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Roberts 100 Diseases
| Disease | Inheritance: Gene | Phenotype | Molecular Testing Details | Treatments | Disease Category |
|---|---|---|---|---|---|
| Brugada syndrome | AD: SCN5A, AD | ST-segment abnormalities on ECG, high risk of arrhythmia and sudden death. May present as SIDS (particularly SE Asians) | Defibrillator | Cardio | |
| Cardio-facio-cutaneous syndrome | AD: BRAF1, MEK1, MEK2, KRAS | Cardiac abnormalities (septal defects, HCM, arrythmia), facial features (Downslanting eyes, cupids bow lips, more coarse than Noonan), cutaneous abnormalities (hyperkeratosis, ichthyosis, eczema), mild-moderate ID | Majority de novo | Cardio | |
| Costello syndrome | AD: HRAS | Feeding issues, DD, ID, coarse features, loose, soft skin, HCM, pulmonary stenosis, arrhythmia | Majority de novo | Cardio | |
| HHT | AD: ENG (60-80%), ACVRL1 | Nosebleeds, telangiectases on lips, oral cavities, fingers/toes, visceral AV malformation presenting as hemorrhage | Embolization, liver transplant if liver AVMs are causing heart failure | Cardio | |
| Holt-Oram syndrome | AD: TBX5, SALL4 (rare) | Fully penetrant malformation of carpal bones (thumb), sometimes radial and/or thenar bones. CHD (ASD/VSD), arrhythmia | Majority de novo | Cardio | |
| Noonan syndrome with multiple lentigenes (LEOPARD) | AD: PTPN11 LOF (80%), RAF1 (3%) | Lentigenes, ECG abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of the genitalia, Retardation of growth, Deafness. Most have HCM | Cardio | ||
| Noonan syndrome | AD: GOF PTPN11 (50%), SOS1 (10%), KRAS, RAF1, NRAS, CBL, SHOC2, BRAF | Characteristic facial features, short stature, pulmonary valve stenosis, HCM, cryptorchidism, renal malformation, lymphedema, bleeding disorder, myeloproliferative disorder, learning disabilities | Cardio | ||
| Williams syndrome | AD: 7q11 deletions including ELN | Supravalvular aortic stenosis, stellate/lacy iris, long philtrum, wide mouth, hernia, rectal prolapse, joint limitation/laxity, ID, overfriendly, anxiety, hypercalcemia/hypothyroidism. FTT. | Majority de novo | Cardio | |
| Ataxia telangiectasia | AR: ATM (>95%) | Progressive ataxia, oculomotor apraxia, conjunctival telangiectasia, immunodeficiency, choreoathetosis, risk of cancer | Amish founder mutation | IVIG | Chromosome breakage |
| Bloom syndrome | AR: BLM | IUGR, hyper and hypopigmentation, butterfly rash, telangiectasia, microcephaly, high pitched voice, immunodef, axoospermia, POF, cancer risk | 97% AJ chromosomes 2881del6ins7; Chromatid/chromosome breaks; triradial and quadriradial figures | Chromosome breakage | |
| Fanconi anemia | AR: FANCA (66%),B,C,D2,E,F,G | Short, pigment abnl, radial malformation, GU, ear, heart, GI, or CNS malformation, HL, hypogonad, DD. Progressive marrow failure, anemia, MDS, AML, tumors | Chromosome breakage, cells in G2 arrest | Chromosome breakage | |
| Congenital contractural arachnodactyly (Beals) | AD: FBN2 | Marfanoid appearance, arachnodactyly, aortic dilation, CHD, duodenal/esophageal atresia, malrotation | Chromosome breakage | ||
| Classic Ehlers Danlos (Type I and II) | AD: COL5A1, COL5A2AD | Skin hyperextensibility, moluscoid pseudotumors, smooth velvety skin, widened atrophic scars, hypermobility, easy bruising, hernia, aortic root dilation, chronic pain | Connective Tissue | ||
| Hypermobile Ehlers Danlos (Type III) | AD: TNXB | Hypermobility, soft/velvety skin, NO skin or soft tissue fragility, high narrow palate | Not usually done. | Connective Tissue | |
| Vascular Ehlers Danlos (Type IV) | AD: COL3A1 | Arterial rupture, intestinal rupture, uterine rupture during pregnancy, translucent skin, thin lips and philtrum, small chin, large eyes, varicose veins, pneumothorax, CHD | COL3A1 sequence analysis identifies 98-99% of cases | Connective Tissue | |
| Kyphoscoliotic Ehlers Danlos (Type VI) | AR: PLOD1 | Hyperextensible skin with thin scars, easy bruising, joint laxity, severe hyotonia, progressive scoliosis that can cause breathing probs, eye rupture. May have artery rupture, widened scars, marfanoid habitus. | A urine test (ratio of deoxypyridinoline to pyridinoline crosslinks ) can diagnose those without mutations | Connective Tissue | |
| Loeys Dietz | AD: TGFBR1, TGFBR2, SMAD3, TGFB2 | Arterial toruosity, aneurysms/dissections, skeletal (pectus, scoliosis, arachnodactyly, foot deformity), hypertelorism, bifid uvula, CS, cutaneous manifestations | Connective Tissue | ||
| Marfan | AD: FBN1 | DIlation/dissection of ascending aorta, pectus, arm span=height, pes planus, high palate, ectopia lentis, hypermobility, striae, hernia | FBN1 sequencing identifies 70-90% | Connective Tissue | |
| Hydrotic ectodermal dysplasia | AD: GJB6 | Malformed nails, partial or total alopecia, palmoplantar hyperkeratosis, normal sweating and teeth | 3 mutations account for almost all cases: G11R, A88V, V37E | Derm | |
