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119 Cards in this Set
- Front
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Acute Intermittent Porphyria
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Gene: HMBS
AD Features: onset after puberty, acute attacks, abdominal pain, muscle weakness, neuropathy, hysteria, anxiety, hepatocellular carcinoma, NO CUTANEOUS FINDINGS |
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Alpha Thalassemia
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Gene: HBA1, HBA2
AR: if parents have trait, risk for HBH disease if one parent's mutations are in cis, at risk for HB Bart if both parents are in cis At-risk populations: sub-Saharan Africa, Mediterranean Basin, Middle East, South Asia, and Southeast Asia Features: HB Bart: loss or dysfunction of all 4 alleles, hydrops fetalis, severe hypochromic anemia, death in neonatal period HBH: loss of dysfunction of 3 of 4 alleles, microcytic hypochromic hemolytic anemia, HSM, jaundice Trait: loss of dysfunction of 2 alleles, low MCV/MCH, nl levels Hgb A2 and F "Silent carrier": loss or dysfunction of one allele, none or mild thal-like effect |
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Beta-Thalassemia
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Gene: HBB
AR At-risk populations: Mediterranean, Middle East, Indian, Thai, Chinese, African, African American Features: severe anemia and HSM; without treatment have severe FTT and shortened life expectancy; intermedia: presents later, milder anemia, only rarely requires transfusion; at risk for iron overload due to increased intestinal absorption of iron. Clinical severity is based on extent of globin alpha chain/non-globin alpha chain imbalance |
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Factor V Leiden Thrombophilia
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Gene: F5
AD: moderately increased risk for VTE AR: significantly increased risk for VTE Features: increased risk venous thromboembolism (VTE), most common is CVT; heterozygotes at modest increased in VTE recurrence risk (2-3x increased pregnancy loss); homozygotes increased VTE recurrence; aterial thrombosis, MI, and stroke NOT associated Common mutations: 1691G>A |
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Hemophilia A
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Gene: F8
XLR Features: hemathrosis or intracranial bleed with mild or no trauma, deep muscle hematomas, prolonged or renewed bleeding after trauma/surgery/tooth extraction/nose bleeds/moth injury/circumcision, excessive bruising Common mutations: severe intron 22-A inversion; mild-moderate missense mutations |
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Hemophilia B
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Gene: F9
XLR Features: hemathrosis or intracranial bleed with mild or no trauma, deep muscle hematomas, prolonged or renewed bleeding after trauma/surgery/tooth extraction/nose bleeds/moth injury/circumcision, excessive bruising |
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HFE-Associated Hereditary Hemochromatosis
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Gene: HFE
AR: penetrance is low, a large fraction of homozygotes never develop symptoms Carrier frequency: 11% (1/9) in Europeans Features: inappropriately high iron absorption by the GI mucosa leads to excessive iron storage in liver, skin, pancreas, heart, joints, and testes; early signs include pain, weakness, lethargy, and weight loss. Common mutations: 60-90% C282Y/C282Y, 3-8% C282Y/H63D |
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22q11 Deletion Syndrome
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Gene: 22q11.2
AD, 93% de novo Features: 74% congenital heart disease (TOF, IAA A, conotruncal defects), immune dysfunction, 69% palate abnormalities, feeding problems, dev delay, 70-90% learning problems, 50% hypocalcemia, 37% renal anomalies, psychiatric disorders, medial deviation of the internal carotids |
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Alagille Syndrome
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Gene: JAG1, NOTCH2
AD: 50-70% de novo Features: bile duct paucity on liver bx and any three of: cardiac defects (PA, TOF), cholestasis, skeletal abnormalities (butterfly vertebrae), eye (posterior embryotoxin), or characteristic facial features. Also dev delay, growth failure |
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Brugada Syndrome
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Gene: SCN5A
AD Features: syncope or nocturnal agonal respiration; ST-segment abnormalities in leads V1-V3 of ECG and a high-risk of ventricular arrhythmias and sudden death; manifests primarly during adulthood (range 2 days to 85 years); mean age of sudden death is 40; may present as SIDS or sudden unexpected nocturnal death |
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Hereditary Hemorrhagic Telangiectasia
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Gene: ACVRL1, ENG
AD Feaures: nosebleeds, mucocutaneous telangiectases (lips, oral cavity, fingers, nose), visceral AVMs (pulmonary, cerebral, hepatic, spinal, GI); hemorrhage often presenting symptom of cerebral AVM; visceral AVMs presnt as result of blood shunting through abnormal vessel and bypassing capillary beds |
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Holt-Oram Syndrome
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Gene: TBX5
AD: 85% de novo Features: malformation of the carpal bones (100%) and (variably), the radial and/or thenar bones; 70% CHD (ASD, VSD, arrhythmia including AV block) |
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Leopard Syndrome
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Gene: PTPN11
AD Features: L: lentigines E: electrocardiographic conduction abnormalities O: ocular hypertelorism P: pulmonary stenosis A: abnormalities of the genitalia R: retardation of growth D: sensorineural deafness HCM |
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Noonan Syndrome
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Gene: PTPN11, SOS1, KRAS
AD Features: characteristic facial features, short stature, feeding problems, pulmonary valve stenosis, HCM, cryptorchidism, renal malformation, lymphedema, scoliosis, bleeding disorders, myeloproliferative disorder, increased risk of leukemia and learning disabilities |
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Williams Syndrome
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Gene: 7q11.23
AD: majority of cases de novo Features: CV: any artery may be narrowed, supravalvar aortic stenosis (SVAS) most common (75%) CT: hoarse voice, distinctive facial features, hernia, rectal prolapse, joint limitation or laxity, MR, overfriendly, anxiety, ADD Endo: hypercalcemia, hypercalciuria, hypothyroidism, FTT |
