20- One Hundred Syndromes Flashcards

Question

MARFAN SYNDROME

Answer 1

Responsible gene: FBN1 Protein: Fibrillin 1 Cytogenetic locus: 15q21.1 Inheritance: AD Clinical Features and Diagnostic Criteria: Major involvement of 2 body systems and minor involvement of a 3rd. Major Criteria CV: Dilation or dissection of the ascending aorta Skeletal: pectus carinatum or excavatum, reduced upper:lower segment or arm span:ht, scoliosis, pes planus, high palate, reduced elbow extension, protrusio acetabulae, Eye: ectopia lentis, Dura: lumbosacral dural ectasia, FH: pathogenic FBN1 mutation, 1st degree relative with Marfan syndrome. Minor Criteria CV: MV, MR, dilation of main PA, mitral annulus calcification, dilation or dissection of the descending thoracic or abdominal aorta age <50yrs, Skeletal: moderate pectus excavatum, joint hypermobility, high palate with crowding of teeth, typical facial features Eye: flat cornea, increased length of globe, decreased pupillary meiosis, Lung: pneumothorax, apical lung blebs, Skin: skin striae, hernia Clinical Tests: CXR: apical blebs, Echocardiogram: MVP, aortic measurements, CT or MRI: dural ectasia Molecular Tests: FBN1 seqencing (70-90%) Disease Mechanism: Dominant negative effect of mutant forms of fibrillin Treatment/Prognosis: Beta blockers/Losartan for aortic root dilation, bracing/surgery for scoliosis, annual dilated eye exam, glasses for myopia

Answer 2

Responsible gene: GJB6 Protein: Gap junction beta-6 protein (Connexin 30) Cytogenetic locus: 13q12 Inheritance: AD Clinical Features and Diagnostic Criteria: malformed, thickened, small nails; hypotrichosis (partial or total alopecia), palmoplantar hyperkeratosis, normal sweating and teeth. Clinical Tests: None Molecular Tests: Three GJB6 mutations (G11R, A88V, V37E) account for 100% of indentified mutant alleles Disease Mechanism: Helps form a gap junction channel which mediates ion diffusion. Mutations are thought to affect trafficking of the protein and thus the formation of the gap junction Treatment/Prognosis: No specific treatment. Skin emollients for hyperkeratosis

Answer 3

Responsible genes: EDA, EDAR, EDARADD Proteins: Ectodysplasin-A, Tumor necrosis factor receptor superfamily member EDAR, ectodysplasin A receptor-associated adapter protein Cytogenetic loci: Xq12-q13.1, 2q11-q13, 1q42.2-q43 Inheritance: XL (95%), AD or AR (5%) Clinical Features and Diagnostic Criteria: At birth: peeling skin and perioral hyperpigmentation. Hypotrichosis (sparse scalp and body hair), hypohidrosis (inability to sweat in response to heat leads to hyperthermia), hypodontia (usually only 5-7 teeth develop, teeth are smaller with conical crowns. Carriers of XL HED show mosaic pattern of sweat pore function and some degree of hypodontia. Clinical Tests: dental xray. Molecular Tests: EDA sequencing (~95% XL HED), EDAR and EDARADD sequencing Disease Mechanism: Defective ectodysplasin A cannot be activated to mediate the cell-to-cell signaling that regulates morphogenesis of ectodermal appendages. Defective EDAR cannot bind ectodysplasin. The protein encoded by EDARADD is co-expressed with EDAR. Treatment/Prognosis: During hot weather maintain hydration and keep down body temp with A/C, "cooling vests", and/or spray bottle of water. Tooth restoration, orthodontics, and/or dentures may be necessary

Answer 4

Responsible gene: IKBKG (aka NEMO) Protein: NF-kappaB essential modulator Cytogenetic locus: Xq28 Inheritance: XLD (most male fetuses miscarry) Clinical Features and Diagnostic Criteria: Major: Four stages of skin changes: erythema->blister->hyperpigmented streaks->atrophic skin patches. Minor: hypo/andontia, small or malformed teeth, alopecia, woolly hair, nail ridging or pitting, retinal neovascularization causing retinal detachment. ID is rare. Clinical Tests: Free melanin granules if hyperpigmented streak biopsied. Molecular Tests: Southern blot: Exon 4-10 deletion (80%). Skewed X inactivation in females (not diagnostic). Disease Mechanism: Lack of NF-kappa beta activation leads to cells that are sensitive to proapoptotic signals and apopose easily. Treatment/Prognosis: Regular retinal exams in first 1-2 yrs. Cosmetic dentistry. Normal life expectancy.

Answer 5

Responsible genes: TYR and OCA2 Proteins: Tyrosinase protein, P protein Cytogenetic loci: 11q14-q21, 15q11.2-q12 (in PWS/Angelman region) Inheritance: AR Clinical Features and Diagnostic Criteria: OCA1A (no melanin synthesis) nystagmus, dec iris pigment, foveal hypoplasia, dec visual acuity, strabismus, white hair and skin, translucent iris. OCA1B (some melanin synthesis) milder eye and skin manifestation than OCA1. OCA2 ocular problems same as OCA1 but better vision, range of skin and eye pigmentation from minimal to near normal Clinical Tests: Skin and eye exam, VEP Molecular Tests: TYR sequencing (OCA1A: 2 mutations 83%; OCA1B: 2 mutations 37%). 2kb OCA2 deletion testing (most of Sub-Saharin African heritage) Disease Mechanism: Lack of melanin production Treatment/Prognosis: Yearly eye exam, sun screen and monitoring for skin cancer.

Answer 6

Responsible gene: NROB1 Protein: Nuclear receptor 0B1 Cytogenetic locus: Xp21.3-p21.2 Inheritance: X-LR Clinical Features and Diagnostic Criteria: acute onset adrenal insufficiency (hyperkalemia, acidosis, hypoglycemia, shock), cryptorchidism, delayed puberty. Carrier females: may have adrenal insufficiency or hypogonadotropic hypogonadism 1/3 contiguous gene deletion with glycerol kinase, DMD del 2/3 isolated CAH (half are de novo) Clinical Tests: Dec Na+, Inc K+, acidosis, inc ACTH with low cortisol, dec 17 hydroxyprogesterone. If GKD: serum triglyceride, urine glycerol. If DMD: elevated CK Molecular Tests: NROB1 FISH deletion (100%) Disease Mechanism: OB1 is a negative regulator of nuclear receptor pathways Treatment/Prognosis: Treat adrenal crisis, replacement steroids and stress dosing, HRT for hypogonadism

Answer 7

Responsible gene: CYP21A2 Protein: Cytochrome P450 XXI Cytogenetic locus: 6p21.3 Inheritance: AR Clinical Features and Diagnostic Criteria: virilized female, precocious puberty or adrenarche, childhood virilization in males, infant with Na+ losing crisis at birth. Nonclassic form: moderate enzyme deficiency with variable postnatal virilization, no salt wasting, but rare cortisol def. Clinical Tests: Elevated serum 17-OHD at baseline or after ACTH stim, elevated testosterone and adrenal androgen precursors in females and prepubertal males. Part of NBS (17-OHD level) Molecular Tests: CYP21A2 common mutation and deletion panel detects 80-98% Disease Mechanism: cortisol production pathway is blocked-> accumulation of 17-OHP->shunted into the intact androgen pathway->17,20-lyase enzyme converts the 17-OHP to -androstenedione->converted into androgens. The mineralocorticoid pathway requires minimal 21-hydroxylase activity->salt wasting Treatment/Prognosis: Hydrocortisone (monitor closely: too little will have excess androgen, too much causes Cushing's, skeletal maturation), stress dose steroids

Answer 8

Responsible gene: AR Protein: Androgen receptor Cytogenetic locus: Xq11-q12 Inheritance: XLR Clinical Features and Diagnostic Criteria: Evidence of feminization (i.e., undermasculinization) of the ext. genitalia, abnl secondary sexual development, and infertility in those with a 46,XY karyotype. Spectrum: complete androgen insens. syndrome (CAIS), with typical female genitalia; partial androgen insens. syndrome (PAIS) with predominantly female, predominantly male, or ambiguous genitalia; and mild androgen insens. syndrome (MAIS) with nl male genitalia. Clinical Tests: impaired spermatogenesis, absent or rudimentary müllerian structures, evidence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, normal or increased LH, and deficient or defective androgen-binding activity of genital skin fibroblasts Molecular Tests: AR sequence analysis (>95% CAIS, <50% PAIS, unknown %MAIS) Disease Mechanism: Impaired androgen binding Treatment/Prognosis: To prevent testicular malignancy, treatment of CAIS includes either removal of the testes after puberty when feminization is complete or prepubertal gonadectomy accompanied by estrogen replacement therapy. Systematic disclosure of the diagnosis of AIS in an empathic environment

Answer 9

Responsible genes: KAL, FGFR1 Proteins: Anosmin 1, fibroblast growth factor receptor 1 Cytogenetic loci: Xp22.3, 8p11.1-11.2 Inheritance: XLR, AD Clinical Features and Diagnostic Criteria: Type 1and 2: hypogonadotropic hypogonadism and anosmia. Usually present with delayed pubertal development. Type 1 can also include mirror hand movements, ataxia, GU anomaly, high palate, pes cavus. Type 2 ID, CL/P, cryptorchidism, choanal atresia, CHD, SNHL. Clinical Tests: Low FSH and LH; low testosterone in males; low estradiol in females. MRI: hypo/aplasia olfactory bulbs and tracts. Molecular Tests: Sequencing KAL (5-10%), FGFR1 (8-16%) Disease Mechanism: Lack of anosmin stops olfactory axons from interecting with their target. It is thought that FGFR1 may play a role in olfactory bulb formation and possibly interacts with anosmin Treatment/Prognosis: Normalize gonadal steroid levels.

Answer 10

Clinical Features and Diagnostic Criteria: Tall stature, slightly delayed motor and language skills, inc learning probs, testosterone plateaus age 14, small fibrosed testes, azoospermia and infertility, gynecomastia, inc cholesterol, slightly inc risk of autoimmune disorders and mediastinal germ cell tumors (1% risk) Clinical Tests: karyotype, at least one extra chromosome to a 46,XY Karyotype Disease Mechanism: 1st or 2nd meiotic division nondisjunction of either parent. Maternal>paternal origin. +AMA effect Treatment/Prognosis: Testosterone in mid-late adolescence for bone density, secondary sex characteristic development, muscle mass, cholesterol, increase libido, improved energy. Can do testicular biopsy and use any retrieved sperm for ICSI (inc risk sex chrom abnormality so follow with PGD

Answer 11

Responsible gene: GNAS Protein: Guanine nucleotide-binding protein G(s), alpha subunit Cytogenetic locus: 20q13.2 Inheritance: sporadic Clinical Features and Diagnostic Criteria: polyostotic fibrous dysplasia, pathologic fracture, cranial foramina thickening->deafness and blindness, large irregular café au lait ("coast of Maine"), precocious puberty, hyperthyoidism, inc GH, PRL, or PTH, ovarian cysts Clinical Tests: x-ray, pelvic US, vision and hearing testing, pituitary hormone analysis Molecular Tests: Targeted mutation analysis Disease Mechanism: Activating mutations (a stimulatory G-protein) leads to persistently high cAMP (de-activating mutations cause Albright Heredity Osteodystrophy) Treatment/Prognosis: Aromatase inhibitor to block testosterone, bisphosphonate for fibrous dysplasia, anti-thyroid meds, octreotide (somatostatin analog) and bromocriptine (dopamine receptor agonist)

Answer 12

Responsible genes: HYMAI, PLAGL1 Proteins: unknown (HYMAI), zinc finger protein PLAG1 Cytogenetic loci: 6q24 (HYMAi and PLAG1) Inheritance: UPD isodisomy chromosome 6, paternal 6q24 duplication, or 6q24 methylation defect Clinical Features and Diagnostic Criteria: DM in the first six weeks of life, resolves by 18 months, severe IUGR, dehydration, hyperglycemia. Occassional macroglossia and umbilical hernia. Clinical Tests: High serum glucose and low plasma insulin, no islet cell antibodies, no ketoacidosis. 2% have a visible 6q24 duplication Molecular Tests: UPD6 (35%), 6q24 duplication (35%), imprinting mutation (20%) Disease Mechanism: PLAGL1 and HYMAI are normally only expressed on the paternal allele, unclear why overexpression causes DM. HYMAI may regulate PLAGL1 expression Treatment/Prognosis: Rehydration, IV insulin and then subcutaneous insulin within two weeks, close blood glucose monitoring. Inc risk to later develop type II DM during illness, puberty or during pregnancy

Answer 13

Responsible genes: X genes that escape inactivation, SHOX Proteins: SHOX: Short stature homeobox protein Cytogenetic locus: SHOX: Xpter-p22.32 Inheritance: sporadic Clinical Features and Diagnostic Criteria: congenital lymphedema, growth failure, normal intelligence (10% sig delays), coarctation of the aorta, bicuspid aortic valve, HLHS, hyperlipidemia, gonadal dysgenesis (10% 45,X go into puberty), hypothyroidism, diabetes, strabismus, recurrent OM, SNHL, Crohns, renal malformation, osteoporosis. Clinical Tests: echo, renal US, TFTs, GH testing, FISH SRY Molecular Tests: Karyotype Disease Mechanism: SHOX: thought to act as a transcription regulator with many down-stream targets that modify growth and stature. SHOX protein has been id'ed in the growth plate from 12 weeks GA to late childhood. Treatment/Prognosis: GH, HRT, gonadectomy if Y chromosome mosaicism (risk for gonadoblastoma). Need lifelong cardiac follow-up, at risk for aortic dilation and dissection with bicuspid aortic valve.

