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Case presentation -
Diagnosis
Diagnosis of a genetic disorder can be made based upon recognition of classic presentation pathognomonic feature subdivision into category and differential Dx recognition of special inheritance pattern guess based on the most common Brief overview of syndromes and their classic presentations Review of pathognomonic feature of common disorders Symptom category and differential diagnosis Review of inheritance pattern
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A. B. C. D. E.
Coronary artery disease Canada-Cronkhite syndrome Gluten enteropathy celiac disease Mixed hyperlipidemia SLE
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A. B. C. D. E.
Pseudodominant Consanguinity
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A. B. C. D. E.
Diabetes mellitus type 2 Senile dementia Hyporeninemic hypertension Distal IP osteoarthritis Coronary heart disease
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Which is incorrect ?
A. Marfan syndrome ascending aortitis B. Turner syndrome aortic coarctation C. DiGeorge syndrome interrupted Ao arch D. Ehlers-Danlos syndrome aortic dilatation E. Williams syndrome aortic stenosis
Acute chest pain, Aortic dissection, CHF, Aortic regurgitation, Dilated aortic root Lens subluxation/dislocation Skeletal finding: tall stature, pectus, scoliosis, pes planus, dolichostenomelia, joint laxity Characteristic signs: thumb, wrist, arachnodactyly, onycho-umbilical, dural ectasia, striae atrophica W/U: echo, eye Rx: beta blocker, Bentall operation for root >5.5 cm
G:FBN1 15q
P:Fibrillin 1
Marfan syndrome
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A. B. C. D. E.
Treatment for Marfan syndrome include all except Avoidance of weight lifting Bental operation for severe AR Beta adrenergic blocker for Ao dilatation Lens removal for subluxation Hormonal treatment for excessive height
Velocardiofacial syndrome
DiGeorge sequence 22q11 microdeletion (contiguous gene syndrome) Sporadic or familial Conotruncal heart defect + thymus hypoplasia + transient hypocalcemia + cleft palate Long fingers, abnormal nose, smooth philtrum W/U: FISH with 22q11 probe
Down syndrome
Short, flat facies, upslant palpebral fissure, low set ear, epicanthus, large tongue, simian crease, toe 1-2 gap Adult issue: hypothyroidism, C1-2 instability, dementia, DM, CHD CHD: AV canal, VSD, TOF W/U: chromosome, echo, TSH Almost always sporadic trisomy 21 by maternal nondisjunction Recurrent risk only in translocation Down commonly t(14;21) t(21;22) t(21;21) Male infertile, female possibly fertile
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A. B. C. D. E.
Begin before puberty Be given lifelong Be used with estrogen Never be given Always be attempted if pt is short
Turner syndrome
Short, prepubertal, broad chest, increased carrying angle, nevi, ptosis, neck webbing, short 4 MCP Amenorrhea primary / secondary Adult issue: infertility, HTN, CVA risk, DM, thyroiditis W/U: BP, chromosome Commonly 45,X 50% mat nondisjuction Less common: 46,Xi(Xq) 46,Xr(X) or mosaic abnormality Rx: HRT prevent osteoporosis, growth hormone in children
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A. B. C. D.
A Turner syndrome pt A pt with chromosomal translocation A product of carrier father and mother A product of carrier mother plus new mutation E. A sex reversal pt
Klinefelter syndrome
Normal to slightly high normal height, gynecomastia, small firm testes Variable intelligence from normal in most to borderline Adult issue: hypogonadism, chronic stasis ulcer, mediastinal germ cell tumor W/U: chromosome Extra X such as 47,XXY 48,XXYY etc. All sporadic 50% paternal nondisjuction Rx: testosterone IM
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Neurocutaneous syndrome
Which of the following cutaneous disorders is NOT likely to be associated with mental deficiency ? A. B. C. D. E. Multiple lentigenes over the whole body Multiple caf-au-lait spots Multiple unilateral facial hemangioma Multiple nasolabial angiofibroma Multiple linear verrucous multistaged pigmentary abnormality along Blaschkos line
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Neurofibromatosis I - AD
Caf au lait macule, NF, optic glioma Diff Dx: familial CAL Variant: NF-Noonan, Watson Risk of malignancy: PNST 14%, juvenile MMoL Adult issue: HTN, renal a stenosis, pheochromocytoma, CVA W/U: None Rx: symptomatic, surgery rarely
G:NF1 17q
P:Neurofibromin
Neurofibromatosis II- AD
Hearing impairment, tinnitus, weakness Small amount of Caf-au-lait macules, subcutaneous nodules, posterior subcapsular cataract, retinal hamartoma CNS tumor: schwannoma, meningioma, ependymoma, glioma Two subtype : Wishart early severe, Gardner late mild to moderate W/U: MRI whole brain-spine, hearing Rx: surgery G:NF2 22q P:MERLIN
Tuberous sclerosis
Hamartomata in many organs: tuber MR, seizures Periungual fibroma Glioma in brain/fundus Angiofibroma on face Angiomyolipoma in kidneys W/U: U/S, CT, echo Rx: anti-epileptic
Li-Fraumeni syndrome - AD
Multiple tumors esp: brain, sarcoma, breast, leukemia Two hit theory (Knudson) Tumor suppressor gene mutation 1st hit = germline mutation 2nd hit = somatic mutation
Bilateral Breast, 40
Breast, 35 Brain tumor, 32 Soft tissue sarcoma, 7 Leukemia, 6 G:TP53 17p P:p53
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A. B. C. D. E.
