1788458
| Question | Answer |
| Van der woude Syndrome | Gene: IRF6 Chromosome: 1q32-41 Phenotype: Lower lip pits (80%) Cleft lip, Cleft palate Hypodontia, Missing teeth Allelic - Popliteal pterygium syndrome (AD; lip pits, popliteal web, genital anomalies) |
| Holt Oram Syndrome | Gene: TBX5 (12q24.1, seq >70%, del/dup <1%), SALL4 (20q13.2, rare); AD, 85% de novo Sx: malformation of carpal bones (+ radial or thenar, L>R, 100%), CHD (ASD, VSD, 75%), arrhythmia Path: TBX5 is transcription factor with an important role in cardiogenesis and limb development Monitor: hand x-ray Rx: pacemaker if severe heart block, annual EKG, annual Holter if hx abnl EKG |
| Cri du Chat | Genetics: Chr Deletion 5p- (5p15.2); 12% due to unequal segregation of a translocation or recombination involving a pericentric inversion in one parent, 85% de novo (80% on paternal chr) Sx: cat-like cry (abnl laryngeal development), slow growth, microcephaly, ID, hypotonia, strabismus Dx: most visible on karyotype, few submicroscopic, if only band 5p15.32 cat-like cry only |
| Williams Syndrome | Gene: Chr deletion 7q11.23 (ELN critical); AD, majority de novo Sx: Any artery may be narrow, supravalvular aortic stenosis 75%, distinctive facial features, hoarse voice, hernia, rectal prolapse, joint laxity, anxiety, hypercalciuria, hypothyroidism, FTT infancy Monitor: serum and urine calcium & creatinine, TFT, hearing, vision, renal US, echo Rx: PT, OT, ST, monitor for hypercalciuria, manage constipation aggressively |
| Angelman Syndrome | 1 in 15,000 births Pheno: epilepsy, severe DD and speech impairment, ataxia, happy affect, acquired microcephaly Cause: 70% Maternal Chr 15q11-q13 deletion, 5% paternal UPD, 10% mutations UBE3A (exclusively expressed from maternal chr 15 in brain), 5% mutation ICR |
| Prader-Willi syndrome | 1 in 15,000 births Sx: neonatal hypotonia, short stature, obesity, hypogonadism, learning difficulty, dysmorphism (narrow bifrontal diameter, almond-shaped eyes, triangular mouth, small hands and feet), ID Cause: Paternal chr 15q11-q13 deletion (50-60% 2 Mb, 15% submicroscopic), 25-30% maternal UPD, 2% mutation ICR Rx: growth hormone replacement, behavioral management, monitor for OSA |
| Miller-Dieker syndrome | Contiguous gene deletion syndrome 17p13.3 involving LIS1 gene. Sx: lissencephaly, hypotonia, FTT, facial dysmorphism (bitemporal narrowing, depressed nasal bridge, small nose with anteverted nares, micrognathia) |
| Ochoa Syndrome | Gene: HPSE2 Chromosome: 10q23-q24 Phenotype: Inverted smile, Facial palsy Occult neuropathic bladder, Hydronephrosis |
| Wolf Hirschhorn Syndrome | Chromosome: 4p- syndrome, 87% de novo, 13% due to unbalanced translocation from balanced parent Sx: "greek warrior helmet", microcephaly, Growth deficiency of prenatal onset, hypertelorism, ID variable degree, facial asymmetry, ptosis, IgA deficiency, seizures, cleft lip/palate, low set ears, cryptorchidism, hypospadias, CHD. Eval: distinctive EEG, brain MRI, echo, plasma IgA Rx: 2/3 develop valproate response atypical absence seizures |
| Jacobsen Syndrome | Chromosome: terminal deletion 11q Phenotype: DD, growth retardation, trigonocephaly, telecanthus, down slanting palpebral fissures, carp shaped mouth, congenital heart defects, eye anomalies |
| Pallister Killian Syndrome | Cause: tetrasomy 12p (not found in peripheral blood, need skin bx). Phenotype: hypotonia, seizures, diaphragmatic hernia, mental retardation, short nose, prominent high forehead, bitemporal sparsity scalp hair, hypertelorism, epicentral folds, ptosis, depigmented areas of skin. |
| Edward Syndrome (Trisomy 18) | Incidence: 1/6000-1/8000 births Sx: clenched hands, fingers 2/5 overlap 3/4, IUGR, rocker botom feet, microphthalmia, micro/retrognathia, microstomia, low set ears, prominent occiput, short sternum, mental retardation, FTT, cardiac malformation. Predominately females. Cause: maternal nondysfunction (90%), mosaicism (10%), translocation <1% |
| Patau Syndrome (Trisomy 13) | Incidence: 1/25,000 live births Phenotype: congenital heart defects, holoprosencephaly, microphthalmia, cleft lip/palate, coloboma, polydactyly, hernias, scalp defects, hypotonia, severe MR, limb abnormalities, seizures Cause: 75% maternal nondysjunction, 20% due to translocation, 5% mosaicism Eval: Brain MRI, EEG |
| Mosaic Trisomy 8 | Phenotype: deep palmar and plantar creases, reports of hematological malignancies |
| Turner Syndrome | Genetics: 45, X (SHOX escapes X-inactivation Xpter-p22.32) Incidence: 1/5000 Sx: cystic hygroma, lymphedema, coarctation of aorta, short stature, gonadal dysgenesis, infertility, 50% bicuspid aortic valve, HLHS, hyperlipidemia, hypothyroidism, diabetes, strabismus, recurrent OM, SNHL, crohns, renal malformation, osteoporosis. Accounts for 20% SAB, 99% conceptuses are lost. Eval: echo, renal US, TFTs, GH testing, FISH SRY Path: 70-80% failure to transmit a paternal sex chromosome for 45,X. Loss of sex chromosome from cell in early embryo is likely cause of 45,X mosaicism |
| Klinefelter Syndrome | 46,XXY Incidence: 1/1000 male live births. Sx: tall stature, slightly delayed motor and language skills, learning problems, testosterone plateau age 14, small fibrosed testes, azoospermia, infertility, gynecomastia, high cholesterol, high risk autoimmune disorders and mediastinal germ cell tumors Path: 1st or 2nd meiotic division nondisjunction, mat > pat Rx: testosterone in mid-adolescence for bone density, secondary sex characteristics, muscle mass, cholesterol, libido, and energy; can do ICSI |
| 47,XXX | 1/1000 female births. Usually normal fertility, many taller than average, IQ 10-15 points lower than that of siblings. |
| Microtia | Malformed and underdeveloped ear. Usually unilateral, R > L. Typically isolated, no increase in kidney abnormalities. 1 in 10,000 7% empiric recurrence risk. |
| Beckwith-Wiedemann Syndrome | Pheno: overgrowth, macrosomia, macroglossia, omphalocele, visceromegaly, neonatal hypoglycemia, hemihyperplasia, embryonal tumors, renal abnormalities, adrenocortical cytomegaly 50-60% cases: loss of methylation at maternal IC2. 10-20% cases: PATERNAL UPD chr 11p15. 5-10% cases: pathogenic variants in maternal CDKN1C (40% of AD familial cases). 5% cases: gain of methylation on maternal IC1. Rare: mat translocation, inv chr 11, dup pat 11p15, microdeletion KCNQOT1 or H19. IC1: normally methylated on paternal allele. Regulates H19 (mom expresses) and IGF2 (dad expresses, promotes growth). IC2: normally methylated on maternal allele. Regulates KCNQ10T1 (dad expresses), KCNQ1, and CDKN1C (mom expresses, cell cycle suppressor, constrains growth). |
| CDKN1C | Loss of function -> BWS Mutation increasing stability -> growth inhibition and IMAGe syndrome (IUGR, metaphysical dysplasia, congenital adrenal hypoplasia, genital anomalies) |
