2946515
| Question | Answer |
| Hereditary Motor and Sensory Neuropathy, Type I | AD, 70% 1.5 Mb duplication of chr 17p with PMP22 gene (due to homologous regions), mutation in gene MPZ Pheno - slowly progressive distal muscle weakness and wasting between 10-30 yo lower limbs then upper limbs, pes cavus, absent DTR. Dx - motor nerve conduction velocity reduced. nerve bx with segmental demyelination accompanied by hypertrophic changes with 'onion bulb' formation Path: decreased mRNA message for PMP22 and decreased myelin protein 22 in peripheral nerve |
| Hereditary Motor and Sensory Neuropathy, Type II | Pheno - slowly progressive distal muscle weakness and wasting, later onset. Dx - motor nerve conduction velocity normal, nerve bx with axonal degeneration. |
| Hereditary Motor and Sensory Neuropathy, type III | Rare. Pheno - Slowly progressive distal muscle weakness and wasting in early childhood, delay in motor milestones. |
| Brugada Syndrome | Gene: SCN5A (3p21) 20%, many other genes account for <1% cases each, AD Common southwest Asia, M:F 8:1 Sx: syncope, nocturnal agonal respiration, ST segment abnl V1-V3 on EKG and high risk of ventricular arrhythmias. Mean age of sudden death 40 yo (range 2 days to 85 yo). May present as SIDS or unexpected nocturnal death. Rx: implantable defibrillator, isoproterenol, avoid inducing medications |
| Dilated Cardiomyopathy | Gene: 30+ genes 40-50% cases, TTN mutations in 20%, others LMNA, MYH7, MYH6, SCN5A, MYBPC3, TNNT2, BAG3 Sx: CHD, arrhythmima, thromboemolic events, surveillance q2-5y for first degree relatives (EKG, echocardiogram) |
| Hypertrophic Cardiomyopathy | AD, ~20 genes encoding cardiac sarcomere Two most common genes; MYH7, MYBPC3 3-4% Fabry disease Sx: LVH, asymptomatic, progressive heart failure, sudden cardiac death Rx: medical management of diastolic dysfunction, implantable defibrillator, avoid competitive endurance training, dehyration, hypovalemia, meds that decrease afterload (ACE-I, ARB) |
| Spinal Muscular Atrophy Type I | Homozygous deletion of SMN1 (telomeric) exons 7-8 in 95-98% of all patients with childhood SMA. SMN2 (centromeric) copies can modify phenotype. Carriers with 2 copies in cis can be misdiagnosed as non-carriers. Pheno: normal IQ, onset <6 mo profound muscle weakenss, death first 2 years of life. Dx: electromyography |
| Spinal Muscular Atrophy Type II | Pheno: onset 6-18 mo severe hypotonia, survival early adult life |
| Spinal Muscular Atrophy Type III | Pheno: childhood or juvenile-onset with weakness after 18 mo, slowly progressive muscle weakness, wheelchair by early adult life. |
| Duchenne Muscular Dystrophy Becker Muscular Dystrophy | DMD 1 in 3500, BMD 1 in 20,000 High mutation rate 1:10,000 Genetics: Dystrophin, largest gene on X, most mutations are deletions (MLPA for dx), 5-15% maternal germline mosaicism DMD - 1/3 new mutations, 2/3 carrier mom BMD - most inherited, 10% new mutations Sx: DMD 3-5 yo progressive proximal muscle weakness, gower's sign, enlarged calves, wheelchair by 11 yo, lumbar lordosis, joint contractures, cardiorespiratory failure, IQ decrease ~20 points, pseudohypertrophy, BMD - onset 11 yo. Carrier females: 20% have some weakness, 8% life-threatening cardiomyopathy and proximal muscle disability Rx: glucocorticoid therapy can slow progression New Rx?: antisense oligonucleotides are used for exon skipping of frame-disrupting mutations in pre-mRNA |
| Hemophilia A | Gene: F8 (Xq28; Factor VIII), XLR. 45% severe cases inversion (IVS22) deleting the carboxyl terminus. 1:5000 males. Sx: hemarthrosis, intracranial bleed, deep muscle hematomas, prolonged or renewed bleeding after injury or surgery Eval: prolonged PTT, Factor VIII activity (severe <1%, moderate 1-5%, mild 6-35%). Rx: IV Factor VIII prophylactically 3x/wk in severe cases and after trauma, avoid IM injection. |
| Hemophilia B Christmas Disease | Gene: F9 (Xq27.1; Factor IX), XLR. Many mutations identified. 1:100,000 males Sx: hemarthrosis, intracranial blled, deep muscle hematomas, prolonged or renewed bleeding after injury or surgery Eval: prolonged PTT, Factor IX activity (severe<1%, moderate 1-5%, mild 6-30%) Path: F9 activates F10 - critical step in rate of thrombin generation in coagulation. Rx: Recombinant factor IX concentrate 2-3x/wk for severe deficiency and within 1hour of trauma Rare: Factor IX Leyden is unusual variant caused by point mutation in F9 promoter associated with severe hemophilia during childhood, but spontaneous resolution at puberty. |
| Neurofibromatosis Type I | Gene: NF1 (chr 17), 1 in 3000, AD, 50% de novo, gene deletions more severe Path: GTPase signaling protein, makes RAS tyrosine kinase inactive, protein deficiency keeps signal active Sx: cafe au lait spots (min 6 at least 5 mm diameter pre-puberty, 15 mm post-puberty), neurofibromas, skin fold freckling, macrocephaly, lisch nodules, optic glioma, orbital dysplasia, tibial dysplasia, scoliosis |
| Neurofibromatosis Type 2 | AD, 1 in 25,000 Gene: NF2 (chr 22) Dx: bilateral vestibular schwanommas, schwanommas of other cranial nerves, meningioma, ependymoma, juvenile posterior subcapsular cataract/cortical wedge opacity |
