Board Simulation in Genetic Diseases Franklin A. Michota, MD, FACP, FHM Associate Professor of Medicine Cleveland Clinic Lerner College of Medicine at Case Western Reserve University Director of Academic Affairs Department of Hospital Medicine Cleveland Clinic

Medical Genetics • Most diseases encountered in the practice of medicine have genetic components in both cause and pathogenesis • Clues to genetic disorders are often discovered during routine health care visits • Expanding availability of testing for “genetic diseases”

“Genetic” Testing • Cytogenetic testing – Chromosomal analysis

• Molecular genetic testing – PCR, southern blot, restriction enzymes, and sequencing

• Biochemical testing – Metabolite analysis

Please examine this karyotype.

Which of the following photographs best represents the karyotype shown? A.

B.

C.

Klinefelter’s Syndrome XXY

Turner Syndrome X,0

Patterns of Transmission Johann Gregor Mendel

Autosomal Dominant Autosomal Recessive X-linked Dominant X-linked Recessive

Case Questions

1. A 44 y/o man presents to the office with intermittent gross hematuria. He is very concerned about his health following the recent death of his younger brother from a subarachnoid hemorrhage. Family history is remarkable for “kidney disease.”

On exam he is hypertensive, with a mitral regurgitation murmur. His urinalysis has >25 RBC’s, without WBC’s, casts, protein, or stones. His BUN/Cr = 31/2.1 Which of the following statements regarding this patient’s condition is FALSE?

A. Cardiovascular disease is the leading cause of death. B. Symptoms typically present in the second decade. C. Urinary tract infections with nephrolithiasis are common D. Both autosomal dominant and autosomal recessive forms exist E. MRI screening should be offered to affected patients with a family history of ICH.

Polycystic Kidney Disease

Autosomal Dominant

Multigenerational involvement with consistent vertical transmission, equal sex involvement

Polycystic Kidney Disease • The most common hereditary renal disease – Autosomal dominant PKD (PKD1, PKD2, ?PKD3) • Polycystin - regulates differentiation of epithelial cells – Autosomal recessive PKD is very rare

• Wide phenotypic variation • Systemic disorder with renal and extrarenal manifestations • Represents 10% of ESRD cases – Kidney failure generally occurs around age 55

Polycystic Kidney Disease • Cysts are seen by age 25 with CT or U/S – symptoms typically present in the 4th-5th decade • FLANK PAIN + HEMATURIA

• UTI’s and stones are common • Other associations include diverticulosis, cardiac valve myxomatous degeneration, intracranial aneurysms, and hypertension – –

HTN and LVH are common early complications Cardiovascular disease is the leading cause of death

Polycystic Kidney Disease

MRI screening should be offered to APKD patients with a history of brain hemorrhage

2. A 56 y/o white male with a history of pseudogout and NIDDM, presents with fatigue and weight loss. His family history is significant for diabetes, liver cancer, and arthritis. On exam, he is noticed to have a mildly enlarged liver, palmar erythema, and knee effusions.

Chemistries reveal elevated ALT and AST, bilirubin = 2.0 mg/dl, INR = 2.3, and a ferritin = 2500 ng/ml

The treatment most likely to decrease this patient’s risk for hepatocellular carcinoma is which of the following?

A. B. C. D. E.

Ursodeoxycholic acid Repeated phlebotomy Penicillamine Deferoxamine None of the above

Hereditary Hemochromatosis • One of the most common autosomal recessive disorders – European ethnic predominance (8/1000) – expressed 5-10x more frequently in men – 25%-50% will develop a life-threatening complication • HFE gene (HFE1, HFE2, HFE3) • The first manifestation of the disease is an elevated serum transferrin saturation

Hereditary Hemochromatosis Hepatomegaly Arthropathy Skin pigmentation Diabetes mellitus Cardiac dysfunction Hypogonadism

Hereditary Hemochromatosis Hepatomegaly Arthropathy Skin pigmentation Diabetes mellitus Cardiac dysfunction Hypogonadism

Treat

McCarthy et al. Clev Clin J Med. March 2002

Treat

Hemochromatosis • Treatment is targeted at reducing iron stores – most common cause of death in treated patients with cirrhosis is hepatocellular carcinoma

• Treatment does not reverse arthropathy or risk of hepatocellular carcinoma (30%)

Hemochromatosis • Standard for diagnosis includes liver biopsy with quantitation of hepatic iron stores

Genetic Testing • Known mutations of the HFE gene are C282Y and H63D • 90% of patients with HHC are C282Y/C282Y or C282Y/H63D • No genetic test for H63D available • New autosomal dominant form of HC – Non-HFE HC – SLC11A3 mutation

• Testing benefits – Differentiate HHC from other primary iron overload disorders – May clarify diagnosis in setting of contradictory serum results – May obviate the need for liver biopsy – Prognostic