| Huntington Disease | Genetics: HD gene; AD, anticipation; Repeat CAG (Coding) in exon 1 Normal <26, mutable 27-35, reduced penetrance 36-39, Pathogenic 40+. 97% inherit from parent, 3% new. Meiotic instability is greater in spermatogenesis than oogenesis. Sx: progressive motor disability (chorea, dysarthria, dysphagia progress to bradykinesia, rigidity, dystonia), psych disturbance; mean onset 35-44 yo. Path: Results in protein with elongated polyglutamine tract that forms toxic aggregates. Rx: capsase inhibitors? fetal neuronal cell transfer? |
| Myotonic Dystrophy type 1 (DM1) | AD, Repeat CTG (location 3'UTR of DMPK) Normal 5-35, Mild 50-150, Classic 100-1000, Congenital >2000 Sx: Mild - cataract, mild myotonia; Classic - muscle weakness and wasting, myotonia, cataract, and arrhythmia, grip myotonia, testicular atrophy, insulin resistance; congenital - hypotonia, generalized weakness at birth, early death Eval: EMG, CK, muscle bx (internal nuclei, ring fibers, sarcoplasmic masses, type I fiber atrophy, high intrafusal muscle fibers), slitlamp exam Dx: southern blot for repeats >100 Path: Expanded transcripts bind splice regulatory proteins with RNA-protein complexes that accumulate in the nuclei. Abnormal developmental processing leads to embryonic isoforms of proteins expressed in adult tissues. |
| Fragile X | Most common cause of inherited learning difficulties. FMR-1 "Site A" CGG Repeat (5' UTR) Normal 6-50, Pathogenic 200-2000 Path: epigenetic silencing of mutant FMR1 by own mRNA that forms RNA:DNA duplex Pheno: high forehead, large ears, long face, prominent jaw, large testes, connective tissue weakness, MVP Premutation 59-200 are at increased risk of fragile X tremor/ataxia syndrome. Path: 2-5x increased FMR1 mRNA leads to GOF leading to intranuclear neuronal inclusions. Dx: PCR for premutation, southern blot for full mutation |
| Kennedy disease (SBMA) | X-lined form of motor neuron disease that affects adult men, onset mid 40s, slow progression CAG repeat (coding) in first exon of androgen receptor gene normal: 13-30, pathogenic: 40-62 |
| Spinocerebellar ataxia 1 (SCA1) | CAG repeat (coding) Normal 6-38, pathogenic 39-80 |
| Spinocerebellar ataxia 2 (SCA2) | CAG repeat (coding) Normal: 16-30, Pathogenic: 36-52 |
| Machado-Joseph Disease (MJD, SCA3) | CAG repeat (coding) Normal 14-40, Pathogenic 60 -> 85 |
| PSEN1 | Encodes presenilin-1. Causes early onset Alzheimer's disease. AD, 20-70% FAD Path: Abnl cleavage at position 42 of beta-amyloid precursor protein (BAPP). Fully penetrant, mean onset 45 yo. |
| Proteus Syndrome | Genetics: somatic mosaicism for activating AKT1 mutation, 90% c.49G>A (p.Glu17Lys) Sx: Normal at birth, develop asymmetrical and disproportionate overgrowth of body parts with multiple malformations of vascular system, osseus system, and connective tissue |
| Stickler Syndrome | Genetics: AD, 6 genes, COL2A1 most common Sx: myopia, cataracts, retinal detachment, hearing loss, robin sequence, premature arthritis, mild spondyloepiphyseal dysplasia |
| Rubinstein-Taybi Syndrome | Genes: CREBBP, EP300; AD Sx: microcephaly, beaked nose, broad thumbs and toes, cryptorchidism, growth delay, severe ID ,congenital heart defect, stabismus, ptosis, sleep apnea, tumors, behavior problems Eval: vision, hearing, echo Dx: FISH CREBBP (~10%), seq CREBBP (40-60%), EP300 (~3%) Path: transcriptional cofactors, abnl acetylation of histones Rx: standard care for vision, hearing loss, heart defects, feeding problems. |
| Transthyretin Amyloidosis | Path: Missense mutations in transthyretin, protein that transports retinol and thyroxine. Amyloid deposits in peripheral nerves and heart. Sx: amyloidotic polyneuropathy, amyloidotic cardiomyopathy Rx: liver transplant New Rx? RNA interference. Phase 1 clinical trial siRNA against transthyretin has been proof of concept. |
| Cardio-Facio-Cutaneous Syndrome | Genetics: BRAF (7q34), MEK1 (15q22.31), MEK2 (19p13.3), KRAS (12p12.1); AD, majority de novo Sx: CHD (pulmonic stenosis, septal defects, hypertrophic CMP, arrhythmia), distinctive facial features, cutaneous abnormalities (xerosis, hyperkeratosis, ichthyosis, eczema, ulerythema ophyrogenes), mild to mod ID, neoplasia in some (ALL) Monitor: echo, renal US, cognitive testing Path: sustained activation of the Ras MAPK pathway downstream effectors (MEK and/or ERK) |
| Friedreich Ataxia (FA) | Genetics: AR, GAA repeat (Intron 1), Normal: 7-34, Premutation 34-65, borderline clinical 44-66, pathogenic 66-1700; point mutations can occur Sx: limb and gait ataxia before age 25 yo, ataxia, impaired position and vibration sensation, loss of DTR, pes cavus, extensor plantars Path: impaired transcriptional elongation leads to LOF, increased Fe in mitochondria, reduced heme synthesis, reduced activity of Fe-S complex proteins |
| Fragile X site E (FRAXE) | CCG repeat (promoter) Normal: 6-25, Pathogenic: >200 Expansions occur less frequently than with site A. Pheno: mild learning difficulties, some as severe as site A expansion |
| Oculopharyngeal muscular dystrophy | GCG repeat (coding) Normal: 6, Pathogenic: 8-13 |
| Myotonic Dystrophy type 2 | CCTG expansion within intron 1 ZNF9 gene. Most families are of German descent from founder mutation. Expanded transcripts binds splice regulatory proteins to form RNA-protein complexes that accumulate in nuclei. Abnormal developmental processing where embryonic isoforms of the proteins are expressed in adult tissues. |
| Unverricht-Lundborg Disease (Progressive myoclonic epilepsy) | Dodecamer repeat expansion upstream from cystitis B (CSTB) gene. Neurodegenerative disorder. Onset 6-15 yo. Stimulus-sensitive myoclonus, tonic-clonic epileptic seizures, later ataxia, incoordination, intentional tremor, and dysarthria. |
| Spinocerebellar ataxia type 10 | Pentanucleotide repeat (ATTCT) expansion in intron 9 of ATXN10. |
| Fibrodysplasia Ossificans Progressiva | Hyperactive signalling of BMP4 Disabling heterotypic bone deposition occurs. Due to mutated ACVR1 encoding BMP type 1 receptor. |
| Noonan Syndrome with Multiple Lentigines (formerly LEOPARD Syndrome) | Gene: PTPN11 (12q24, seq 80%), RAF1 (3p25, 3%); AD Sx: Lentigines, EKG abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnl of Genitalia, Retardation of growth, sensorineural Deafness, Hypertrophic CMP Monitor: audiogram, EKG, echo Path: LOF in PTPN11 (note versus GOF in Noonan) |
| Holoprosencephaly | Most common human congenital brain defect. F>M. variable expressivity. Continuum of severity: alobar, semilobar (posterior interhemispheric fissure only), lobar. facial features cyclopia to normal. Genetic heterogeneity: 25-50% assoc with chromosomal abnormality (trisomy 13, 7q36, 13q32, 2p21, 18p11.3, 21q22.3) 30-40% AD nonsyndromic SHH (7q26) 5% AD nonsyndromic ZIC2 Other loci: SIX3, TGIF, PTCH1, CDON, GLI2, FOXH1, NODAL, HPE6, HPE8 Diabetic mothers have 1% risk of child with HPE. |
| Hand-Foot-Genital Syndrome | Mutations in HOXA13. AD Shortening of the first and fifth digits. Hypospadias in males, Bicornate uterus in females. |