Answer 14

Responsible gene: FOXL2 Protein: Forkhead Box Protein L2 Cytogenetic locus: 3q23 Inheritance: AD (50% de novo) Clinical Features and Diagnostic Criteria: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. BPES type I includes the four major features and premature ovarian failure (POF); BPES type II includes only the four major features. Can also see: lacrimal duct anomalies, amblyopia, strabismus, and refractive errors. Minor features: broad nasal bridge, low-set ears, and a short philtrum. Molecular Tests: Combination of seq analysis and deletion testing Disease Mechanism: FOXL2 is a transcriptional repressor of granulosa cell differentiation; mutations cause accelerated differentiation of granulosa cells and secondary depletion of the primordial follicle pool Treatment/Prognosis: Surgical correction of eye anomalies, ovum donation if POF

Answer 15

Responsible genes: GJB2 (Cx26), GJB6 (Cx30) Proteins: Gap junction proteins 2 and 6 Cytogenetic loci: 13q11-12 Inheritance: AR Clinical Features and Diagnostic Criteria: Congenital mild-profound SNHL. Rare patients can have AD Cx26 HL which can include skin findings: palmarplanter keratoderma, KID syndrome Clinical Tests: Newborn hearing screen, ABR diagnostic, monitor with standard audiometry. Molecular Tests: GJB2: sequencing of exon 2 and exon 1 for splice site mutation (4th most common mutation). 35delG common in caucasians, 235delC in Asians, 167delT, del35Gand Cx30 gene deletion in Ashkenazi Jewish. GJB6-D13S1830 deletion: deletion that includes Cx30, causes HL if homozygous or combined with single Cn26 mutation. Disease Mechanism: Loss of gap junction prevents recycling of toxic ions and metabolites away from hair cells leading to their death Treatment/Prognosis: Some have progressive HL. Habilitation with hearing aids or cochlear implants.