| Schwannomatosis | Gene: AD, rare, incomplete penetrance, INI1/SMARCB1 (chromatin remodeling protein, near NF2 on chr22, deletion in NF2 plays role in ) or LZTR1 (also near NF2) Sx: painful schwannomas |
| Legius Syndrome | SPRED1 mutation Regulator of RAS pathway |
| Tuberous Sclerosis Complex | Gene: TSC1 (9q34), TSC2 (16p13), AD, complete penetrance, 1/6,000 Path: tumor suppressor (mTOR inhibition) Dx: Major criteria (3+ angiogibromas, 2+ ungual fibromas, 3+ hypomelanotic macules, shagreen patch, retinal hamartomas, subependymal giant cell astrocytoma, 2+ subependymal nodules, 3+ cortical dysplasias, cardiac rhabdomyoma, renal angiomyolipoma, lymphangioleiomyomatosis), Minor (dental enamel pits, intraoral fibromas, non-renal hamartomas, retinal achromic patch, confetti skin lesions, multiple renal cysts) Rx: everolimus Surveillance: Renal US q1-3y, renal CT/MRI if numerous lesions on US, semiannual US if angiomyolipomas <3.5-4 cm, chest CT if pulm sx (lymphagiomatosis in women 20-40 yo) |
| Parkinson Disease | Gene: multiple loci, PARK2 (6q25.2, juvenile onset biallelic, AR); het carrer for glucocerebrosidase (Gaucher), SNCA (alpha-synuclein, GOF, AD), AD/AR/multifactorial Sx: tremor, rigidity, bradykinesia Rx: dopamine, palliodoctomy, deep brain stimulation of subthalamic nucleus |
| Fragile X Tremor Ataxia Syndrome | Sx: ataxia, intention temor, short term memory loss, dementia, parkinson, symptoms, premutation, > 50 yo Premutation 59-200 are at increased risk of fragile X tremor/ataxia syndrome. |
| DYT1 | Mutation in Torsin A (9q34), AD Ashkenazi Jewish population GAG deletion most common mutation. Sx: focal to generalized dystonia |
| DYT5 | AD Sx: diurnal pattern of dystonia GTP cyclohydrolase I/tyrosine hydroxylase Easily treatable! DOPA-responsive. |
| Pantothenate Kinase Associated Neurodegeneration | Sx: movement disorder (dystonia, choreoathetosis, rigidity), ophthalmologic signs (RP, optic atrophy), progressive, iron accumulation of basal ganglia (eye of tiger) Genetics: AR, PANK2 mutations |
| Prion-Associated Dementia | PRNP mutations (familial or infectious). Spongiform encephalopathies: Cruezfeld-Jacob disease Gerstmann-Staussler-Scheinker disease Fatal familial insomnia |
| Cerebral Autosomal Dominant Arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) | Gene: NOTCH3 (19p13.2), AD Sx: stroke-like episodes before age 60 yo, cognitive disturbance, behavioral abnl, migraine with aura Eval: skin bx with dense granules in media of arterioles, Brain MRI T2 signal abnl in WM of temporal pole and external capsule, subcortical lacunar lesions (groups of rounded lesions at the jxn of GM and WM. WM changes seen as early as age 21 yo). Path: encodes transmembane receptor involved in cell fate specification during development. |
| Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) | AR, HTRA1 Small vessel cerebrovascular disorders |
| Hereditary Spastic Paraplegia | Sx: progressive weakness and spasticity in lower extremities, bladder disturbance, may be complicated by seizures, dementia, or movement disorder Genetics: multiple causes, most common AD Spastin gene |
| Facioscapulohumeral Dystrophy | Sx: weakness of facial and upper shoulder girdle muscles, retinal vasculopathy, SNHL Genetics: abnormal DUX4 expression, deletions in D4Z4 3.3 kb repeat (11-100 normal, 1-10 abnormal) |
| Adenosine Deaminase Deficiency | SCID with FTT, marked lymphocytopenia Rx: PEG ADA ERT, bone marrow, IVIg, abx, retroviral vector in allogenic hematopoietic stem cells |
| Common Variable Immune Deficiency | Sx: sinopulmonary infections, meningitis after bacterial infections, chronic diarrhea, lymphoid hyperplasia, autoimmune, lymphomas Dx: IgG<100 mg/dL Rx: IVIg, Abx, monitor for lymphoma, thyroid function |
| Hyper IgE Syndrome | Sx: boils, cyst forming pneumonia, characteristic face, chiari malformation, eczema, candidiasis, arterial tortuosity, scoliosis, osteopenia, fractures, may have cold abscess Dx: IgE >2000 IU/mL Genetics: STAT3 - AD, AR - DOCK8 Rx: Abx |
| Osteogenesis Imperfecta Type 1 | Genetics: COL1A/2, AD, >95% sequence changes, 2% del/dup Path: all collagen made is normal but the quantity is reduced by half Sx: Mild, blue sclerae, brittle bones but no bone deformity |
| Osteogenesis Imperfecta Type 2 | Genetics: COL1A/2, AD, new mutations Sx: Perinatal lethal, severe skeletal deformities, dark sclerae, death within 1 month |
| Osteogenesis Imperfecta Type 3 | Genetics: COL1A/2, AD Sx: Progressive deforming, blue sclerae, fractures (often at birth), progressive bone deformity, limited growth, obstructive hydrocephalus, syringomyelia |
| Osteogenesis Imperfecta Type 4 | Genetics: COL1A/2, AD Sx: Normal sclerae, deforming, mild-moderate bone deformity, short stature, fractures |
| SLCO1B1 | Associated with statin-induced myopathy |
| HLA B*1502 | Stevens Johnson Syndrome with Abx such as carbamazepine |
| Camptomelic Dysplasia | Mutations in SOX9, AD Skeletal malformation Complete gonadal dysgenesis in 75% 46,XY cases |
| Male-Limited Precocious Puberty | AD, LCGR gene (receptor luteinizing hormone) Boys develop secondary sex characteristics at approximately 4 yo. Early epiphyseal fusion. No effect in heterozygous females. |
