Medical Genetics

1. Medical Genetics

2. Autosomal Dominant Dz’s • Neurofibromatosis 1 (NF1/von Recklinghausen’s dz) • Genetics and Cell Level: • Mutation on chromosome 17q11 (long arm of 17) • This neurofibronin gene is a negative regulator of Ras oncogene (Increases incidence of cancers like Juvenile myelomonocytic leukemia and Malignant Nerve Sheet Tumor

3. Neurofibromatosis 1 (NF1/von Recklinghausen’s dz) • Clinical Presentation: café-au-lait spots • neural tumors • Lisch nodules (pigmented iris hamartomas) • Misc info: • Increased incidence of Optic Gliomas, pheochromocytomas, susceptibility to tumors, and skeletal disorders

4. NF1 Café Au lait spots Lisch Nodule

5. Autosomal Dominant Dz’s • Neurofibromatosis 2 (NF2) • MISME Multiple inherited Schwanomas, Meningeomas and Ependymomas • Genetics and Cell Level: • Mutation on chromosome 22q12 • Merlin gene

6. Autosomal Dominant Dz’s • Neurofibromatosis 2 (NF2) Clinical Presentation: • Bilateral acoustic neuromas on CN8 is the diagnostic • Tumors may cause tinnitus, hearing loss, balance problems, vertigo, etc. • Juvenile Subscapular Cataract • Brain and other crainial nerve tumors: Schwanomas, meningiomas, astrocytomas • Spine; astrocytomas and ependymomas. • If unilateral acoustic neuroma with meningioma, glioma , schwanoma, Cataract or First degree relative with NF II

7. NF-2 may be inherited in an autosomal dominant fashion, as well as through random mutation

8. Question • A 27-year-old Caucasian man presents for a routine visit to his primary care physician. He does not have any complaints at this time. On physical exam he is noted to have numerous firm, rubbery nodules of varying sizes on his back (see Figure A). He also has small darkly pigmented spots on his irises as well as a hyperpigmented, macular skin lesion measuring 3x5 cm on his right medial thigh.

9. Which of the following is a complication of this patient's genetic condition? 1. Bilateral acoustic schwannomas 2. Cardiac rhabdomyomas 3. Optic gliomas 4. Retinal hemangioblastomas 5. Renal angiomyolipomas

10. Autosomal Dominant Dz’s • Tuberous Sclerosis • Genetics and Cell Level: • mutation of either of two genes, TSC1 and TSC2 • code for the proteins hamartin and tuberin, respectively. • These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation • causes benign tumors called as HAMARTOMAS to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin.

11. Most common cause of Morbidity in Tuberous Sclerosis is Seizures • Mostly patient present with a type of seizures called as infantile spasm • hypsarrythmia can be seen on EEG • Rx with ACTH therapy to reduce CRH levels • CRH is known to have excitatory physiological actions on neurons and can induce seizures

13. Autosomal Dominant Dz’s • Tuberous Sclerosis

14. Tuberous Sclerosis: facial angiofibromas in characteristic butterfly pattern Ash Leaf Spot Adenoma Sebaceum

15. Autosomal Dominant Dz’s • Von Hippel-Lindau disease • Genetics and Cell Level: • Deletion of VHL gene (tumor suppressor) on chromosome 3, results in expression of  hypoxia inducible factor 1α (HIF1α) and activation of angiogenic growth factors • Phenotypic Traits: • Hemangioblastomas of retina/cerebellum/medulla • About ½ of affected develop multiple renal cell carcinomas and other tumors • Pheochromocytomas • Clinical Presentation: miscellaneous can be discomfort from growing tumors or blindness 2/2 tumors in retina

16. Question • A 35-year-old man presents to his primary care physician complaining of blood in his urine. He has also has had changes in his vision over the last several months. He reports a family history of renal cancer. The patient undergoes an abdominal CT, which shows lesions suspicious for renal cell carcinoma on both kidneys. MRI of the brain shows the findings in Figure A. Fundoscopic examination reveals the finding shown in Figure B. B

17. Which of the following genetic defects does this patient most likely have?         1. Mutation on chromosome 3 2. Mutation on chromosome 22 3. Mutation on chromosome 17 4. Increased trinucleotide repeats 5. Mutation on chromosome 16

18. Autosomal recessive

19. Autosomal Recessive Dz’s • a1-antitrypsin deficiency (14q32.1) • Genetics and Cell Level: • A1AT is Serine protease inhibitor produced by the liver and protects the lungs from Neutrophil Elastase

20. It is a genetically inherited autosomal-codominant condition with more than 120 alleles identified . •  There are several forms and degrees of deficiency; the form and degree depend on whether the sufferer has one or two copies of a defective allele. In the literature it has been described as either a recessive or co-dominant trait as there is some evidence that smoking heterozygotes are affected.