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Hereditary Breast and Ovarian Cancer
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Genes: BRCA1, BRCA2
AD Carrier frequency: 2.5% (1/40) in AJs Common mutations: AJ: 185delAG (BRCA1), 5382insC )BRCA1), 6174delT (BRCA2) Dutch: 3 large BRCA1 deletions Iceland: 999del5 (BRCA2) |
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Familial Adenomatous Polyposis
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Gene: APC
AD: 30% de novo Features: 100-1000 adenomas, CHRPE, Upper GI tumors (duodenal) tumors, desmoid tumors, jaw osteomas, hepatoblastoma, thyroid cancer Gardner Variant: supernumerary/malformed teeth, CHRPE, skin tumors,desmoid, osteomas. Attenuated form: milder, fewer polyps, more proximal in colon, later presentation Turcot: colon + brain CNS (medulloblastoma) |
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Lynch Syndrome
(used to be HNPCC) |
Gene: MLH1, MSH2, MSH6, PMS2
AD Features: right-sided colon(rectum), endometrium, stomach, ovary, hepatobiliary tract, unrinary tract, small bowel, CNS Amsterdam II: 3 or more family members (at least one 1st degree of the other 2) with HNPCC-related cancers; 2 successive affected generations; 1 or more of the HNPCC-related cancers diagnosed before age 50; exclusion of FAP Muir-Torre: colon + sebaceous neoplasms; include sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratoacanthomas Turcot: colon + brain/CNS tumors, Glioblastoma |
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Li-Fraumeni Syndrome
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Gene: p53
AD Features: proband with sarcoma <45, 1st degree relative with cancer <45, and 1st/2nd relative with any cancer <45 or a sarcoma at any age; increased risk of multiple primary tumors: bone cartilage, and soft tissue sarcomas; early onset breast; spine or brain; childhood adrenocortical tumors; Wilm's tumor |
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Multiple Endocrine Neoplasia type1
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Gene: MEN1
AD Features: tumor in 2 of: parathyroid, enteropancreatic endocrine tissue, or anterior pituitary OR tumor in one and 1st degree relative with condition; facial angiofibroma, collagenoma, café au lait, lipoma |
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Multiple Endocrine Neoplasia type 2
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Gene: RET
AD Type 2A: two or more of medullary thyroid carcinoma, pheochromocytoma, or parathyroid adenoma/hyperplasia in a single person or close relative Type 2B: mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, Marfanoid habitus, and medullary thyroid carcinoma Testing: Exon 10/11 2A and Exon 16 2B |
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Neurofibromatosis type II
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Gene: NF2
AD Features: Benign nerve tumors (schwannomas, meningiomas, ependymonas, astrocytoma); hallmark is bilateral vestibular schwannoma, onset 18-24 years, hearing loss, tinnitus, balance problems, cataracts, mononeuropathy, café au lait |
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PTEN Hamartoma Tumor Syndrome
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Gene: PTEN
AD Features: Cowden: presents 2nd/3rd decade; mucocutaneous facial and oral papules; gingival cobblestoning; acral keratosis; dystrophic and adenomatous multinodular goiter; GI polyps; adenosis and fibrocystic breast lesions; macrocephaly; dolichocephaly; lipomas; high risk for breast, thyroid, and endometrial cancers Bannayan-Riley-Ruvalcaba: macrocephaly, polyposis, lipomas, pigmented macules of the glans penis Proteus: CT nevi, disproportionate overgrowth, dysregulated adipose tissue, vascular malformation, risk for ovarian or parotid tumor in 2nd decade |
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Tuberous Sclerosis
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Gene: TSC1, TSC2
AD: 66% de novo Features: Skin: hypomelanotic macules, facial angiofibroma, shagreen patch, ungula fibromata CNS: subependymal glial nodules, cortical tubers, giant cell astrocytoma, seizures Renal: angiomuolipomas, epithelial cysts, <1% malignant transformation Heart: cardiac rhabdomyoma, tend to regress in infancy without intervention Lung: lymphangiomatosis (TSC2) Eye: hamartomas or achromic patches TSC2/PCKD contiguous gene deletion syndrome with features of both |
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Von Hippel-Lindau Syndrome
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Gene: VHL
AD Features: hemangioblastoma (cerebellum, retina, spinal cord), pheochromocytoma (hypertension), renal cell carcinoma (40%) |
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Xeroderma Pigmentosum
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Gene: XPA, XPC, ERCC2, POLH
AR Features: severe sun sensitivity, UV exposure to conjunctive, cornea, and lids leads to severe keratitis; progressive neurologic deterioration; acquired microcephaly; dec/absent DTR's; progressive sensorineural hearing loss; cognitive impairment; >1000 increased risk of skin and eye neoplasms |
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Aarskog Syndrome
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Gene: FGD1
XLR (some AR/AD cases reported) Features: hypertelorism, shawl scrotum, brachydactyly, short stature, cryptorchidism, cervical vertebral abnormalities, MR in 30%, milder manifestations in females |
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Antley-Bixler Syndrome
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Gene: POR
AR Features: ambiguous genitalia, enlarged cystic ovaries, poor masculinization in males, maternal virilization during a pregnancy with an affected fetus, craniosynostosis, choanal stenosis or atresia, stenotic external auditory canals, hydrocephalus, neonatal fractures, bowing of the long bones, joint contractures, renal malformations |
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Bardet-Biedl Syndrome
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Gene: BBS1, BBS10
AR: 10% thought be tri-allelic Features: cone-rod dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotrophic hypogonadism, complex female GU malformations, renal dysfunction; night blindness by age 7-8, legally blind by 15.5; majority have significant learning difficulties, only a minority have severe impairment; renal disease is major cause of morbidity/mortality |
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Branchiootorenal Syndrome
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Gene: EYA1, SIX1