| Hypohydrotic ectodermal dysplasia | XL: EDA (95%), AD or AR: EDAR, EDARADD | Hypotrichosis, hypohidrosis (inability to sweat), hypodontia with conical teeth. | 95% of cases due to EDA mutations. Female carriers have mosaic sweat pore function, some hypodontia. | Derm | |
| Incontinentia pigmenti | XLD: IKBKG (aka NEMO) | 4 stages of skin changes: erytheia - blister - hyperpigmented streak - atrophic patches. Also hypodontia, alopecia, woolly hair, nail ridging retinal detachment | 80% of variants are exon 4-10 deletion. Male lethal. | Derm | |
| Oculocutaneous albinism | AR: TYR, OCA2 | Tyrosinase associated with severe and milder albinism (OCA1A/1B). OCA2 usually has better vision and pigmentary abnormalities range from mild to near normal. | OCA2 is in the PWS/Angelman region on chr15 - reason why PWS /AS patients are often fairer than family members | Derm | |
| X-linked Adrenal Hypoplasia congenita | XLR: NROB1 | Males with acute-onset infantile adrenal insufficiency (hyperkalemia, acidosis, hypoglycemia, shock), cryptorchidism, delayed puberty. Carrier females may have adrenal insufficiency or hypogonadotropic hypogonadism | 1/3 contig gene deletion with glycerol kinase, DMD 2/3 isolated CAH (half de novo) Point mutations have also been found | Endocrine | |
| 21-Hydroxylase Deficiency | AR: CYP21A2 | Classic: Virilized female, precocious puberty, childhood virilization in males, infant with salt wasting crisis at birth Nonclassic: Variable postnatal virilization, no salt wasting, cortisol deficiency | 17-OHD elevation screened on NBS Elevated testosterone and adrenal androgen precursors in females | Hydrocortisone | Endocrine |
| Androgen insensitivity syndrome (Testicular feminization) | XLR: AR | In boys, feminization of external genitalia (complete = fully female; mild = normal male; partial = spectrum in between), abnormal secondary sexual development, and infertility. | Testes removal to prevent malignancy | Endocrine | |
| Kallman Syndrome | XLR: ANOS1, AD: CHD7, SOX10, FGFR1 | Hypogonadotropic hypogonadism and anosmia (some genes lack anosmia). Additional features of disorders related to KS genes (ie CHARGE syndrome, Waardenburg) may be present. | Endocrine | ||
| Klinefelter syndrome | 46XXY (50/50 maternal/paternal meiotic errors) | Tall stature, slightly delayed motor/language skills, small fibrosed testes, infertility, gynecomastia, increased cholesterol | Can conceive with ICSI | Endocrine | |
| Mccune-Albright syndrome | Somatic: GNAS | Polyostotic fibrous dysplasia (bone replaced by fibrous tissue leading to weak bones, deformity), cranial foramina thickening leading to deafness and blindness, large irregular cafe au lait spots, precocious puberty, hyperthyroidisim, ovarian cysts | Endocrine | ||
| Transient neonatal diabetes mellitus | HYMA1, PLAGL1 UPD isodisomy 6 (35%), paternal 6q24dup (35%), 6q24 methylation defect (20%) | DM in the first six weeks of life, resolves by 18 mos, severe IUGR, dehydration | High serum glucose with no islet cell antibodies and no ketoacidosis | Endocrine | |
| Turner | 45, X (75% paternal error) | Congenital lymphedema, growth failure, CHD, hyperlipidemia, gonadal dysgenesis, hypothydroidism, diabetes, hearing loss, crohns, renal malformation, osteoporosis, LOW HAIRLINE, HYPERTELORISM AND LOW SET EARS | Endocrine | ||
| Blepharophimosis, ptosis, and epicanthus inversus (BPES) | AD: FOXL2 | Horizontally narrow palpebral fissure, ptosis, and an upward fold of the skin of the lower eyelid near the inner corner of the eye; with or without premature ovarian failure | 50% de novo | Hearing/Vision | |
| Hermansky-Pudlak syndrome | AR: HPS1, AP3B1, HPS3-8 | Oculocutaneous albinism, bleeding diathesis. Can develop skin cancer, pumonary fibrosis, colitis | Absent platelet dense bodies ALWAYS. 16bp duplication common in Puerto Rico | Hearing/Vision | |
| Jervell and Lange-Nielsen syndrome | AR: KCNQ1 (90%) and KCNE1 (10%) | Congenital severe-profound bilateral SNHL and prolonged QT interval. At risk for arrhythmia, syncope, and sudden death | Heterozygotes are at risk for AD long QT | Hearing/Vision | |
| Leber hereditary optic neuropathy | Mito: MT-ND1, MT-ND4, MT-ND5, MT-ND6 | Blurred/clouded vision, progresses to retinal nerve degeneration and optic atrophy. Tortuosity of retinal vessels and swelling of nerve fiber layer at fundus. | G11778A accounts for 70% of cases | Hearing/Vision | |
| Pendred syndrome | AR: SLC26A4 | SNHL, temporal bone abnormalities, vestibular abnormalities, goiter | Hearing/Vision | ||
| Usher syndrome | AR: 11 genes. Most common causes are USH2A, MYO7A | Hearing loss, retinal degeneration, vestibular dysfunction | Hearing/Vision | ||
| Waardenburg syndrome | AD: PAX3 (90%), SOX10, MITF | Hearing loss, heterochromia, white forelock, early greying, dystopia canthorum, neural tube defect. Type 3 - added limb hypoplasia or contracture, syndactyly | Hearing/Vision | ||
| Acute intermittent porphyria | AD: HMBS | After puberty, acute attacks, abdominal pain, muscle weakness, neuropathy, hysteria, anxiety, hepatocellular carcinoma, but NO cutaneous findings | Urine looks like red wine diluted with water | Hematologic | |