A 16 yo woman who was found to have numerous colonic polyposis should her her her her her polypectomy attempted brain imaged chromosome studied fundi examined mammogram performed
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A. Urine cytology annually B. Sigmoidoscopy biannually C. Pelvic exam with endometrial aspirate annually D. Sputum cytology annually E. PSA annually
Gardner syndrome- AD
Desmoid tumor of rectus sheath Adenomatous polyposis Site: colon to rectum, sparse elsewhere Risk of malignancy : 100% Symptom: tumor W/U: GIFT, biopsy Rx: total colectomy with colostomy, proctocolectomy with ileoanal anastomosis or ileal pouch ileorectal anastomosis, COX2 inhibitor (celecoxib preferred)
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A female with Peutz-Jeghers syndrome could have all of the followings except Chronic abdominal pain Rectal polyp Iron deficiency anemia Pancreatic carcinoma Retinal hyperpigment abnormality
A. B. C. D. E.
Peutz-Jegher syndrome
Hypermelanosis at oral/acral Hamartomatous polyposis Site: throughout GI tract, most at intestines Risk of malignancy : low to moderate: colon, pancreas, breast, sex cord tumor Symptom: IDA, colics W/U: GIFT, biopsy Rx: surgery if obstruction occurs
Osler-Weber-Rendu disease- AD
HHT 2 genes: endoglin and activinlike growth factor AD AVM in organs: liver multiple nodules, hemoptysis W/U: CT w contrast or MRA, liver CT
Dystrophinopathy
3 subtypes Duchenne early severe, very high CK, life span less than 30 Becker early or late, mild CK elevation, near normal span upto 40-50 yrs. Cardiomyopathy only Balf pseudohypertrophy is seen is both Becker and Duchenne subtypes DNA testing available, prenatal diagnosis possible
Wilson disease
KF ring, low ceruloplasmin, high urine copper >200 ug/D Liver hepatitis or cholestasis, low ALP CNS- parkinsonism, dementia Others: hemolytic anemia Rx: zinc SO4 as 1st line, use Dpenicillamine only when life threatening such as impending liver failure, severe neurologic disease Asymptomatic member workup: eye, ceruloplasmin,24 hr urine Cu
Symptom category
Skeletal abnormality short stature tall stature CVS abnormality CHF chest pain sudden death malignant HTN Respiratory abnormality hemoptysis lung lesion on CXR pneumothorax GI abnormality bleeding polyposis jaundice/cirrhosis Hematologic abnormality anemia thrombosis bleeding (systemic) Neurologic abnormality myopathy neuropathy encephalopathy dementia abnormal movement seizures Urinary abnormality hematuria Oncologic abnormality Skin abnormality
Skeletal abnormality
Short stature proportionate or not associated findings Diff Dx: familial short stature, familail delayed maturation, bone dysplasia, endocrine esp hypothyroidism, primordial short stature, specific syndrome W/U: dysmorphic exam, bone age, specific testing, chromosome if multiple anomalies or DNA if suspect a specific syndrome Tall stature Gigantism Sotos syndrome Marfan Androgen insensitivity Klinefelter Major point MR ? -> Sotos female XY ? -> AIS Marfanoid ? Advanced bone age -> Sotos W/U: chromosome, specific test for each syndrome
CVS abnormality
CHF cardiomyopathy X-linked Dystrophinopathy HOCM :myosin heavy chain and many other genes Chest pain MI homocystinuria, thrombophilia dissection - Marfan Sudden death WPW AD type Brugada AD; SCN5A LQT syndrome AD; KVLQT1 Malignant HTN pheochromocytoma MEN I and II von Hippel-Lindau s. Neurofibromatosis type 1
Myopathy
Muscular dystrophy elevated CK, muscle wasting, biopsy showed necrosis+regeneration AD- facioscapulohumeral dystrophy AD- oculopharyngeal muscular dystrophy XR- Duchenne and Becker subtype of dystrophinopathy XR- Emery-Dreyfuss dystrophy AR- Limb girdle muscular dystrophy
Peripheral Neuropathy
Hereditary sensorimotor neuropathy (Charcot-Marie-Tooth disease) AD non-progressive absent reflexes claw hand and pes cavus deformity champagne bottle leg consistent NCV Porphyria acute intermittent porphyria AIP AD intermittent pure motor respiratory failure dark colored urine elevated plasma porphobilinogen
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A.
Pure motor neuropathy is halmark of acute intermittent porphyria (AD) B. Pure motor neuropathy is hallmark of familial amyloid neuropathy (AD) C. Pure sensory neuropathy is hallmark of metachromatic leukodystrophy (AR) D. Pure sensory neuropathy is hallmark of Charcot-MarieTooth disease (AD) E. Mixed sensorimotor neuropathy is hallmark of spinal muscular atrophy (AR)
Pathognomonic features
KF ring Wilson disease Orthodeoxia HHT Osteoma of mandible Gardner syndrome (FAP) CHRPE- FAP Oral hamartoma MEN 2B Ectopia lentis Marfan or Homocystinuria Chorea Huntington disease Primary lactic acidemia mitochondrial diseases Winged scapula - FSHD Myotonia Myotonic dystrophy (adult) Myotonia congenita (children)