| X-linked epilepsy and cognitive impairment | X-linked dominant disorder with male sparing. affected females develop seizures in 2nd year of life with developmental regression. males completely unaffected. Protocadherin gene 19 - encodes cell surface molecule expressed on neurons in the CNS. |
| Charcot-Marie-Tooth disease type 1A | Genetics: Duplication PMP22 on chr 17p11.2. AD. Fully Penetrant. 70-80% of all CMT1 90% duplications arise during male meiosis Sx: onset childhood to adulthood, progressive distal weakness, distal muscle wasting, hyporeflexia, enlarged peroneal nerves, pes cavus, hammer toes Eval: Slow nerve conduction velocity. Nerve bx segmental demyelination, myelin sheath hypertrophy. Path: demyelination. PMP22 is an integral membrane glycoprotein that plays a role in myelin compaction. |
| ATR-X syndrome | X-linked Sx: Alpha-thalassemia, ID, characteristic facial features, skeletal defects, urogenital malformations. Path: LOF in chromatin remodeling protein that functions in trans to activate the expression of alpha-globin genes. Likely other targets. |
| Mendelian susceptibility to mycobacterial disease (MSMD) | Sx: susceptible to disseminated infections when exposed to moderately virulent mycobacteria (ex. BCG vaccine) Path: defect in any of several genes regulating defense against infection Example: missense mutation in interferon-gamma 2 receptor (IFNGR2) generates novel N-glycosylation site leading to large, overlyglycosylated receptor that cannot respond to interferon-gamma |
| Cystic Fibrosis | AR, CFTR gene Genetics: most common mutation deltaF508; R117H influenced by 5T/7T/9T which affects whether exon 9 is in transcript (9T best, 5T worst) Path: anion channel that conducts Cl and HCO3. facilitates maintenance of hydration of airway secretions by transport of Cl and inhibition of Na update. Evaluation: sweat chloride Rx: Gly551Asp (2% alleles) where ion channel is at cell surface w/ impaired opening and closing can be treated with Ivacaftor that corrects function |
| Normal Type I Collagen | Triple helix formed from two proalpha1 chains (encoded by COL1A1) and one proalpha2 chain (encoded by COL1A2). Assembled from carboxyl terminus to amino terminus. Triple helix section is repeat of Gly-X-Y repeats. Gly is only AA small enough for axial part of helix (very disruptive if substituted). X is usually proline. Y is usually hydroxyproline or hydroxylysine. |
| X-linked SCID | IL2RG mutation Rx: gene therapy with retroviral vector in allogenic hematopoietic stem cells (some have developed treatable leukemia-like illness) |
| Hereditary Neuropathy with Pressure Palsies | Deletion 17p11.2 |
| CHARGE Syndrome | Gene: CHD7 (8q12) 50%, AD, almost all de novo from paternal germline, rare SEMA3E Sx: Coloboma, Heart defects, Atresia of choanae, Retardation of growth and development, Genital abnormalities, Ear anomalies, facial palsy, cleft lip, TEF Eval: echo, hearing, temporal bone CT, renal US Path: chromodomain helicase DNA-binding genes affect chromatin structure and gene expression in early embryonic development |
| Crohn Disease | multifactorial inheritance. 3 common variants in NOD2 gene significantly increase risk of Crohn's disease. Heterozygotes 1.5x increased risk. Homozygotes 15-40x increased risk. Path: NOD2 binds to gram-negative bacterial cell walls and participates in inflammatory response to bacteria by activating NF-kB in monocytes. The variants reduce the ability to activate NF-kB |
| Long QT Syndromes | Locus heterogenity: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2 Path: repolarization defects in cardiac cells, usually due to LOF in subunit or regulatory protein of potassium channel (start with KCN) or gain of function in sodium channel (SCN5A) Sx: long QT, T-wave abnormalites, tachyarrhythmia, torsades de pointes, v tach Allelic - Jervelle and Lange-Nielsen syndrome (KCNQ1, KCNE1) with LQT and SNHL. |
| Marfan Syndrome | Gene: FBN1, AD, 1 in 5000, 25-35% de novo Sx: aortic dilitation, pectus, reduced upper/lower segment OR arm span/height, scoliosis, pes planus, high palate, reduced elbow extension, protrusio acetabulae, ectopia lentus, lumbrosacral dural ectasia Path: extracellular matrix glycoprotein usually polymerizes to form microfibrils in both elastic and nonelastic tissues, loss of fibrillin 1 leads to increase of unbound TGF-beta and its signaling. Rx: beta-blockers, losartan, bracing for scoliosis, eye exams |
| Type 2 Diabetes Mellitus | Polygenic disease with environmental modifiers. TCF7L2 - short tandem repeat polymorphism in intron has increased relative risk for PPARG - Pro12Ala variant increased risk |
| Rett Syndrome | Gene: MECP2 (Xq28, XLD), LOF, females 1 in 10,000; Males: dup of MECP2 -> severe ID Sx: classic females nl until 6-18 mo, ID, developmental regression (esp language and hand use), acquired microcephaly, stereotypical wringing hand movements, hyperventilation, bruxism, paroxysmal laughing, prolonged QT, scoliosis, increased sudden death Eval: EEG, ECG Path: ?mediates transcriptional silencing and epigenetic regulation -> dysfxn causes inappropriate activation of target genes Rett-like phenotypes: CDKL5 (XL), FOXG1 (AD) Rx: symptomatic for seizures, rigidity, and sleep disturbance |