| Alpha thalassemia | AR: HBA1, HBA2 | If all 4 copies lost - Hb Barts/hydrops fetalis, severe anemia, neonatal death. If loss of 3 copies, HbH, microcytic hemolytic anemia, hepatosplenomegaly, jaundice. If loss of 2 alleles - trait - low MCV, low MCH. If loss of one copy - silent carrier | Most commonly caused by deletions of HBA1 and 2. Hemoglobin electrophoresis shows HbH or HbBarts | HbH only: Transfusions | Hematologic |
| Beta thalassemia | AR: HBB | Severe anemia and hepatosplenomegaly. FTT and shortened life expectancy without treatment. Thal intermedia: milder anemia, presents later. | Caused by many single nucleotide variants that render HBB completely or partially dysfunctional. Several founder mutations. Hb electrophoresis shows increased HbA2, HbF | Transfusions and chelation therapy | Hematologic |
| Factor V Leiden Thrombophilia | AD/AR: F5 (increased risk with two alleles) | Risk of VTE, mostly DVT. Recurrent pregnancy loss. Low penetrance | G1691A variant Biochemical test: APC resistance assay | Hematologic | |
| Hemophilia A | XLR: F8 | Hemarthrosis, intracranial bleeds with mild/no trauma; muscle hematomas, prolonged bleeding, excessive bruising | Inversions, deletions, and LOF most common Biochemical test: Prolonged PTT, factor 8 activity (severe form <1% activity) | IV delivery of F8 | Hematologic |
| Hemophilia B | XLR: F9 | Hemarthrosis, intracranial bleeds with mild/no trauma; muscle hematomas, prolonged bleeding, excessive bruising | Deletions, LOF Biochemical test: Prolonged PTT, factor IX activity (severe form <1% activity) | Recombinant F9 | Hematologic |
| Hereditary Hemochromatosis | AR:HFE | Inappropriately high iron absorption leading to excessive storage in liver, skin, pancreas, heart, joints, testes. Leads to liver damage, skin pigmentation, DM, CHF, cardiomyopathy, arthritis, hypogonadism. | C282Y most common followed by H63D Biochemical tests: Transferrin-iron saturation, iron levels, ferritin | Phlebotomy | Hematologic |
| X-linked agammaglobulinemia | XLR: BTK | Recurrent otitis media, pneumonia, sinusitis in young children, sepsis, meningitis, cellulitis, paucity of lymphoid tissue | Low but measurable IgG, <1% B Cells | Gammaglobulin injections | Immune |
| Familial Mediterranean Fever | AR: MEFV | Type I recurrent fevers with inflammation of abdominal wall lining (peritonitis), joints (synovitis), lining of lungs (pleuritis), erythema, AA amyloidosis (impacts kidneys, result of chronic inflammation). Type 2 begins with amyloidosis only | Colchicine | Immune | |
| Aarskog syndrome | XLR: FGD1 | Hypertelorism, shawl scrotum, brachydactyly, short stature, cryptorchidism, vertebral anomalies, ID | Milder in females | MCA | |
| Antley-Bixler (Severe cytochrome P450 oxidoreductase deficiency) | AR: POR | Ambiguous genitalia, enlarged cystic ovaries, poor masculinization, maternal virilization during pregnancy. Infants have craniosynostosis, hydrocephaly, choanal stenosis,/atresia, contractures, arachnodactyly, bowing of long bones, dysplastic ears | MCA | ||
| Bardet-Biedl syndrome | AR: BBS1-11 | Cone-rod dystrophy, obesity, postaxial polydactyly, ID, hypogonadotropic hypogonadism, renal dysfunction | MCA | ||
| Branchiootorenal syndrome | AD: EYA1, SIX1 | Ear malformations, conductive/SN/mixed HL, branchial fistulae/cysts, renal malformation | MCA | ||
| CHARGE syndrome | AD: CHD7 | Coloboma, Heart malformation, choanal Atresia, growth and mental Retardation, Genitourinary malformation (microphallus), Ear anomaly. Facial play, cleft palate, dysphasia also common. | MCA | ||
| Coffin-Lowry Syndrome | XLD: RPS6KA3 | Normal to profound ID (males usually severe), soft fleshy hands, small terminal phalanges, short stature, microcephaly, drop episodes, large mouth, everted lip, prominent ears, thick skull | MCA | ||
| Cornelia de Lange | AD: NIPBL (50%), SMC3, XLR: SMC1L1 | Growth retardation, low anterior hairline, synophrys, diaphragmatic hernia, limb anomalies, ptosis, ID, heart defect, nystagmus, high palate with clefts, | MCA | ||
| Cri du chat | AD: 5p15 deletion | Unique cry, slow growth, microcephaly, ID, hypotonia, strabismus, epicanthal folds, micrognathia | Karyotype or FISH, 85% de novo (mostly paternal chromosome), 12% unequal segregation of translocation OR recombination involving pericentric inversion | MCA | |
| Fryns syndrome | AR: Unknown | Large for gestational age, coarse face, clefting, diaphragm defect, distal digit hypoplasia, ID, agenesis CC, optic/olfactory hypoplasia, encephalocele, GU malformation, hypolastic nails. Only 14% survive newborn period | MCA | ||
| Greig cephalopolysyndactyly | AD: GLI3 | Macrocephaly, cutaneous syndactyly, preaxial polydactyly, ID, seizures, | Allelic with pallister-hall Some large deletions , but mostly sequence variants. | MCA | |