AD Features: malformations of the outer, middle, and inner ear associated with conductive, senorineural, or mixed hearing impairment; branchial fistulae and cysts; renal malformations, ranging from mild renal hypoplasia to bilateral renal agenesis |
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Charge Association
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Gene: CHD7
AD Features: 4/7 needed; eye coloboma, heart anomaly (conotruncal defects, arch abnormalities), choanal atresia, growth and mental retardation, GU malformations (microphallus), ear anomalies (ossicular malformations, Mondini defect of the cochlea) and/or deafness; facial palsy, cleft palate, TE fistula, and dysphagia; 20-25% mortality in the first year |
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Coffin-Lowry Syndrome
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Gene: RPS6KA3
XLD Features: severe to profound MR in males; short, soft, fleshy hands tapering fingers with small terminal phalanges; males <3% height, microcephaly, stimulus induced drop episodes, kyphoscoliosis, characteristic facial features in older males, normal to profound MR in females |
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Cornelia de Lange Syndrome
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Gene: NIPBL, SMC1L1
AD, XLR Features: pre/postnatal growth retardation, low anterior hairline and synophrys, diaphragmatic hernia, upper limb anomalies (hypoplastic middle phalanx of the index finger, hypoplastic thenar eminence), ptosis, nystagmus, mod-severe MR, pulmonary valve stenosis and/or VSD |
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Cri du Chat (5p Minus Syndrome)
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Gene: 5p15.2
12% due to unequal segregation of a translocation or recombination involing a pericentric inversion in one of the parents; 85% sporadic de novo deletions (80% are paternal) Features: cat-like cry (abnormal laryngeal development), slow growth, microcephaly, MR, hypotonia, strabismus, characterstic facial features |
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Fryns Syndrome
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AR
Features: large for gestational age, corase face, CL/CP, diaphragmatic defect, distal digital hypoplasia, MR in survivors, agenesis of the corpus callosum, optic and olfactory tract hypoplasia, GU malformations; majority are stillborn or die in early neonatal period, 14% survive |
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Greig Cephalopolysyndactyly
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Gene: GLI3
AD Features: macrocephaly, ocular hypertelorism, preaxial polydactyly, cutaneous syndactyly, developmental delay, MR or seizures (<10%) though more common in larger deletions (>300 kb) |
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Joubert Syndrome
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Gene: NPHP1, AHI1, CEP290, TMEM67
AR Features: hypotonia in infancy leading to ataxia later, DD/MR, alternating tachypnea and/or apnea, pigmentary retinopathy, oculomotor apraxia or difficulty in smooth visual pursuits and jerkiness in gaze tracking, M:F 2:1, renal disease in those with retinal involvement, rarely hepatic fibrosis |
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Monosomy 1p36
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Gene: 1p36
Most common terminal deletion syndrome Features: hypotonia, developmental delay, growth retardation, obesity, microcephaly, orofacial clefting, typical facial features, minor cardiac malformations, cardiomyopathy, seizures, ventricular dilation, sensorineural hearing loss |
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Prader-Willi Syndrome
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Gene: 15q11-13
Paternal expression Features: hypothalmanic insufficiency, neonatal hypotonia, developmental delay, hyperphagia leading to obesity, short stature, small hands and feet, hypogonadism, MR Common mutations: 3-5 Mb deletion of 1511.2-13 (70%), matUPD (15%), imprinting defect (1-2%) |
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Rubenstein-Taybi Syndrome
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Gene: CREBBP, EP300
AD: only a few cases of affected parent and child Features: microcephaly, beaked nose, broad thumbs and toes, cryptorchidism, growth delay, severe MR, CHD, strabismus, ptosis, sleep apnea, tumors (meningiomas, pilomatrixomas, leukemias), behavioral problems |
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Smith-Magenis Syndrome
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Gene: RAI1, 17p11.2
AD: sporadic unless secondary to a parental balanced translocation Features: mild-moderate infantile hypotonia, feeing problems and FTT, short stature, brachydactyly, ophthalmologic and ORL abnormalities, early speech delay with or without hearing loss, peripheral neuropathy, sleep problems, stereotypic maladaptive behaviors (self-injurious behaviors, inattention + hyperactivity, impulsivity, disobedience, "self-hug" and "lick and flip" page turning motion), mild-moderate MR, coarsening face over time |
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Triploidy
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69,XXY>69,XXX (69,XYY rare)
Sporadic without increased recurrence risk Features: >99% lost in first trimester, accounts for 6-10% of SABs and 16-20% of all chromosomally abnormal SABs;dysplastic calvaria with large posterior fontanelle, 3/4 finger syndactyly, ASD, VSD, hydrocephalus, holoprosensephaly Maternal: small placenta, severe asymmetric IUGR with large head Paternal: hydropic large placenta, well grown to moderate symmetric IUGR, normal to microcephalic head |
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Trisomy 13; Patau Syndrome
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75% due to maternal nondisjunction, 20% to translocation, 5% to mosaicism
Least common live born trisomy disorder Features: holoprosencephaly, polydactyly, seizures, HL, microcephaly, midline CL/CP, omphalocele, cardiac and renal anomalies, MR 44% die in first month, >70% die within one year, severe MR for survivors |
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Trisomy 18, Edwards Syndrome
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90% due to maternal nondisjunction, 10% mosaicism, <1% to translocation
Features: clenched hand, fingers 2/5 overlap 3/4, IUGR, rocker bottom feet, micrognathia, prominent occiput, microphthalmia, VSD, ASD, PDA, generalized muscle spasm, renal anomalies, MR 50% die in first week, 90% die by one year |
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Trisomy 21; Down Syndrome