| Synpolydactyly | Genetics: HOXD13. Incompletely dominant. Expansion of polyalanine tract in amino terminal domain of protein, leading to likely GOF with interphalangeal webbing and extra digits in hands and feet. LOF mutations have mild effect with a rudimentary extra digit between 1st and 2nd metatarsals, and 4th and 5th metatarsals of the feet. More severe in homozygotes. |
| Bosley-Saleh-Alorainy syndrome | Mutations in HOXA1 rare, AR CNS abnormalities, deafness, cardiac, laryngotracheal anomalies |
| Congenital Vertical Talus | Mutation in HOXD10 AD |
| Waardenburg Syndrome type 1 | Gene: PAX3, AD Sx: SNHL, heterochromic irides, depigmented skin and hair, early graying, leukoderma, dystrophia canthorum, neural tube defect. Eval: ABR, audiogram, W-index for dystopia canthorum Dx: PAX3 gene seq 90% Path: homeobox transcription factor involved in melanocyte development Rx: hearing aids, cochlear implants, folic acid supplementation for pregnancies at risk for WS1 |
| Waardenburg Syndrome type 2 | More common MITF gene (chr3) SNHL, depigmented hair and skin, abnormal pigmentation of iris, inner canthi are not widely separated |
| Renal-Coloboma Syndrome | PAX3 AD Renal malformations. Structural defects of eye |
| WAGR Syndrome | Contiguous gene deletion syndrome of 11p13 PAX6 - aniridia WT1 - Wilms Tumor |
| Campomelic Dysplasia | Loss-of-function SOX9 chr 17, Rare Bowing of long bones, sex reversal in chromosomal males, very poor long term survival |
| Waardenburg Syndrome type IV | Mutations in SOX10 (chr22), EDNRB, or EDN3 Sx: hirschsprung disease, deafness, absence of epidermal melanocytes |
| Anopthalmia-esophageal-genital Syndrome | SOX2 (3q26) Anopthalmia, microphthalmia esophageal atresia genital hypoplasia in males |
| Ulnar-Mammary Syndrome | Loss-of-function TBX3 Phenotype: ulnar ray developmental abnormalities in the upper limbs, hypoplasia of the mammary glands |
| Greig Cephalopolysyndactyly | Gene: GLI3 (7p13, AD) Sx: macrocephaly, ocular hypertelorism, preaxial polydactyly, cutaneous syndactyly, DD, ID, seizures (<10% usually in deletions) Dx: 500-600 band karyotype 7p13 translocation or interstitial deletion (5-10%); sequence analysis (70%) Path: Haploinsufficiency of GLI proteins regulate genes distal to sonic hedgehog in SHH pathway. |
| Pallister-Hall Syndrome | Frameshift mutations in GLI3 Phenotype: polydactyly, hypothalamic hamartoma, imperforate anus |
| Denys-Drash Syndrome | WT1 gene (chr 11) External genitalia are ambiguous, Progressive renal failure (nephritis) |
| Nonsyndromic Deafness | Locus Heterogenity. 50% cases: GJB2 mutations, AR or AD, 35delG accounts for 2/3rds of recessive mutations in caucasian populations, encodes connexin 26 highly a protein that forms gap junctions expressed in the cochlea |
| Laterality defects | ZIC3 (Xp26) |
| Apert Syndrome | FGFR2 (10q25) Mutation in one of the adjacent FGFR2 residues that links 2nd and 3rd Ig-like group. Phenotype: craniosynostosis, syndactyly, variable degrees DD/ID, mod-severe midface hypoplasia, fused cervical bertebrae, ovarian dysgerminoma |
| Crouzon Syndrome | FGFR2 (100%) w/ acanthosis nigricans FGFR3 (100%) Mutation in 3rd Ig-like loop Phenotype: craniosynostosis, proptosis, external strabismus, mandibular prognathism, progressive hydrocephalus 30%, normal IQ, normal limbs |
| Pfeiffer Syndrome | Type 1 - 95% FGFR2 (chr10q25), 5% FGFR1; usually nl IQ, mod-severe midface hypoplasia, broad thumbs & toes, hearing loss, hydrocephalus, more favorable Type 2 - 100% FGFR2; DD/ID common, cloverleaf skull, extreme proptosis, broad and medially deviated thumbs and great toes, choanal stenosis, CP, seizures, inc risk early death Type 3 - 100% FGFR2; DD/ID common, turribrachycephalic skull, extreme proptosis, broad tumbs and toes, larnygotracheal abnl, seizures, inc risk early death Craniosynostosis, Thumbs and big toes are broad |
| Achondroplasia | Genetics: FGFR3 (chr 4p16). AD. Lethal homozygous. De novo associated with advanced paternal age, methylated CG dinucleotide. 1138G>A (Gly380Arg) 98%. 1138G>C (Gly380Arg) 1-2%. GOF - Transmembrane domain mutation that cause ligand-independent activation of FGFR3, inappropriately inhibits chondrocyte proliferation. Sx: rhizomelia, macrocephaly, frontal bossing, cranio-cervical compression, spinal stenosis, trident hand Prenatal detection only after 24 weeks. Rx: surgery or CPAP for OSA, role of GH unclear, leg lengthening, suboccipital decompression, spinal fusion, LPA support group |
| Hypochondroplasia | Gene: FGFR3 mutation (4p16, N540K common); AD Mutations in proximal tyrosine kinase (intracellular) domain. Sx: Milder skeletal dysplasia, Rhizomelic limb changes, normal head shape and size, limited elbow extension, mild joint laxity, macrocephaly, scoliosis, genu varum, lumbar lordosis, mild-mod ID, LD, adult onset osteoarthritis |
| Thanatophoric Dysplasia | FGFR3 (4p16) Mutations in peptides linking 2nd and 3rd Ig-link domains or distal TK domain. Severe, lethal form of skeletal dysplasia. |
| 22q11 deletion syndrome | Genetics: 3 Mb del 22q11 with loss of ~30 genes, AD, 93% de novo Sx: CHD 74% (TOF, IAA B, Conotruncal), immune dysfunction, palate abnormalities 69%, feeding problems, DD, leadning problems 70-90%, hypocalcemia 50%, renal anomalies 37%, psych d/o, medial deviation of internal carotids Path: TBX1 strongly expressed throughout pharnygeal apparatus Management: serum Ca, PTH, T/B Cell subsets, Ig, post-vaccine Ab, renal US, video laryngoscopy |
| Oculo-auriculo-vertebral spectrum (OAVS) | ?probable non-genetic factors, ?locus 14q32.1, usually sporadic, occ AR/AD Phenotype: hemifacial microsomia, ear malformations, epibulbar dermoids, occasional clefts (cervical vertebral anomalies) |
| Treacher Collins Syndrome | Mutation in TCOF1 gene AD Phenotype: Hypoplasia of the maxilla and mandible, downs landing palpebral fissures with coloboma of lower lid, cleft palate, hearing impairment |
| Branchio-oto-renal syndrome | Gene AD, Mutation in EYA1, SIX5, SIX1 Sx: ear pits, tags, anomalies, deafness, branchial fistulae, renal anomalies (range mild hypoplasia to b/l aplasia) Eval: temporal bone CT, hearing test, renal US Dx: mutation (30%), del/dup (10%) Path: EYA1 products inner-ear, kidney, and branchial-arch development; SIX1 needed for nl development ear, nose, thymus, kidney, kidney, skeletal muscle Rx: excision of branchial cleft cysts, dialysis or transplant as needed. |
| Pierre-Robin Sequence | Sporadic cases may be deformation secondary to oligohydramnios, SOX9 with campomelic dysplasia, AD or AR Pheno: micrognathia, cleft palate, glossoptosis (posteriorly placed tongue). Can be syndromic. |
| Townes-Brock Syndrome | Mutation in SALL1. AD. Pheno: malformed ('satyr') ear, SNHL, preauricular skin tags, imperforate anus, triphalangeal thumbs, cardiac/renal defects, preaxial polydactyly |
| Auriculo-condylar syndrome | AD Pheno: Prominent, malformed ears, abnormal temporomandibular joint, microstomia |
| Oro-facial-digital syndrome (types I to X) | OFD1 due to CXORF5 (Xp22), Ciliopathy XLD, XLR, AR, AD Pheno: cleft or lobulated tongue, cleft palate, oral frenulae, digital anomalies, brachydactyly, polydactyly, syndactyly, clinodactyly |