| Joubert syndrome | AR: NPHP1, AHI1, CEP290, TMEM67 | Hypotonia in infancy, ataxia later, DD/ID, tachypnea/apnea, pigmentary retinopathy, oculomotor apraxia, renal disease, molar tooth sign | NPHP1 deletions are a rare cause | MCA | |
| Kabuki syndrome | AD: KMT2D, XLD: KDM6A | Everted lower eyelid, big eyes, big ears, fetal finger pads, IQ<80, joint laxity, high palate, hypotonia, short stature, CHD, clefts, renal anomalies, hearing loss | Majority de novo | MCA | |
| Monosomy 1p36 | 1p36 del | Hypotonia, dev delay, slow growth, obesity, microcephaly, clefting, cardaic malformations, cardiomyopathy, seizures, HL, straight low-set eyebrows, deep eyes, midface hypoplasia, bushy hair | Most common terminal deletion syndrome, FISH required for detection in most cases. 2:1 female. | MCA | |
| Prader-willi | 15q11-13 deletion on paternal chromosome, maternal UPD, or imprinting center defect | Hypothalamic insufficiency, neonatal hypotonia, dev delay, hyperphagia leading to obesity, short stature, small hands and feet, hypogonadism, ID | 70% deletion, 15% UPD, 2% imprinting mutation | MCA | |
| Rubenstein-Taybi | AD: CREBBP, EP300 | Microcephaly, beaked nose, broad thumbs and first toes, cryptorchidism, growth delay, severe ID, CHD, ptosis, sleep apnea, tumors, behavioral problems, thick black hair at birth, ear infections | CREBBP deletions account for ~10%, but CREBBP SNVs most common | MCA | |
| Smith-Magenis | AD: RAI1, 17p11 deletion | Early hypotonia, feeding problems, brachydactyly, speech delay, ID, HL, neuropathy, sleep problems, behavior problems: SELF-INJURY, hyperactivity, impulsivity, SELF HUG, LICK AND FLIP; hypercholesterolemia, square face, tented lip, hypotelorism | ~90% 17p11 deletion, FISH required | MCA | |
| Triploidy | 69 XXY or XXX | 3,4 syndactyly, ASD, VSD, hydrocephalus, large fontanelle, holoprosencephaly. Maternal origin will produce small placenta, large head, asymmetry. Paternal origin will produce large placenta | Most common cause is dispermy though diploid sperm possible. In digyny, can have diploid oocyte, fertilization of primary oocyte, or polar body retention. | MCA | |
| Patau | Trisomy 13 | Holoprosencephaly, polydactyly, seizures, HL, microcephaly, midline clefts, omph, cardiac/renal anomalies, ID, cutis aplasia | Karyotype, mostly maternal nondisjunction | MCA | |
| Edwards | Trisomy 18 | Clenched hand with fingers 2 and 5 overlapping 3/4. rocker bottom feet, microphthalmia, micrognathia, VSD, ASD, muscle spasms, ID, | On serum screen: low AFP, hCG, and E3. Karyotype diagnostic, mostly maternal nondisjunction | MCA | |
| Downs | Trisomy 21 | ID, hypotonia, growth delay, strabismus, cataracts, myopia, HL, macroglossia, hypodontia, hyperflexible, hypogenital, CHD, duodenal atresia, hirschsprung, early alzheimers, ALL | Karyotype, mostly maternal nondisjunction (usually meiosis I). Serum screen: high hCG, high inhibin A, low E3, low AFP | MCA | |
| VACTERL/VATER | Unknown | Vertebral anomalies, anal atresia, cardiac malformation, tracheoesophageal fistula, esophageal atresia, renal anomalies, limb anomalies (radii) with hydrocephalus (VACTERL) | Rule out aneuploidy, fanconi (via DEB), Townes-Brocks (SALL1) | MCA | |
| Wolf-Hirschorn | 4p deletions | Greek warrior helmet appearance, downturned mouth, ear pits/tags, microcephaly, growth deficiency, ID, seizures, facial asymmetry, ptosis, igA deficiency, brain anomalies, clefting, CHD | 87% de novo, rest unbalanced translocation. Distinctive EEG and IgA levels. FISH usually used. | MCA | |
| X-linked Adrenoleukodystrophy | XLR: ABCD1 | Childhood cerebral leads to total disability within 2 yrs of onset. Adrenomyeloneuropathy is progressive paraparesis starting in late 20s with sphincter disturbance and adrenocortical dysfunction. Third is adrenocortical insufficiency only, child onset | Accumulation of VLCFA (peroxisomal disorder) | Lorenzos oil, corticosteroid replacement | Neuro |
| Early Onset Alzheimers | AD: PSEN1, APP, PSEN2 | Onset <60 of dimentia, confusion, poor judgement, language disturbance, agitation, withdrawal, hallucinations. Cortical atrophy with beta-amyloid plaques | Neuro | ||
| Angelman | Imprinted: 15q11 | Severe dev delay/ID, speech impairment, ataxia, inappropriate LAUGHING HAPPY DEMEANOR, acquired microcephaly, seizures, wide mouth, widely spaced teeth, strabismus | Deletion of maternal copy is the most common cause, followed by imprinting defect, paternal UPD, unbalanced translocation, deletion of imprinting center | Neuro | |
| CADASIL | AD: NOTCH3 | Stroke-like episodes before 60, cognitive disturbance, behavioral abnormalities, migraine with aura. Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy. | Electron dense granules on skin biopsy. T2 white matter abnormalities. | Neuro | |
| Canavan | AR: ASPA (aspartoacylase) | Macrocephaly, lack of head control, dev delay, hypotonia evolving to spasticity | High urine N-actely aspartic acid (NAA). 3 common variants make up for 99% AJ alleles. | Neuro | |