Answer 16

``` Responsible gene (protein, cytogenetic locus): HPS1 (10q23.1, HPS 1 protein), AP3B1 (5q14.1, AP-3 complex subunit beta), HPS3,4,5,6,7and 8 (3q24, 22q11.2-q12.2, 11p15-p13, 10q24.3, 6p22.3, 19q13, HPS 3,4,5,and 6 proteins, dysbindin, and biogenesis of lysosome-related organelles complex - 1sununit2) ``` Inheritance: AR Clinical Features and Diagnostic Criteria: Findings of oculocutaneous albanism and a bleeding diathesis: hypopigmentation of the skin and the hair, nystagmus, reduced iris pigment, reduced retinal pigment, foveal hypoplasia, increased crossing of optic nerve fibers. Can develop skin cancer, pulmonary fibrosis, colitis Clinical Tests: Absent platelet dense bodies (sine qua non) on platelet EM. Prolonged bleeding time. Molecular Tests: Del/Dup analysis HPS1 (~75% Puerto Rican HPS), HPS3 (~25% Puerto Rican HPS). Targeted mutation analysis HPS3 (~5% non Puerto Rican HPS) Disease Mechanism: The HPS genes protein products have unknown fxn Treatment/Prognosis: DDAVP prior to dental work, thrombin-soaked gel foam for minor cuts, skin protection, annual eye exam, skin exam, and in adulthood PFT's.

Answer 17

Responsible gene: KCNQ1 and KCNE1 Protein: Voltage-gated K+ channel protein KvLQT1; K+ voltage-gated channel subfamily E member 1 Cytogenetic loci: 11p15.5, 21q22.1-q22.2 Inheritance: AR (Heterozygotes at risk for AD long QT a.k.a. Romano Ward syndrome) Clinical Features and Diagnostic Criteria: Congenital severe- profound bilateral SNHL and prolonged QT interval. At risk for arrhythmia, syncope, and sudden death Clinical Tests: Hearing tests (ABR, audiogram) Molecular Tests: KCNQ1 sequencing (90%), KCNE1 (10%) Disease Mechanism: In cardiac cells: abnormal repolarization of the ventricular action potential. In cochlear cells: abnormal depolarization of the auditory nerve ``` Treatment/Prognosis: Cochlear implants for HL, beta blockers, cardiac pacemakers, and/or implantable defibrillators. Avoid QT prolonging drugs (http://www.arizonacert.org/). If left untreated, over ½ of children with JLNS die prior to age 15 yrs ```

Answer 18

Responsible genes: MTND1, MTND4, MTND5, MTND6' Proteins: Complex I subunits of the mitochondrial respiratory chain Cytogenetic loci: Mitochondrial Inheritance: Mitochondrial Clinical Features and Diagnostic Criteria: Blurred or clouded vision progressing to degeneration of the retinal nerve and then optic atrophy. Fundus: vascular tortuosity of central retinal vessels, circumpapillary telangiectatic macroangiopathy, and swelling of the retinal nerve fibers Clinical Tests: Visual field assessments, ERG, VEP Molecular Tests: Targeted mutation analysis: G11778A (70% cases), G3460A, T14484C (15%) Disease Mechanism: Focal degeneration of the retinal ganglion cell layer and optic nerve Treatment/Prognosis: No treatment available, worsened by smoking or EtOH

Answer 19

Responsible gene: SLC26A4 (PDS) Protein: solute carrier 26A4 Cytogenetic locus: 7q31 Inheritance: AR Clinical Features and Diagnostic Criteria: bilateral severe SNHL, temporal bone abnormalities, vestibular abnormalities, goiter in 75% though only 10% have abnormal thyroid function. Clinical Tests: Hearing test. CT/MRI: dilation of the vestibular aqueduct with or without cochlear hypoplasia (Mondini malformation) Molecular Tests: l236P, T416P, H723R, IVS8+G>A represent 50% of all mutations. SLC26A4 sequencing available. Disease Mechanism: SLC26A4 is a chloride/iodide exchanger in the inner ear and thyroid, mutation leads to inner ear malformation and abnormal iodide processing in the thyroid Treatment/Prognosis: Hearing aids, cochlear implant, monitor thyroid function

Answer 20

Responsible genes: 11 genes, majority of cases due to MYO7A, USH2A Proteins: Myosin-VIIa, Usherin Cytogenetic loci: 11q13.5, 1q41 Inheritance: AR Clinical Features and Diagnostic Criteria: Type I congenital profound HL, congenital balance problems, retinitis pigmentosa (RP) onset prepuberty. Type II congenital mild-severe HL, normal balance, RP onset in teens-20's, Type III progressive later onset HL, progressive balance problems, variable onset RP. Clinical Tests: hearing tests, ERG, eye exam for pigment changes Molecular Tests: Type I MYO7A sequence analysis (40-50%) Type II USH2A sequencing (65%) Disease Mechanism: RP is caused by degeneration of rod and cone functions of the retina. For at least some gene, inner hair cell function and structure are affected in the ear. Treatment/Prognosis: RP is progressive, bilateral, and symmetric resulting in progressively constricted visual fields though not complete blindness. Vitamin A may slow progression. HL is complete in Usher Type I and progressive in types II and III. Cochlear implants and hearing aids for HL

Answer 21

Responsible gene: PAX3 Protein: Paired box protein Pax-3 Cytogenetic locus: 2q35 Inheritance: AD Clinical Features and Diagnostic Criteria: WS1: SNHL, heterochromic irides, white forelock, early graying, leukoderma, dystopia canthorum, neural tube defect. WS2: WS1 without dystopia canthorum WS3: WS1 features and limb hypoplasia or contracture, carpal bone fusion, or syndactyly WS4: WS1 with Hirschprung disease Clinical Tests: ABR, audiogram, calculation of W-index to identify dystopia canthorum Molecular Tests: PAX3 gene sequencing (90% WS1) Disease Mechanism: Haploinsufficiency. PAX3 is a homeobox transcription factor involved in melanocyte development. Treatment/Prognosis: Hearing aids or cochlear implants. Folic acid supplementation of pregnancies at risk for WS1 related neural tube defect

Answer 22

Responsible gene: HMBS Protein: Porphobilinogen deaminase Cytogenetic locus: 11q23.3 Inheritance: AD Clinical Features and Diagnostic Criteria: Onset after puberty, acute attacks, abdominal pain, muscle weakness, neuropathy, hysteria, anxiety, hepatocellular carcinoma, NO CUTANEOUS FINDINGS Clinical Tests: inc urine delta-amonolevulinic acid (ALA) and porphobilinogen (PBG) during acute attack Molecular Tests: HMBS gene sequencing (>98%) Disease Mechanism: ?direct neurotoxicity of PBG, ?generation of reactive oxygen species or inhibition of GABA release at central synapses by ALA, ?loss of heme in the CNS Treatment: Stop or treat precipitant (medication, infection, EtOH, dehydration, smoking, poor caloric intake); intubate if bulbar paralysis; IV dextrose; IV hemin (repress ALAS-N enzyme activity); pain control

Answer 23

Responsible genes: HBA1, HBA2 Protein names: Hemoglobin subunit alpha 1 and 2 Cytogenetic locus (loci): 16pter-p13.3 Inheritance: AR; if parents Alpha Thal trait, risk for HbH disease if one parent's mutations are in cis, at risk for HB Bart if both parents in cis Clinical Features and Diagnostic Criteria: HB Bart: loss or dysfunction of all 4 alpha thal alleles, hydrops fetalis, severe hypochromic anemia, death in neonatal period; HbH: loss or dysfunction of 3 of 4 alpha thal alleles, microcytic hypochromic hemolytic anemia, HSM, jaundice Alpha Trait: loss or dysfunction of 2 alpha thal alleles, low MCV, low MCH, nl levels Hgb A2 and F; Alpha "silent" carrier: loss or dysfunction of one alpha thal allele, none or mild thalassemia-like effect Clinical Tests: MCV, MCH, peripheral smear, reticulocyte count, hemoglobin electrophoresis. Prenatal screen at risk populations! Molecular Tests: Targeted mutation analysis for common deletions (90%); gene sequencing (10%) Disease Mechanism: Inability to form normal Hb A (normally composed of two alpha and two beta chains) Treatment/Prognosis: No tx for HB Bart, rec termination due to maternal complications with hydrops. Hb H: prbc transfusions during hemolytic crisis, anemia causing cardiac sx, or severe bony changes; splenectomy with abx prophylaxis (if <5y) for splenomegaly

Answer 24

Responsible gene: HBB Protein: Hemoglobin subunit beta Cytogenetic locus: 11p15.5 Inheritance: AR Clinical Features and Diagnostic Criteria: severe anemia and HSM. Without Tx: severe FTT and shortened life expectancy. Thal. intermedia: present later, milder anemia, only rarely requires transfusion; at risk for iron overload due to inc intestinal absorption of iron. The clinical severity of the beta-thal syndromes depends on the extent of globin alpha chain/non-globin alpha chain imbalance. At risk pop's: Mediterranean, middle eastern, Indian, Thai, Chinese, African, African American. Clinical Tests: microcytic hypochromic anemia, an abnl peripheral blood smear with nucleated RBCs, and reduced amounts of hemoglobin A (HbA) on hemoglobin analysis. Carriers: reduced MCV, MCH, and RBC morphologic changes that are less severe than in affected individuals. Molecular Tests: Mutation scanning/sequencing. In each at-risk population, 4-10 mutations account for the large majority of HBB disease. Compound heterozygosity for a mild/silent mutation and a severe mutation produces a variable phenotype, ranging from thalassemia intermedia to thalassemia major. Disease Mechanism: Absence of globin beta chains. The non-assembled globin alpha chains that result from unbalanced globin alpha chain/non-globin alpha chain synthesis precipitate in the form of inclusions which damage the erythroid precursors in the bone marrow and spleen, causing ineffective erythropoiesis. Treatment/Prognosis: Treat with a regular transfusion program and chelation therapy (to reduce transfusion iron overload), allows for normal growth and development and extends life expectancy into the third to fifth decade.

Answer 25

Responsible gene: F5 Protein: Coagulation factor V Cytogenetic locus: 1q23 Inheritance: AD (moderately inc. risk VTE), AR (significantly inc .risk VTE) Clinical Features and Diagnostic Criteria: inc. risk venous thromboembolism (VTE), most commonly deep venous thrombosis (DVT). Heterozygous: at most modest inc. in VTE recurrence risk, 2-3x inc RR pregnancy loss. Homozygous: Inc. chance VTE recurrence. Arterial thrombosis, MI, and stroke not associated with factor V Leiden. Clinical Tests: APC resistance assay, sensitivity and specificity for factor V Leiden approaches 100% Molecular Tests: F5 G to A substitution at nt 1691 (100%) Disease Mechanism: The G>A substitution affects an APC cleavage site and the mutant factor V Leiden is inactivated 10x more slowly and persists longer in circulation-> inc. thrombin generation Treatment/Prognosis: Risk of VTE compounded by coexisting thromboembolic d/o, malignancy, travel, central venous catheters, pregnancy, OCP, HRT, advancing age, surgery, organ transplant. Heterozygotes with first VTE with no id'ed risk factor or a persistent risk factor require longer course of anticoagulation than those with a transient risk factor (eg surgery). Long term anticoagulation with LMW Heparin or Warfarin if recurrent VTE, multiple thrombophilic d/o, coexistent circumstantial risk factors, and factor V Leiden homozygotes

Answer 26

Responsible gene: F8 Protein: Coagulation Factor VIII Cytogenetic locus: Xq28 Inheritance: XLR Clinical Features and Diagnostic Criteria: hemarthrosis or intracranial bleed with mild or no trauma; deep muscle hematomas; prolonged or renewed bleeding after trauma, surgery, tooth extraction, nose bleeds, mouth injury, or circumcision, excessive bruising. Clinical Tests: Prolonged PTT, severe hemophilia: <1%, moderate: 1-5%, and mild hemophilia 6-35% Factor VIII activity. 10% of carrier females have Factor VIII activity <35%. ``` Molecular Tests: Severe: F8 intron 22-A gene inversion (45%), F8 intron 1 gene inversion (3%), F8 gene del or rearrangement, frameshift, splice junction, or nonsense mutations (40%), missense mutation (10%). Mild-moderate: missense mutation (97%) ``` Disease Mechanism: Normal Factor VIII circulates as an inactivated clotting cofactor activated by thrombin. Severe mutations lead to absent protein, mild-mod mutations to abnormal protein. Treatment/Prognosis: IV Factor VIII prophylactically 3x/wk in severe cases and after trauma, avoid IM injection. Consider HIV, Hep A, B, and C testing if history of receiving blood products.

Answer 27

Responsible gene: F9 Protein: Coagulation factor IX Cytogenetic locus: Xq27.1-q27.2 Inheritance: XLR Clinical Features and Diagnostic Criteria: hemarthrosis or intracranial bleed with mild or no trauma; deep muscle hematomas; prolonged or renewed bleeding after trauma, surgery, tooth extraction, nose bleeds, mouth injury, or circumcision, excessive bruising. Clinical Tests: Prolonged PTT, severe hemophilia: <1%, moderate: 1-5%, and mild hemophilia 6-30% Factor IX activity. 10% of carrier females have Factor VIII activity <30%. Molecular Tests: F9 sequence analysis (99%). Large gene deletions, nonsense mutations, and most frameshift mutations cause severe disease. Disease Mechanism: Factor IX activates Factor X which is a critical early step that can regulate the overall rate of thrombin generation in coagulation. Treatment/Prognosis: Recombinant factor IX concentrate 2-3x/wk for severe deficiency and within one hour of trauma. Avoid IM injection. Consider HIV, Hep A, B, and C testing if history of receiving blood products.

Answer 28

Responsible gene: HFE Protein: Hereditary hemochromatosis protein Cytogenetic locus: 6p21.3 Inheritance: AR (penetrance is low, a large fraction of homozygotes never develop symptoms. Clinical Features and Diagnostic Criteria: Inappropriately high iron absorption by the GI mucosa leads to excessive iron storage in the liver, skin, pancreas, heart, joints, and testes. Early Sx: abdominal pain, weakness, lethargy, and weight loss. Clinical Tests: Inc. fasting transferrin-iron saturation (men >60%, women >50%; some use >45% as cutoff for both men and women) on at least 2 occasions, inc. serum ferritin concentration (nonspecific for HHC), quantitative phlebotomy to determine iron quantity., liver biopsy, hepatic MRI Molecular Tests: Targeted mutation testing (60-90%C282Y/C282Y; 3-8% C282Y/H63D. Disease Mechanism: HFE protein binds transferrin receptor 1 and is thought to reduce cellular iron uptake- mutation leads to inc. iron uptake Treatment/Prognosis: If untreated: hepatic fibrosis or cirrhosis, increased skin pigmentation, DM, CHF and/or arrhythmias, cardiomyopathy, arthritis, or hypogonadism. Treat with phlebotomy if symptomatic, aim for ferritin <50, transferrin-iron saturation <50%

Answer 29

Responsible gene: BTK Protein: BTK Cytogenetic locus: Xq21.3-q22 Inheritance: X-LR Clinical Features and Diagnostic Criteria: recurrent OM, pneumonia, sinusitis <5yrs; sepsis, meningitis, or cellulitis, paucity of lymphoid tissue Clinical Tests: Low but measureable IgG, <1% B Cells CD19) Molecular Tests: 90% BTK sequence variant, 10% del/dupl/inv Disease Mechanism: Immune deficiency; BTK protein expressed in myeloid cells, platelets, B lineage cells Treatment/Prognosis: Monthly IV or weekly SC gammaglobulin