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90% due to maternal nondisjunction (3/4 MI, 1/4 MII); 95% de novo, 5% due to Robertsonian translocation or isochromosome
Features: mild-moderate MR, hypotonia, growth delay, strabismus, adult cataracts, myopia, conductive hearing loss, macroglossa, hypodontia, joint hyperflexibility, hypogenitalism, CHD, duodenal atresia, hirschprung, thyroid disease, early onset Alzheimers, transient myeloproliferation, ALL |
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VACTERAL (VATER) Association
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Diagnosis of exclusion
Features: 3/7; vertebral anomalies, anal atresia, cardiac malformations (VSD, PDA, TOF, TOV), treachoesophageal fistula, esophageal atresia, renal anomalies, limb anomlies (polydactyly, humeral hypoplasia, radial aplasia, proximally placed thumb |
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Wolf-Hirschorn Syndrome (4p minus, Monosomy 4p)
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4p16.3
87% de novo, 13% to unbalanced translocation from a balanced parent Features: "greek warrior helmet appearance" microcephaly, pre/postnatal growth deficiency, MR, seizures, facial asymmetry, ptosis, IgA deficiency, structural brain anomalies, CL/CP, CHD (ASD>PVS>VSD>PDA>AI>TOF), renal anomlies |
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Hidrotic Ectodermal Dysplasia
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Gene: GJB6
AD Features: malformed, thickened, small nails; hypotrichosis (partial or total alopecia); palmoplantar hyperkeratosis; normal sweating and teeth Common mutations: G11R, A88V, V37E) |
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Hypohidrotic Ectodermal Dysplasia
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Gene: EDA, EDAR, EDARADD
XL (95%), AD/AR (5%) Features: peeling skin and perioral hyperpigmentation at birth; hypotrichosis (sparse scalp and body hair); hypohidrosis (inability to sweat in response to heat leads to hyperthermia), hypodontia (usually only 5-7 teeth develop, are small with conical crowns); carriers show mosaic pattern of sweat pore function and some degree of hypodontia |
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Incontinentia Pigmenti
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Gene: IKBKG (NEMO)
ELD: most male fetuses miscarry Features: stages of skin changes (erythema to blister to hyperpigmented streaks to atrophic skin patches); hypo/adontia, small or malformed teeth, alopecia, woolly hair, nail ridging or pitting, retinal neovasculatization causing retinal detachment, MR is rare |
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Oculocutaneous Albanism
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Gene: TYR, OCA2
AR 1A: no melanin synthesis, nystagmus, decreased iris pigment, foveal hypoplasia, decreased vidual acuity, strabismus, white hair and skin, translucent iris 1B: some melanin synthesis, milder eye skin manifestation 2: ocular problems some as 1A but better vision, range of skin and eye pigmentation from minimal to near normal |
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Amyotrophic Lateral Sclerosis (Lou Gehrig Disease)
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Gene: SOD1
AD Features: frontotemporal dementia Upper-motor neuron dominant: hyperreflexia, extensor plantar response, increased muscle tone, weakness Lower-motor neuron dominant: weakness, muscle wasting, hyporelexia, muscle cramps, fasciculations |
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Charcot Marie Tooth Disease
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Type 1: abnormal myelin, AD, 50% of cases, PMP22
Type 2: axonopathy, AD, 20-40% of cases, KIF1B and MFN2 Intermediate: combination of myelinopath and axonopathy, AD, rare, DNM2 Type 4: either myelinopathy or axonopathy, AR< rare, GDAP1 Type X: axonopathy with secondary myelin changes, XLD, 10-20% of cases, GJB1 Features: slowly progressive weakness and atrophy of distal muscle in the feet and/or hands beginning in the 1st-3rd decade, hearing loss, pes cavus foot deformity, hip dysplasia |
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Duchenne and Becker Muscular Dystrophies
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Gene: DMD
XLR Features: Severe: symptoms present before age 5, progressive symmetrical muscular weakness (proximal>distal), calf hypertrophy, DCM Milder: later onset, weakness of quadriceps may be only sign, activity induced cramping, preservation of neck flexor muscles, isolated DCM |
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Freidreich's Ataxia
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Gene: FRDA
AR Features: progressive degeneration of the dorsal root ganglia, posterior columns, corticospinal tracts, and the dorsal spinocerebellar tracts of the spinal cord and cerebellum; progressive limb and gait ataxia before age 25; absent tendon reflexes in the lower extremities; within 5 years, dysarthia, areflexia, pyramidal weakness of the legs, extensor plantar responses and distal loss of joint position and vibration sense; scoliosis, pes cavus, optic nerve atrophy, HCM, diabetes/glucose intolerance Mutations: GAA triplet repeat in FRDA intron 1 (96% homozygous); normal 5-33, permutation 34-65, disease causing 66-17000 |
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Hereditary Neuropathy with Liability to Pressure Palsies
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Gene: PMP22
AD Features: adult with recurrent focal pressure palsies, mild polyneuropathy, absent ankle reflexes, reduced DTRs, mild-moderate pes cavus deformity |
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Limb-Girdle Muscular Dystrophy
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Gene: CAPN3, FKRP, LMNA, SGCA, SGCB, SGCD, SGCG, DYSF
AR: some rare AD Features: Sacroglycans: proximal limb weakness, difficult running and walking, calf hypertrophy, onset age 3-15 (68% childhood, 10% adult) Calpai: proximal limb weakness, difficult running and walking, calf atrophy, onset 2-40 years (10-30% AR) Dysferlin: problems running and walking, foot drop, distal and/or pelvic weakness, transient calf hypertrophy, onset 17-23 years |
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Myotonic Dystrophy type 1
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Gene: DMPK
AD Features: multisystem disorder of skeletal and smooth muscle, eyes, heart, endocrine, and CNS Mild: cataract and mild myotonia Classic: muscle weakness and wasting, myotonia, cataract, arrhythmia, grip myotonia (sustained muscle contraction leads to inability to quickly release a hand grip) Congenital: hypotonia and severe generalized weakness at birth often with respiratory insufficiency and early death, MR is common Mutations: repeats in the 3'-UTR region; mild 50-150; classic 100-1000; congenital >2000 |