| Familial dysautonomia | AR: IKBKAP | Progressive: GI dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain, cardiovascular instability, autonomic crises, hypotonia, ataxia, decreased taste due to absent fungiform papillae (SMOOTH TONGUE), ABSENT TEARS when crying | Pupillary hypersensitivity. 2 mutations make up >99% of AJ alleles (IVS20+6T>C, R696P | Neuro | |
| Fragile X | XL: FMR1, FRAXE | Delayed motor/verbal dev, ID, autistic features, big ears, macroorchidsim. Anxiety, OCD, depression in carrier females. Carrier males might have late onset tremor, autonomic dysfunction. | CGG expansion requires southern or pcr assay. Intermediate = 45-58 repeats, premutation = 59-200, full mutation >200 | Neuro | |
| Huntingtons | AD: HTT | Progressive motor disease leading to rigidity, dystonia, cognitive decline, psychiatric disturbances, psychosis. Avg onset ~40. Atrophy of caudate and putamen on MRI. Low glucose metabolism in caudate on CT. | CAG repeat expansion >40 for fully penetrant disease. If 27-35, risk of expansion to pathogenic from if passed from father to children. 36-39 = reduced penetrance doisease. If >60 repeats, juvenile onset. | Neuro | |
| Krabbe | AR: GALC (galactocerebrosidase) | Defective myelin production leads to two forms. Infantile has sensory irratibility, hypertonicity, neurologic deterioration, neuropathy, white matter disease. Late onset: weakness, vision loss, intellectual regression. | Elevated CSF protein, GALC enzyme assay. 330kb deletion accounts for ~ half of European infantile cases. 809G>A accounts for ~half late onset cases. | HSC transplat in presymptomatic infants | Neuro |
| Neurofibromatosis type 1 | AD: NF1 | Cafe au lait macules, neurofibromas, axillary/inguinal freckling, OPTIC GLIOMA, Lisch nodules, thinned long bone cortex, SPHENOID DYSPLASIA (can lead to asymmetric proptosis) | Neuro | ||
| Parkinson | AD: LRRK2, SNCA, AR: PARK7, PRKN, PINK1 | Bradykinesia, rigidity, tremor. Juvenile onset ~20-40ys for PRKN mutations | Dopamine | Neuro | |
| Rett | XLD: MECP2 | ID, dev regression, acquired microcephaly, WRINGING HAND MOVEMENTS, hyperventilation, paroxysmal laughing, prolonged QT, scoliosis, bruxism | ~16% deletions in MECP2. FOXG1 and CDKL5 cause similar phenotypes. | Neuro | |
| Wilson | AR: ATP7B | Hepatitis, liver failure, movement disorder, personality disorganization, KAYSER-FLEISHER RING | Low serum copper and ceruloplasmin, increased excretion of copper in urine. Common variants in Europeans, Asians, and Russians | Chelating agent (Penicillamine), liver transplant | Neuro |
| Biotinidase deficiency | AR: BTD | Form of multiple carboxylase deficiency: In the first few months, seizures, hypotonia, breathing problems, hearing/vision loss, ataxia, SKIN RASHES, ALOPECIA, CANDIDIASIS. Mild form presents with hypotonia, rashes, hair loss during illness or stress. | Biotin supplementation | Biochem | |
| ALS/ Lou Gehrig | AD: C9ORF72, SOD1, TARDP, FUS | UMN: Hyperreflexia, extensor plantar response, increased muscle tone, weakness. LMN: Weakness, muscle wasting, hyporeflexia, muscle cramps, fasciculations. Also frontotemporal dementia | There are rare AR and XLD forms. Degeneration of motor neurons in anterior horns, motor nuclei of cranial nerves, hypoglossal nucleus. Axonal loss with decreased myelin staining in latern and anterior corticospinal tracts. | FDA approved glutamate inhibitor | Neuromuscular |
| CMT1 | AD: PMP22, MPZ, LITAF, EGR2, NEFL | Slowly progressive weakness and atrophy of distal muscles in feet and/or hands beginning in first-third decade, HL, pes cavus, hip dysplasia | Characterized by abnormalities in myelin. Nerve conduction is slow. PMP22 variants are DUPLICATIONS or sequence variants impairing processing. | Neuromuscular | |
| CMT2 | AD: KIF1B and MFN2, RAB7, LMNA, GARS, NEFL, HSPB1, MPZ, GDAP1 | Slowly progressive weakness and atrophy of distal muscles in feet and/or hands beginning in first-third decade, HL, pes cavus, hip dysplasia | Characterized by axon abnormalities leading to reduced strength of nerve impulse | Neuromuscular | |
| CMT Intermediate | AD: DNM2, YARS | Slowly progressive weakness and atrophy of distal muscles in feet and/or hands beginning in first-third decade, HL, pes cavus, hip dysplasia | Combination of myelinopathy and axonopathy | Neuromuscular | |
| CMTX | XLD: GJB1 | Slowly progressive weakness and atrophy of distal muscles in feet and/or hands beginning in first-third decade, HL, pes cavus, hip dysplasia | Axonopathy with secondary myelin changes | Neuromuscular | |
| CMT4 | AR: GDAP1, MTR2, CMT4B2, SH3TC2, NDRG1, EGR2, PRX | Slowly progressive weakness and atrophy of distal muscles in feet and/or hands beginning in first-third decade, HL, pes cavus, hip dysplasia | Characterized by pattern of inheritance | Neuromuscular | |
| Duchenne muscular dystrophy | XLR: DMD | Present before age 5 with progressive symmetrical muscle weakness, proximal>distal, calf hypertrophy, DCM. Typically wheelchair dependent by 13, survival into 20s. | Dystrophinopathy. Gene deletions, duplications, and some sequence variants. CK will be 10x normal | Steroids can extend walking years | Neuromuscular |