Answer 30

Responsible gene: MEFV Protein: Pyrin Cytogenetic locus: 16p13 Inheritance: AR Clinical Features and Diagnostic Criteria: Type 1 recurrent febrile episodes with peritonitis, synovitis, or pleuritis, recurrent erysipelas-like erythema, AA type amyloidosis, favorable response to continuous colchicine treatment, at risk ethnic group (Armenian, Turkish, Arab, North African Jewish, Iraqi Jewish, Ashkenazi Jewish). Type 2 amyloidosis as first clinical presentation Clinical Tests: Inc ESR, leukocytosis, inc serum fibrinogen, proteinuria Molecular Tests: MEFV targeted mutation analysis (70-90% depending on panel and ethnicity), MEFV sequencing (90% all ethnic groups) Disease Mechanism: Mutations result in less IL-1beta activation and as a result inc IL-1 responsiveness-> inc inflammatory attacks Treatment/Prognosis: M694V homozygotes or compound heterozygotes with another FMF allele treated with daily colchicine for life. Colchicine decreases inflammatory attacks and deposition of amyloid.

Answer 31

Responsible gene: FGD1 Protein: Rho/Rac guanine nucleotide exchange factor Cytogenetic locus: Xp11.22 Inheritance: XLR (some AR, AD cases reported) Clinical Features and Diagnostic Criteria: hypertelorism, shawl scrotum, brachydactyly, short stature, cryptorchidism, cervical vertebral abnormalities, ID (30%), milder manifestations in females Clinical Tests: xray Molecular Tests: FGD1 sequencing (7-20%) Disease Mechanism: unclear, FGD1/Rho GTPase Cdc42 implicated in cytoskeletal organization, and potentially in skeletal formation and morphogenesis Treatment/Prognosis: orchiopexy, growth hormone trials have not been successful

Answer 32

Responsible gene: POR Protein: NADPH-cytochrome P450 reductase Cytogenetic locus: 7q11.2 Inheritance: AR Clinical Features and Diagnostic Criteria: Ambiguous genitalia, enlarged cystic ovaries, poor masculinization in males, maternal virilization during pregnancy with an affected fetus. craniosynostosis, choanal stenosis or atresia, stenotic external auditory canals, hydrocephalus. Neonatal fractures, bowing of the long bones, joint contractures, renal malformations Clinical Tests: Sterol or or steroid abnormalities using GC-MS, increased urinary pregnenolone and progesterone metabolites Molecular Tests: POR sequence variants Disease Mechanism: Disorder of steroid and cholesterol synthesis due to cytochrome P450 reductase deficiency Treatment/Prognosis: Airway management, hydrocortisone replacement, stress dose steroids, surgical correction of genital abnormalities, VP shunt for significant hydrocephalus, PT to minimize joint contracture

Answer 33

Responsible genes: BBS1, BBS10 (11 additional genes id'ed) Proteins: BBS1 protein, BBS10 protein Cytogenetic loci: 11q13, 12q21.2 Inheritance: AR (though 10% BBS thought to be tri-allelic) Clinical Features and Diagnostic Criteria: cone-rod dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotrophic hypogonadism, complex female genitourinary malformations, and renal dysfunction. Night blindness by age 7-8 yrs, legally blind by age 15.5 yrs. A majority have significant learning difficulties, only a minority have severe impairment. Renal disease is a major cause of morbidity and mortality. Clinical Tests: atypical pigmentary retinal dystrophy with early macular involvement, renal anomalies on US Molecular Tests: Targeted mutation analysis: p.M390R BBS1 (18%-32% of BBS) and C91fsX95 BBS10 (10% of BBS). Disease Mechanism: Defects in cilia or intraflagellar transport (IFT) Treatment/Prognosis: visual aids and educational programs for the visually impaired; diet, exercise, and behavioral therapies for obesity; surgery to remove accessory digits; surgical repair of hydrocolpos, vaginal atresia, or hypospadias; HRT for hypogonadism.

Answer 34

Responsible gene: EYA1, SIX1 Proteins: Eyes absent homolog 1, Homobox protein SIX1 Cytogenetic loci: 8q13.3, 14q23 Inheritance: AD Clinical Features and Diagnostic Criteria: malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment; branchial fistulae and cysts; renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis Clinical Tests: Temporal bone CT, hearing test, renal US Molecular Tests: Mutation scanning (30%), Dupl/del testing (10%) Disease Mechanism: EYA1 encodes products important for inner-ear, kidney, and branchial-arch development. Some mutations encode proteins that are rapidly degraded. Expression of SIX1 is necessary for normal development of the inner ear, nose, thymus, kidney, and skeletal muscle Treatment/Prognosis: excision of branchial cleft cysts/fistulae, fitting with appropriate aural habilitation, hearing impaired education programs. Endstage renal disease may require dialysis or renal transplantation. Surveillance includes semiannual examination for hearing impairment and annual audiometry to assess stability of hearing loss and semiannual/annual examination by a nephrologist if indicated

Answer 35

Responsible gene: CHD7 Protein: Chromodomain-helicase-DNA-binding protein 7 Cytogenetic locus: 8q12.1 Inheritance: AD Clinical Features and Diagnostic Criteria: 4/7: eye coloboma, heart anomaly (conotruncal defects, arch abnormalities), choanal atresia, growth and mental retardation, genitourinary malformations (microphallus), ear anomalies (ossicular malformations, Mondini defect of the cochlea) and/or deafness. Facial palsy, cleft palate, TE fistula, and dysphagia are commonly associated. 20-25% mortality in the first year Clinical Tests: echocardiogram, audiology evaluation, temporal bone CT, renal ultrasound Molecular Tests: CHD7 sequencing (60-65%) ``` Disease Mechanism: Haploinsufficiency. This class of proteins is thought to have pivotal roles in early embryonic development by affecting chromatin structure and gene expression ``` Treatment/Prognosis: Assess for airway compromise, swallowing problems, typical surgical correction of heart and GI malformations

Answer 36

Responsible gene: RPS6KA3 Protein: Ribosomal protein S6 kinase alpha-3 Cytogenetic locus: Xp22.2-p22.1 Inheritance: XLD Clinical Features and Diagnostic Criteria: severe to profound ID in males, short, soft fleshy hands, tapering fingers with small terminal phalanges, males <3% in height, microcephaly, stimulus induced drop episodes, kyphoscoliosis, characteristic facial features in older males, normal to profound ID in females. Clinical Tests: x-ray: thickened skull, anterior vertebrae beaking, metacarpal pseudoepiphyses Molecular Tests: RPS6KA3 sequencing (35-40%) Disease Mechanism: unclear, RPS6KA3 is a member of the Ras signaling cascade and participates in cellular events such as proliferation and differentiation Treatment/Prognosis: Medication for drop episodes, Rispieridone for self-injurious behavior, annual cardiac exam with echo every 5-10 years.

Answer 37

Prominent forehead and eyebrows Full supraorbital ridges Marked ocular hypertelorism with downslanting palpebrae Low nasal bridge, blunt tip, and thick alae nasi and septum Large mouth, usually held open Patulous lips with everted lower lip Prominent ears

Answer 38

Responsible gene: NIPBL, SMC1L1, SMC3 Protein: Nipped-B-like protein, Structural maintenance of chromosomes protein 1A and 3 Cytogenetic loci: 5p13.1, Xp11.22-p11.21, 10q25.2 Inheritance: AD (NIPBL and SMC3), XLR (SMC1L1) Clinical Features and Diagnostic Criteria: pre/postnatal growth retardation, low anterior hairline and synophrys, diaphragmatic hernia, upper limb anomalies (hypoplastic middle phalanx of the index finger, hypoplastic thenar eminence), ptosis, nystagmus, mod-severe ID, pulmonary valve stenosis and/or VSD Molecular Tests: NIPBL sequencing (~50%), SMC1L1 sequencing (4%), SMC3 (<1%) Disease Mechanism: Unknown, the majority of mutations are truncating, likely leading to protein haploinsufficiency Treatment/Prognosis: Treat individual medical and developmental issues

Answer 39

Microbrachycephaly Synophrys, arched eyebrows Long, thick eyelashes Low‐set posteriorly rotated and/or hirsute ears with thickened helices Depressed or broad nasal bridge, upturned nasal tip with anteverted nares, and prominence of the lateral aspects Long smooth philtrum, thin vermillion border of the upper lip with a midline "drip" appearance, downturned corners of the mouth High and arched palate with clefts Small widely‐spaced teeth Micrognathia Short neck

Answer 40

Responsible gene(s): RPS14?, microRNA 145 and 146a? Cytogenetic locus: 5p15.2 Inheritance: 12% due to unequal segregation of a translocation or recombination involving a pericentric inversion in one of the parents, 85% sporadic de novo deletions (80% are on the paternal chromosome) Clinical Features and Diagnostic Criteria: Cat-like cry (abnormal laryngeal development), slow growth, microcephaly, ID, hypotonia, strabismus, characteristic facial features. Cat-like cry only when deletion limited to band 5p15.32 Molecular Tests: Most are visible, a few are submicroscopic and diagnosed by FISH for the critical region. Disease Mechanism: A study of 50 patients with deletions ranging from 5p15.2 to 5p13 and found no correlation with size of deletion and degree of mental impairment Treatment/Prognosis: Supportive care

Answer 41

Microcephaly Round face Hypertelorism Micrognathia Epicanthal folds Low‐set ears

Answer 42

Responsible gene(s), Protein(s), Cytogenetic locus (loci): unknown Inheritance: AR Clinical Features and Diagnostic Criteria: LGA, coarse face, CL/CP, diaphragmatic defect, distal digital hypoplasia, ID in survivors, agenesis of the CC, optic and olfactory tract hypoplasia, encephalocele, GU malformation Disease Mechanism: unknown Treatment/Prognosis: The majority are stillborn or die in early neonatal period, 14% survive

Answer 43

Responsible gene: GLI3 Protein: Zinc finger protein GLI3 Cytogenetic locus: 7p13 Inheritance: AD Clinical Features and Diagnostic Criteria: Major findings: macrocephaly, ocular hypertelorism, preaxial polydactyly, cutaneous syndactyly. Developmental delay, ID, or seizures (<10%)- more common in those with large (>300 kb) deletions including GLI3. Allelic with Pallister-Hall syndrome (caused by GLI3 frame shifting mutations). Clinical Tests: 500-600 band karyotype 7p13 translocation or interstitial deletion (5-10%) Molecular Tests: GLI3 sequence analysis (70%) Disease Mechanism: GLI proteins regulate genes distal to Sonic Hedgehog in the SHH pathway. Pathogenesis of GCPS is haploinsufficiency Treatment/Prognosis: Surgical correction of polydactyly and syndactyly as indicated. CNS imaging if HC increasing faster than normal to r/o hydrocephalus

Answer 44

Responsible genes: NPHP1, AHI1, CEP290, TMEM67 Proteins: Nephrocystin-1, Jouberin, Centrosomal protein Cep290, Meckelin Cytogenetic loci: 2q13, 6q23.3, 12q21.32, 8q21.1-q22.1 Inheritance: AR Clinical Features and Diagnostic Criteria: Hypotonia in infancy leading to ataxia later, DD/ID, alternating tachypnea and/or apnea), pigmentary retinopathy, oculomotor apraxia or difficulty in smooth visual pursuits and jerkiness in gaze tracking. M:F, 2:1. Renal disease seen in those with retinal involvement. Rarely hepatic fibrosis. Clinical Tests: Molar tooth sign (cerebellar vermis hypoplasia) on MRI, ERG, renal US, LFT's Molecular Tests: NPHP1 FISH or deletion analysis (1-2%), Sequencing AHI1 (11%), CEP290 (10%), TMEM67 (10%) Disease Mechanism: The CEP290 protein product modulates ATF4, a transcription factor implicated in renal cyst formation. Meckelin localizes to the primary cilium and plasma membrane of renal and biliary epithelial cells and other ciliated cells Treatment/Prognosis: apnea monitoring, ST, G tube if severe dysphagia, surgery as needed for eye disease, dialysis for nephronophthisis

Answer 45

Responsible genes: MLL2 (66%), KDM6A Proteins: MLL2, Lysine-specific demethylase 6A Cytogenetic loci: 12q12-q14, Xp11.3 Inheritance: AD, XLD Clinical Features and Diagnostic Criteria: unique facial features, fetal finger pads, IQ<80, joint laxity, high palate, hypotonia, short stature, CHD, CL/P, scoliosis, renal anomalies, hearing loss, speech delay Clinical Tests: echocardiogram, renal ultrasound, eye exam, neuropsychological testing Molecular Tests: MLL2 gene sequencing, KDM6A gene sequencing and deletion testing Disease Mechanism: MLL2 encodes a protein that is part of the SET family of proteins, important to the epigenetic control of active chromatin states. Mutations are predicted to truncate the polypeptide chain before translation of the SET domain. H3K4 methylation by MLL2 is linked to the demethylation of H3K27 by KDM6A. Treatment/Prognosis: Individual medical problems are treated as in the general population. GH for short stature if deficient. At risk for immunodeficiency.

Answer 46

Elongated palpebral fissures Eversion of the lateral third of the lower eyelid Arched and broad eyebrows Short columella with depressed nasal tip Large, prominent, or cupped ears

Answer 47

Responsible genes, Proteins: unknown Cytogenetic locus: 1p36 Clinical Features and Diagnostic Criteria: The most common terminal deletion syndrome. Hypotonia, developmental delay, growth retardation, obesity, microcephaly, orofacial clefting, typical facial features. Also minor cardiac malformations, cardiomyopathy, seizures, ventricular dilation, SNHL Clinical Tests: Brain CT/MRI Molecular Tests: The deletion can be detected by HR karyotype, confirmatory FISH required in most cases. The majority are maternally derived. Disease Mechanism: contiguous gene deletion syndrome Treatment/Prognosis: symptomatic treatment

Answer 48

Straight eyebrows Deep‐set eyes Midface hypoplasia Broad and flat nasal root/bridge Long philtrum Pointed chin Microbrachycephaly Epicanthal folds Posteriorly rotated, low‐set, abnormal ears.

Answer 49

Responsible genes: Paternally expressed genes within imprinted locus on 15q11-13 (SNURF-SNRPN, MKRN3, MAGEL2, and NDN) Cytogenetic locus: 15q11-13 Inheritance: autosomal, expressed from paternal Ch 15 Clinical Features and Diagnostic Criteria: Hypothalamic insufficiency, neonatal hypotonia, developmental delay, hyperphagia leading to obesity, short stature, small hands and feet, hypogonadism, ID Molecular Tests: 3-5 Mb deletion of 15q11.2-q13 (~70%), matUPD (15%), PWS imprinting center defect (1-2%) Disease Mechanism: unknown Treatment/Prognosis: Monitor for feeding problems in infancy, obesity, OCD, psychosis, scoliosis, obstructive sleep apnea, diabetes, osteopenia

Answer 50