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Nemalin Myopathy
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Gene: ACTA1, NEB
AR or AD Features: weakness, most severe in face, neck flexors, and proximal limb muscles; hypotonia; depressed or absent DTRs; age of onset varies, from congenital to adulthood; hallmark is rod-like inclusions in sarcoplasm on muscle biopsy |
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Spinal Muscular Atrophy
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Gene: SMN1, SMN2
AR Features: arthrogryposis multiplex congenital, peripheral nerve hypomyelination Type I: onset 0-6 months, muscle weakness, tongue fasiculations, absent DTRs Type II: muscle weakness, onset after 6 months, finger trembling, low tone, absent DTRs Type III: weakness lead sto frequent falls or trouble with stairs, onset 2-3 years, proximal weakness (legs>arms) Type IV: adult onset |
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Syndromic Congenital Muscular Dystrophy
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Gene: FCMD, POMGNT1, POMT1, POMT2, LARGE
AR Features: muscle weakness present at birth; hypotonia; joint contratures |
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Tay Sachs Disease
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Gene: HEXA
AR Carrier frequency: 1/25 (4%) in AJs Features: Infantile: weakness starts at 6 months, exaggerated startle, seizures, vision loss by end of the first year, neurodegeneration, cannot swallow, eventual paralysis, death in toddler years Juvenile: muscle coordination problems, seizures, vision problems starting as young children Chronic/adult onset: start later, progress more slowly, more rare |
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Beckwith-Wiedemann Syndrome
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Gene: maternally expressed 11p15.5
AD: only about 15% Features: hemihyperplasia, macrosomia, macroglossia, visceromegaly, embryonal tumors (Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, renal abnormalities Mutations: 50% loss of methylation, 10-20% paternal UPD, mutations in CDKN1C (40% familial cases, 5-10% sporadic cases) |
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Sotos Syndrome
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Gene: NSD1, 5q35
AD Features: Classic: macrocephaly; pointed chin; tall stature and increased body mass; delayed motor skills; delayed cognitive, verbal, and social development Less common: phobies, aggression, OCD, ADD, abnormal EEG and seizures, chronic OM and constipation, congenital heart defects, strabismus, hyper/hypothyroidism, possible increased risk for tumors (saccrococcygeal teratome and neuroblastoma) |
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Ataxia-Telangiectasia
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Gene: ATM
AR Features: progressive cerebellar ataxia (onset age 1-4 yaer), oculomotor apraxia, conjunctival telangiectasia, immunodeficiency, choreoathetosis, ionizing radiation sensitivity, risk of cancer (lymphoma and leukemia) |
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Bloom Syndrome
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Gene: BLM
AR Frequency: 1/100 carrier frequency in AJ Features: IUGR, hyper and hypopigmentation, butterfly distribution sun sensitive telangiectasia, microcephaly, high pitched voice, normal intelligence, immunodeficiency, azoospermia, POF, increased risk of cancer (colon most common, variable in general, often multiple primaries) Common mutations: 2881del6ins7 97% in AJ |
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Fanconi Anemia
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Gene: FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG,BRACA2, BRIP1, FANCL
AR Features: short stature; abnormal pigmentation; radial, GU, ear, heart, GI, or CNS malformation; hearing loss; hypogonadism; developmental delay; progressive bone marrow failure, aplastic anemia, myelodysplastic syndrome, AML, solid tumor of head, neck, esophagus, cervix, vulva, or liver at unusually young age |
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X-Linked Adrenoleukodystrophy
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Gene: ABCD1
XLR Features: Type A: childhood cerebral, ADHD -> total disability within 2 years Type B: adrenomyeloneuropathy, late 20s progressive paraparesis, sphincter disturbance, adrenocortical dysfunction Type C: adrenocortical insufficiency, majority by age 7.5 (seen in 20% of carrier females) |
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Early Onset Familial Alzheimer Disease
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Gene: PSEN1, APP, PSEN2
AD Features: dementia, confusion, poor judgment, language, disturbance, abitation, withdrawal, hallucinations; early onset < age 60 Early-onset: 1-6% of all Alzheimer's, 60% of which is familial, and 13% inherited in an AD manner Later-onset: appears to be associated with APOE e4, but not sensitive or specific, just supports diagnosis; APOE e2 may be protective |
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Angelman Syndrome
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Gene: UBE3A
65-75% 4-6 Mb deletion of region, 11% UE3BA mutation, 2.5% imprinting defect, <1% unbalanced translocation, <1% pat UPD, 0.5% deletion of imprinting center Features: severe developmental delay, severe speech impairment, gait ataxia and/or tremulousness of limbs, inappropriate happy demeanor that includes frequent laughing, smiling, and excitability, microcephaly, seizures |
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CADASIL: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leuoencephalopathy
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Gene: NOTCH3
AD Features: stroke-like episodes before age 60, cognitive disturbance, behavioral abnormalities, migraine with aura |
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Canavan Disease
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Gene: ASPA
AR Carrier Frequency: 1/40 (2.5%) in AJs Features: macrocephaly, lack of head control, developmental delays by age 3-5 months, severe hypotonia leading to spasticity, never sit, walk, or speak Common mutations: account for 99% of disease causing alleles in Ashkenazi Jewish, 50-55% in non-Jewish |
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Familial Dysautonomia
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Gene: IKBKAP