| Disorders of sex development 46,XX Males | 80% have translocation of SRY onto X Sx: hypogonadism, azoospermia, hyalinization of seminiferous tubules, gynecomastia, normal to short stature, usually enter puberty spontaneously Rx: androgen supplementation for virilization (does not treat azoospermia or gynecomastia) |
| Disorders of sex development 46,XY Females | 20-30% have mutation or deletion of SRY Sx: Develop oocytes, but ovarian follicles degenerate by birth or shortly thereafter, taller than average woman, usually do NOT enter puberty spontaneously Rx: estrogen 14-15 yo, progesteron added to induce menses later, dysgenic gonads removed once skeletal growth is complete |
| Cockayne Syndrome | Gene: ERCC6 (75%), ERCC8 (25%); AR Sx: Type 1 - normal prenatal growth, severe FTT 1st 2 years, progressive deterioration of vision, hearing, CNS, peripheral nervous syndrome; Type 2 - growth failure at birth, little or no postnatal neurological development, kyphosis, scoliosis, joint contracture; Type 3 - normal growth and development; Xeroderma Pigmentosa-CS - facial freckling, early skin cancer, ID, spasticity, short stature, hypogonadism Path: Defect in mechanism for repair of UV-induced DNA damage with abnl transcription-coupled nucleotide excision repair (preferential removal of UV-induced pyrimidine dimers and other transcription blocking lesions) Rx: PT, dental exams, skin exams, sunscreen if photosensitive, death in 1st to 2nd decade type I, by age 7 in Type II |
| Trichothiodystrophy | Defect in mechanism for repair of UV-induced DNA damage Sx: poor postnatal growth, diminished subcutaneous tissue, joint contractures, thin skin with photosensitivity, MR, neuro deterioration, ichthyosis, brittle hair and nails |
| Congenital Contractural Arachnodactyly (Beals Syndrome) | Genes: FBN2 (5q23-q31), AD Sx: marfanoid appearance, long slender fingers and toes, crumbled ears, major joint contracture, muscle hypoplasia, kyphosis/scoliosis, aortic dilatation, ASD, VSD, IAA, duodenal or esophageal atresia, malroation Eval: X-ray, echo, UGI with SBFT Dx: FBN2 seq (75%) Path: glycoprotein of the extracellular matrix microfibrils, co-distributed with fibrillin 1 in many tissues. Rx: echo q2 yr until clear aorta is not involved |
| Ehlers-Danlos Syndrome, Classic Type (Type I and Type II) | Gene: COL5A1 (9q34.2-q34.3), COL5A2 (2q31); AD Sx: skin hyperextensibility, abnl wound healing, joint hypermobility, hypotonia, delayed motor development, smooth skin, molluscoid pseudotumors, easy bruising, aortic root dilatation. Eval: ultrastructural studies by EM suggest disturbed collagen fibrillogenesis ("cauliflower" deformity is characteristic) Dx: COL5A1 (null testing, 30%), COL5A1 & COL5A2 sequencing (50%) Path: dominant negative activity of abnl collagen alpha-1 or alpha-2 (V) chains |
| Ehlers-Danlos Syndrome, Hypermobility Type (Type III) | Sx: going hypermobility, soft or velvety skin, absense of skin fragility, recurrent joint dislocation/subluxation, chronic joint or limb pain, easy bruising, high narrow palate, dental crowding, low bone density. Gene: unknown in most cases, ? TNXB (6p21.3) Path: abnormal dermal elastic fibers |
| Ehlers-Danlos Syndrome, Vascular Type (Type IV) | Gene: COL3A1 (2q31), AD Sx: 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 Path: abnl type III procollagen production, intracellular retention, reduced secretion, and/or altered mobility |
| Ehlers-Danlos Syndrome, Kyphoscoliotic Type (Type VI) | Gene: PLOD1 (1p36.3-p36.2); AR Sx: friable hyperextensible skin, thin scars, easy bruising, generalized joint laxity, severe hypotonia, progressive scoliosis, scleral fragility and globe rupture, widened atrophic scars, marfanoid habitus, rupture of medium sized arteries, delay motor milestones Eval: crosslinked telopeptides in urine (increased ratio of deoxypyridinoline to pyridinoline by urine HPLC), enzyme activity in fibroblasts <25% Path: enzyme procollagen-lysine,2-oxoglyterate 5-dioxygenase 1 deficiency leads to deficiency in hydroxylysine-based pyridinoline crosslines in types 1 and 3 collagen Rx: can correct scoliosis, PT, echo, BP control, eye exams |
| Hidrotic Ectodermal Dysplasia | Gene: GJB6 (13q12); AD Sx: malformed and thickened small nails, hypotrichosis, palmoplantar hyperkeratosis, normal sweating and teeth Dx: Three common GJB6 mutations (G11R, A88V, V37E) Path: Helps form gap junction channel which mediates ion diffusion. mutations are thought to affect trafficking of the protein and thus the formation of the gap junction. |
| Oculocutaneous Albinism | Gene: TYR (OCA1), OCA2 (P), SLC45A2 Sx: Type 1A - no melanin, nystagmus, transillumination, foveal hypoplasia, decreased visual acuity, strabismus, white hair, 1B - some melanin, better vision Eval: skin and eye exam, VEP Dx: Seq, OCA2 deletion (2kb common in sub-Saharan Africa) |
| X-linked Adrenal Hypoplasia Congenita | Gene: NROB1 (Xp21.3), X-LR Sx: acute onset adrenal insufficiency (hyperkalemia, acidosis, hypoglycemia, shock), cryptorchidism, delayed puberty. Carrier females - adrenal insufficiency or hypogonadotropic hypogonadism Eval: electrolytes (low Na, high K), high ACTH, low cortisol, low 17-hydroxyprogesterone Dx: FISH deletion (100%), 1/3rd with contiguous with glycerol kinase and DMD. Path: Nuclear receptor OB1 is a negative regulator of nuclear receptor pathways Rx: replace steroids, stress dosing, HRT for hypogonadism |