Responsible gene: CREBBP, EP300 Protein: CREB-binding protein, histone acetyltransferase-p300 Cytogenetic locus: 16p13.3, 22q13 Inheritance: AD though only a few cases of affected parent and child Clinical Features and Diagnostic Criteria: microcephaly, beaked nose, broad thumbs and toes, cryptorchidism, growth delay, severe ID (35-50), congenital heart defect, strabismus, ptosis, sleep apnea, tumors (meningioma, pilomatrixoma, leukemia), behavior problems Clinical Tests: ERG, echocardiogram, deletion or translocation occasionally seen on karyotype Molecular Tests: FISH CREBBP (~10%), direct sequencing CREBBP (40-60%), EP300 (~3%) Disease Mechanism: Some CREBBP mutations lead to abnormal acetylation of histones, an important step in transcription activation Treatment/Prognosis: Standard care for vision, hearing loss, heart defects, feeding problems. Some require thumb/toe surgery, behavior modification programs

Answer 51

Responsible gene: RAI1 Protein: Retinoic acid-induced protein 1 Cytogenetic locus: 17p11.2 Inheritance: AD (sporadic unless secondary to a parental balanced translocation) Clinical Features and Diagnostic Criteria: mild-moderate infantile hypotonia, feeding problems and FTT, short stature, brachydactyly, ophthalmologic and ENT abnormalities, early speech delay with or without hearing loss, peripheral neuropathy, sleep problems, and stereotypic maladaptive behaviors (self-injurious behaviors, inattention(+-)hyperactivity, impulsivity, disobedience, "self-hug" and "lick and flip" page turning motion), mild-mod ID, coarsening face over time Clinical Tests: Renal US, echo, spine x-ray, FISH for 17p11.2 deletion (~90%) Molecular Tests: RAI1 sequencing (5-10%) Disease Mechanism: The RAI1 gene product is thought to function in transcriptional regulation Treatment/Prognosis: ST, sensory integration, psychotropic meds for attention issues, behavioral therapies, melatonin may help with sleep, monitoring for hypercholesterolemia. Annual team eval, TFTs, fasting lipid profile, UA, scoliosis check, eye exam

Answer 52

Brachycephaly Midface retrusion Relative prognathism with age Broad, square‐shaped face Everted, "tented" vermilion of the upper lip Deep‐set, close‐spaced eyes

Answer 53

Cytogenetic abnormality: 69,XXY>69,XXX (69,XYY very rare) Inheritance: Sporadic without inc risk of recurrence Clinical Features and Diagnostic Criteria: >99% lost in first trimester, accounts for 6-10% of all SAb's and 16-20% of all chromosomally abnormal SAb's. Dysplastic calvaria with large posterior fontanelle, ¾ finger syndactyly, ASD, VSD, hydrocephalus, holoprosencephaly. Parent of origin effect: If Maternal: small placenta, severe asymmetric IUGR with a large head. If Paternal: hydropic large placenta, well grown to mod symmetric IUGR, nl or microcephalic head Clinical Tests: Prenatal US, maternal serum hCG low Molecular Tests: Karyotype Disease Mechanism: Gynogenic triploidy (digyny): NDJ producing diploid oocyte, fertilization of ovulated primary oocyte, or polar body retention. Androgenic triploidy (Diandry) NDJ producing a diplod sperm or dispermy (most common) Treatment/Prognosis: Very poor prognosis, may be better if triploid mosaic

Answer 54

Inheritance: 20% due to translocation Clinical Features and Diagnostic Criteria: The LEAST common of live born trisomy disorders. HPE, POLYDACTYLY, seizures, HL, microcephaly, midline CL/P, omphalocele, cardiac and renal anomalies, ID, CUTIS APLASIA. Mosaic Tri 13: very broad phenotype from typical features of full trisomy to more mild ID and physical features and longer survival. Clinical Tests: Brain MRI, EEG, audiogram, echo, renal US Molecular Tests: Karyotype is diagnostic Disease Mechanism: 75% due to maternal nondysjunction, 20% to translocation, and 5% to mosaicism. Defect in fusion of midline prechordial mesoderm in first three weeks of gestation cause major midline dysmorphic features. Treatment/Prognosis: 44% die in first month, >70% die within one year. Severe ID exists in all survivors.

Answer 55

Inheritance: Less than 1% due to translocation Clinical Features and Diagnostic Criteria: TRISOMIC HAND-- fingers 2/5 overlap 3/4, IUGR, ROCKER BOTTOM FEET, micrognathia, prominent occiput, MICROPHTHALMIA, VSD, ASD, PDA, generalized muscle spasm, renal anomalies, ID. Mosaic Tri 18 has variable but usually somewhat milder expression. Clinical Tests: Echo, abdominal US. Maternal serum screen: low AFP, hCG, and UE3. Molecular Tests: karytype is diagnostic Disease Mechanism: Maternal nondysjunction (90%), mosaicism (10%) Treatment/Prognosis: 50% die in first week, 90% die by one year

Answer 56

Cytogenetic locus (loci): (21.22.1-22.2 has been called DS critical region though there have been cases of duplication outside of this region who manifest DS Inheritance: 95% de novo, 5% due to Robertsonian Translocation or isochromosome 21 Clinical Features and Diagnostic Criteria: mild-mod ID, hypotonia, growth delay, strabismus, adult cataracts, myopia, conductive HL, macroglossia, hypodontia, joint hyperflexibility, hypogenitalism, congenital heart defect, duodenal atresia, hirschprung, thyroid disease, early onset Alzheimers, transient myeloproliferation, ALL Clinical Tests: prenatal US abnormalities detected in 50%, maternal serum screen: high free beta HCG, low PAPP-A Molecular Tests: maternal fetal free DNA testing, karyotype is diagnostic Disease Mechanism: 90% due to maternal meiosis nondisjunction (¾ MI error, ¼ MII error) Treatment/Prognosis: Supportive care, overall life expectancy is reduced

Answer 57

Responsible genes: unknown (HOXD13 21 bp deletions: 1 case report) Proteins, Cytogenetic locus: unknown Inheritance: Isolated Clinical Features and Diagnostic Criteria: Vertebral anomalies, Anal atresia, Cardiac malformations (VSD, PDA, TOF, TOV), Treacheoesophageal fistula, Esophageal atresia, Renal anomalies, and Limb anomalies (polydactyly, humeral hypoplasia, radial aplasia, proximally placed thumb). Diagnosis requires 3 of 7 features and it is diagnosis of exclusion. A variant is VACTERL with hydrocephalus which can be AR or XL. Clinical Tests: echo, spinal x-ray, limb x-ray, and renal US Molecular Tests: There isn't a molecular test but rule out aneuploidy with karyotype, Fanconi anemia with DEB testing, and consider SALL1 sequencing to rule out Townes-Brocks syndrome. Disease Mechanism: unknown Treatment/Prognosis: Severe cardiac malformation, anal atresia, TE fistula, and EA require surgical repair in neonatal period

Answer 58

Responsible genes: 4p deletion, critical region includes 2 genes, WHSC1 and WHSC2 of unknown significance Protein: unknown Cytogenetic locus: 4p; critical region: 165-kb region between markers D4S166 and D4S3327 Inheritance: 87% de novo, 13% due to unbalanced translocation from a balanced parent Clinical Features and Diagnostic Criteria: "greek warrior helmet appearance", microcephaly, pre and postnatal growth deficiency, ID of variable degree, seizures, facial asymmetry, ptosis, IgA deficiency, structural brain anomalies, CL/P, CHD (ASD>PVS>VSD>PDA>AI>TOF), renal US Clinical Tests: Distinctive EEG, Brain MRI, echo, plasma IgA level Molecular Tests: HR karyotype for 4p16.3 deletion (60-70%), FISH/array CGH for critical region deletion (>95%) Disease Mechanism: The function of WHSC1, WHSC2, and LETM1 in normal development and in WHS patients is not known Treatment/Prognosis: 2/3 develop valproate responsive atypical absence seizures, standard treatment of other medical problems

Answer 59

"Greek warrior helmet appearance" of nose (broad bridge of nose continuing to forehead) Microcephaly High forehead with prominent glabella Ocular hypertelorism Epicanthus Highly arched eyebrows Short philtrum Downturned mouth Micrognathia Poorly formed ears with pits/tags

Answer 60

Responsible gene: ABCD1 Protein: ATP-binding cassette sub-family D member 1 Cytogenetic locus: Xq28 Inheritance: X-LR Clinical Features and Diagnostic Criteria: a. Childhood cerebral: ADHD->total disability within 2 yrs b. Adrenomyeloneuropathy: late 20's progressive paraparesis, sphincter disturbance, adrenocortical dysfunction c. Adrenocortical insufficiency (only); majority by age 7.5 (seen in 20% carrier females Clinical Tests: Brain MRI, VLCFA (not reliably abnl in carrier females) Molecular Tests: ABCD1 seq (92%); ABCD1 del/dup (6%) Disease Mechanism: Peroxisomal disorder, accumulation of saturated VLCFA Treatment/Prognosis: Corticosteroid replacement, BMT if diagnosed after changes visible on brain MRI but before significant neuropsych problems develop (Lorenzo's Oil)

Answer 61

Responsible genes: PSEN1, APP, PSEN2 Proteins: Presenelin-1, Amyloid beta A4, Presenilin-2 Cytogenetic loci: 14q24.3, 21q21, 1q31-q42 Inheritance:AD Clinical Features and Diagnostic Criteria: Dimentia, confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Early onset:

Answer 62

Responsible gene: UBE3A Protein: Ubiquitin protein ligase E3A Cytogenetic locus: 15q11-q13 Inheritance: loss of the maternally imprinted contribution in the 15q11.2-q13 (AS/PWS) region Clinical Features and Diagnostic Criteria: severe developmental delay or ID, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability, microcephaly and seizures Clinical Tests: acquired microcephaly by age two years, Seizures before age three, abnl EEG: large amp. slow-spike waves ``` Molecular Tests: 4-6 Mb del (65-75%), UBE3A mutation (11%), imprinting defect (2.5%), unbal chrom transloc (<1%), Pat UPD 15 (<1%), del of imprinting center (0.5%) ``` Disease Mechanism: Disruption of E6AP ultimately causes an abnormality in the ubiquitin protein degradation pathway, but no clear AS-causing target protein yet identified Treatment/Prognosis: Typical care for medical issues, PT, OT, ST, and individualized education and behavior program.

Answer 63

Protruding tongue Prognathia Wide mouth Widely spaced teeth Strabismus Light hair and eye color

Answer 64

Responsible gene: NOTCH3 Protein: Neurogenic locus notch homolog protein 3 Cytogenetic locus: 19p13.2-p13.1 Inheritance: AD Clinical Features and Diagnostic Criteria: Stroke-like episodes before age 60, cognitive disturbance, behavioral abnormalities, migraine with aura Clinical Tests: Skin Bx EM: e- dense granules in media of arterioles. Brain MRI: T2 signal abnormalities in the WM of the temporal pole and external capsule, subcortical lacunar lesions (groups of rounded lesions at the junction of GM and WM. WM changes seen as early as age 21 yrs. Molecular Tests: NOTCH3 sequencing (>90%) Disease Mechanism: NOTCH genes encode transmembrane receptors involved in cell fate specification during development. The functional consequences of NOTCH3 mutations in the abnormal protein are not known. Treatment/Prognosis: supportive care, angiography and anticoagulants may precipitate CVA, smoking increases risk of stroke. Mean age to walk with asst.: 60yrs, bedridden by 64yrs, med. age of death 68 yrs.

Answer 65

Responsible gene: ASPA Protein: Aspartoacylase Cytogenetic locus: 17pter-p13 Inheritance: AR Clinical Features and Diagnostic Criteria: Macrocephaly, lack of head control, developmental delays by age 3-5 mos, severe hypotonia, never sit, walk, or speak. Hypotonia evolves to spasticity. Clinical Tests: High urine N-acetyl aspartic acid (NAA) Molecular Tests: 3 common mutations account for 99% of disease-causing alleles in Ash. Jewish, 50-55% in non-jewish. Disease Mechanism: Absence of aspartoacylase leads to build up of NAA in the brain leading to demyelination Treatment/Prognosis: Supportive care: nutrition, hydration, managing infectious disease, protecting airway. Life expectancy to the teens.

Answer 66

Responsible gene: IKBKAP Protein: IkappaB kinase complex-associated protein Cytogenetic locus: 9q31 Inheritance: AR Clinical Features and Diagnostic Criteria: Progressive, GI dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain and temperature, CV instability, autonomic crises, hypotonia, broad based ataxic gate deteriorates, decreased life expectancy. Dec taste and absence of fungiform papillae of the tongue, dec or absent DTR's, absence of overflow tears with crying Clinical Tests: Pupillary hypersensitivity to parasympathetic agents, absence of axon flare response after intradermal histamine injection Molecular Tests: IVS20 (+6T>C); R696P in IKBKAP (>99% Ashkenazi Jewish population) Disease Mechanism: Abnormal development and survival of sensory, sympathetic and parasympathetic neurons Treatment/Prognosis: Aspiration precautions, hydration and elastic stockings for orthostatic hypotension, protect cornea with artificial tears, PT for contracture

Answer 67

Responsible gene: FMR-1 Protein: FMRP (Fragile X Mental Retardation Protein) Cytogenetic locus: Xq27.3 Inheritance: X-linked triplet repeat Clinical Features and Diagnostic Criteria: Delayed motor and verbal development, ID (mod-severe in boys, milder in girls), prominent jaw and forehead, high activity, autistic features. Carrier females: anxiety, OCD, depression, 20% have POF. Carrier Males: (>30% of males >50y), progressive intention tremor, ataxia, parkinsonism, and autonomic dysfunction. Two other loci: FraXE: only ID, FraXF: no phenotype Clinical Tests: None Molecular Tests: CGG triplet repeat detection. Southern Blot: good for small or large expansions, doesn't give repeat #. PCR: Better quantification of repeat number, subject to allele dropout with large expansions. NL: 5-44 repeats, Intermediate: 45-58 repeats (gray zone), Pre-mutation: 59-200 repeats, Mutation: >200 repeats Disease Mechanism: >200 repeats leads to silencing by methylation. POF and ataxia thought to be due to toxic gain of function. Treatment/Prognosis: No specific treatment.

Answer 68

Long face Prominent forehead Large ears Prominent jaw

Answer 69

Responsible gene: HD Protein: Huntington Cytogenetic locus: 4p16.3 Inheritance: AD Clinical Features and Diagnostic Criteria: progressive motor disability involving both involuntary and voluntary movement (chorea, dysarthria, dysphagia progress to bradykinesia, rigidity, and dystonia) , cognitive decline (problems with planning or organization), psychiatric disturbances (personality change, affective psychosis, or schizophrenic psychosis. Mean age of onset 35-44 yrs (juvenile onset <20yrs ~10%). Clinical Tests: CT or MRI: characteristic atrophy of caudate and putamen. PET scan: dec uptake and metab. of glucose in the caudate nucleus (often abnl before MRI or CT). Molecular Tests: Targeted mut. analysis: trinucleotide CAG repeat expansion >36. 27-35: no symptoms but, if male, risk of expansion in children (6-10% risk of expansion with 35 repeats). 36-39: reduced penetrance, may never develop symptoms. >40: fully penetrant. >60 repeats: juvenile onset. Disease Mechanism: Unknown Treatment/Prognosis: Tx is symptomatic: neurolepetics, benzo's, psychotropics, Median survival time: 15-18 yrs after onset, average age of death is 55 yrs. Suicide in 12%.

Answer 70