AR Features: progressive GI dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain and temperature, CV instability, autonomic crises, hypotonia, broad based ataxic gate deteriorates, decreased life expectancy, decreased taste and absence of fungiform papillae of the tongue, decreased or absent DTRs, absence of overflow tears with crying Common mutations: IVS20 (+6T>C); R696P (<99% Ashkenazi Jewish population) |
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Fragile X
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Gene: FMR1
X-linked triplet repeat Features: delayed motor and verbal development, MR (moderate-severe in boys, milder in girls), prominent jaw and forehead, high activity, autistic features; carrier females with anxiety, POF (20%), depression, OCD; carrier males (>30% of males > age 50) progressive intention tremor, ataxia, parkinsonism, autonomic dysfunction Mutations: normal 5-44 repeats, intermediate 45-58 repeats (grey zone), pre mutation 59-200 repeats, mutation >200 repeats |
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Huntington Disease
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Gene: HD
AD Features: progressive motor disability involving both involuntary and voluntary movement (chorea, dysarthria, dysphagia progress to bradykinesia, rigidity, and dystonia), cognitive decline (problems with planning and organization), psychiatric disturbances (personality change, affective psychosis, schizophrenic psychosis); mean age of onset 35-44 years (juvenile onset <20 years in 10%) Mutation: 27-35 repeats no symptoms but risk of expansion if male (6-10% risk of expansion with 35 repeats), 36-39 reduced penetrance, may never develop symptoms, >40 fully penetrant, >60 juvenile onset |
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Krabbe Disease
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Gene: GALC
AR Features: Infantile form: irritability to sensory stimuli, muscle hypertonicity, progressive neurologic deterioration, peripheral neuropathy, white matter disease, elevated CSF protein Later onset (6 mo to 5th decade): weakness, vision loss, intellectual regression |
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Neurofibromatosis type I
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Gene: NF1
AD Features: 6x5mm (prepubertal) or 6x15mm (postpubertal) café au lait, 2 or more neurofibromas, one plexiform neurofibroma, axillary or inguinal freckling, optic glioma, 2 or more lisch nodules, sphenoid dysplasia or thinned long bone cortex |
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Parksinson Disease
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Gene: PARK2
AD, AR, multifactorial Features: bradykinesia, rigidity, tremor, asymmetric limb involvement; juvenile onset AR PARK2 mutations, typical features with onset 20-40 years |
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Rett Syndrome
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Gene: MECP2
XLD Features: MR, developmental regression (especially language and hand use), acquired microcephaly, stereotypical wringing hand movements, hyperventilation, bruxism, paroxysmal laughing, prolonged QT, scoliosis |
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Wilson Disease
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Gene: ATP7B
AR Features: can present age 3-50 years, liver disease (jaundice, self-limited hepatitis-like illness, autoimmune hepatitis, hepatic failure, chronic liver disease); neurologic presentation includes movement disorder, disorganized of personality |
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X-Linked Agammaglobulinemia
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Gene: BTK
XLR Features: recurrent otitis media, pneumonia, sinusitis <5years, meningitis or cellulitis, paucity of lymphoid tissue |
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Familial Mediterranean Fever
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Gene: MEFV
AR Features: Type 1: recurrent febrile episodes with peritonitis, synovitis, or pleuritis; recurrent erysipelas-like erythema; AA type amyloidosis; favorable response to continuous colchicine treatment Type 2: amyloidosis as first clinical presentation At-risk groups: Armenian, Turkish, Arab, North African Jewish, Iraqi Jewish, Ashkenazi Jewish |
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Alpha-1-Antitrypsin Deficiency
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Gene: SERPINA1
AR Features: adult COPD, childhood and adult liver disease (obstructive jaundice and raised transaminases in kids, cirrhosis and fibrosis in adults), age of onset 40-50years if smoker, 60s if not |
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CFTR-related disorders
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Gene: CFTR
AR Carrier Frequency: 1/25 (4%) in Europeans Features: chronic airway infection, chronic sinusitis, meconium ileus, malabsorption due to pancreatic insufficiency, male infertility due to azoospermia; progressive to end stage lung disease; congenital bilateral absence of the vas deferens occurs in men without pulmonary or GI sx Mutations: Class I: reduced or absent synthesis Class II: block in protein processing Class III: block in regulation of CFTR chloride channel Class IV: altered conductance of CFTR chloride channel |
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Blepharophimosis, Ptosis, and Epicanthus Inversus (BPES)
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Gene: FOXL2
AD, 50% de novo Features: blepharophimosis, ptosis, epicanthus inversus, and telecanthus Type I: includes POF Type II: may also include lacrimal duct anomalies, amblyopia, strabismus, and refractive errors |
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Congenital Hearing Loss: Connexin 26 and 30
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Gene: GJB2, GJB6
AR Features: congenital mild-profound SNHL; rare AD Cx26 include palmarplanter keratoderma, KID syndrome |
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Hermansy-Pudlak Syndrome
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Gene: HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, HPS7, HPS8
AR Features: hypopigmentation of the skin and hair, nystagmus, reduced iris pigment, reduced retinal pigment, foveal hypoplasia, increased crossing of optic nerve fibers, development of skin cancer, pulmonary fibrosis, colitis |
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Jervell and Lange-Nielsen Syndrome
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Gene: KCNQ1 and KCNE1
AR; carriers at risk for long OT (Romano-Ward syndrome) Features: congenital severe-profound bilateral SNHL and prolonged QT interval; risk for arrhythmia, syncope, sudden death |
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Leber Herditary Optic Neuropathy
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Gene: MTND1, MTND4, MTND5, MTND6