| 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia | Gene: CYP21A2, AR Sx: virilized female, precocious puberty or adrenarche, childhood virilization in males, infant w/ Na losing crisis at birth Non-classic Sx: moderate enzyme deficiency, variable postnatal virilization, no salt wasting, rare low cortisol Eval: high serum 17-OHD baseline or after ACTH stim, high testosterone and androgen precursors in females Path: cortisol production is blocked leading to accumulated 17-OHP which is shunted into the intact androgen pathway. blocks mineralcorticoid pathway causing salt wasting. Rx: hydrocortisone, stress dose steroids |
| Androgen Insensitivity Syndrome (Testicular Feminization) | Gene: AR (Androgen receptor; Xq11-12; XLR Sx: feminization of external genitalia, abnl secondary sex development, infertility Complete - typical female genitalia Partial - predominantly female/male, or ambiguous genitalia Mild - normal male genitalia Eval: impaired spermatogenesis, absent or rudimentary mullerian structures, nl or increased synthesis of testosterone, nl or incr LH, low of devective androgen-binding activity of genital skin fibroblasts Rx: removal of testes after puberty when feminization is complete or prepubertal gonadectomy accompanied by estrogen replacement therapy |
| Kallman Syndrome | Gene Type 1: KAL (Xp22.3), XLR Gene Type 2: FGFR1 (8p11.1), AD Sx: 1&2 - hypogonadotropic hypogonadism, anosmia, delayed puberty; 1 - mirror hand movements, ataxia, GU anomaly, high palate, pes cavus; 2 - ID, CL/P, cryptorchisim, choanal atresia, CHD, SNHL. Eval: low FSH and LH, low testosterone in males, low estradiol in females, MRI hypoplasia olfactory bulbs and tracts Rx: normalize gonadal steroid levels |
| McCune-Albright Syndrome | Gene: GNAS (20q13.2) sporadic mutation Sx: polyostotic fibrous dysplasia, pathologic fracture, cranial foramina thickening can lead to deafness and blindness, hyperthyroidism, high GH/PRL/PTH, ovarian cysts Eval: X-ray, pelvic US, vision, hearing, pituitary hormone Path: activating mutations (stimulatory G-protein) leads to persistently high cAMP Rx: aromatase inhibitor to block testosterone, bisphosphonate for fibrous dysplasia, anti-thyroid meds, octreotide (somatostatin analog) and bromocriptine (dopamine receptor agonist) |
| Blepharophimosis, Ptosis, and Epicanthus Inversus (BPES) | Gene: FOXL2 (3q23); AD (50% de novo) Sx: blepharophimosis, ptosis, epicanthus inversus, and telecanthus, POF (type 1 only), lacrimal duct anomalies, amblyopia, strabismus, refractive errors Path: transcriptional repressor of granulosa cell differentiation, mutations cause accelerated differentiation of granulosa cells and secondary depletion of primordial follicle pool. Rx: Surgery for eyes, ovum donation for POF |
| Congenital Hearing Loss | Genes: GJB2 (Connexin 26), GJB6 (Connexin 30); AR Sx: Congenital mild-profound SNHL, rare AD Cx26 HL which can include palmarplanter keratoderma, KID syndrome Dx: GJB2 sequencing exon 2 and exon 1 for splice site mutation (4th most common), 35delG Caucasians, 235delC Asian, del35G; GJB6 gene deletion Ashkenazi; GJB6-D13S1830 del causes hearing loss if homozygous or combined with single Cn26 Path: loss of gap junction prevents recycling of toxin ions and metabolites away from hair cells leading to their death. |
| Hermansky-Pudlak Syndrome | Genes: HPS1, AP3B1, HPS3-8; AR Sx: oculocutaneous albinism, bleeding diathesis, reduced iris pigment, reduced retinal pigment, foveal hypoplasia, increased crossing of optic nerve fibers, skin cancer, pulmonary fibrosis, colitis. Eval: absent platelet dense bodies on platelet EM, prolonged bleeding time Dx: del/dup HPS1 (75% Puerto Rican), HPS3 testing (~25% PR, 5% non PR-HPS) Rx: DDAVP prior to dental work, thrombin-soaked gel foam for minor cuts, skin protection, annual eye exam, skin exam, adult PFT |
| Jervell and Lange-Nielsen Syndrome | Gene: KCNQ1 and KCNE1; AR; Hetero at risk Long QT (aka Romano-Ward) Sx: congenital severe-profound SNHL, prolonged QT interval, risk arrhythmia, syncope, sudden death Eval: ABR, audiogram Dx: KCNQ1 seq (90%), KCNE1 (10%) Path: abnml repolarization of the ventricular action potential. abnl depolarization of auditory nerve. Rx: cochlear implants, beta-blockers, pacemakers and/or defibrillators, avoid QU prolonging drugs |
| Pendred Syndrome | Gene: SLC26A4 (7q31); AR Sx: bilateral severe SNHL, temporal bone abnl (enlarged vestibular aqueduct), goiter in 75% (only 10% abnl thyroid fxn) Eval: hearing, CT/MRI vestibular aqueduct with or without cochlear hypoplasia (Mondini malformation) Dx: 50% mutations common (I236P, T416P, H723R, IVS8+G>A) Path: nl chloride/iodide exchanger in inner ear and thyroid, mutation leads to inner ear malformation and abnl iodide processing in thyroid. Rx: hearing aids, cochlear implant, monitor thyroid fxn |