| Becker muscular dystrophy | XLR: DMD | Later onset, less severe than Duchenne. Quad weakness may be only sign, or activity induced cramping. NECK FLEXORS ARE PRESERVED. DCM can occur in isolation. Survival to 40s-50s. Ladies at risk for DCM | Dystrophinopathy. Tends to be dels/dups/etc that preserve some function (ie in frame). Decreased but not absent dystrophin staining. | Neuromuscular | |
| Friedreich's Ataxia | AR: FRDA | Degeneration of dorsal root ganglia, tracts of spinal cord and cerebellum. Progressive ataxia before age 25, absent tendon reflexes in lower extremities. Within Progress to dysarthria. Also scoliosis, pes cavs, optic atrophy, HCM, DIABETES | Intronic GAA triplet repeat expansion: Normal 5-33, Pre 34-65, Dz 66-1700 | Neuromuscular | |
| Hereditary neuropathy with liability to pressure palsies | AD: PMP22 | Adult with recurrent focal pressure palsies, mild polyneuropathy, absent ankle reflexes, reduced deep tendon reflexes, mild-mod pes cavus | PMP22 DELETION most common cause. Prolonged distal nerve conduction LATENCY, but normal motor nerve conduction velocity. Demyelination, focal nerve enlargement | Neuromuscular | |
| Limb-girdle muscular dystrophy | AD: CAV3, LMNA; AR: DYSF, CAPN3, FKRP, SGCA, SGCB, SGCD, SGCG; | All have difficulty running/walking. Sarcoglycan - Prox. weakness, calf hypertrophgy, onset 3-15y. Calpain: Prox. weakness, calf ATROPHY, onset 2-40y. Dysferlin: Foot drop, distal and/or pelvic weakness, transient calf hyp. , onset 17-23y | Increased serum CPK, sarcoglycan protein staining. | Neuromuscular | |
| Myotonic Dystrophy Type I | AD: DMPK | Mild: cataract and mild myotonia. Classic: Muscle weakness/wasting, myotonia (esp in GRIP), cataract, arrhythmia. Congenital: Hypotonia and severe weakness at birth, respiratory insufficiency, early death, MR common. | CTG expansion. Mild: 50-150 repeats, Classic : 100-1000 repeats, Congenital: >2000 repeats. Muscle biopsy shows INTERNAL NUCLEI, RING FIBERS. EMG and serum CK also tested. | Neuromuscular | |
| Nemaline myopathy | AD: ACTA1, AR: NEB, ACTA1; other genes are rare causes | Weakness, hypotonia, depressed/absent deep tendon reflexes. Weakness most severe in face, neck flexors, prox limb. Onset varies from congenital-adult. NEB associated with earlier onset. Resp insufficiency in severe cases | ROD-LIKE INCLUSIONS on muscle biopsy (aka nemaline bodies). NEB exon 55 deletion is a founder mutation. | Neuromuscular | |
| Spinal muscular atrophy | AR: SMN1, SMN2 | Arthrogryposis multiplex, hypomyelination, progressive degeneration and loss of LMNs. Onset of muscle weakness ranges from birth to adulthood. Tongue fasciculations, absent DTRs, finger trembling, FTT, restrictive lung disease, sleep issues. | Most cases result from hom loss SMN1 ex 7. Cmp het for deletion and sequence variant rare (need long range assay to confirm variant is in 1). Ex 7 loss due to hom deletions or gene conversion - requires qPCR or MLPA. SMN2 copy number modifies severity. | Neuromuscular | |
| Walker-Warburg | AR: POMT1, POMT2, ISPD, FKTN, FKRP, LARGE1 | Most severe congenital muscular dystrophy. Hypotonia, cobblestone lissencephaly hydrocephalus, abnormal eyeball size, cataracts, optic nerve issues | Defective α-dystroglycan glycosylation. Inc serum CK | Neuromuscular | |
| Fukuyama | AR: FKTN | Weak cry, poor feeding, hypotonia, ptosis, open mouth, contractures, cobblestone lissencephaly, ID, seizures, vision problems, heart problems, aspiration pneumonia. Most never stand or walk | Unknown mechanism, expected to involve α-dystroglycan. 3' UTR founder variant in Japanese population (retrotransposon insertion) | Neuromuscular | |
| Tay Sachs | AR:HEXA (hexaminidase) | Infantile: weakness starting 6mo, exaggerated startle, seizures, vision/hearing loss, no swallow, leads to paralysis, Juvenile: coordination issues, seizures, vision loss. Chronic/late onset: starts later, slow progr. CHERRY RED SPOT. GM2 ganglioside | HEXA enzyme activity testing followed by DNA test -pseudodeficiency allele in some, not associated with disease. 6 variants common in AJ population. | Neuromuscular | |
| Hereditary breast and ovarian cancer | AD: BRCA1/BRCA2 | Breast (triple negative, <60), ovarian cancer (ov. risk higher with BRCA1 variant). BRCA2 has higher risk for male breast cancer, prostate, pancreatic, melanoma. | Jewish founder mutations BRCA1 185delAG, BRCA2 6174delT. 3 large BRCA1 deletions in Dutch. | Clinical breast exam every 6-12 mos beginning 25y. Annual breast MRI beginning 25y. Annual mammograms beginning 30y. risk-reducing mastectomy. Oopherectomy/salpingectomy between 35 and 40 and upon completion of child bearing. | Cancer |
| Familial adenomatous polyposis | AD: APC | 100-1000 colon polyps in childhood to adolescence, abdominal desmoid tumors, jaw osteoma, tooth phenotypes, hepatoblastoma, thyroid cancer, epidermoid cyst. Attenuated: fewer polyps. Gardner: +osteomas+soft tissue tumor. Turcot: +medulloblastoma | Colectomy necessary - mean age of cancer if untreated is 39y. | Cancer | |