| Otopalatodigital syndrome | Mutation in FLNA (Xp28) XL semidominant Pheno: prominent supraorbital ridge, wide nasal bridge, down slanting palpebral fissures, low set ears, microstomia, micrognathia, skeletal abnormalities, restricted growth, narrow thorax, platyspondyly, bowed long bones |
| Alstrom Syndrome | Ciliopathy ALMS1 (2p13) Affects: retina, adipose, endocrine, heart |
| Jeune asphyxiating thoracic dystrophy | Ciliopathy IFT80 (chr 15q13) affects: skeleton |
| Bardet-Biedl Syndrome | Gene: Multiple genes, BBS1 (11q13), BBS10 (12q21.2); AR (10% thought to be tri-allelic) Sx: cone-rod dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotrophic hypogonadism, complex female GU malformation, renal dysfunction, night blindness by 7-8 yo, legally bling by 15.5 yo, majority have significant learning difficulties, renal disease (M&M) Eval: ERG, renal US Dx: panel tests, targeted BBS1 (p.M390R - 18-32%) & BBS10 (C91fsX95 - 10%) Path: defects in cilia or intraflagellar transport Rx: visual aids, diet, exercise, surgery for polydactyly, HRT for hypogonadism |
| Cranioectodermal dysplasia (Sensenbrenner syndrome) | ciliopathy affects: kidney, liver |
| Ellis-van Crefeld Syndrome | Gene: AR; EVC1, EVC2 (4p16) Sx: postaxial polydactyly (hands, occ feet), shortening of limbs, small deepset nails, multiple oral frenulae, natal teeth, ASD, short ribs Path: Ciliopathy |
| Joubert Syndrome | Gene: NPHP1, AHI1, CEP290, TMEM67; AR, many more loci with rare prevalence Dx: hypotonia, later ataxia, DD/ID, alternating tachypnea and apnea, pigmentary retinopathy, oculomotor apraxia, difficulty in smooth visual pursuits, M:F = 2:1, renal disease, rare hepatic fibrosis Eval: MRI with molar tooth sign (cerebellar vermis hypoplasia), ERG, renal US, LFT Dx: NPHP1 deletion (1-2%), seq AHI1 (11%), CEP290 (10%), TMEM67 (10%) Path: ciliopathy |
| Leber Congenital Amaurosis | Ciliopathy GUCY2D (17p13), RPE65 (11p31) |
| McKusick-Kaufman Syndrome | Ciliopathy BBS6 (20p12) affects: limb, heart, urogenital tract |
| Meckel-Gruber Syndrome | Ciliopathy MSK1 (17q23) Affects: brain, kidney, liver |
| Nephronophthisis types 1-4 | ciliopathy affects: kidney |
| AD Polycystic Kidney Disease | Gene: PKD1 (85%, younger onset); PKD2 (15%) Sx: late onset, bilateral renal cysts, other cysts (hepatic, ovarian, pancreatic, splenic), CNS/aortic aneurysms, MVP, colonic diverticula Path: polycystin 1 is transmembrane receptor-like protein of unknown fxn. polycystin 2 is integral membrane protein with homology to voltage-activated sodium and calcium channels. Cyst formation follow "two-hit" mechanism. Genetics: 85% PKD1, 15% PKD2, contiguous gene deletion with PKD1 and TSC2 with tuberous sclerosis |
| Primary ciliary dyskinesia (Kartegener syndrome) | Ciliopathy |
| Short-rib polydactyly syndrome | DYNC2H1 (11q13) affects: skeleton, kidney, urogential tract pheno: fetus chest narrow, post axial polydactyly in all 4 limbs |
| Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome | TP63 mutations Split hand-foot, oral clefting |
| Limb-Girdle Muscular Dystrophy | Gene: Multiple loci, CAPN3, FKRP, LMNA, SGCA, SGCB, SGCG, DYSF; most AR Sx: SGCA (sarcoglycan) - proximal limb weakness, difficulty running and walking, calf hypertrophy, onset age 3-15; CAPN3 (Calpain) - proximal limb weakness, difficulty running and walking, calf atrophy, onset 2-40 yo; DYSF (dysferlin) - running and walking, foot drop, distal or pelvic weakness, transient calf hypertrophy, onset 17-23 yo Eval: high CPK, dystrophic on muscle bx, sarcoglycan protein staining |
| LMNA | Can lead to: Emery-Dreifuss Muscular Dystrophy Dilated cardiomyopathy with conduction abnormality Dunnigan-type familiail partial lipodystrophy Mandibuloacral dysplasia Hutchinson-Gilford progeria |
| FLNA | Can cause: Oto-palato-digital syndrome Melnick-Needles syndrome Frontometaphyseal dysplasia Periventricular nodular heterotopia |
| X-linked hypophosphatemia | Vitamin D-resistent rickets X-linked dominant trait Both males and females affected with short stature due to short and often bowed long bones. Direct male-to-male transmission cannot occur. |
| Leri-Weil dyschondrosteosis | SHOX gene, pseudoautosomal region Pheno: short stature, madelung deformity |
| Russell-Silver Syndrome | Pheno: growth retardation, normal HC, small triangular face, body asymmetry Cause: 10% maternal UPD 11, maternal duplications 11p15, ~33% abnormal imprinting at 11p15.5 locus (hypomethylation of H19) |
| Cleft Lip and Palate | Multifactorial Inheritance RR with affected first degree relative 6% if index case bilateral CL/P, 2% if index case unilateral CL. |
| Pyloric Stenosis | Male:Female 5:1 Multifactorial inheritance Affected offspring of male index patients 5.5% for sons, 2.4% for daughters. Affected offspring of female index patients 19.4% for sons, 7.3% for daughters |
| Ankylosing Spondylitis | HLA-B27 allele present in 90% patients and 5% of controls with an odds ratio of 171. |
| Hemoglobin Protein | Tetramer - two pairs of polypeptides (alpha and beta-globin chains), each with own iron-containing heme Alpha subunits on chr 16 Beta subunits on chr 11 64,000 Da |
| Hb A | Normal hemoglobin alpha2beta2 |
| Hb A2 | Tetramer of two normal alpha chains and two other polypeptide chains (delta). Minor fraction of adult hemoglobin. |
| Hb F | Tetramer of two alpha chains and two gamma chains. 0.5% hemoglobin in normal adults. Preceded in early gestation by embryonic hemoglobins (Gower I and II, Portland). Decitabine can inhibit gamma-globin gene methylation and increase expression for treatment of hemoglobinopathies. BCL11A and MYB normally silences expression. Therapeutic targets to increased Hb F expression. |
| Locus control region (lcr) | Region 5' to epsilon-globin gene. Required for expression of all genes in the beta-globin cluster (epsilon, gamma, delta, beta) Involved in the timing and tissue specificity of expression, or switching, in development. |
| Hb S | missense mutation. beta chain, Glu6Val Decreases solubility of deoxygenated hgb, causes it to form gelatinous network of stiff fibrous polymers that distort RBC to sickle shape. Oxygen can cause polymer to dissolve and RBC to regain normal shape, but repeat sickling and unsickling can make irreversibly sickled cells. |
| Hb C | Missense mutation Beta chain, 6 glu to lys |
| Hb Kempsey | AD. Missense mutation Beta chain: Asp99Asn. Locks hemoglobin into its high oxygen affinity state, reducing oxygen delivery to tissues. Sx: Polycythemia |
| Hb Hammersmith | AD. Beta chain: Phe42Ser. Substituted Phe is one of two amino acids conserved in all globins in nature. Normally wedges the heme into a "pocket" in the folded beta-globin. Unstable Hb with Hb precipitation, hemolysis, and low O2 affinity. |
