation, diarrhea, peripheral neuropathy - muscle weakness, neuropathy, psych - hysteria, anxiety, hepatocellular carcinoma, *no cutaneous findings tests: high urine delta-amonolevulinic acid (ALA) and porphobilinogen (PBG) during attack genetic tests: sequencing (>98%) tx: stop or treat precipitant (medication, infection, alcohol, dehydration, smoking, etc.); intubate if needed; IV dextrose: IV hemin; pain control |
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Alagille syndrome
JAG1 (95%), NOTCH2 (<1%) |
AD, 60% de novo, possible germline mosaicism
seq JAG1 (88%), FISH 20p12 (7%, includes JAG1) liver, heart, eyes, face, skeleton highly variable cholestatis (96%) (bile duct paucity on liver biopsy) (85%) congenital heart defects - pulmonary arteries posterior embryotoxon of eye (78%) DD (16%), growth failure dysmorph - prom't forehead, deep-set eyes, moderate hypertelorism, pointed chin, saddle or straight nose w bulbous tip (triangular face) butterfly vertebrae (51%) |
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HHT - Hereditary Hemoorrhagic Telangectasia
ENG, ACVRL1(ALK1), SMAD4 (total - 85%) |
AD, marked intrafamilial variability
arteriovenous malformations - multiple - in skin (telangectasias), nose, brain, liver, lungs age-dependent, usually not dx'd until adolescence or later easy bleeding after slight trauma spontaneous and recurrent nosebleeds (most common feature, onset 12yo) GI bleeding (25%, after 50yo) genetic testing - seq'g all 3 genes: 85%, dup/del (10%) annual eval: for anemia, pulmonary AVM by pulse oximetry or echo (?head MRI, u/s for hepatic AVM) |
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Holt-Oram syndrome
TBX5 (70%) |
AD - 85% de novo
upper-extremity malformations (radial, thenar, carpal bones) - carpal (100%, may require hand x-ray), symmetric or asymmetric CHD - ASD, VSD - (75%) cardiac cnduction disease genetic testing - 70% |
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LEOPARD syndrome
PTPN11 (80%), RAF1 (3%) |
AD, de novo (?%)
LoF mtn (vs. GoF in Noonan) L-letigines - onset 405yo, increase to thousands by puberty, flat black-brown macules on face, neck, upper trunk E-ECG conduction abnlts O-ocular hypertelorism Pulmonic stenosis (+ HCM) - 85% R - retardation of growth, postnatal, short stature - 50% D - SNHL MR - mild, 30% genetic test - 83-93% yield |
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Greig cephalopolysyndactyly syndrome (GCPS)
GLI3 @ 7p13 |
AD, de novo (esp. cytogenetic)
preaxial polydactyly or mixed pre and postaxial polydactyly, also syndactyly of fingers 3-4 and toes 1-3 microcephaly, ocular hypertelorism, subtle craniofacial findings seizures, hydrocephalus, MR karyotype for gross cytogenetic abnormalities involving 7p13 FISH (array?) - 5-10% sequencing - 70% |
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Joubert syndrome
MPHP1, CEP290, AHI1, TMEM67 (total - 40%) |
AR, M:F 2:1
hypotonia in infancy DD - severe MR to normal apnea - episodic - improves with age abnormal eye movements MRI - *molar tooth sign |
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VACTERL (VATER) association
gene unknown |
sporadic, dx of exclusion, dx requires 3/7 features
V - vertebral anomalies A - anal atresia C - cardiac defect (VSD, PDA, TOF, TOV) T - treacheoesophageal fistula E - esophageal atresia R - renal anomalies L - limb anomalies (polydactyly, humeral hypoplasia, radial aplasia, proximally placed thumb) variant - VACTERL - with hydrocephalus (AR or XL) -differential dx: fanconi anemia, townes-brocks, infant of diabetic embryopathy, feingold syndrome |
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X-linked adrenoleukodystrophy
ABCD1 @ Xq28 |
XLR, 7% de novo
peroxismal disorder, defect in peroxismal membrane protein that may be a transporter, accumulation of saturated VLCFA tests: childhood cerebral presentation: ADHD -> total disability within 2 years, mild adrenal dysfxn, decreasing intellectual performance, MRI white matter changes adrenomyeloneuropathy: late 20s, progressive paraparesis, sphincter disturbance, adrenocortical dysfunction adrenocortical insufficiency (only) - majority by 8yo (20% of carrier females) tests: abnl plasma very long chain fatty acids, MRI white matter changes genetic tests: ABCD1 sequencing (92%), del/dup (6%) |
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CADASIL
NOTCH3 @ 19p13.2 |
AD
C - cerebral AD - autosomal dominant A - arteriopathy S - with subcortical I - infarcts and L - leukoencephalopathy stroke-like episodes before 60yo, cognitive disturbances, bhvrl abnlts, migraine and aura tests: skin bx EM, brain MRI genetic tests: NOTCH2 sequencing (>90%) mean age to walk with asst: 60yo, bedridden by 64y, med. age of death 68y |
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Hereditary diffuse gastric cancer (HDGC)
CDH1 |
AD
diffuse gastric ca (aka signet ring type ca or isolate cell ca) adult onset (avg age 38yo) lifetime risk of ca - 67% for men, 83% for women lobular breast ca risk - 39% dx - 2 cases that are FDR or SDR and one <50yo OR 3 cases in FDR or SDR |
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Canavan disease
ASPA |
AR - enzyme deficiency
AJ carrier rate - 1/40 3 common mtn account for 99% of mutations in AJ; 50-55% of mutn in non-AJ leukodystrophy; accumulation of n-acetyl-aspartic acid macrocephaly, lack of head control DD by 3-5 mos - never sit, walk, speak severe hypotonia, evolves to spasticity life expectancy - teens demyelination tests: high urine n-acetyl aspartic acid (NAA) on UOA |
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Familial dysautonomia
IKBKAP @ 9q31 |
AR