| Lynch/HNPCC | AD: PMS2, MLH1, MSH2, MSH6 | Tumors of the colon, endometrium, stomach, ovary, hepatobiliary tract, urinary tract, small bowel, brain/CNS | Microsatellite instability, immunohistochemistry of MMR proteins | 80% lifetime risk of CRC, colectomy if CRC present. Colonoscopy every 1-2y by age 20-25. Consider annual pap smear, transvaginal US, endometrial biopsy | Cancer |
| Li-Fraumeni | AD: TP53, CHEK2 | Increased risk of bone cartilage, soft tissue sarcoma (often <45y). Early onset breast cancer (malignant phyllodes), spine or brain tumor, childhood adrenocortical tumors, Wilms tumor, leukemia. | Annual exam and mammography for women >40y. Avoid/minimize radiation exposure. | Cancer | |
| Multiple endocrine neoplasia type 1 | AD: MEN1 (tumor suppressor) | 3Ps: Tumors in Parathyroid, enteroPancreatic endocrine tissue (islet), anterior Pituitary. Facial angiofibroma, collagenoma, cafe au lait, lipoma also seen. | Parathyroid function, pituitary hormone tests. | Brain/abdominal MRI from 20y. Head MRI from 5y. | Cancer |
| Multiple endocrine neoplasia type 2 | AD: RET (oncogene) | 2A: Medullary thyroid carcinoma, pheochromocytoma, parathyroid adenoma/hyperplasia. 2B: Mucosal neuroma of lips/tongue, medullated corneal nerve fibres, marfanoid habitus, medullary thyroid carcinoma. | Most variants in exon 10 and 11. 2A often Cys634Arg; 2B usually Met918Thr | Prophylactic thyroidectomy, annual PCC screening, annual calcitonin stim test, annual PTH screening. | Cancer |
| Neurofibromatosis type 2 | AD: NF2 (tumor suppressor) | Benign nerve tumors (schwannomas, meningiomas, ependymomas, astrocytomas). Often bilateral ACOUSTIC SCHWANNOMA results in HL, tinnitus, balance issues. Also cataracts, mononeuropathy, cafe au lait (fewer than NF1). Onset 18-24y | Tumors surgically removed as they become symptomatic | Cancer | |
| Cowden | AD: PTEN (tumor suppressor) | Presents 2nd/3rd decade. Mucocutaneous facial/oral papules, gingivival cobblestoning, acral keratosis, dystrophic goiter, GI polyps, breast lesions, MACROCEPHALY, DOLICHOCEPHALY, lipomas, GU anomalies. HIGH RISK FOR BR, THYROID, ENDOMET CANCER | Annual derm, breast exam, annual MRI, mammography starting 30y. Annual thyroid US starting 18y. Annual endometrial biopsy starting 35y until menopause - then US. | Cancer | |
| Bannayan-Riley-Ruvalcaba | AD: PTEN | Macrocephaly, polyposis, lipomas, pigmented macules of glans penis | Cancer | ||
| Proteus | Somatic: AKT1 (some evidence for PTEN) | Cutaneous nevi, disproportionate overgrowth, dysregulated adipose tissue, vascular malformation, risk ovarian/parotid tumor in second decade | Cancer | ||
| Tuberous sclerosis | AD: TSC1, TSC2 | Hypomelanotic macules, facial angiofibroma, shagreen patch, ungual fibromata. Subependymal glial nodules, cortical tubers, giant cell astrocytoma, seizures. Renal angiomyolypoma, epilethial cysts, cardiac rhabdomyoma, lymphangiomatosis (2), eye hamartomas | 2/3 de novo. There is a TSC2/PKD1 contiguous gene deletion resulting in features of TS and PKD. | Quarterly renal ultrasound 1-3 y, chest CT if pulmonary symptoms | Cancer |
| Vin Hippel-Lindau | AD: VHL (tumor suppressor) | HEMANGIOBLASTOMA, pheochromocytoma, renal cell carcinoma, endolymphatic sac tumor. | Partial or complete VHL deletion in ~30%. Truncating/missense mutations that grossly disrupt folding lead to low risk for PCC. Complete deletion has low risk of renal cancer. | Annual eye exam and urine catecholamines, BP beginning 5y, Annual abdominal US starting 15y. | Cancer |
| Xeroderma pigmentosum | AR: XPA, XPC, ERCC2, POLH | Severe sun sensitivity, severe keratitis from UV exposure to conjunctiva, cornea, lids, progressive neurologic deterioration: acquired microcephaly, low/absent DTRs, progressive HL, cognitive impairment. Hugely increased risk of skin and eye neoplasms | Cellular UV hypersensitivity assay. | Protection from UV | Cancer |
| Beckwith-Wiedemann | AD: 11p15.5/CDKN1C, H19, KCNQ1OT1 | Hemihyperplasia, macrosomia, macroglossia, visceromegaly, tumors (Wilms, hepatoblastoma, neuroblastoma, rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, renal abnormalities, rosy cheeks (nevus flameus) | Loss of methylation at DMR2 (50%), mutations in CDKN1C, paternal UPD 11p15 (10-20%), gain of methylation at DMR1. | Abdominal US every 3 mos until 8y. | Overgrowth |
| Sotos syndrome | AD: NSD1 | Macrocephaly, pointed chin, tall stature, increased body mass, delayed motor skills, delayed cognitive, verbal, social dev, advanced bone age. | MLPA or FISH for 5q35 microdeletion (common in Japanese) | Overgrowth | |
| Ataxia with oculomotor apraxia | AR: APTX, SETX | Childhood onset slowly progressive ataxia, followed by oculomotor apraxia and severe primary motor peripheral axonal motor neuropathy. Cerebellar atrophy, high cholesterol. Increased sensitivity to agents that cause single strand breaks | Increased AFP. APTX mutations more common in Portugal and Japan. | Aging | |