| Hb E | AR Beta-chain: Glu26Lys. Abnormal Hb and decreased synthesis from abnormal RNA splicing leading to mild thalassemia. Most common structurally abnormal hgb in world, highest in Southeast Asia. Homozygotes are asymptomatic, mildly anemic. |
| PSEN2 | Encodes Presenilin-2. Causes Early Onset Alzheimer's Disease. AD, accounts for <5% familial AD. Not fully penetrant, usually consistent age of onset within family. |
| 16p11.2 Deletion Syndrome | AD, ~550 kb contiguous gene deletion. Recurs due to low-copy repeat sequences with high sequence homology & NAHR. Sx: onset birth-6mo, ID, ASD, minor dysmorhisms (low set ears, single palmar crease, 2-3-4 toe syndactyly). Incomplete penetrance. Found in 1% with Autism, 0.1% with DD, 0.03% general population. Reciprocal duplication carries 14.5x increased risk for schizophrenia. Also found in DD, ASD, bipolar disorder, healthy controls. |
| Hirschsprung Disease | Congenital absence of parasympathetic ganglion cells in submucosal and myenteric plexuses. 70% isolated trait. AD, AR, or multigenetic RET is major susceptibility gene for isolated and familial cases. Incomplete penetrance with sex differences (male>female). Dx: biopsy with absence of enteric ganglion cells in distal rectum |
| Hb Lepore/anti-lepore | Unequal crossing over events in meiosis lead to fusion polypeptide. Non-alpha, delta-like residues at N-terminal end, and beta-like residues at C-terminal end, and vice versa respectively |
| Methmoglobin | Mutations interfere with normal oxygen transport function of Hb, leading to either enhanced, or reduced oxygen affinity. Example: Hb Hyde Park. AD. Substitution of highly conserved His92 (covalently binds heme) to Tyr. Makes oxidized heme iron resistant to methemoglobin reductase. Asymptomatic cyanosis in heterozygotes, homozygote state presumably lethal. |
| Sickle Cell Disease | AR. Pheno: anemia, FTT, splenomegaly, repeated infection (pneumococcal sepsis, salmonella osteomyelitis), dactylitis, vaso-occlusive infarctions causing strokes, acute chest syndrome, renal papillary necrosis, autosplenectomy, leg ulcers, priapism, bone aseptic necrosis, visual loss, aplastic anemia from parvovirus Treatment: prophylactic penicillin, hydroxyurea (increases Hb F), allogeneic bone marrow transplantation |
| Sickle Cell Trait | Severe hypoxia (ascent to high altitudes) -> erthyrocytes may sickle and cause sx seen in sickle cell disease Extreme exertion or dehydration -> rhabdomyolysis |
| Thalassemias | Decreased synthesis or stability of either alpha-globin or beta-globin chains. Imbalance of chain ratio leads to extra chains that precipitate in cells, damage membrane, premature cell destruction. Compensatory hyperplasia of the bone marrow. |
| Alpha-thalassemia | Gene: HBA1, HBA2; AR; 90% deletion due to two identical genes on chr 16 with misalignment due to homologous pairing and recombination. Silent carrier: deletion 1/4 copies. Trait: deletion of 2/4. Trans or cis. Hb H disease: deletion of 3/4. Severe (Hb Bart): deletion of 4/4 (Southeast Asia) Sx: Hb Bart - hydrops fetalis, severe hyochromic anemia, neonatal death; HbH - mild microcytic hypochromic hemolytic anemia, HSM, jaundice; Trait - low MCV, low MCH, nl levels Hgb A2 and F Path: Decreased production of alpha-globin chains. O2 affinity similar to myoglobin, do not release oxygen as normal to peripheral tissue. Unstable, insoluble, precipitate, leading to hemolysis. Rx: Hb Bart - rec termination due to mat complications with hydrops; Hb H - PRBC transfusions during hemolytic crisis, anemia causing cardiac sx, or severe bony changes; splenectomy with Abx prophylaxis for splenomegaly. |
| Beta-Thalassemia | Gene: HBB, AR Sx: Major - severe anemia. Beta zero no HbA. Beta plus with detectable HbA. Minor - carriers of one allele. slight anemia, often misdiagnosed as iron def, increased intestinal absorption of iron. Eval: Hgb Electrophoresis with high Hb A2 and Hb F. Path: Decreased production of the beta-globin chain with excess alpha-chains. Dx: usually single base pair substitution. Need gene sequencing. Rx: treat with regular transfusion and chelation |
| Hb Contant Spring | Abnormally long alpha chain resulting from a mutation in the normal termination codon at position 142 in the alpha-globin gene. Translation of alpha-glbin mRNA continues until another termination codon is reached resulting in an abnormally long alpha-globin chain which is unstable leading to a relative deficiency of alpha chains and the presence of the beta-tetramer (Hb H). |
| Hereditary Persistence of Fetal Hemoglobin | HbF production persists into childhood and beyond. Impaired switch from gamma-globin to beta-globin. Usually sx free. |
| N-acetyltransferase activity | Action: transfer of acetyl groups to amine and hydrazine substrates Slow acetylators: ~50% population, homozygous for allelic variants, increased toxicity from isoniazid (Tb Rx), hydralazine (HTN Rx), and other drugs. because blood levels remain higher for longer periods. High activity - rapid inactivators, increased risk of liver damage from isoniazid. |
| Pseudocholinesterase deficiency | AR trait, mutations in CHE1 gene Usually breaks down succinylcholine. Deficiency or reduced activity leads to prolonged effects of succinylcholine used for induction of anesthesia. |
| Glucose 6-phosphate dehydrogenase Deficiency | X-linked recessive trait. 10% afro-carribean males, common in Mediterranean. Leads to increased resistance to malaria. Drug sensitivity leading to hemolysis: primaquine, phenacetin, nitrofurantoin, sulfonamides. Path: first enzyme in hexose monophophate shunt pathway that generates NADPH. Insufficient NADPH available to regenerate reduced glutathione during oxidative stress leads to aggregation of intracellular proteins (Heinz bodies) and rigid RBC that hemolyze |
| CYP2C9 Gene | Cytochrome P450 is encoded by this gene. Two variants have lower activity. CYP2C9*2 and CYP2C9*3 with decreased metabolism. Require lower warfarin dose to maintain target INR. |
| CYP2D6 | Cytochrome P450 family of genes Poor metabolizer: AR mutations, 5-10% of Europeans, 1-2% African Americans Ultrarapid metabolizer: duplication 0.8% europeans, 29% Ethiopians Drugs: metoprolol, carvedilol, thioridazine, haloperidol, codeine, tamoxifen |
| Malignant Hyperthermia | AD, 1 in 50,000 adults undergoing anesthesia, 10x higher in kids Sx: adverse response to inhalational anesthetics (ex. halothane) and depolarizing muscle relaxants (ex. succinylcholine) Path: Elevated ionized calcium in sarcoplasm of muscle leads to sustained muscle contraction, hyperthermia. Genetics: Locus heterogenity, RYR1 70%, CACNL1A3 1% Rx: cooling blankets, muscle relaxants, cardiac antiarrhythmics |
| Thiopurine S-Methyltransferase | Action: S-methylation inactivation of heterocyclic sulfhydryls (azathioprine, 6-mercaptopurine, 6-thioguanine) used in leukemia and autoimmune disease. Low activity associated with increased dug toxicity, requires lower dose. Drugs can cause leukopenia and serious liver damage in 10-15% patients which are likely to have variant allele of TPMT gene. |