| Usher Syndrome | Gene: 11 genes, majority MYO7A (can also cause AD deafness), USH2A; AR Sx: Type 1 - congenital profound HL, balance problems, RP pre-puberty; Type II - congenital mild-severe HL, nl balance, RP teens; Type III - progressive later onset HL, progressive balance problems, variable RP Eval: hearing, ERG Path: RP caused by degeneration of rod and cone fxn of retina. Rx: vitamin A may slow RP, cochlear implants and hearing aids |
| Factor V Leiden Thrombophilia | Gene: F5 (1q23, coag factor V) Sx: Venous thromboembolism (DVT); heterozygous - modest increase VTE recurrence risk, 2-3x increased RR pregnancy loss. homozygous - increased change VTE recurrence. Eval: APC resistance assay, sensitivity and specificity for factor V Leiden Dx: 100% 1691G>A Path: G>A substitution affects APC cleavage site and mutant factor V Leiden is inactivated 10x more slowly and persists longer in circulation. Rx: long term anticoagulation if recurrent VTE or other increased risk factors |
| Familial Mediterranean Fever | Gene: MEFV (16p13, Pyrin), AR Sx: Type 1 - recurrent febrile episodes w/ peritonitis, synovitis, pleuritis, recurrent erysipelas-like erythema, AA type amyloidosis, favorable response to colchicine (Mid Eastern, N African); Type 2 - amyloidosis first clinical presentation. Eval: High ESR, leukocytosis, High serum fibrinogen, proteinuria Dx: targeted ethnicity mutation (70-90%) Path: mutations result in less IL-1beta activation -> more IL-1 response -> inc. inflammatory attacks Rx: cholchicine (M694V) decreases inflammation and deposition of amyloid |
| Aarskog Syndrome | Gene: FGD1 (Xp11.22, ALR) Sx: hypertelorism, shawl scrotum, brachydactyly, short stature, cryptorchidism, cervical vertebral abnl, ID (30%), milder in females Eval: X-ray Dx: FGD1 sequencing (7-20%) Rx: orchiopexy, growth hormone trials not successful |
| Antley-Bixler Syndrome | Gene: POR (7q11.2, AR) Sx: ambiguous genitalia, enlarged cystic ovaries, poor masculinization in males, maternal virilization during 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 Eval: low cortisol, sterol or steroid abnl on GC-MS, high urinary pregnenolone and progesterone metabolites Path: NADPH-cytochrome P450 reductase deficiency leading to disorder of steroid and cholesterol synthesis Rx: airway management, hydrocortisone replacement, stress dose steroids, surgical correction of genital abnl, VP shunt for significant hydrocephalus, PT |
| Coffin-Lowry Syndrome | Gene: RPS6KA3 (Xp22.2); XLD Sx: ID (severe to profound in M; normal to profound in F), short (M <3%ile), soft fleshy hands, tapering fingers with small terminal phalanges, microcephaly, stimulus induced drop episodes, kyphoscoliosis, cardiac abnl Eval: X-ray (thickened skull, anterior vertebrae beaking, metacarpal pseudoepiphyses) Dx: RPS6KA3 sequencing (35-40%) Rx: meds for drop episodes, risperidone for self-inury, annual heart exam, echo q5-10 years |
| Cornelia de Lange Syndrome | Gene: NIPBL (AD), SMC1L1 (XLR), SMC3 (AD) Sx: pre/postnatal growth restriction, low anterior hairline, synophrys, diaphragmatic hernia, upper limb abnl), ptosis, nystagmus, mod-severe ID, pulmonary valve stenosis, VSD Dx: 50% NIPBL seq, 4% SMC1L1, <1% SMC3 |
| Fryns Syndrome | Gene: unknown, AR Sx: LGA, coarse face, CL/CP, diaphragmatic defect, distal digital hypoplasia, ID in survivors, agenesis of CC, optic and olfactory tract hypoplasia, encephalocele, GU malformation Prognosis: majority are stillborn or die in early neonatal period, 14% survive |
| Kabuki Syndrome | Gene: MLL2 (66%, 12q12, AD), KDM6A (Xp11.3, XLD) Sx: fetal figer pads, IQ<80, joint laxity, high palate, hypotonia, short stature, CHD, CL/P, scoliosis, renal anomalies, hearing loss, speech delay Eval: echo, renal US, eye exam, neuropsych testing Path: MLL2 encodes protein in part of SET proteins important to epigenetic control of active chromatin states, H3K4 methylation of MLL2 is linked to demethylation of H3K27 by KDM6A Rx: GH if deficient, eval for immunodeficiency |
| VACTERL Association | Genes: unknown (HOXD13 in 1 case) Sx: Vertebral anomalies, anal atresia, CHD, TEF, EA, Renal abnl, Limb anomalies. Dx 3 of 7, Dx of exclusion. Eval: echo, spine x-ray, limb x-ray, renal US |
| Familial Dysautonomia | Gene: IKBKAP (9q31); AR Sx: progressive, GI dysfxn, vomiting crises, recurrent PNA, altered sensitivity to pain and temperature, CV instability, autonomic crises, hypotonia, broad based ataxic gate, decreased life expectancy, decreased taste, absent fungiform papillae of tongue, absent DTR, absence of overflow tears with crying Eval: pupillary hypersensitivity to parasympathetic agents, absence of axon flare response after intradermal histamine injection Dx: IVS20(+6T>C); R696P (>99% AJ) Path: abnl development and survival of sensory, sympathetic and parasympathetic neurons |
| Amyotrophic Lateral Sclerosis (Lou Gehrig Disease) | Gene: SOD1 (21q22, superoxide dismutase); AD; other loci rare, ARLS2 and SPG20 AR Sx: Onset 46 yo if familial, 56 yo if sporadic. UMN - hyperreflexia, extensor plantar response, increased muscle tone, weakness; LMN - weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations. frontotemporal dimentia. Eval: EMG, Bx. Degeneration and loss of motor neuron in anterior horns and in motor nuclei of CN VII, X, XI (most commonly hypoglossal nucleus), axonal loss with decreased myelin staining in lat and anterior corticospinal tracts. Path: Toxic gain of function Dx: SOD1 mtuation (20% familial, 3% sporadic) Rx: riluzole (glutamate inhibitor), palliative |