| Cockayne syndrome | AR: ERCC6, ERCC8 (NER DNA repair) | Type I - Norm prenatal growth, FTT w/in 2 y, deterioration of vision, hearing, CNS, peripheral nerves. II: Growth failure at birth, little neurological dev after birth, scoliosis, contracture. Type III: Late onset. XP: Freckling, skin cancer, ID, short | Abnormal DNA repair in skin fibroblasts | Aging | |
| Hutchinson Gilford Progeria | AD: LMNA | Short, diminished sc fat, large head, scalp veins, alopecia, delayed/crowded teeth, pear shaped thorax, wide gait | 100% de novo G608G (altered splicing, DN). Elevated urine hyaluronic acid | Aging | |
| Alpha anti-trypsin deficiency | AR: SERPINA1 | Adult COPD (40-50y if smoker, 60s if not), childhood and adult liver disease, | E342K (Z allele) common | Liver transplant | Pulmo |
| CF (and related disorders) | AR: CFTR | CF: Chronic airway infection, sinusitis, meconium ileus, malabsorption due to pancreatic insufficiency, male infertility. CBAVD can occur without pulm or GI symptoms. | Sweat test. R117H variant warrants testing for 5T with 12-13 TG. delta508 accounts for 30-80% of alleles | Tezacaftor/ivacaftor therapeutic for delta 508 homozygotes as well as ~26 other mutations | Pulmo |
| Alport syndrome | AR/AD: COL4A3, COL4A4; XL: COL4A5 | Progressive renal disease with cochlear and ocular abnormalities to isolated hematuria with benign course. ANTERIOR LENTICONUS | 80% X-linked | Renal | |
| Polycystic kidney disease | AD: PKD1, PKD2; AR: PKHD1 | AD: Enlargement of kidneys, cysts, hematuria, polyuria, flank pain, stones, UTI; also cysts in liver, pancreas, intestine, MVP, aneurysm. AR: ~neonatal death, imparied lung formation, pulmonary hypoplasia, oligohydramnios, renal failure, hepatic fibrosis. | Large deletion including PKD1 and TSC2. PKD2 variants show later onset and slower progression. | Renal | |
| Achondroplasia | AD: FGFR3 | Short, rhizomelic shortening, trident hand, frontal bossing, midface hypoplasia, macrocephaly, apnea, spinal cord compression., genu varum. Narrowing of interpediculate distance, | 80% de novo. 98% G1138A | Skeletal | |
| Cleidocranial dysplasia | AD: RUNX2 | Delayed closure of sutures, hypoplastic/aplastic clavicles, dental abnormalities, wide open anterior fontanel, midface hypoplasia, brachydactyly, recurrent OM, HL, wormian bones, normal intellect | Skeletal | ||
| Diastrophic dysplasia | AR: SLC26A2 | Limb shortening, normal head size, HITCHHIKER THUMBS, small chest, large joint contracture, cleft palate, cystic ear swelling, ulnar deviation of fingers, clubfoot, low tone, normal IQ, coronal clefting of vertebrae, clubfoot | 5 common mutations. Undersulfation of proteoglycans. | Skeletal | |
| FGFR-related craniosynostosis | AD: FGFR1, FGFR2, FGFR3 | Bicoronal CS or cloverleaf (all but muenke and FGFR2), distinctive facial features, hand/foot anomalies, developmental dleay/ID, HL, visual impairment | FGFR1 - Pfeiffer; FGFR2 - Crouzon, Apert, Pfeiffer; FGFR3 - Crouzon with acanthosis nigricans; FGFR3 Muenke | Skeletal | |
| Hypochondroplasia | AD: FGFR3 | Short stature, stocky build, rhizo or mesomelia, limited elbow extension, brachydactyly, mild joint laxity, macrocephaly, scoliosis, genu varum, lumbar lordosis, mild-mod ID, LD, adult onset osteoarthritis, narrowed foramen magnum | Skeletal | ||
| Multiple exostosis syndrome | AD: EXT1, EXT2 | Exostoses from growth plate or surface of long bones, limb length discrepancy, bowed long bones, short metacarpals, risk of chondrosarcoma | Skeletal | ||
| Osteogenesis imperfecta | AD (rarely AR): COL1A1, COL1A2; AR: CRTAP, P3H1 | Fractures without trauma, short stature, BLUE SCLERA, dentinogenesis imperfecta, HL, ligamentous laxity, easy bruising. Type II: perinatal lethal, frog leg, short bowed extremeties. Type III: Severe, brainstem compression, hydrocephalus, syringomelia | Type I nonsense mutation | Bisphosphonate, GH | Skeletal |
| Saethre-Chotzen | AD: TWIST1 | Coronal synostosis, facial asymmetry, ptosis, 2/3 syndactyly, dev delay, short stature, pareital foramina, vertebral fusions, radioulnar synostosis, cleft palate, maxillary hypoplasia, congenital heart defect | Skeletal | ||
| DiGeorge/Velocardiofacial syndrome | AD: 22q11.2 deletion or 10p13-p14 deletion | Congenital heart disease (TOF, conotruncal defects, interrupted aortic arch B), immune dysfunction, palate abnormalities, developmental delay, hypocalcemia, renal anomalies, psychiatric disorders, medial deviation of the internal carotids | FISH or MLPA for deletion (22q11 3Mb most common), mostly de novo deletions | MCA | |
| Alagille syndrome | AD: JAG1 88%; NOTCH2 <1% | Bile duct paucity and any three of: cardiac defects, cholestasis, skeletal abnormalities (butterfly vertebrae), posterior embryotoxin (corneal abnormality), facial features. Dev delay, growth failure. | 50-70% de novo | Liver transplant, fat soluble vitamins | Cardio |
Created by:
christse