AJ carrier rate: 1/35, 2 common mtn - 99% of alleles disease affects dev'l and survival of sensory, sympathetic, parasympathetic neurons onset: birth, progressive GI dysfunction, vomiting crises, recurrent pneumonia, CV instability altered sensitivity to pain and temp autonomic crises, hyptonia, in adulthood broad base degenerative gait, decreased life expectancy absence of overflow tears with crying |
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Krabbe disease
GALC @ 14q31 |
AR, enzyme deficiency
infantile onset (most cases) - normal at birth, then irritability, spasticity, DD. psychomotor regression -> no voluntary mvmt. progressive. death by 2yo. later onset (6mos-5th decade): weakness, vision loss, intellectual regression abnl CT, MRI, EEG enzyme testing: 0-5% of normal activity targeted mtn analysis: 30kb del (35-45%), 809G>A (50% of late onset), sequencing (100%) |
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Wilson disease
ATP7B |
AR, defect in copper-transporting ATPase 2
present 3-50you, variable liver disease: jaundice, self-limited hepatitis-like illness, autoimmune hepatitis, chronic liver disease neuro/psych: mvmt disorder, rigid dystonia, depression, neurotic bhvr, disorganization of personality tests (for dx): kayser-fleisher rings on cornlea exam (Cu deposition), low serum cu and ceruloplasmin, increased urinary copper, increased copper storage on liver bx genetic tests: sequencing (98%), common mutations tx: chelating agents, liver transplant |
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FMF - familial mediterranean fever
MEFV |
AR (but in prevalent areas may be pseudo-dominant) - (armenian, turkish, arab, north african jewish, iraqi jewish, AJ)
type 1: recurrent febrile episodes with peritonitis, synovitis, or pleurotis, also erythema - presents as fever and pain at site of inflamation; amyloidosis (AA type, can lead to renal failure) type 2: amyloidosis as first presentation tests: increased erythrocyte sedimentation rate (ERS); leukocytosis; increases serum fibrinogen; proteinuria genetic testing: targted mtn analsyis = 70-90%, sequencing - 90% tx: colchicine |
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Hermansky-Pudlak syndrome
HPS1, AP3B1,HPS4,5,6,7,8 |
AR
oculocutaneous albinism - skin, hair and eye pigment decreased bleeding diathesis - platelet storage pool deficiency - easy bruising, frequent epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, prolonged bleeding with menses, surgery, etc. decreased visual acuity, nystagmus, foveal hypoplasia, increased crossing of optic nerve fibers may have skin ca, pulmonary fibrosis, colitis tests: prolonged bleeding time; absent platelet dense bodies (sine qua non) on platelet EM genetic tests: depends on ancestry |
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Hutchinson-Gilford Progeria syndrome
LMNA |
100% G608G
AD, all de novo, paternal age effect normal at birth, profound FTT in 1st year short stature, wt |
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Androgen insensitivity syndrome
AR @ Xq11-q12 |
XLR
46,XY - feminization of external genitalia, abnl secondary sexual dev't, infertility spectrum of severity: complete (female genitalia), partial (ambiguous genitalia) mild (nl male genitalia) tests: normal or increased testosterone; normal or increased LH; deficient androgen binding activity of genital skin fibroblasts genetic tests: sequencing (>95% yield in complete, <50% yield in partial) treatment: removal of testes after pregnancy (ca prevention), estrogen replacement therapy |
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Kallman syndrome - type 1 and 2
KAL @ Xp22.3, FGFR1 @ 8p11.1-11.2 |
XLR, AD
hypogonadotropic hypogonadism, delayed pubertal dev't anosmia type1: mirror hand movements, ataxia, GU anomaly, high palate, pes cavus type2: MR, CL/P, cryptorchidism, choanal atresia, CHD, SNHL tests: low FSH and LH, low testosterone in males, low estradiol in females, MRI: hypo/aplasia of olfactory bulbs and tracts genetic tests: sequencing - 13-26% yield (total tx: normalize gonadal steroid levels |
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Klinefelter syndrome
47XXY |
tall stature,
slightly delayed motor and language skills, learning problems testosterone plateaus at age 14, small fibrosed testes, azoospermia and infertility gynecomastia increased cholesterol, increased risk autoimmune disorders and mediastinal germ cell tumors (1%) maternal > paternal origin, AMA affect tx: testosterone in mid-late adolescence (bone density, secondary sex dev't, sucle mass, chol, increased libido, improved energy). |
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McCune-Albright syndrome
GNAS @ 20q13.2 |
sporadic
polyostotic fibrous dysplasia, pathologic fracture, cranial foramina thickening --> deafness and blindness large irregular cafe aut lait ('coast of maine') precocious puberty, hyperthyroidism, increased growth hormone, PRL (?) or PTH ovarian cysts tests: x-ray, pevlic u/s vision and hearing testing, pituitary hormone analysis genetic testing: targeted - GoF mtn |
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Biotinidase deficiency
MRD |
AR
neuro - seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss cutaneous - alopecia, skin rash, candidiases older children/teens - motor limb weakness, spastic paresis, decreases visual acuity treatable with biotin BUT DD, HL and vision problems are irreversible testing: <10% biotinidase enzyme activity NBS; genetic test - targeted (60%), sequencing (99%) |
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2nd week
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2nd week of conditions
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