Genetic Testing • HFE HC – Early increase in transferrin saturation before increase of serum ferritin – No haematological abnormalities – Early parenchymal cell iron load – During phlebotomy, serum ferritin declines in parallel with decrease of transferrin saturation and haemoglobin

• Non HFE HC – – – –

Early increase of ferritin before increase of transferrin Hypochromic anemia with normal or high serum ferritin Early reticuloendothelial cell iron load During phlebotomy, low transferrin saturation and low Hgb may be reached rapidly despite high-normal serum ferritin

Wilson’s disease Kayser-Fleischner Rings

Blue-grey nails

3. A 19 y/o black male patient presents to the ED with severe abdominal pain and jaundice. Past medical history is unremarkable, although his mother reports “growing pains” as a child. Further questioning reveals the patient is adopted. He is febrile and tachycardic. Abdomen is diffusely tender. There is no rebound and positive bowel sounds are present throughout. A skin ulcer is noted on the left lower extremity.

Na – 141 K – 4.3 Cl – 94 CO2 – 28 BUN – 35 Cr – 1.1

WBC –17.45 Hgb – 6.1 HCT – 23.6 Plt – 455,000 AST - 35 Tbili – 4.3

Which of the following statements regarding this patient’s condition is TRUE?

A. Infection is the most common cause of death in adults. B. In the United States, few patients survive beyond the 5th decade. C. There is a selective advantage from Plasmodium vivax malaria. D. Transmission is autosomal dominant with variable penetrance. E. Symptoms do not present until the patient is older than 6 months.

Sickle Cell Disease • The most common heritable hematologic disorder affecting humans – Autosomal recessive inheritance – African ethnic predominance – prevalence = 1/500, carriers = 1/10

• Abnormal hemoglobin (HbS) – differs from normal HbA by substitution of valine for glutamic acid

Upon deoxygenation, HbS causes polymerization Time to polymerize varies among RBCs and the concentration of HbS Once polymers are detected, they accumulate rapidly Sickling may be irreversible HbF is protective against polymerization

Sickle Cell Disease • Vasoocclusive disease – microinfarcts (painful crises, bone, skin, CNS) • painful crises occur in 70% of patients • chest, back, abdomen, or extremities

– macroinfarcts (lung, kidney, spleen)

• Anemia – aplastic crisis (folate deficiency, infection) – hemolysis

• Chronic organ damage

Chronic Organ Damage • Autosplenectomy • Cerebral hemorrhage and “moya-moya” vascular abnormalities • Growth disturbances, osteopenia, avascular necrosis (hips and shoulders), osteomyelitis • Vitreal hemorrhage, retinal detachment • Hyposthenuria, hematuria, proteinuria, RTA type-4, priapism • Pulmonary hypertension

Acute Chest Syndrome

Fever Chest pain Lung infiltrates Hypoxia Cough

In regards to treatment, which of the following statements is TRUE?

A. Exchange tranfusions are superior to simple transfusions. B. In pregnancy, transfusion is required to keep the Hgb>10. C. Prior to general anesthesia, transfusions are indicated to increase the HCT to 30 percent. D. Hydroxyurea should be prescribed to all sickle cell anemia patients. E. Bone marrow transplantation can reverse existing organ damage.

Transfusion Therapy • Straight transfusion is best used used when the Hgb < 8-9 mg/dL – Increasing Hgb to over 11mg/dL may cause complications due to viscosity – Exchange transfusion is better when the Hgb concentration is high

• Indications – Acute chest syndrome, heart failure, MODS, stroke, splenic sequestration, aplastic crisis, priapism, general anesthesia, symptomatic anemia

4. A thin 21 y/o white female presents to the ED with acute onset shortness of breath.

She states that she was a “sickly” child, with numerous episodes of sinusitis and bronchitis, and that she has a chronic productive cough. Which of the following statements regarding this patient’s condition is FALSE?

A. By 2005, adults will make up >40% of all patients with this disease. B. Pneumothorax and female sex are poor prognostic indicators. C. Pseudomonas aeruginosa is associated with rapid deterioration in lung function. D. Two-year survival in lung transplant patients exceeds 50% E. Allergic bronchopulmonary aspergillosis has been noted in 10% of patients

Cystic Fibrosis

Cystic Fibrosis • Most common lethal autosomal recessive disorder among whites in the U.S. – prevalence is 1/2000, with 1/20 carriers – 3% patients are diagnosed as adults – European ethnic predominance

• Monogenetic disorder that presents as a multi-system disease – CFTR gene on chromosome 7

Autosomal Recessive

Skipped generations, affected individuals in the same generation, equal sex involvement

Cystic Fibrosis • In 1970, the median survival was 16 years, today it is 32 years • Among adults with CF – – – –

64% are 18-30 yrs 25% are 30-40 yrs 10% are 40-50 years 2% are over 50

• Majority of diagnoses are made in the first year of life; 4% of CF patients are diagnosed after age 18