Responsible gene: GALC Protein: Galactocerebrocidase Cytogenetic locus: 14q31 Inheritance: AR Clinical Features and Diagnostic Criteria: Infantile form: irritability to sensory stimuli, muscle hypertonicity, progressive neurologic deterioration, peripheral neuropathy, white matter disease, elevated CSF protein. Later onset (6 mos to 5th decade): weakness, vision loss, intellectual regression. Clinical Tests: CT: nonspecific- diffuse cerebral atrophy of grey and white matter. MRI: demyelination of the brainstem and cerebellum. Dec GALC enzyme activity (0-5% of normal activity). Abnl EEG, low nerve conduction velocity Molecular Tests: GALC targeted mutation analysis: GALC 30-kb deletion (45% of Europeans, 35% of Mexicans); 809G>A mutation (50% of late onset Krabbe). GALC sequencing (virtually 100%) Disease Mechanism: Missense mutations result in unstable protein that is rapidly degraded Treatment/Prognosis: Hematopoietic stem cell transplant decreases morbidity and mortality when given to infants before they show symptoms. Supportive care to control irritability and spasticity if diagnosed when symptomatic. Infantile form: average age of death is 13 mos due to infections or resp failure.

Answer 71

Responsible gene: NF1 Protein: Neurofibromin Cytogenetic locus: 17q11 Inheritance: AD Clinical Features and Diagnostic Criteria: 2 or more of: 6x5mm (prepubertal) or 6x15mm (postpubertal) café au lait, 2 or more neurofibromas, one plexiform neurofibroma, axillary or inguinal freckling, optic glioma, 2 or more Lisch nodules, sphenoid dysplasia or thinned long bone cortex, 1st degree relative with NF-1 Clinical Tests: x-ray, eye exam, brain MRI Molecular Tests: >500 mutations reported, usually unique to a particular family Disease Mechanism: Loss of function mutations impair ras GTPase mediated cellular proliferation and tumor suppression Treatment/Prognosis: The majority live normal lifespan. Surgery for bone malformations or painful or disfiguring tumors

Answer 72

Responsible gene: Multiple, main gene PARK2 Protein: Parkin Cytogenetic locus: 6q25.2-q27 Inheritance: AD, AR, multifactorial Clinical Features and Diagnostic Criteria: bradykinesia, rigidity, and tremor, asymmetric limb involvement. Juvenile Onset AR PARK2 mutations, typical features, onset 20-40yrs. Clinical Tests: Good response to L-Dopa Molecular Tests: PARK2 sequencing Disease Mechanism: Unclear but thought to be due to loss of function by absent protein or protein inactivation Treatment/Prognosis: Dopamine therapy, PT, OT, ST. Some patients may benefit from palliodotomy or deep brain stimulation of the subthalamic nucleus.

Answer 73

Responsible genes: MECP2 Proteins: MECP2 Cytogenetic loci: Xq28 Inheritance: XLD Clinical Features and Diagnostic Criteria: ID, developmental regression (especially language and hand use), acquired microcephaly, stereotypical wringing hand movements, hyperventilation, bruxism, paroxysmal laughing, prolonged QT, scoliosis Clinical Tests: EEG (nonspecific for Rett), ECG Molecular Tests: MECP2 sequencing (>80%), Need to test parents if a novel variant found. MECP2 MLPA or quantitative PCR testing for deletion (~16%). Disease Mechanism: Decreased function of loss-of-function of MECP2. Normally MECP2 binds methylated CpG islands. Treatment/Prognosis: Seizures are often difficult to manage, SSRI's for agitation, monitor for scoliosis, periodic ECG to monitor for long QT. Small subset have CDKL5 mutations and present atypically with early onset seizures

Answer 74

Responsible gene: ATP7B Protein: Copper-transporting ATPase 2 Cytogenetic locus: 13q14.3-q21.1 Inheritance: AR Clinical Features and Diagnostic Criteria: Can present age 3-50 yrs. Liver disease: jaundice, self-limited hepatitis-like illness, autoimmune hepatitis, hepatic failure, chronic liver disease. Neurologic presentation: movement disorder, disorganization of personality Clinical Tests: Kayser-Fleisher rings on corneal exam, low serum Cu and ceruloplasmin, inc urinary copper excretion. Liver bx: inc copper storage. Molecular Tests: ATP7B sequencing (98%). H1069Q (35-45% Europeans), R779L (57% Asians), H714Q and delC2337 (40% Russians). Disease Mechanism: Loss of ATP7b function impairs holoceruloplasmin biosynthesis and biliary copper excretion with resultant copper-mediated oxidative damage, activation of cell death pathways, leakage of copper into plasma and eventual tissue copper overload. Treatment/Prognosis: Chelating agents, liver transplant

Answer 75

Responsible genes: SOD1 (rare: SETX, VAPB, BSCL2, VCP, ALS2, SPG20) Protein: Superoxide dismutase Cytogenetic locus: 21q22 Inheritance: AD (AR ALS2 and SPG20) Clinical Features and Diagnostic Criteria: UMN: hyperreflexia, extensor plantar response, inc muscle tone, and weakness. LMN: weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations. Frontotemporal dementia Clinical Tests: EMG; Path: (1) degeneration and loss of the motor neurons in the anterior horns and in the motor nuclei of cranial nerves VII, X, and XI and most commonly the hypoglossal nucleus; and (2) axonal loss with decreased myelin staining in the lateral and anterior corticospinal tracts Molecular Tests: SOD1 mutation (20% familial, 3% sporadic ALS- 50% have the A4V Exon 1 mutation) Disease Mechanism: Toxic gain of function, not enzyme deficiency (SOD1 prevents oxidative damage to cells) Treatment/Prognosis: Primarily palliative, Riluzole (glutamate inhibitor)-the only FDA-approved drug. Mean age of onset: 46 yrs if familial, 56 yrs if sporadic. Death usually caused by resp. muscle compromise.

Answer 76

CMT1: Abnormal myelin, AD, 50% of all CMT, PMP22 (17p11.2), MPZ (1q22), LITAF (16p13.1-p12.3), EGR2 (10q21.1-q22.1), NEFL (8p21) CMT2: Axonopathy, AD, 20-40% of all CMT, KIF1B and MFN2 (1p36.2), RAB7 (3q21), LMNA (1q21.2), GARS (7p15), NEFL (8p21), HSPB1 (7q), MPZ (1q22), GDAP1 (8q12-q21.1) CMT Intermediate Form: Combination of myelinopathy and axonopathy, AD, rare cause of CMT, DNM2 (19p12-p13.2), YARS (1p34-p35) CMT 4: Either myelinopathy or axonopathy, AR, rare cause of CMT, GDAP1 (8q13-q21.1), MTMR2 (11q22), CMT4B2 (11p15), SH3TC2 (5q32), NDRG1 (8q24.3), EGR2 (10q21.1-q22.1), PRX (19q13.1-q13.2 CMTX: Axonopathy with secondary myelin changes, XLD, 10-20% of all CMT, GJB1 (Xq13.1). Clinical Features and Diagnostic Criteria: slowly progressive weakness and atrophy of distal muscles in the feet and/or hands beginning in the 1st-3rd decade; hearing loss; pes cavus foot deformity, hip dysplasia. Clinical Tests: nerve conduction studies, nerve biopsy Molecular Tests: Gene sequencing Disease Mechanism: Abnormal peripheral myelination Treatment/Prognosis: orthopaedic surgery, TCA's, carbamazepine, or gabapentin for neuropathic pain.

Answer 77

Responsible gene: DMD Protein: Dystrophin Cytogenetic locus: Xp21.2 Inheritance: XLR Clinical Features and Diagnostic Criteria: DMD: Symptoms present before age 5, progressive symmetrical muscular weakness, proximal>distal, calf hypertrophy, dilated cardiomyopathy (DCM). BMD: Later onset, less severe, weakness of quadriceps may be only sign, activity induced cramping. Preservation of neck flexor muscles (unlike DMD). DCM can occur in isolation Clinical Tests: CK 10x nl in DMD, 5x nl in BMD. Unreliable test for carrier females, tends to decrease with age. Molecular Tests: Multiplex PCR: DMD gene deletion (65% DMD, 85% BMD). Southern or quantitative PCR for gene duplication (6% DMD), DMD sequencing for small del/ins or point mutations (30% DMD) Disease Mechanism: Dystrophin binds actin and other membrane proteins. Mutations that lead to lack of dystrophin expression: DMD, those that lead to abnormal quality or quantity of dystrophin: BMD. Treatment/Prognosis: Supportive therapy, steroids may prolong walking 2-3 yrs. DMD: wheelchair dependent by age 13, ventilator by age 20, survival into 20's. BMiDs: Wheelchair after age 16 (if at all), survival 40-50's. Carrier females at risk for DCM.

Answer 78

Responsible gene: FRDA Protein: Frataxin Cytogenetic locus: 9q13 Inheritance: AR Clinical Features and Diagnostic Criteria: Progressive degeneration of the dorsal root ganglia, posterior columns, corticospinal tracts, and the dorsal spinocerebellar tracts of the spinal cord and cerebellum. There is progressive limb and gait ataxia before age 25 yrs, absent tendon reflexes in the lower extremities. Within 5 years of disease onset: dysarthria, areflexia, pyrimidal weakness of the legs, extensor plantar responses and distal loss of joint position and vibration sense. Also, scoliosis, pes cavus, optic nerve atrophy, hypertrophic cardiomyopathy, DM or glucose intolerance Clinical Tests: electrophysiologic evidence of axonal sensory neuropathy Molecular Tests: GAA triplet repeat expansion in FRDA intron 1 (96% homozygous) Normal 5-33, premutation 34-65, and disease causing: 66-1700 repeats. Disease Mechanism: It is believed that GAA expansion forms a stable DNA structure that interferes with transcription Treatment/Prognosis: Treatment is supportive:psychological, prostheses, walking aids, wheelchairs, PT, and ST

Answer 79

Responsible gene: PMP22 Protein: Peripheral myelin protein 22 Cytogenetic locus: 17p11.2 Inheritance: AD Clinical Features and Diagnostic Criteria: adult with recurrent focal pressure palsies, mild polyneuropathy, absent ankle reflexes, reduced DTRs, mild-mod pes cavus deformity Clinical Tests: Prolongation of distal nerve conduction latencies (virtually 100%), normal general motor nerve conduction velocities, demyelination and tomaculous (focal nerve enlargement) on sural nerve biopsy Molecular Tests: PMP22 sequencing (20%), 1.5-Mb PMP22 deletion (80%) Disease Mechanism: HNPP is associated with decreased mRNA message for PMP22 and decreased peripheral myelin protein 22 in peripheral nerve. Treatment/Prognosis: Bracing, AFO for foot drop, unclear if surgical nerve decompression is helpful, avoid risk factors for pressure palsy: prolonged sitting with legs crossed, repetitive wrist movements, prolonged leaning on elbows, and rapid weight loss.

Answer 80

Responsible gene (protein, cytogenetic locus): CAPN3 (Calpain 3, 15q15.1-q21.1), FKRP (Fukutin related protein, 19q13.1), LMNA (Lamin-A/C, 1q21.2), SGCA (alpha sarcoglycan, 17q12), SGCB beta sarcoglycan, 4q12), SGCD (delta-sarcoglycan, 5q33), SGCG (gamma-sarcoglycan, 13q12), DYSF (Dysferlin, 2p13.3) Inheritance: most AR, some rare AD subtypes Clinical Features and Diagnostic Criteria: AR Sarcoglycan LGMD: proximal limb weakness, difficulty running and walking, calf hypertrophy, onset age 3-15 (68% of childhood onset, 10% adult onset) Calpain AR LGMD proximal limb weakness, difficulty running and walking, calf atrophy, onset 2-40 yrs (10-30% AR LGMD). Dysferlin AR LGMD problems running and walking, foot drop, distal and/or pelvic weakness, transient calf hypertrophy, onset 17-23 yrs Clinical Tests: Inc serum CPK, dystrophic changes on muscle biopsy, sarcoglycan protein staining Molecular Tests: Gene sequencing (80-99%) Disease Mechanism: Sarcoglycanopathies disrupt dystrophin-dystroglycan complex, calpainopathy: unknown, dysferlinopathy: may be die to abnl membrane fusion Treatment/Prognosis: Supportive care to promote mobility and ambulation. Monitor for respiratory and orthopedic complications and for cardiomyopathy

Answer 81

Responsible gene: DMPK Protein: Myotonin-protein kinase Cytogenetic locus: 19q13.32 Inheritance: AD Clinical Features and Diagnostic Criteria: Multisystem disorder of skeletal and smooth muscle, eyes, heart, endocrine system, and CNS. MILD cataract and mild myotonia (50-150 repeats) Classic muscle weakness and wasting, myotonia, cataract, and arrhythmia (100-1000 repeats). Have grip myotonia (sustained muscle contraction leads to inability to quickly release a hand grip) Congenital hypotonia and severe generalized weakness at birth often with resp. insufficiency and early death, MR is common (>2000 repeats) Clinical Tests: EMG, serum CK, muscle biopsy (internal nuclei, ring fibers, sarcoplasmic masses, type I fiber atrophy, inc # intrafusal muscle fibers), slit lamp exam Molecular Tests: CTG triplet repeat at the 3'-UTR of the DMPK (100%). PCR: detect repeats up to ~100, southern blot (detect repeats>100) Disease Mechanism: Cause thought to be due to gain of function RNA mechanism- the CUG repeats alter alternative splicing of other genes, including a CL- channel, resulting in myotonia Treatment/Prognosis: Symptomatic only

Answer 82

Gene (protein, chromosomal locus): ACTA1 (Actin, alpha skeletal muscle, 1q42.1), NEB (Nebulin, 2q22), TNNT1 (Troponin T, slow skeletal muscle, 19q13.4), TPM2 (Tropomyosin beta chain, 9p13.2-p13.1), TPM3 (Tropomyosin alpha-3 chain, 1q22-q23) Inheritance: AR or AD Clinical Features and Diagnostic Criteria: weakness, hypotonia, and depressed or absent DTR's. Weakness is usually most severe in the face, neck flexors, and proximal limb muscles. Age of onset: congenital, childhood, or adulthood. Clinical Tests: Muscle biopsy: the diagnostic hallmark is the presence of rod-like inclusions, nemaline bodies, in the sarcoplasm of skeletal muscle fibers with trichrome staining. Molecular Tests: ACTA sequencing: 15-25% of NM, ACTA Del/dup analysis: Exon 55. Disease Mechanism: NM is a disorder of thin filament anchoring proteins Treatment/Prognosis: No definitive correlation between # of rods and severity of the myopathy. Walking prior to 18 months is predictive of survival.

Answer 83

Responsible genes: SMN1, SMN2 Proteins: survival motor neuron protein 1 and 2 Cytogenetic loci: 5q12.2-q13.3 Inheritance: AR Clinical Features and Diagnostic Criteria: arthrogryposis multiplex congenita, peripheral nerve hypomyelination. SMA I onset 0-6mo, muscle weakness, tongue fasiculations, absent DTRs SMA II muscle weakness onset after 6 months, finger trembling, low tone, absent DTRs, SMA III Weakness leads to frequent falls or trouble with stairs, onset 2-3yrs, proximal weakness (legs>arms), SMA IV adult onset Clinical Tests: EMG: denervation and diminished motor action potential amplitude. Muscle Bx: atrophy of type 1 and type 2 fibers Molecular Tests: Targeted mutation analysis: deletion of SMN1 exon 7 deletion (95-98%), SMN1 sequencing (2-5%). Carriers who have two copies of SMN1 in cis (~4% of the population) will be misdiagnosed as non-carriers. SMN2 copy # modifies the severity. 2 copies SMN2- SMA I, 3 copies- SMA II, 4-8 copies- SMA III. Absence of both SMN genes: lethal Disease Mechanism: Mutant SMN lacks the splicing-regeneration activity of wild type. Treatment/Prognosis: Optimize feeding and nutrition, PFT's, sleep study for OSA, treat contractures, dislocations, and scoliosis

Answer 84