Mitochondrial Features: blured or clouded vision progressing to degeneration of the retinal nerve and then optic atrophy; vascular tortuosity of central retinal vessels, circumpapillary telangiectatic macroangiopathy, swelling of the retinal nerve fibers Common mutations: 70% G11778A, 15% G3460A and T14484C |
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Pendred Syndrome
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Gene: SLC264A (PDS)
AR Features: bilateral severe SNHL, temporal bone abnormalities, vestibular abnormalities, goiter in 78% though only 10% have abnormal thyroid function |
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Usher Syndrome
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Gene: MYO7A, USH2A
AR Features: Type I: congenital profound HL, congenital balance problems, retinitis pigmentosa onset pre-puberty Type II: congenital mild-severe HL, normal balance, renities pigmentose onset teens-20s Type III: progressive later onset HL, progressive balance problems, variable onset retinitis pigmentosa |
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Waardenburg Syndrome
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Gene: PAX3
AD Features Type I: SNHL, heterochromic irides, white forelock, early greying, leukoderma, dystrophia conthorum, neural tube defect Type II: type I without dystrophia conthorum Type III: type I with limb hypoplasia or contracture, carpal bone fusion or syndactyly Type IV: type I with hirschprung |
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Achondroplasia
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Gene: FGFR3
AD; 80% de novo Features: short stature, rhizomelic shortening, trident hand, frontal bossing, midface hypoplasia, macrocephaly, obstructive sleep apnea, spinal cord compression Mutations: 98% G1138A, ~1% G1138C |
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Cleidocranial Dysplasia
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Gene: RUNX2
AD; high proportion de novo Features: delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, multiple dental abnormalities; abnormally large wide open anterior fontanel, midface hypoplasia, brachdactyly, recurrent OM, HL, normal intellect |
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Diastrophic Dysplasia
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Gene: SLC26A2
AR Features: limb shortening, normal-sized skull, hitchhiker thumbs, small chest, large joint contracture, cleft palate, cystic ear swelling, ulnar deviation of fingers, clubfoot, low tone, normal IQ |
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FGFR-Related Craniosynostosis: Pfeiffer, Apert, Crouzon, Beare-Stevenson, FGFR2-related Isolated Coronal Synostosis, Jackson-Weiss, Crouzon with Acanthosis Nigricans, and Muenke
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Gene: FGFR1, FGFR2, FGFR3
AD Features: Bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand/foot anomalies; developmental delay, HL, visual impairment |
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Hypochondroplasia
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Gene: FGFR3
AD Features: short stature, stocky build, rhizo- or mesomelia, limited elbow extension, brachydactyly, mild joint laxity, macrocephaly, scoliosis, geru varum, lumbar lordosis, mild-moderate MR, LD, adult onset asteoarthritis |
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Multiple Exostoses Syndrome
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Gene: EXT1, EXT2
AD Features: exostoses (benign cartilage-capped bony growths) arising from the growth plate of the long bones or from the surface of flat bones (scapula); limb length inequity and bowed long bones can develop; short metacarpals; can have mass effect compression of nerves and blood vessels |
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Osteogenesis Imperfecta
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Gene: COL1A1, COL1A2
AD, rare AR Features: fractures with little or no trauma, relative short stature, blue sclera, dentinogenesis imperfect, post-pubertal HL, ligamentous laxity, easy bruising Type II: perinatal lethal, palable callus formation on ribs, hips in frog-leg position, short bowed extremities Type III: severe, skull descends on cervical spine-brainstem compression, obstructive hydrocephalus, syringomyelia |
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Saethre-Chotzen Syndrome
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Gene: TWIST1
AD Features: coronal synostosis, facial asymmetry, ptosis, 2/3 syndactyly, mild-moderate developmental delay in a minority, short stature, parietal foramina, vertebral fusions, radioulnar synostosis, cleft palate, maxillary hypoplasia, congenital heart defect |
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Congenital Contractural Arachnodactyly: Beals Syndrome
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Gene: FBN2
AD Features: Marfanoid appearance, long slender fingers and toes, crumpled ears, major joint contracture, muscle hypoplasia, kyphosis/scoliosis, severe/lethal aortic dilation, ASD, VSD, IAA, duodenal or esophageal atresia |
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Ehlers-Danlos Syndrome Classic Type (I and II)
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Gene: COL5A1, COL5A2
AD Features: skin hyperextensibility, widened atrophic scars, joint hypermobility, smooth velvety skin, molluscoid pseduotumors (heaped up scar-like lesions over pressure points), subcutaneous spheroid (cyst-like lesions, feel like grains of rice, over bony prominence of legs and arms), joint sprains/dislocations/subluxations, hypotonia, easy bruising, hernia, chronic pain, aortic root dilation |
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Ehlers-Danlos Syndrome Hypermobility Type (III)
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Gene: TNXB
AD Features: joint hypermobility, soft/velvety skin with normal or slightly increased elasticity, absence of skin or soft tissue fragility, recurrent joint dislocation/subluxation, chronic joint or limb pain, easy bruising, high narrow palate, dental crowding, low bone density |
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Ehlers-Danlos Syndrome Vascular Type (IV)
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Gene: COL3A1
AD Features: arterial rupture, intestinal rupture, uterine rupture during pregnancy; thin translucent skin, easy bruising, thin lips and philtrum, small chin, thin nose, large eyes, aged appearance of hands, small joint hypermobility, tendon/muscle rupture, varicose veins, AV carotid-cavernous sinus fistula, pneumothorax, CHD, clubfoot, gum recession |