Cystic Fibrosis • Chronic airway infection – sinusitis, cough – bronchiectasis and bronchiolectasis lead to obstructive airway disease • Pancreatic insufficiency – fat malabsorption, diarrhea, steatorrhea – biliary cirrhosis • Abnormal sweat gland and urogenital dysfunction

Cystic Fibrosis • Aggressive antibiotics – Moderate to severe symptomatic exacerbations require 2-3 weeks of intravenous therapy – Chronic suppressive antibiotic therapy • nebulized aminoglycosides have been shown to improve lung function and decrease exacerbations • trials with PO azithromycin, PO colistin, or intermittent IV antibiotics have shown some promise

Cystic Fibrosis • Inadequate trial evidence – inhaled/oral corticosteroids, oral antibiotic prophylaxis, flu or Pseudomonas vaccines, nebulized saline, NSAIDs, chest physiotherapy, enteral feeding, oral calorie supplements

A. By 2005, adults will make up >40% of all patients with this disease. B. Pneumothorax and female sex are poor prognostic indicators. C. Pseudomonas aeruginosa is associated with rapid deterioration in lung function. D. Two-year survival in lung transplant patients exceeds 50% E. Allergic bronchopulmonary aspergillosis has been noted in 10% of patients

5. A 43 y/o man presents for preoperative evaluation for inguinal hernia repair. He is a tall, thin man without previous medical problems. Exam displays normal vital signs, mild kyphoscoliosis, and a 3/6 holosystolic murmur at the apex radiating to the axilla.

Patient

Control

An echocardiogram is performed.

Which of the following is the most likely diagnosis? A. B. C. D. E. F.

Ehlers-Danlos, Type IV Homocystinuria Marfan syndrome Familial aortic aneurysm Ehlers-Danlos, Type VI Fragile X syndrome

Marfan Syndrome • Autosomal dominant condition with variable expression – prevalence is 1/5-10,000 – 25% arise from new mutations – FBN1 and FBN2 • Involves the musculoskeletal, cardiovascular, and ocular systems • Life expectancy is shortened by cardiovascular disease

Ehlers-Danlos

Autosomal dominant disorder with up to 15 different sub-types Type I most characterized by fragile, hyperextensible skin with hypermobile joints

Homocystinuria

Fragile X Syndrome

What is this Picture?

Which of the following diseases is most associated with this picture? Huntington Charcot-Marie-Tooth Gaucher Von Hippel Lindau Osler-Weber-Rendu Duchenne’s Dystrophy Von Recklinghausen

Von Recklinghausen Disease

Von Recklinghausen Disease

Two genetically distinct types of neurofibromatosis, both are autosomal dominant

Type 1 clinical features include café-au-lait macules, inguinal freckling, multiple neurofibromas, occasionally pheochromocytomas and scoliosis

Type 2 is associated with café-au-lait macules, acoustic neuromas with deafness, deafness nervous system gliomas and cataracts

What is this Picture?

Which of the following diseases is most associated with this picture? Huntington Charcot-Marie-Tooth Gaucher Von Hippel Lindau Osler-Weber-Rendu Duchenne’s Dystrophy

Hereditary hemorrhagic telangiectasia is autosomal dominant. Occult or overt gastrointestinal bleeding is often present. Pulmonary arterio-venous malformations are seen in 20% of patients

Osler-WeberRendu Disease

Cerebral involvement is said to affect 5-10% of patients with HHT, but a much a higher incidence is found on screening

What is this Picture?

Which of the following diseases is most associated with this picture? Huntington Charcot-Marie-Tooth Gaucher Von Hippel Lindau Fabry Disease Duchenne’s Dystrophy

Von Hippel-Lindau Disease

Autosomal dominant disorder characterized by retinal, spinal cord, and cerebellar hemangioblastomas, cysts of the kidneys, pancreas, and epididymis, pheochromocytomas, and renal cell cancers. RCC is the most common cause of death. If RCC occurs, hematuria and anemia are typical, but erthrocytosis may be seen in up to 5% of cases.

Which of the following would you expect to see in a patient with Gaucher Disease? Telangiectatic angiokeratomas Splenomegaly Dextrocardia Erythrocytosis Proteinuria

Gaucher’s Disease

Autosomal recessive lysosomal storage disorder due to deficiency of beta-glucocerebrosidase. Three types based on the presence and nature of CNS involvement. Type 1 is the most common, responds well to enzyme replacement, and is most frequent in the Ashkenazi jewish population. Untreated patients may develop hepatosplenomegaly, splenomegaly anemia, thrombocytopenia, and degenerative bone disease.

X-linked recessive; lysosomal storage disease due to deficiency of alphagalactosidase A

Fabry Disease

Clinical signs include telangiectatic angiokeratomas, acroparesthesias, cataracts, LVH, short P-R interval on EKG, and renal disease with HTN

Infiltrative cardiac disease, LVH, arrhythmias, short P-R interval on ECG

Proteinuria is common, with renal failure being the most common cause of death

We [the human race] do not have much time to prove that we are not the product of a lethal mutation. -- Science 263: 181, 1994