(Fukuyama (FCMD), Muscle-Eye-Brain (MEB), Walker-Warburg (WWS), Congenital Muscular Dystrophy Type 1D (MDC1D) Responsible gene (protein, cytogenetic locus): FCMD; FCMD (Fukutin, 9q31); MEB: POMGNT1 (protein O-mannosidase beta-1,2-Nacetylglucosaminyltransferase, 1p34-p33); WWS: POMT1 and POMT2 (Protein O-mannosyltransferase 1 and 2, 9q34.1, and 14q24.3); MDC1D (LARGE, glycosyltransferase-like protein LARGE, 22q12.3-q13.1 Inheritance: AR Clinical Features and Diagnostic Criteria: Muscle weakness present at birth. Hypotonia and weakness. Joint contracture (MEB and WWS: elbow, FMD: hip, knee, ankle, elbow). Clinical Tests: Muscle bx: dystrophic or myopathic pattern; inc serum CK; Muscle Bx: immunostaining; Brain MRI: Cobblestone complex (enlarged lat ventricles, flat brainstem, cerebellar hypoplasia) Disease Mechanism: Disruption of alpha dystroglycan (an integral component of the dystrophin-glycoprotein complex) Treatment/Prognosis: Weight control, PT, assist devices for ambulation, surgical correction of orthopaedic problems, monitoring of respiratory function

Answer 85

Responsible gene: HEXA Protein: Hexosaminidase A Cytogenetic locus: 15q23-q24 Inheritance: AR Clinical Features and Diagnostic Criteria: Infantile weakness starts at 6 mo, exaggerated startle, seizures and vision loss by the end of the first year, neurodegeneration continues- deaf, cannot swallow, weakening of muscles, and eventual paralysis, death in toddler years. Juvenile muscle coordination problems, seizures, and vision problems starting as young children. Chronic and adult onset start later, progress more slowly, more rare. Clinical Tests: HEXA enzyme activity, cherry red spot on eye exam Molecular Tests: Follow enzyme testing with DNA testing (some with a positive enzyme assay have a pseudodeficiency allele that does not cause Tay Sachs). HEXA 6 common mutation panel: 92% of Ashkenazi Jewish Disease Mechanism: Accumulation of GM2 gangliosides in the brain Treatment/Prognosis: Supportive only

Answer 86

Responsible genes: BRCA1 and BRCA2 Proteins: Breast cancer type 1 and 2 susceptibility protein Cytogenetic loci: 17q21, 13q12.3 Inheritance: AD Clinical Features and Diagnostic Criteria: BRCA 1 and 2: Br, ovarian, prostate cancer; ?colon. BRCA2:larynx, esophagus, colon, stomach, gallbladder, bile duct, hematopoietic system, and melanomas. Clinical Tests: mammography, MRI, BRCA1-related breast tumors show an excess of medullary histopathology, are of higher histological grade, and are more likely to be estrogen receptor-negative and progesterone receptor-negative. BRCA1-related ovarian cancer: excess of serous adenocarcinomas Molecular Tests: Common mutation analysis or full gene sequencing (about one third of mutations identified in BRCA1 and BRCA2 sequencing are of uncertain clinical significance). 185delAG (BRCA1) and 6174delT (BRCA2) mutation s are found in 20-30% of Jewish women with early breast cancer and in 45-60% of Jewish women diagnosed with ovarian cancer. Dutch women with early br or ovarian ca: often one of 3 large BRCA1 deletions. BRCA2 999del5 occurs in 7.7% of women and 40% of men with breast cancer from Iceland. BRCA2 mutation 6174delT found in 1% of women of Ashkenazi Jewish descent. Disease Mechanism: BRCA1 and 2 are tumor suppressor genes Treatment/Prognosis: discussion of cancer screening protocols, chemoprevention trials, and options for prophylactic surgery. 85% will develop Br ca by age 70 yrs.

Answer 87

Responsible gene: APC Protein: Adenomatous polyposis coli protein Cytogenetic locus: 5q21-22 Inheritance: AD (15-30% new mutation) Clinical Features and Diagnostic Criteria: adenomatous colonic polyps (100-1000) in childhood to adolesence, abdominal desmoid tumors, jaw osteoma, absent/ supernumerary/ malformed teeth, hepatoblastoma, thyroid cancer, epidermoid cysts. Attenuated FAP: fewer polyps, more proximal in the colon. Gardner syndrome: colonic adenomatous polyposis, osteomas, and soft tissue tumors. Turcot syndrome: colon cancer and CNS tumors (medulloblastoma) Clinical Tests: Clinical findings on colonoscopy Molecular Tests: APC sequence analysis (up to 90%), protein truncation testing (up to 80%) Disease Mechanism: When abnormal protein is present, high levels of free cytosolic b-catenin result which migrates to the nucleus, binds to a transcription factor Tcf-4 or Lef-1 (T cell factor-lymphoid enhancer factor), and may activate the oncogenes c-Myc and cyclin D1 Treatment/Prognosis: Without colectomy, colon cancer is inevitable, and colectomy is recommended when adenomas emerge. The mean age of cancer in untreated individuals is 39 years.

Answer 88

Responsible gene (protein and cytogenetic locus): MLH1 (3p21.3, DNA mismatch repair protein MLH1), MSH2 (2p22-p21, DNA mismatch repair protein Msh2), MSH6 (2p16, DNA mismatch repair protein MSH6), and PMS2 (7p22, PMS1 protein homolog 2) Inheritance: AD Clinical Features and Diagnostic Criteria: Amsterdam II Criteria: 3 or more family members (at least one 1st degree of the other 2) with HNPCC related cancers; 2 successive affected generations; 1 or more of the HNPCC-related cancers diagnosed before age 50; exclusion of FAP. Bethesda 2004: CRC diagnosed under age 50yrs, 2 HNPCC related tumors at once, CRC with high MSI in someone

Answer 89

Responsible genes: P53, CHEK2 Proteins: Cellular tumor antigen P53, Serine/threonine protein kinase Chk2 Cytogenetic loci: 17p13, 22q12.1 Inheritance: AD Clinical Features and Diagnostic Criteria: Proband with sarcoma

Answer 90

Responsible gene: MEN1 Protein: Menin Cytogenetic locus: 11q13 Inheritance: AD Clinical Features and Diagnostic Criteria: MEN1= tumor in 2 of: parathyroid, enteropancreatic endocrine tissue, or anterior pituitary OR Tumor in one and 1st degree relative with MEN1. Facial angiofibroma, collagenoma, café au lait, lipoma Clinical Tests: Parathyroid function studies, anterior pituitary hormone abnormalities, Brain MRI Molecular Tests: MEN1 sequencing (70-90% familial, 65% sporadic), Dup/del testing (1-3%) Disease Mechanism: MEN1 is a tumor suppressor gene by regulating transcription of proteins involved in the regulation of cell proliferation and development Treatment/Prognosis: biochemical testing of serum concentrations of calcium (from age 8 yrs), gastrin (from age 20 yrs), pancreatic polypeptide (from age 10 yrs), prolactin (from age 5 yrs), abdominal CT or MRI (from age 20 yrs) and head MRI (from age 5 yrs).

Answer 91

Responsible gene: RET Protein: proto-oncogene tyrosine-protein kinase receptor ret Cytogenetic locus: 10q11.2 Inheritance: AD Clinical Features and Diagnostic Criteria: MEN2A two or more of medullary thyroid carcinoma, pheochromocytoma, or parathyroid adenoma/hyperplasia in a single person or close relatives. MEN2B mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, Marfanoid habitus, and medullary thyroid carcinoma Clinical Tests: Calcitonin, catecholamines, catecholamine metabolites, Ca, PTH Molecular Tests: RET sequencing: Exon 10 and 11 (95% MEN2A), Exon 16 (95% MEN2B) Disease Mechanism: Gain of function mutations in RET lead to consitutive activation of tyrosine kinase Treatment/Prognosis: Prophylactic thyroidectomy, screen for pheochromocytoma annually and prior to any surgery, annual calcitonin stim test, annual PTH screening

Answer 92

Responsible gene: NF2 Protein: Neurofibromin-2 (aka Merlin or Schwannomin) Cytogenetic locus: 22q12.2 Inheritance: AD Clinical Features and Diagnostic Criteria: Benign nerve tumors (schwannomas, meningiomas, ependymonas, astrocytoma). Hallmark is bilateral acoustic schwannoma, onset age 18-24 yrs, hearing loss, tinnitus, balance problems. Also cataracts, mononeuropathy, café au lait (fewer than in NF-1). Clinical Tests: MRI/CT, BAER, audiology evaluation, eye exam Molecular Tests: NF2 sequencing (75%), dupl/del testing (10- 15%) Disease Mechanism: NF2 is a tumor suppressor, 2nd hit leads to complete loss of function when one germline mutation present Treatment/Prognosis: Symptomatic tumors removed surgically (XRT may induce tumor formation). Ave age of death: 36 yrs.

Answer 93

Responsible gene: PTEN Protein: Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual specificity protein phosphatase Cytogenetic locus: 10q23 Inheritance: AD Clinical Features and Diagnostic Criteria: Cowden: Presents 2nd/3rd decade: mucocutaneous facial and oral papules, gingival cobblestoning, acral keratosis; dystrophic and adenomatous multinodular goiter, GI polyps, adenosis and fibrocystic breast lesions, macrocephaly, dolichocephaly, lipomas, GU anom. High risk for breast, thyroid, and endometrial cancer. Bannayan-Riley- Ruvalcaba (BRR) macroceph, polyposis, lipomas, pigmented macules of the glans penis. Proteus: CT nevi, disprop. overgrowth, dysregulated adipose tissue, vascular malformation, risk of ovarian or parotid tumor in 2nd decade Clinical Tests: Lesion pathology, MRA/MRI, CT Molecular Tests: PTEN seq (80%), promoter region mutations (10%) Disease Mechanism: Wild-type protein is a major lipid phosphatase that downregulates the PI3K/Akt pathway to cause G1 arrest and apoptosis Treatment/Prognosis: Annual derm exam, annual breast exam, annual breast MRI and mammography starting age 30, annual thyroid US starting age 18, annual endometrial bx starting age 35 until menopause then annual transvaginal US with bx of suspicious lesions

Answer 94

Responsible genes: TSC1 and TSC2 Proteins: Hamartin and Tuberin Cytogenetic loci: 9q34, 16p13 Inheritance: AD (2/3 de novo) Clinical Features and Diagnostic Criteria: Skin: hypomelanotic macules, facial angiofibroma, shagreen patch, ungual fibromata. CNS: subependymal glial nodules, cortical tubers, giant cell astrocytoma, seizures. Renal: angiomyolipomas, epithelial cysts, <1% malignant transformation Heart: cardiac rhabdomyoma, tend to regress in infancy without intervention. Lung: lymphangiomatosis (TSC2, women aged 20-40 yrs) Eye: hamartomas or achromic patches. There is a TSC2/PCKD contiguous gene deletion syndrome with features of TS and PKD. Clinical Tests: brain MRI, echo, renal ultrasound, Wood's lamp exam, eye exam, EEG Molecular Tests: TSC1 sequencing (30% familial, 15% sporadic) and TSC2 sequencing (50% familial and 60-70% sporadic) Disease Mechanism: Abnormal tumor suppressor activity Treatment/Prognosis: Renal US q1-3 yrs, renal CT/MRI if numerous lesions on US, semiannual renal US if angiomyolipomas <3.5-4.0 cm, chest CT if pulmonary symptoms

Answer 95

Responsible gene: VHL Protein: Von Hippel -Lindau disease tumor suppressor Cytogenetic locus: 3p25 Inheritance: AD Clinical Features and Diagnostic Criteria: Hemangioblastoma (cerebellum, retina, spinal cord), pheochromocytoma (hypertension), renal cell carcinoma (40%). Acquired VHL mutations can give rise to sporadic VHL associated tumors. Clinical Tests: CT or MRI, urine catecholamine metabolites, renal US Molecular Tests: VHL sequencing (72%), southern blot for partial or complete gene deletion (28%) Disease Mechanism: Abnormal tumor suppressor function. Truncating or missense mutations that grossly disrupt protein folding lead to VHL Type I: low risk for pheo. Other missense mutations lead to VHL Type II: high risk of pheo. Treatment/Prognosis: Reduced risk of renal cancer in those with complete gene deletion. Starting at age 5: annual eye exam, urine catecholamines, BP. Starting age 15 annual abdominal US. Temporal bone MRI if documented HL.

Answer 96

Responsible genes: Most common: XPA, XPC, ERCC2, POLH Proteins: DNA-repair protein complementing XP-A cells, DNA-repair protein complementing XP-C cells, TFIIH basal transcription factor complex helicase subunit, DNA polymerase theta Cytogenetic loci: 9q22.3, 3p25, 19q13.2-q13.3, 6p21.1-p12 Inheritance: AR Clinical Features and Diagnostic Criteria: severe sun sensitivity, UV exposure to conjunctiva, cornea, and lids-> severe keratitis, progressive neurologic deterioration: acquired microcephaly, dec/absent DTR's, prog. SNHL, cognitive impairment. > 1000x inc. risk of skin and eye neoplasms Clinical Tests: Cellular UV hypersensitivity (a post UV exposure cellular survival plot reflecting capacity for DNA repair. Molecular Tests: Research only direct DNA testing of XPA (25%), XPC (25%), ERCC2 (15%), POLH (21%) Disease Mechanism: Impaired ability to sense, excise, and repair UV induced DNA damage Treatment/Prognosis: Regular detailed skin and eye exam, regular audiometry, protection of all body surfaces from UV light, UV meter to detect unexpected sources of high levels of UV light (eg halogen lamps). Treat cancers

Answer 97

Responsible genes: CDKN1C, H19, KCNQ1OT1 Proteins: cyclin-dep kinase inhib 1C, H19 maternally expressed untranslated mRNA, potassium voltage-gated channel, KQT-like subfamily, member 1 Cytogenetic locus: 11p15.5 Inheritance: AD (15%) Clinical Features and Diagnostic Criteria: hemihyperplasia, macrosomia, macroglossia, visceromegaly, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities Clinical Tests: AFP, abdominal CT Molecular Tests: Cytogenetically detectable abnormalities of 11p15 (<1%); loss of methylation at DMR2 (50%); gain of methylation at DMR1 (2% -7%); pat. UPD for 11p15 (10-20%); mutations in the CDKN1C (40% of familial cases and 5-10% of sporadic cases) Disease Mechanism: imprinted genes including growth factors and tumor suppressor genes in the 11p15.5 region Treatment/Prognosis: 20% mortality, Screening for embryonal tumors: abdominal US every three months until eight years. Serum AFP concentration is monitored in the first few yrs of life for hepatoblastoma.

Answer 98

Anterior linear ear lobe creases Posterior helical ear pits Macroglossia Hemihyperplasia Facial nevus flammeus Midface hypoplasia Infraorbital creases

Answer 99

Responsible gene: NSD1 Protein: Histone-lysine N-methyltransferase, H3 lysine-36 and H4 lysine-20 specific Cytogenetic locus: 5q35 Inheritance: AD Clinical Features and Diagnostic Criteria: classic: macrocephaly, pointed chin, tall stature and increased body mass, delayed motor skills, delayed cognitive, verbal, and social development, advanced BA. Less common: phobias, aggression, OCD, ADD, abnormal EEG and seizure, chronic OM and constipation, congenital heart defects, strabismus, hyper/hypothyroidism, possible inc risk of tumors (saccrococcygeal teratoma and neuroblastoma). Clinical Tests: Bone age. Brain MRI or CT may show inc ventricles Molecular Tests: MLPA or FISH for 5q35 microdeletion including NSD1: ~15% (70% in Japanese). NSD1 sequencing: 27-93% (12% in Japanese) Disease Mechanism: Haploinsufficiency of NSD1. May be related to genes affecting growth. Treatment/Prognosis: Supportive treatment, most end up of ave adult Ht, IQ ranges from normal to ID. Cancer screening is not rec. (risk ~1%)

Answer 100

malar flushing sparse frontotemporal hair high bossed forehead downslanting palpebral fissures long narrow face prominent narrow jaw head is said to resemble an inverted pear