| Charcot-Marie-Tooth Type 1B | Gene: MPZ point mutations (6-10% of all CMT1) Sx: onset childhood to adulthood, progressive distal weakness, distal muscle wasting, hyporeflexia, enlarged peroneal nerves, pes cavus, hammer toes Eval: Slow nerve conduction velocity. Nerve bx segmental demyelination, myelin sheath hypertrophy. |
| Charcot-Marie-Tooth Type 2 | Gene: multiple loci, 20% MFN2 Sx: axonal (non-demyelinating) peripheral neuropathy, distal muscle weakness and atrophy, mild sensory loss, normal or near-normal nerve conduction velocities, less severe than CMT1 |
| Charcot-Marie-Tooth Neuropathy X Type 1 (CMTX1) | Gene: GJB1 (Cx32; Xq13.1) 90% cases Sx: mod to severe motor and sensory neuropathy, sensorineural deafness and CNS sx in some families, mild to no sx in carrier females |
| Nemalin Myopathy | Gene: multiple loci, ACTA 15-25% (seq, del/dup exon 55), NEB, TNNT1, TPM2, TPM3; AR or AD Sx: weakness, hypotonia, depressed or absent DTR, weakness face, neck flexors, proximal limb muscles Eval: muscle bx - rod-like inclusions in sarcoplasm of skeletal muscle fibers with trichrome staining Path: d/o thin filament anchoring proteins Eval: No definitive correlation between # of rods and severity of the myopathy, walking prior to 18 months is predictive of survival |
| Fukuyama Congenital Muscular Dystrophy | Gene: FKTN mutation; AR Sx: hypotonia, generalized muscle weakness, CNS migration disturbances (cobblestone, lissencephaly), onset typically in infancy, floppy, contractures (hips, knees, IP joints), myopathic face, pseudohypertrophy of calves and forearms, motor and speech retardation, ID, seizures, retinal dysplasia, progressive cardiac, swallowing disturbance Eval: CK, MRI, EMG, muscle bx |
| Muscle-Eye-Brain Disease | Gene: POMGNT1; AR Sx: ambulation may be acquired, common eye findings, frotoparietal pachygyria, polymicrogyria, vermis hypoplasia, cerebellum dysplastic, small brainstem, hydrocephalus, macrocephaly, epilepsy |
| Walker-Warburg Syndrome | Gene: AR; any of 6 genes in DAG1 glycosylation (POMT2 7-20%, POMT2, POMGNT1, FKTN, FKRP, LARGE) Sx: absent psychomotor acquisitions, severe eye, cobblestone lissencephaly, very hypoplastic cerebelum, very small brainstem kinked at jxn of midbrain and pons, hydrocephalus |
| Congenital Muscular Dystrophy, type 1D | Gene: LARGE; AR Sx: Ambulation may be acquired, ID, abnl glycosylation |
| Ataxia with Oculomotor Apraxia Type 1 and Type 2 | Gene: APTX, SETX; AR Sx: 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 Eval: MRI - severe cerebellar atrophy, EMG - axonal neuropathy, low albumin, high chol, type 2 high AFP Path: aprataxin is involved in DNA single-strand break repair mechanisms Rx: PT, wheelchair age 15-20 yo, educational support, high protein low cholesterol diet |
| Hutchinson-Gilford Progeria Syndrome | Gene: LMNA G608G Exon 11 (100%); AD; all de novo, paternal age effect Sx: short stature, head large for face, diminished subq 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, severe atherosclerosis Eval: elevated urine hyaluronic acid (unreliable for dx), EKG, echo, carotid duplex, X-ray - clavicular absorption, acroosteolysis, coxa valga Path: dominant negative effect leading to progressive defects in nuclear architecture Rx: optimize nutrition, age appropriate school, PT, aspirin, EKG, echo, carotid duplex, lipid profiles, dental exam, x-ray (hips q few years for avascular necrosis) |
| Alport Syndrome with Thin BM Nephropathy | Gene: XL - COL4A5 (80%); AR (15%) - COL4A3, COL4A4; AD (5%) - COL4A3, COL4A4 Sx: spectrum from progressive renal disease with cochlear and ocular abnl to isolated hematuria with benign course Eval: microhematuria, eventually proteinuria, anterior lenticonus virtually pathognomonic, EM on renal bx Path: Type IV collagen major collagen component of BMs, alport due to abnl secretion of collagen alpha 3, 4, and 5 chains. |
| Cleidocranial Dysplasia | Gene: RUNX2 (6p21); AD Sx: delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, multiple dental abnl, midface hypoplasia, brachydactyly, recurrent OM, hearing loss, nl intellect Eval: X-ray - clavicular hypoplasia, open sutures, wormian bones, poor or absent sinus pneumatization, hypoplastic scapulae, wide symphysis pubis and sacroiliac joints, large femoral neck and epiphyses, pseudoepiphyses of metacarpals and metatarsals, deformed and short run middle phalanges, osteopenia |
| Diastrophic Dysplasia | Gene: SLC26A2 (Sulfate transporter); AR Sx: limb shortening, normal skull, hitchhiker thumb, small chest, large joint contracture, CP, cystic ear swelling, ulnar deviation of fingers, club foot, low tone, normal IQ Eval: X-ray - cervical kyphosis, incomplete thoracic and lumbar vertebrae, narrowed interpedicular distance L1 to L5, distal humerous bifid or v-shaped, rounded distal femur, advanced bone age; cartilage bx - paucidty of sulfated proteoglycans in cartilage matrix and abnl incorporation of sulfate into macromolecules in cx chondrocytes Path: undersulfation of proteoglycans affects the composition of the extracellular matrix and leads to impaired proteoglycan deposition necessary for proper enchondral bone formation |