| Dihydropyrimidine Dehydrogenase | DPYD gene Rate limiting enzyme in catapolism of drug 5-fluorouracil. Deficiency of enzyme leads to 5FU toxicity. |
| Maturity-Onset Diabetes of the Young | Monogenic form of diabetes. Dominant inheritance. Beta-cell dysfunction. Onset usually before age 25 years. |
| Transient Neonatal Diabetes Mellitus | Genes: HYMAI & PLAG1 (6q24 - paternal duplication, 6q24 methylation, UPD) Sx: DM in first 6 weeks of life, resolves by 18 months, severe IUGR, occasional macroglossia & umbilical hernia. Inc risk to later develop type II DM during illness, puberty, or pregnancy |
| Abacavir | Reverse transcriptase inhibitor used for treatment of HIV. 5% people have potentially fatal hypersensitivity -> Standard of care to assess for HLA B*5701 50% risk for Stevens Johnson Syndrome or Toxic Epidermal necrolysis |
| Macrophage | Cell-mediated innate immunity. Circulating monocytes that use surface receptors to distinguish between self and pathogen leading to phagocytosis of foreign material which is destroyed by fusion with intracellular granules and exposure to hydrogen peroxide, hydroxyl radicals and nitrous oxide. Followed by triggering inflammatory process and neutrophil recruitment. |
| Toll-like Receptor pathway | Transmembrane receptors that function in innate immune responses and microbial recognition. 10 TLR in humans. TLR2 - recognizes peptidoglycans and lipoproteins associated with gram positive bacteria. activation of pathway activates NF-(kappa)B which results in expression of co-stimulatory molecules and inflammatory cytokines (IL-1, IL-6, TNF-alpha). Certain ligands can activate pathway leading to systemic release of TNF-alpha and septic shock. |
| Natural Killer Cells | Large granular lymphocytes. Carbohydrate-binding receptors on cell surface that recognize high molecular weight glycoproteins of MHC class 1 expressed on surface of cell infected by virus. Activated by cytokines from macrophages. Attach to infected cell and lead to cell death. |
| Interferon | Interferon alpha and beta have a role in promoting the cellular response to viral infection by NK cell activation and upregulation of MHC class I. They also interfere with viral replication by reducing mRNA stability and interfering with translation. |
| Mannose-Binding Lectin Pathway | Mannose-binding lectin in blood binds serine protease called MASP. When MBL binds to target, the MASP protein converts C3 to C3a and C3b. C3a mediates inflammation. C3b binds to pathogen surface acting as an opsonin. |
| Opsonisation | C3b and C4b are opsonins that coat foreign organisms greatly enhancing their phagocytosis |
| Inflammatory cytokines | C5a, C4a, C3a Induce vascular permeability. Recruit and activate phagoctyes. |
| Membrane Attack Complex (MAC) | C5b binds and recruits C6 and C7 forming a complex eventually with C8, which catalyzes the polymerization of the final component C9 forming a transmembrane pore and cell lysis. |
| IgG | Heavy chain type gamma. 150,000 Da 8-16 mg/mL Binds to microorganisms and neutralizes bacterial toxins. |
| IgM | Heavy chain type mu. 900,000 Da 0.5-2 mg/mL Produced in early immune response, especially in bacteremia. |
| IgA | Heavy chain type alpha. 160,000 Da 1.4-4 mg/mL Guards mucosal surface. Complement fixation. |
| IgD | Heavy chain type delta. 185,000 Da 0-0.4 mg/mL On lymphocyte cell surface, involved in control of activation and suppression. |
| IgE | Heavy chain subtype epsilon 200,000 Da Trace serum concentration. In parasite and allergic reactions. |
| Light chain | kappa or lambda. Occur in all five classes of antibody, but only one occurs in each individual antibody. |
| Major Histocompatibility Complex Type I | Occur on all cells. Present cytotoxic T cells. |
| Major Histocompatibility Complex Type II | Occur on B cells and macrophages. Signal T-helper cells to present further B cells and macrophages. Genes encoding: DR, DQ, and DP |
| Human Leukocytes Antigen (HLA, Class III MHC) | Involved in immunologic function: TNF, heat-shock proteins, components of complement Chromosome 6. |
| HLADR4 | Celiac Disease Rheumatoid arthritis |
| HLA A3 | Hemochromatosis |
| HLA DR3 HLA DR4 | Insulin dependent diabetes type 1 |
| Hereditary Angioedema | AD inheritance C1 inhibitor deficiency Type 1 - low levels Type 2 - non-functioning protein Inappropriate activation of complement with breakdown of C2 and C4. Accumulation of bradykinin in the tissue, can trigger edema. Rx - Danazol (androgen, modulates transcription of gene increasing mRNA) |
| Chronic Granulomatous Disease | X-linked (CYBB) or AR Disorder of phagocytic function due to defect in NADPH oxidase enzyme complex. Hypergammaglobulinemia may be present. Recurrent bacterial or fungal infections, suppurative lymphadenitis, HSM, pulmonary infiltrates, eczema Rx - bone marrow transplant, peripheral blood stem cell transplant from HLA-matched sibling |
| Congenital Neutropenia | Autosomal dominant - ELA2 (also can cause cyclic neutropenia) or GFI1 mutation. Autosomal recessive - HAX1 (Kostmann disease), G6PC3. If they acquire mutation in CSF3R, high risk of AML. |
| Wiskott-Aldrich Syndrome | X-linked Eczema, Diarrhea, Recurrent infections, thrombocytopenia, low serum IgM, impaired T-cell function and numbers. Rx: Gene therapy with lentiviral vector in autologous hematopoietic stem cells with improvement in first 3 treated patients |
| Leukocyte adhesion deficiency | Life-theratening bacterial infections of the skin and mucous membranes and impaired pus formation. Defective migration of phagocytes from abnormal adhesion-related functions of chemotaxis and phagocytosis. LAD I (most common, ITGB2) and II (Bombay blood group) - AR. LAD III - ? |
| Autoimmune-Poly Endocrinopathy-Candidosis Ectodermal Dysplasia Syndrome | AIRE mutations. 2 of 3 major clinical sx: addison disease, hypoparathyroidism, chronic mucocutaneous candidiasis. Malabsorption, diarrhea, and immune disorders can be present. |
| Bruton-type agammaglobulinemia | Gene: BTK (Xq21.3-q22), X-LR Sx: recurrent OM, PNA, sinusitis <5 yo, sepsis, meningitis, cellulitis, paucity of lymphoid tissue Eval: Low but measurable IgG, <1% B Cells (CD19) Dx: 90% sequence variant, 10% del/dup/inv Path: BTK protein expressed in myeloid cells, plt, B-lineage cells which produce reactive oxygen species when protein absent leading to apoptosis with mild stimulation Rx: IV Ig |
| Hyper-IgM syndrome | Sx: Increased IgM, usually IgD too. Susceptivle to pyogentic infections (pneumocystis, cryptosporidium) Gen: X-linked - CD40LG (aka TNFSF5/CD154), AR - HIGM2, HIGM3 Rx: Allogenic hematopoietic cell transplantation, recombinant granulocyte stim factor for neutropenia, Abx, pneumocystis prophylaxis |
| GATA1 Related XL Cytopenia | Sx: thrombocytopenia, anemia, platelet dysfunction, mild beta thal, neutropenia, congenital erythropoietic porphyria in males Dx: macrothrombopenia with anemia Genetics: GATA1 mutations in >95% affected males (XL) |