Answer 101

Responsible genes: APTX, SETX Proteins: Aprataxin, Probable Helicase Senataxin Cytogenetic loci: 9p13.3, 9q34 Inheritance: AR Clinical Features and Diagnostic Criteria: childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy. Oculomotor apraxia progresses to external ophthalmoplegia. Clinical Tests: Cerebellar atrophy, axonal neuropathy on EMG and biopsy, low serum albumin, high cholesterol. Type 2: Inc AFP Molecular Tests: sequencing APTX (Inc incidence in Portugal and Japan) and SETX. Mutation detection rate unknown. Disease Mechanism: There is direct involvement of aprataxin in the DNA single-strand break repair mechanisms; mutations in the APTX gene destabilize aprataxin and cells from individuals with AOA1 are characterized by enhanced sensitivity to agents that cause single-strand breaks in DNA Treatment/Prognosis: PT, wheelchair by age 15-20 yrs, educational support, high protein low cholesterol diet

Answer 102

Responsible genes: ERCC6, ERCC8 Proteins: DNA excision repair protein ERCC-6 and ERCC-8 Cytogenetic loci: 10q11, Chromosome 5 Inheritance: AR Clinical Features and Diagnostic Criteria: CS Type I: normal prenatal growth, severe FTT in first 2 years, progressive deterioration of vision, hearing, CNS, and peripheral nervous syndrome. Type II: growth failure at birth, little or no postnatal neurological development, kyphosis, scoliosis, joint contracture. Type III: normal growth and development or late onset. Xeroderma Pigmentosum-CS: facial freckling, early skin cancer, ID, spasticity, short stature, hypogonadism (no demyelination). Clinical Tests: Brain MRI: leukodystrophy. Eye exam: pigmentary retinopathy, cataracts, demyelinating peripheral neuropathy. Abnormal DNA repair on skin fibroblasts Molecular Tests: Gene sequencing ERCC6 (75%), ERCC8 (25%) ``` Disease Mechanism: Abnormal transcription-coupled nucleotide excision repair (preferential removal of UV-induced pyrimidine dimers and other transcription blocking lesions) ``` Treatment/Prognosis: PT, dental exams, skin exams, sunscreen if photosensitive. Death in 1st-2nd decade Type I, by age 7 yrs Type II.

Answer 103

Responsible gene: LMNA Protein: Lamin-A/C Cytogenetic locus: 1q21.2 Inheritance: AD (all de novo, paternal age effect) Clinical Features and Diagnostic Criteria: short stature, wt<

Answer 104

Responsible gene: SERPINA1 Protein: AAT Cytogenetic locus: 14q32.1 Inheritance: AR Clinical Features and Diagnostic Criteria: Adult COPD, childhood and adult liver disease (obstructive jaundice and raised transaminases in kids, cirrhosis and fibrosis in adults). Age of onset 40-50y if a smoker, 60's if not. Clinical Tests: Low plasma AAT (also low in other resp d/o inc CF), Demonstration of deficient variant of the AAT protein by protease inhibitor typing Molecular Tests: Targeted mutation testing of SERPINA (95% E42K) Disease Mechanism: Loss of sufficient protease inhibition by AAT Treatment/Prognosis: Liver transplant is a cure (donor liver produces AAT). Research: IV AAT if rapid decline in FEV1.

Answer 105

Responsible gene: CFTR Protein: cystic fibrosis transmembrane conductance regulator Cytogenetic locus: 7q31.2 Inheritance: AR Clinical Features and Diagnostic Criteria: Cystic fibrosis (CF): chronic airway infection, chronic sinusitis, meconium ileus, malabsorption due to pancreatic insufficiency, male infertility due to azoospermia. Progression to end stage lung disease. Congenital bilateral absence of the vas deferens (CBAVD) occurs in men without pulm. or GI Sx of CF. Clinical Tests: sweat test, decreased semen volume with low pH, high [citric acid], high [acid phosphatase], low [fructose] Molecular Tests: Common mutation testing or full gene sequencing. Intron 8 5T variant: variably penetrant, test for if R117H mutation. 5T with 12 or 13 TG tract (just 5' of 5T) has the strongest adverse effect on proper intron 8 splicing. deltaF508: 30-80% of mutant alleles depending upon ethnic group. Disease Mechanism: CFTR forms a regulated cell membrane chloride channel. 4 mutation classes: I. reduced or absent synthesis, II. block in protein processing, III. block in regulation of CFTR chloride channel, IV. altered conductance of CFTR chloride channel. Treatment/Prognosis: antibiotics, bronchodilators, steroids, mucolytics, chest PT, lung transplant, pancreatic enzymes, fat soluble vitamins, microscopic sperm aspiration.

Answer 106

Responsible genes: XL: COL4A5, AR: COL4A3 and COL4A4, AD: COL4A3 and COL4A4 Proteins: Collagen alpha-3(IV) chain, Collagen alpha-4(IV) chain, Collagen alpha-5(IV) chain Cytogenetic loci: 2q36-q37 (COL4A3 and COL4A4), Xq22.3 (COL4A5) Inheritance: 80% X linked, 15% AR, 5% AD Clinical Features and Diagnostic Criteria: Spectrum from progressive renal disease with cochlear and ocular abnormalities (Alport) to isolated hematuria with a benign course (thin BM nephropathy). Clinical Tests: Microhematuria, eventually proteinuria. Anterior lenticonus virtually pathognomonic, EM on renal biopsy Molecular Tests: Sequencing and deletion testing COL4A3, COL4A4, COL4A5 (80-100%) Disease Mechanism: Type IV Collagen is found ubiquitously and is the major collagen component of BMs. Alport due to abnl secretion of collagen alpha 3,4,and 5 (IV) chains Treatment/Prognosis: ESRD: 60% by 30 yrs and 90% by 40 yrs and Deafness: 80-90% SN deafness by age 40 in males, later in life in females with XL Alport. Renal progression and deafness is slower in AD Alport and ocular lesions uncommon. Juvenile onset HL in AR Alport.

Answer 107

Responsible genes: PKD1, PKD2 and PKHD1 Proteins: Polycystin-1, Polycystin-2, Fibrocystin Cytogenetic loci: 16p13.1, 4q21, and 6p21.1-p12 Inheritance: AD (PKD1, PKD2) AR (PKHD1) Clinical Features and Diagnostic Criteria: AD PKD Enlargement of both kidneys, renal cysts, hematuria, polyuria, flank pain, renal stones, urinary infection. Cysts in liver, pancreas, and intestine; heart valve defects, intracranial aneurysm. AR PKD Fetal or neonatal death, impaired lung formation, pulmonary hypoplasia due to oligohydramnios, renal failure, hepatic fibrosis. Most present prenatally or early infancy Clinical Tests: Abdominal US, prenatal US, MRI Molecular Tests: PKD1 and PKD2 sequence analysis (85%). Large deletion including PKD1 and TSC2: manifestations off PKD and tuberous sclerosis Disease Mechanism: Unclear, decreased amount of functional protein? Treatment/Prognosis: PKD2 mutations show later onset and slower rate of progression. ESRD age 60 yrs

Answer 108

Responsible gene: FGFR3 Protein: Fibroblast growth factor recepter 3 Cytogenetic locus: 4p16.3 Inheritance: AD; 80% de novo Clinical Features and Diagnostic Criteria: short stature, rhizomelic shortening, trident hand, frontal bossing, midface hypoplasia, macrocephaly, OSA, spinal cord compression Clinical Tests: Narrowing of interpediculate distance, caudal spine; notch-like sacroiliac groove, circumflex or chevron seat on the metaphysis Molecular Tests: 98% FGFR3 G1138A; ~1% FGFR3 G1138C Disease Mechanism: Constitutive activation of FGF R (GOF mutations)- activation of negative growth control Treatment/Prognosis: achondroplasia growth curves, surgery or CPAP for OSA, role of GH unclear, leg lengthening, suboccipital decompression, spinal fusion, LPA support group

Answer 109

Responsible gene: RUNX2 Protein: Runt-related transcription factor 2 Cytogenetic locus: 6p21 Inheritance: AD (high proportion de novo) Clinical Features and Diagnostic Criteria: delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, multiple dental abnormalities. Abnormally large wide open anterior fontanel, midface hypoplasia, brachydactyly, recurrent OM, hearing loss, normal intellect. Clinical Tests: X-ray: clavicular hypoplasia, open sutures, wormian bones, poor or absent sinus pneumatization, hypoplastic scapulae, wide symphysis pubis and sacroiliac joints, large femoral neck and epiphyses, pseudoepiphyses of the metacarpals and metatarsals, deformed and short middle phalanges, osteopenia. Molecular Tests: RUNX2 sequencing and array for microdeletions (60-70%). Disease Mechanism: Independently mediates DNA binding and protein heterodimerization; mutations abolish DNA binding Treatment/Prognosis: Hearing test, dental referral, ear tubes, helmets if large skull defects

Answer 110

Responsible gene: SLC26A2 Protein: Sulfate transporter Cytogenetic locus: 5q32-q33.1 Inheritance: AR Clinical Features and Diagnostic Criteria: limb shortening, normal-sized skull, hitchhiker thumbs, small chest, large joint contracture, cleft palate, cystic ear swelling, ulnar deviation of fingers, clubfoot, low tone, normal IQ Clinical Tests: x-ray: cervical kyphosis, incomplete thoracic vertebrae ossification, coronal clefting of lower thoracic and lumbar vertebrae, narrowed interpedicular distance L1 to L5, distal humerous can be bifid or v shaped, rounded distal femur, advanced bone age. Cartilage histopathology: paucity of sulfated proteoglycans in cartilage matrix. Abnormal incorporation of sulfate into macromolecules in cultured chondrocytes Molecular Tests: SLC26A2 targeted mutation analysis (65% one of 5 mutations), SLC26A2 sequencing(>90%) Disease Mechanism: Undersulfation of proteoglycans affects the composition of the extracellular matrix and leads to impaired proteoglycan deposition which is necessary for proper enchondral bone formation Treatment/Prognosis: Maintain joint positioning and mobility as much as possible, clubfoot deformities tend to recur after surgical correction, scoliosis surgery best if postponed until after puberty. Joint contractures and spine deformity worsen with age. Total arthroplasy may diminish joint pain.

Answer 111

Responsible genes: FGFR1, FGFR2, FGFR3 Proteins: Basic fibroblast growth factor receptor 1, 2, and 3 Cytogenetic loci: 8p11.2-p11.1, 10q26, 4p16.3 Inheritance: AD Clinical Features and Diagnostic Criteria: All but Muenke and FGFR2-related Isolated Coronal craniosynostosis are associated with bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot anomalies (broad and/or syndactylous). Developmental delay/ID, hearing loss, and visual impairment common. Clinical Tests: Brain CT or MRI for hydrocephalus, spinal x-rays for vertebral anomalies Molecular Tests: FGFR1 sequencing (5% Pfeiffer 1); FGFR2 sequencing (100% Crouzon, Jackson-Weiss, Apert, Pfeiffer 2 and 3, and FGFR2-related isolated coronal synostosis); FGFR3 sequencing (100% Crouzon with Acanthosis Nigricans); FGFR3 targeted mutation analysis (100% Muenke) Disease Mechanism: Mutations cause increased R affinity thought to promote excessive receptor down-regulation. Treatment/Prognosis: Coordinated neurosurgical, ENT, and dental care, follow for scoliosis, limb anomalies rarely benefit from surgery

Answer 112

Responsible gene: FGFR3 Protein: Fibroblast growth factor receptor 3 Cytogenetic locus: 4p16.3 Inheritance: AD Clinical Features and Diagnostic Criteria: 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 Clinical Tests: x-ray: elongated distal fibula, short lumbar pedicles, short distal ulna, chevron deformity of distal femur metaphysis, flattened acetabular roof Molecular Tests: Targeted mutation analysis: N540K (C1620A) (49%), N540K (C1620G) (21%). Exon 9, 10, 13, or 15 sequencing (80%) Disease Mechanism: unknown but mouse models suggest FGFR3 is a negative regulator of bone growth Treatment/Prognosis: Monitor for S/Sx spinal cord compression (MRI or CT foramen magnum), sleep study id history c/w OSA, ortho eval if severe genu varum impairs walking.

Answer 113

Responsible genes: EXT1, EXT2 Proteins: Exostosin-1, Exostosin-2 Cytogenetic loci: 8q24.11, 11p11.2 Inheritance: AD Clinical Features and Diagnostic Criteria: Exostoses (benign cartilage-capped bony growths) arising from the growth plate of the long bones or from the surface of flat bones (scapula). Limb length inequity and bowed long bones can develop. Short metacarpals. Can have mass effect compression of nerves and blood vessels. Clinical Tests: x-ray may detect mildly affected individuals Molecular Tests: EXT1 and EXT2 sequencing: >70% detection rate, del/dup studies: 20% Disease Mechanism: EXT1/2 encode glycosyltransferases, mutations lead to actin accumulation and cytoskeletal abnormalities Treatment/Prognosis: Growth ceases after skeletal maturation. 0.5-2% of cases degenerate to chondrosarcoma. Treatment is surgical resection.

Answer 114

Responsible genes: COL1A1 and COL1A2 Proteins: Collagen alpha 1(I) chain, Collagen alpha 2(I) chain Cytogenetic loci: 17q21.33, 7q21.3 Inheritance: AD and rare AR Clinical Features and Diagnostic Criteria: Fractures with little or no trauma, relative short stature, blue sclera, dentinogenesis imperfecta, post-pubertal HL, ligamentous laxity, easy bruising. OI Type II: perinatal lethal, palpable callus formation on ribs, hips in "frog-leg" position, short bowed extremities. OI Type III: severe, skull descends on cervical spinebrainstem compression, obstructive hydrocephalus, syringomyelia Clinical Tests: x-ray: fractures of varying ages, spinal compression fracture, wormian bones, protrusio acetabuli, osteopenia. Cultured fibroblasts (98% Type II, 87% all others) Molecular Tests: COL1A1 and COL2A1 sequencing: ~100% Type I, 98% Type II, 60-70% Type III, 0-80% Type IV Disease Mechanism: Type I: premature stop codon->unstable mRNA->dec amount type I collagen. Types II, III, IV: mutations alter collagen structure Treatment/Prognosis: Bisphosphonate to decrease bone resorption, GH to increase linear growth and bone formation

Answer 115

Responsible gene: TWIST1 Protein: Twist-related protein 1 Cytogenetic locus: 7p21 Inheritance: AD Clinical Features and Diagnostic Criteria: coronal synostosis, facial asymmetry, ptosis, 2/3 hand syndactyly, mild-moderate developmental delay in a minority, short stature, parietal foramina, vertebral fusions, radioulnar synostosis, cleft palate, maxillary hypoplasia, congenital heart defect Clinical Tests: echo, x-ray for vertebral abnormalities, audiologic testing, and karyotype: translocations, inversions, or ring chromsome 7 have been reported Molecular Tests: TWIST1 sequencing: >50%, del/dup testing: complete deletion of the TWIST1 gene 11-28% Disease Mechanism: haploinsufficiency by gene deletion, rapid degradation of abnormal protein, or altered subcellular localization of abnormal protein Treatment/Prognosis: endocrine eval if plateau in growth, craniofacial team management, surgical repair of cleft palate and craniosynostosis, eye exams to monitor for evidence of increase ICP

Answer 116

Facial asymmetry Ptosis Maxillary hypoplasia

20- One Hundred Syndromes Flashcards

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