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Common Genetic Diseases: Case Approach

Chanin Limwongse, MD Dept of Medicine, Faculty of Medicine Siriraj Hospital

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

Q:
A. B. C. D. E.

Which is the least likely to be hereditary ?

Coronary artery disease Canada-Cronkhite syndrome Gluten enteropathy celiac disease Mixed hyperlipidemia SLE

Category of genetic disorders


Chromosomal aberrations numerical : trisomy, monosomy, etc structural : translocation, deletion, etc contiguous gene syndrome Single gene disorders AD,AR,XD,XR,mitochondrial Multifactorial diseases Atypical inheritance bigenic imprinting disorders

Q:
A. B. C. D. E.

The most likely mode of inheritance is (are)


Autosomal dominant Autosomal recessive X-linked recessive X-linked dominant A or C
P

Autosomal dominant inheritance


Affected = heterozygote Affected in both males and Females Multiple generations Transmission through both sexes 50% recurrence risk

New mutation Incomplete penetrance Gonadal mosaicism

Autosomal dominant sex-limited inheritance


Affected = heterozygote Affected in only males or Females Multiple generations Transmission through both sexes skipping in one gender 50% recurrence risk in only one gender

New mutation Incomplete penetrance Gonadal mosaicism

Autosomal recessive inheritance


Affected = homozygote Affected in both males and Females Single generations 25% recurrence risk in siblings

Pseudodominant Consanguinity

X-linked recessive inheritance


Affected = hemizygote Affected in males and rarely females Multiple generations 25% recurrence risk in offsprings of female carrier

Mitochondrial (maternal) inheritance


Affected = homoplasmy or heteroplasmy Affected in both sexes Multiple generations Transmitted only through females

Q:
A. B. C. D. E.

Mendelian forms of following disorders are well known except

Diabetes mellitus type 2 Senile dementia Hyporeninemic hypertension Distal IP osteoarthritis Coronary heart disease

Q:

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

Marfan syndrome- AD,

new mutation 50%

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

Q:
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

Q: Adults with Down syndrome are prone


to all of the following except ? A. B. C. D. E. Premature myocardial infarction Dementia of Alzheimer type Acute leukemia Hypothyroidism Spinal cord injury

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

Q:

Growth hormonal supplement in Turner syndrome should

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

Q:
A. B. C. D.

A female with hemophilia A is least likely to be ?

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

Q: A male with 47,XXY should


A. B. C. D. E. Be mentally retarded Be infertile Be an aggressive male Have gynaecomastia Have two Barr bodies in buccal smear

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

Which of the followings is not true regarding treatment of Klinefelter syndrome


A. B. Assisted reproduction could be attempted Hormone replacement can result in increased sperm count C. Secondary sexual characterisitics can be enhanced D. Lifelong hormonal treatment may not be necessary E. Libido is improved with hormone implementation

Q:

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

Q:

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

Sturge Weber syndrome


Almost always sporadic Port wine stain unilateral Nevus flammeus Cerebral gyral calcification Adult issues: epilepsy W/U: CT brain Rx: anti-epileptic drug

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

G1: TSC1 9q P1: Hamartin G2: TSC2 16p P2: Tuberin

Klippel Trenaunay Weber syndrome


Unilateral AVM Hemihypertrophy of affected side No malignancy risk Sporadic in most cases No CNS symptom

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, 40 Leukemia, 33 Osteosarcoma, 42

Breast, 35 Brain tumor, 32 Soft tissue sarcoma, 7 Leukemia, 6 G:TP53 17p P:p53

Cluster of Cancer in hereditary cancer syndromes


FAP: colon, duodenum, ampulla of Vater, stomach HNPCC: colon, urinary, endometrial, GI tract, brain HBOC: breast, ovarian, male breast, prostate, pancreas VHL: cerebellar hemangioblastoma, renal cell CA, pheochromocytoma, paraganglioma Turcot: brain, colon Muir Torre: acanthoma, colon PJS: colon, pancreas, sex cord LFS: brain, sarcoma, leukemia, adrenal cell CA, breast Familial melanoma: melanoma, pancreas

Q:
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

Have Have Have Have Have

Q:

Indicated testing for HNPCC family members include all except

A. Urine cytology annually B. Sigmoidoscopy biannually C. Pelvic exam with endometrial aspirate annually D. Sputum cytology annually E. PSA annually

Familial adenomatous polyposis- AD


Adenomatous polyposis Site: colon to rectum, sparse elsewhere Risk of malignancy : 100% CHRPE pathognomonic Symptom: tumor W/U: GIFT, biopsy Rx: total colectomy with colostomy, proctocolectomy with ileoanal anastomosis or ileal pouch ileorectal anastomosis, COX2 inhibitor (celecoxib preferred)

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)

Q:

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

G:STK11 19p P:serine/threonine kinase

Spinobulbar muscular dystrophy


SBMA or Kennedy disease CAG expansion in androgen receptor gene Proximal weakness, gynecomastia, hypogonadism XR inheritance DNA test available Rx: testosterone if necessary

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

G:CuATPase 13p P:Copper ATPase

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

Respiratory, GI & Hematologic abnormality


Hemoptysis AVM- Osler Weber Rendu or hereditary hemorrhagic telangiectasia (HHT) Lung lesion on CXR AVM- Osler Weber Rendu or hereditary hemorrhagic telangiectasia (HHT) Spontaneous pneumothorax Marfan, tuberous sclerosis GI abnormality bleeding- HHT polyposis- Familial adenomatous polyposis, Peutz-Jeghers S., Turcot S. jaundice/cirrhosis Wilson disease, hereditary hemochromatosis Hematologic abnormality anemia thalassemia bleeding- hemophilia, von Willebrand disease

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

Q:
A.

Which of the following is true regarding a male with symmetric polyneuropathy ?

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)

Motor neuron disease Spinal neuropathy


Spinal muscular atrophy - AR usually infantile onset absent reflex normal or minimally elevated CK group atrophy on biopsy consistent EMG/NCV DNA test available Spinobulbar muscular atrophy (Kennedy disease)- XR orofacial fasciculation gynecomastia, hypogonadism DNA test for CAG expansion in androgen receptor available

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)

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