| Common Variable immunodeficiency | Most common cause form of Ab deficiency. Gene: most families unknown cause. AR; ICOS, TNFRSF13B (TAC1). Sx: any age (most young adults), low Ig levels, variable T and B cell abnl, often family hx of IgA deficiency, Nodular lymphoid hyperplasia, recurrent infections, GI disorders, autoimmune disorders, allergies, malignancies. Cause: arrest of B-cell differentiation leading to normal number of IgA bearing B-cell precursors but a profound deficit in IgA-producing plasma cells. |
| Severe Combined Immunodeficiency | X-linked - IL2RG AR - JAK3, IL7R Pheno: recurrent opportunistic infection |
| Universal recipients | Blood group AB |
| Universal donor | Blood group O |
| Familial Hyperinsulinism (Permanent Neonatal Diabetes Mellitus) | Activating mutations in KCNJ11 (AR), ABCC8 (97% in AJ), 5% GLUD1 & 5% HNF4A (AD with anticipation) subunits of ATP-sensitive potassium channel in the pancreatic beta cell. Normally channel closure triggers insulin. Sulfonylureas are good treatment because close channel independently of ATP and lead to insulin secretion. EIF2AK3 mutations = Wolcott-Rallison Syndrome. |
| X-linked IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy) | Sx: watery diarrhea, eczema, diabetes, autoimmune thyroid, anemia, low polys and plts, tubular nephropathy Genetics: XL, FOXP3 mutations |
| 1p21.1 deletion | Autism, leadning disability, epilepsy, schizophrenia |
| 15q13.3 deletion | Increased risk ID, seizures, ASD, schizophrenia (Odds ratio 16-18) Subset of individuals with deletion have no obvious findings |
| APP | Encodes beta-amyloid precursor protein. AD, 10-15% FAD. On chr 21 -> pt with down syndrome have sx after age 40 years, 50% with cognitive decline. Path: BAPP is usually cleaved in transmembrane domain so little beta-amyloid peptide (AB) is formed. Increased AB production (especially AB42) is pathogenic. |
| APOE | Apolipoprotein E gene has 3 major isoforms (e2, e3, e4). e4 allele overrepresented in pt with Alzheimer disease. e4 x 2 earlier age of onset (<70 yo). e4 x 1 onset >70 yo, poor outcome after head injury or stroke. e2 allele has a protective affect. Effect varies with sex and ethnicity. |
| Hemochromatosis | Gene: HFE (6p21.3), AR. Variable and incomplete penetrance. Cys282Tyr homozygotes (60-90%) higher risk than Cys282Tyr/His63Asp (3-8%) compound heterozygotes. Male to female 5:1. Sx: early - fatigue, arthralgia, decreased libido, abdominal pain. Late - iron overload, hepatomegaly, cirrhosis, hepatocellular carcinoma, DM, cardiomyopathy, arthritis, bronze skin. Dx: transferrin-iron saturation >45%, high serum ferritin, liver bx, hepatic MRI Path: HFE protein binds transferrin receptor 1 and is thought to reduce cellular iron uptake - mutation leads to increased iron uptake. Rx: treat with phlebotomy with aim for ferritin <50 and transferrin-iron saturation <50%. |
| Venous Thrombosis | Common: Factor V Leiden (F5, Arg506Gln), Prothrombin variant (G20210A), MTHFR homozygous C677T mutation Rare: antithrombin deficiency, protein C deficiency, protein S deficiency |
| Noonan Syndrome | Gene: PTPN11 (seq 50%), SOS1 (10%), RAF1 (10%), RIT1 (10%), SHOC2 (2%), KRAS (1%), SOS2 (1%), NRAS/CBL/BRAF (<1%); AD Sx: short stature, feeding problems, pulmonary valve stenosis, HCM (RAF1/RIT1), cryptorchidism, renal malformation, lymphedema, bleeding d/o, myeloproliferative d/o, inc risk of leukemia and learning disabilities Monitor: echo, renal US, bleeding studies Path: GOF mutations that lead to constitutive activation of the Ras MAP Kinase Pathway Rx: standard stuff, GH replacement |
| RAS-MAPK Pathway | SHP-2 (coded by PTPN11) and SOS1 activate KRAS and HRAS. Positively tranduces signals to Ras-GTP. Mutant RAS proteins display impaired GTPase activity and are resistant to GAPs. RAS binds to GTP which results in activating the pathway (gain-of-function). |
| Sotos Syndrome | Gene: NSD1 (5q35); most de novo; AD Pheno: Overgrowth syndrome, macrocephaly, macrosomia, final adult height may be normal, advanced bone age, mild dilatation of cerebral ventricles, high prominent forehead, hypertelorism, down slanting palpebral fissures, pointed chin, scoliosis. Eval: bone age, Brain MRI |
| Costello Syndrome | Genes: HRAS (11p15.5, GTPase HRas), AD most de novo Sx: feeding issues, DD, ID, coarse facial features, loose, soft skin, hypertrophic CMP, pulmonary stenosis, arrhythmia Monitor: echo, neurocognitive testing Path: constitutive activation of the abnormal protein product resulting in increased signaling through Ras MAP Kinase pathway |
| Hereditary Hemorrhagic Telangiectasia | Gene: ACVRL1 (12q11-q14), ENG (9q34.1, 60-80%), GDF2 (10q11.22), SMAD4 (18q21.2); AD Sx: epistaxis, mucocutaneous telangiectases, visceral AVM (pulmonary, cerebral, hepatic, spinal, GI) Monitor: stool for occult blood, CBC, contract echo for pulmonary AVM, head MRI for cerebral AVM, US for hepatic AVM Rx: Transcatheter embolization of pulmonary AVM, OCP to decrease bleeding, liver tx if hepatic AVM is causing heart failure |
| Neural Tube Defects | Defective closure of the neural tube during first month of embryonic life. Chromosomal - trisomy 13 & 18 Syndromic - Meckel-Gruber syndrome Isolated - susceptibility genes? MTHFR 677C>T, low plasma folate levels, PAX family genes, poor socioeconomic status, valproic acid embryopathy Recurrence Risk for isolated - 2-5% 2 siblings - 12%; Parent - 4% |
| Duplicated 22q11.2 | Phenotype inconsistent, marked variability Mild learning disability, congenital heart disease, cleft palate, hearing loss, growth deficiency |
| Smith-Magenis Syndrome | Genetics: 17p11.2 involving RAI1 (90%), sequencing RAI1 (5-10%); AD Sx: mild-mod infantile hypotonia, feeding problems, FTT, short stature, brachydactyly, ophthalmologic and ORL abnl, early speech delay w/ or w/o hearing loss, peripheral neuropathy, sleep problems, stereotypic maladaptive behaviors, coarsening face over time Eval: Renal US, echo, spine x-ray Path: transcriptional regulation Rx: annual TFT, fasting lipids, UA, scoliosis check, eye exam |
| 1p36 deletion syndrome | Gene: 1p36 deletion (most common terminal deletion syndrome, majority maternally deleted) Sx: hypotonia, microcephaly, growth delay, severe learning difficulties, epilepsy, characteristically straight eyebrows with deep-set eyes and midface hypoplasia, some with dilated cardiomyopathy, SNHL Eval: brain MRI Dx: high resolution karyotype, confirmatory FISH required in most cases |
| 9q34 deletion syndrome | Pheno: learning difficulties, hypotonia, obesity, brachycephaly, arched eyebrows, synophrys, anteverted nostrils, prognathism, sleep disturbances, behavioral problems. May be related to EHMT1 gene in region. |
| 17q21.31 Deletion Syndrome | Pheno: severe DD, hypotonia, long face, high forehead, tubular nose, bulbous nasal tip, large ears, everted lower lip, friendly, epilepsy, heart defects, kidney anomalies, long slender fingers |