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Ehlers-Danlos Syndrome Kyphoscoliotic Type (VI)
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Gene: PLOD1
AR Features: friable hyperextensible skin, thin scars, easy bruising, generalized joint laxity, severe muscle hypotonia, progressive scoliosis, scleral fragility and rupture of the globe; widened atrophic scars, marfanoid habitus, rupture of medium sized arteries, mild-moderate delay of attainment of gross motor milestones |
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Marfan Syndrome
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Gene: FBN1
AD Features: CV: dilation or dissection of the ascending aorta, MV, MR, dilation of main PA, mitral annulus calcification, dilation or dissection of the descending thoracic or abdominal aorta < age 50 Skeletal: pectus carinatum or excavatum, reduced upper:lower segment or arm span:height, scoliosis, pes planus, high palate with crowded teeth, reduced elbow extension, protrusion acetabulae, joint hypermobility Eye: ectopia lentis, flat cornea, increased length of globe, decreaed pupillary miosis Dura: lumbosacral dural ectasia, skin striae, hernia Lung: pneumothorax, apical lung blebs |
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Ataxia with Oculomoter Apraxia Type 1 and Type 2
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Gene: APTX, SETX
AR Features: childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy, oculomotor apraxia progresses to external ophthalmoplegia |
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Cockayne Syndrome
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Gene: ERCC6, ERCC8
AR Features: Type I: normal prenatal growth, severe FTT in first 2 years, progressive deterioration of vision, hearing, CNS, and peripheral nervous syndrome Type II: growth failure at birth, little or no postnatal neurological development, kyphosis, scoliosis, joint contracture Type III: normal growth and development or late onset Type XP: facial freckling, early skin cancer, MR, spasticity, short stature, hypogonadism |
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Hutchinson-Gilford Progeria Syndrome
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Gene: LMNA
AD; all de novo, paternal age effect Features: short stature, wt<<ht, head large for face, diminished sc fat, prominent scalp veins, generalized alopecia, delayed and crowded teeth, delayed fontanelle closure, pear shaped thorax, small chin, thin limbs, tight joints, wide based shuffling gate, sclerodermatous skin changes over lower abdomen and thughs |
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X-Linked Adrenal Hypoplasia Congenita
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Gene: NROB1
XLR Features: actue onset adrenal insufficiency (hyperkalemia acidosis, hypoglycemia, shock), cryptorchidism, delayed puberty, carriers may have adrenal insufficiency or hypogonadotropic hypogonadism |
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21-Hydroxylase-Deficient CAH
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Gene: CYP21A2
AR Features: virilized female, precocious puberty or adrenarche, childhood virilization in males, infant with Na+ losing crisis at birth Non-classic form: moderate enzyme deficiency with variable postnatal virilization, no salt wasting, rare cortisol deficiency |
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Androgen Insensitivity Syndrome: Testicular Feminization
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Gene: AR
XLR Features: evidence of feminization (i.e. undermasculinization) of the external genitalia, abnormal secondary sexual development, and infertility in those with a 46,XY Complete: typical female genitalia Partial: predominantly female, predominantly male, or ambiguous genitalia Mild: normal male genitalia |
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Kallman Syndrome Type 1 and 2
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Gene: KAL, FGFR1
XLR, AD Features: hypogonadotropic hypogonadism and anosmia, usually present with delayed pubertal development Type 1: include mirror hand movements, ataxia, GU anomaly, high palate, pes cavus Type 2: MR, CL/CP, cryptorchidism, choanal atresia, CHD, CNHL |
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Klinefelter Syndrome
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Features: tall stature, slightly delayed motor and language skills, increased learning problems, testerone plateaus age 14, small fibrosed testes, azoospermia and infertility, gynecomastia, increased cholesterol, slightly increased risk of autoimmune disorders and mediastinal germ cell tumors
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McCune-Albright Syndrome
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Gene: GNAS
sporadic Features: polyostotic fibrous dysplasia, pathologic fracture, cranial foramina thickening->deafness and blindness, large irregular café au lait, precocious puberty, hyperthyroidism, increased GH, PRL, or PTH, ovarian cysts |
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Transient Neonatal Diabetes Mellitus
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Gene: HYMAI, PLAGL1
6q24 Features: DM in first six weeks of life, resolves by 18 months, severe IUGR, dehydration, hyperglycemia, occasional macroglossia and umbilical hernia Mutations: maternal UPD 35%, duplication 35%, imprinting mutation 20% |
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Turner Syndrome
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Features: congenital lymphedema, growth failure, normal intelligence (10% significant delays), coartaction of the aorta, bicuspid aortic valve, HLHS, hyperlipidemia, gonadal dysgenesis, (10% 45,X go into puberty), hypothyroidism, diabetes, strabismus, recurrent OM, SNHL, Crohns, renal malformations, osteoporosis
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Alport Syndrome with Thin BM Nephropathy
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Gene: COL4A5, COL4A3, COL4A4, COL4A3, COL4A4
80% XL, 15% AR, 5% AD Features: spectrum from progressive renal disease with cochlear and ocular abnormalities to isolated hematuria with a benign course |
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Polycystic Kidney Disease
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Gene: PKD1, PKD2, PKHD1
AD, AR Features: AD: enlargement of both kidneys, renal cysts, hematuria, polyuria, flank pain, renal stones, urinary infection; cysts in liver pancreas, and intestine; heart valve defects, intracranial aneurysm AR: fetal or neonatal death, impaired lung formation, pulmonary hypoplasia due to oligohydramnios, renal failure, hepatic fibrosis, most present prenatally or early infancy |