| Muenke Syndrome | 100% FGFR3 Sx: normal to mild ID, uni- or bilateral coronal craniosynostosis, megalencephaly, mild to signficant midface hypoplasia, ocular hypertelorism, unicoronal synostosis is more frequently seen in males |
| Hereditary Multiple Osteochondromas Syndrome | Gene: EXT1, EXT2; AD; 70% seq, 20% del/dup Sx: Exostoses (benign cartilage-capped bony growth) arising from 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. 0.5-2% cases degenerate to chondrosarcoma. |
| Saethre-Chotzen Syndrome | Gene: TWIST1 (7p21); AD Sx: coronol synostosis, facial asymmetry, ptosis, 2/3 hand syndactyly, mild-mod DD, short stature, parietal foramina, vertebral fusions, radioulnar synostosis, CP, maxillary hypoplasia, congenital heart defect Eval: echo, X-ray, hearing, katyotype (translocations and rings reported) Dx: >50% sequencing, 11-28% del/dup |
| Thrombocytopenia Absent Radius Syndrome | Genetics: AR; 50-75% 1q21.1 deletion (min 200 kb), RBM8A pathogenic variants Sx: Bilateral absence of radii with the presence of both thumbs, thrombocytopenia, cow's milk allergy, anomalies of heart, skeleton, and GU |
| Simpson-Golabi-Behmel Syndrome | Genetics: XLR; GPC3, GPC4 Sx: pre- and postnatal macrosomia, macrocephaly, mild-severe ID, palate abnl, supernumerary nipples, diastasis recti, umbilical hernia, CHD, diaphragmatic hernia, GU defects, GI abnl, vertebral fusion, postaxial polydactyly, increased risk embryonal tumors Surveillance: check for hypoglycemia, scoliosis, hearing, speech, sleep apnea, heart defects and conduction abnl |
| Poland Anomaly | Congenital absence of the sternal head of pectoralis major often with hypoplasia of the breast on the ipsilateral side, sometimes shortening of phalanges, cutaneous syndactyly Path: multifactorial basis involving vascular disruption in early development |
| Multiple Epiphyseal Dysplasia, Dominant | Gene: AD; COMP, COL9A1, COL9A2, COL9A3, MATN3 Sx: presents early childhood with pain in hips and knees after exercise, height lower range of nl or mildly short, early-onset osteoarthritis in large joints Eval: X-ray with delayed ossification of the epiphyses of long tubular bones, ossification centers small with irregular contours |
| Marinesco-Sjogren Syndrome | Gene: AR; SIL1 mutation Sx: ID, cataracts, weakness, short stature, primary gonadal failure, ataxia, microcephaly Eval: CK elevated, variation in figer type on muscle bx |
| Potocki-Lupski syndrome | Duplication 17p11.2 Sx: hypotonia, FTT, ID |
| Fraser Syndrome | Gene: AR, several proposed loci Sx: cryptophthalmos, cutaneous syndactyly, malformed ears with conductive deafness, renal agenesis, laryngeal stenosis, abnl genitalia (ambigous, cryptorchidism) |
| Langer-Giedion Syndrome | Deletion 8q24 (EXT1 and TRP1) Trichorhinopharnygeal syndrome (fine, sparse hair, brittle nales, bent fingers with cone shaped epiphyses). EXT1 - bony exostoses |
| Crigler-Najjar Syndrome Gilbert Syndrome | Gene: UGT1A1 def, AR CN Type 1 - absent enzyme, unconjugated bilirubin 20-40 mg/dl CN Type 2 - incomplete deficiency, unconjugated bilirubin 5-20 mg/dl Gilbert syndrome - homozygosity for gene promoter polymorphism, mild fluctuating bilirubinemia, prolonged neonatal jaundice |
| Dubin-Johnson Syndrome | Gene: MRP2 (ABCC2), AR Sx: usually asymptomatic |
| Pseudoachondroplasia | Gene: COMP Sx: normal length at birth, nl face, growth declines at 2 years, brachydactyly, loose hands/knees/ankles, restricted elbows and hips, joint pain, 1/2 lumbar lordosis |
| Multiple Epiphyseal Dysplasia, Recessive | Gene: SLC26A2, AR Sx: joint pain (hips and knees), malformations (hands, feet, knees), scoliosis, 50% clubfoot, clinodactyly, adult height 150-180 cm |
| Type II Collagenopathies COL2A1 | Achondrogenesis Type 2 (Langer Saldino)- Sx: micromelic dwarfism, CP, short ribs, abnl vertebrae, AD, de novo Kniest syndrome: short stature, hearing loss, myopia, retinal detachment, cataract Spondyloepiphyseal Dysplasia: flat face, CP, myopia, retinal detachment, abnl vertebrae, cervical myelopathy Stickler: flat face, myopia, retinal, robin, CP detachement |
| Cutis Laxa | Gene: ATP6VOA2 (AR) w/ cerebellar anomalies, EFEMP2 (aka FBLN4, AR) w/ arterial tortuosity, FBLN5 w/ pulmonary emphysema Sx: doughy skin, furrowed skin, myopia, hernias |
| Pseudoxanthoma Elasticum | Gene: ABCC6 seq 90%, 5-30% del; AR Sx: affects elastic tissue of skin, eye, CV, GI, skin papules, retina streaks or hemorrhages, GI bleeds, angina/claudication |
| Lowe Syndrome | Gene: OCRL seq 95% males and carriers, XL Sx: cataracts, glaucoma, poor vision, hypotonia, absent DTR, mild to severe ID, fanconi, renal rickets, phosphaturia, aminoaciduria, renal failure 10-20 yo Eval: enzyme in fibroblasts |
| UMOD associated kidney disease | Gene: UMOD, AD, seq variant >95% Protein: uromodulin/Tamm Horsfall protein Sx: hyperuricemia, gout, low renal excretion, low uric acid, high creatinine 5-40 yo, renal failure >40 yo, isothenuria |
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