| 1q21.1 Deletion Syndrome | Pheno: mild-moderate MR, small head size, growth retardation, heart defects, cataracts, hand deformities, skeletal problems, learning disabilities, seizures, autism Variable penetrance! Some apparently unaffected. |
| Ataxia Telangiectasia | Gene: ATM (11q22.3), AR Sx: progressive cerebellar ataxia (~age 1-4 yo), oculomotor apraxia, conjunctival telangiectasia, immunodeficiency, choreoathetosis, ionizing radiation sensitivity, risk cancer (lymphoma and leukemia) Dx: ATM sequencing (>95%). Amish founder mutation. decreased ATM kinase activity, 7;14 translocation (5-15% lymphocytes after PHA stimulation). Path: Most mutations are null leading to no protein product. Normal protein finds dsDNA breaks and coordinates cell cycle checkpoints prior to repair. |
| Bloom Syndrome | Gene: BLM (15q26.1), AR (1/100 carrier freq Ashkenazi) Sx: IUGR, photosensitive rash, telangiectasia, microcephaly, high pitched voice, normal IQ, immunodeficiency, azoospermia, POF, cancer risk (wide types and sites, colon most common) Dx: chromatid/chromosome breaks, triradial and quadriradial figures, BLM sequencing (2881 del6ins7 in AJ) Path: abnl DNA replication and repair leading to genomic instability |
| Fanconi Anemia | Gene: FANCA (16q24.3), FANCB (Xp22.3), FANCC (9p22.3), FANCD2 (3p25.3), FANCE (6p22-21), FANCF (11p15), FANCG (9p13), BRCA2 (13q12.3), BRIP1 (17q22), FANCL; AR Sx: short stature, abnl pigmentation, radial/GU/ear/heart/GI/CNS malformation, hearing loss, hypogonadism, DD, progressive bone marrow failure (onset age 6-8 yo), aplastic anemia, myelodysplastic syndrome, AML, solid tumors at young age. Dx: chromosome breakage after exposure to diepoxybutane(DEB) & mitomycin C (MMC), macrocytic RBC, immunoblod assay of FANCD2 monoubiquination, increased % cells in G2 arrest Path: defect in repair of DNA strand cross-links. 5 of FA proteins are in a nuclear complex that activates monoubiquitination of FANCD2 protein. |
| Xeroderma Pigmentosa | Gene: XPA, XPC, ERCC2, POLH; AR Path: defective nucleotide excision repair Pheno: light-sensitive pigmented rash, skin malignancy, photophobia, conjunctivitis, blepharitis, ectropion, neoplasia Dx: functional testing to screen cells for abnl in DNA repair |
| Werner Syndrome | Genetics: AR, WRN Sx: premature aging, cataracts, diabetes, atherosclerosis, cancer risk - soft tissue sarcoma, skin cancers |
| Hypohydrotic Ectodermal Dysplasia | Gene: EDA (Xq12) - XL, EDAR (2q11) - AD, EDARADD (1q42) - AD, WNT10A (Odonto-Onycho-Dermal Dysplasia) Sx: peeling skin, perioral hyperpigmentation, hypotrichosis, hyophidrosis, hypodontia; carriers with mosaic pattern of sweating Eval: dental films Path: defective ectodysplasin A cannot be activated to mediate cell-to-cell signaling that regulates morphogenesis of ectodermal appendages. EDAR cannot bind ectodysplasin, EDARADD is co-expressed with EDAR. Rx: cooling vests, hydrdration, tooth restoration and/or dentures |
| Incontinentia Pigmenti | Gene: IKBKG (aka NEMO, Xq28, 80% exon 4-10 deletion, use southern blot); XLD; male lethal Sx: 4 stages of skin changes (erythema -> blister -> hyperpigmented streaks -> atrophic skin patches), hypo/adontia, small or malformed teeth, alopecia, woolly hair, nail ridging or pitting, retinal neovascularization (leads to retinal detachment), ID is rare Eval: free melanin granules in bx of hyperpigmented streak Path: lack of NF-kappa beta activation leads to cells that are sensitive to proapoptotic signals and apopose easily Rx: regular retinal exams 1-2 yo, cosmetic dentistry |
| Ichthyosis | Ichthyosis Vulgaris (most common), X-linked steroid sulfatase. AR congenital ichthyosis (collodion baby), milder form, multiple genes - TGM1 50-60%. |
| Epidermolysis Bullosa | Sx: bilstering of skin EB simplex (in epidermis, suprabasal AR or basal AD/AR) - least severe Junctional EB (within basement membrane): 3 genes, AR (collagen XVII, laminin-332, integrin alpha6beta4) Dystrophic EB (below basement membrane) - COL7A1, most severe Kindler Syndrome (multiple cleavage planes) - FERMT1 |
| Alpha-1 Antitrypsin | AR, SERPINA1 gene, 1 in 6700 white Sx: pulmonary emphysema, hepatic cirrhosis Dx: Pi type (electrophoretic mobility) M is normal allele, Z allele (Glu342Lys) is most common mutant allele Path: Z allele causes protein to aggregate and get trapped in Rough ER of hepatocytes & alters balance of elastase and alpha-1AT which allows degradation of elastin in alveolar walls. Rx: no smoking, antioxidants, transplantation, alpha-1-AT augmentation |
| Alagille Syndrome | Gene: JAG1 (20p12), NOTCH2 (1p13-p11), AD, 50-70% de novo Sx: Bile duct paucity on liver bx + any 3 of: cardiac defects (most often PA disease, TOF), cholestasis, skeletal abnormalities (butterfly vertebrae), eye (posterior embryotoxin); DD, growth failure Dx: seq JAG1 88%, del FISH JAG1 7%, seq NOTCH2 <1% Path: JAG1 truncated protein is unable to bind to cell membrane Rx: liver tx, evaluate head injuries and CNS sx for vascular accidents |
| Heritable Pulmonary Arterial Hypertension | Sx: dyspnea, fatigue, chest pain, palpitation, edema, increased PA, right sided heart failure Genetics: 6% familial, AD, variable penetrance, F:M 2.4:1, BMPR2 most common, others rare (ACVRL1, BMPR1B, CAV1, ENG, SMAD9) |
| Idiopathic Pulmonary Fibrosis | Sx: bibasilar reticular anomalies, nodules, onset 50-70, 50% 5 year survival after onset Genetics: TERT, TERC, SFTPC, AD, reduced penetrance, can be in hermanski pudlak and dyskeratosis congenita Rx: Supp O2, lung transplant, no smoking |
| Thiamine Responsive Megaloblastic Anemia | Sx: megaloblastic anemia, SNHL, DM, +/- optic atrophy, CDH, arrhythmia, strokes Genetics: SLC19A2, AR Rx: high dose thiamine, SNHL irreversible |
| Cartilage Hair Hypoplasia (Anauxetic Dysplasia Spectrum) | Sx: severe short limbs, joint hypermobility, fine silky hair, immunodeficiency anemia, GI dysfunction, risk for malignancy Genetics: RMRP - AR Rx: transfusions, avoid live vaccines, monitor for malignancy, Abx |
| Loeys Dietz Syndrome | Gene: TGFBR1, TGFBR2, SMAD3, TGFB2; AD Sx: arterial aneurysms and/or dissections, pectus excavatum or carinatum, scoliosis, joint laxity, arachnodactyly, clubfeet, some craniofacial in type 1 (hypertelorism, bifid uvula, craniosynostosis) Eval: echo, MRA, spine X-ray Path: Increased TGF-beta signaling in vasculature Rx: vascular surveillance, losartan, beta-blockers, bracing for scoliosis |
| Age-related macular degeneration | Sx: progressive degeneration of macular, large soft drusen, common form of blindness in older adults. Atrophic (dry) or neovascular (wet). Genetics: 50% population-attributable genetic risk due to polymorphic variant (Tyr402His) in complement factor H gene. Polymophic variants in complement factor B and complement component 2 reduce risk. Many loci implicated. Rx: smoking cessation, antioxidants, zinc, for wet AMD intravitreous injection of vascular endothelial growth factor inhibitor (pegaptanib) may slow visual loss. |
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