21. Autosomal Recessive Dz’s • a1-antitrypsin deficiency (14q32.1) Clinical Presentation: • Less A1AT in blood to neutralize the effect of elastase enzyme secreted by neutrophil. The elastase dissolves alveolar septae resulting in COPD • Mutant A1AT protein is not secreted into the blood stream. It accumulates in the liver cells , resulting in cirrhosis in early adulthood • High risk of hepatocellular carcinoma • Misc: • Important when presented with pt who has COPD and has only smoked for a few years

22. Autosomal Recessive Dz’s • Cystic Fibrosis: this one is important • Genetics and Cell Level: • More than 900 genetic mutations in CFTR( cystic fibrosis transmembrane conductance regulator ) gene are known to cause Cystic Fibrosis • CFTR gene mutation on chrom 7 DF508 classically ( the codon for phenylalanine at position 508 ) . • Defective Cl channel

23. In Lungs Normal Cystic Fibrosis

24. In Lungs Normal Cystic Fibrosis

25. In Lungs Normal Cystic Fibrosis

26. In Lungs Normal Cystic Fibrosis

27. In Lungs Normal Cystic Fibrosis

28. Same thing in Pancreas and Vas Deference Normal Cystic Fibrosis

29. Autosomal Recessive Dz’s • Cystic Fibrosis: this one is important • Clinical Presentation: secretion of abnl thick mucus into lungs, pancreas, and liver • Pulm infections (P. aeruginosa and S. aureus) • Chronic bronchitis, bronchiectasis, pancreatic insufficiency, male infertility (absence of vas deferens)

30. Gives rise to hypertonic sweat

31. Autosomal Recessive Dz’s • Cystic Fibrosis (cont.) • Diagnosis: • increased concentration of Cl in sweat test ( 1st test to be done ) • Genetic Testing is not sensitive (Because till now we have mapped more than 900 mutation in CFTR gene linked to cystic fibrosis and many more may be there which we don’t know) • Nasal Potential Test is confirmatory (Confirmatory test )

32. Symptoms • Symptoms respiratory symptoms are more prominent in adulthood • recurrent pulmonary infections • Pseudomonal spp and S. aureus are most common • chronic sinusitis • chronic, productive cough • dyspnea on exertion • hemoptysis

33. Symptoms • Gastrointestinal symptoms are more prominent in infancychronic, frequent diarrhea • greasy stool with flatulence from malabsorption secondary to pancreatic insufficiency • can lead to rectal prolapse • meconium ileus( It is extremely sticky and causes the bowel to be blocked at birth) in infants (15%) • pancreatitis 

34. Symptoms • Other symptoms • calcium oxalate kidney stones • secondary to fat malabosorption • For Patients with Calcium Oxalate Kidney Stones advise decreased Calcium in Diet.

35. Autosomal Recessive Dz’s • Treatment: • N-acetylcysteine to loosen mucus plugs • Nasal Irrigation of Sinuses • Adequate hydration • Antibiotics especially against Pseudomonas Aeruginosa (inhaled Tobramycin) and others • Pancreatic Enzymes • Misc: • If presented with . . . THINK CF! • newborn with meconium ileus or failure to thrive • Fat soluble vitamin deficiency • Pancreatic insufficiency

36. Question • A 4-year-old Caucasian girl previously diagnosed with asthma presents with recurrent sinusitis, otitis media, and clubbing of the nail bed. Family history is significant for a distant cousin with cystic fibrosis. A "sweat test" is performed and comes back normal.

37. What additional diagnostic test would be helpful in establishing a diagnosis? 1.Nasal transepithelial potential difference 2. Chest radiograph 3. Skeletal survey 4. Genetic Analysis 5. Urinalysis • In cystic fibrosis the potential difference between interstitial fluid and the surface of respiratory and sweat duct epithelia is abnormally large

38. Question • A newborn is found to have cystic fibrosis during routine newborn screening. The parents, both biochemists, are curious about the biochemical basis of their newborn's condition. The pediatrician explains that the mutation causing cystic fibrosis affects the CFTR gene which codes for the CFTR channel.

39. Which of the following correctly describes the pathogenesis of the most common CFTR mutation? 1. Insufficient CFTR channel production 2. Defective post-translational glycosylation of the CFTR channel 3. Excess CFTR channel production 4. Defective post-translational hydroxylation of the CFTR channel 5. Defective post-translational phosphorylation of the CFTR channel

40. Question • A child with which of the following diseases would have the highest morbidity from being outside during a hot summer day? • 1. Tay-Sachs disease 2. Cystic fibrosis 3. Cerebral palsy 4. Down syndrome 5. Asthma

41. Question • A 19-year-old Caucasian male underwent a bilateral lung transplant. His past medical history is significant for several severe respiratory infections. A sweat test found chloride levels of 70 mmol/L, and digital clubbing was present on physical examination. Which of the following is most likely to also be present in this patient • 1. Hypertrophic cardiomyopathy 2. Azoospermia 3. Ghon complex 4. Low serum alpha1-antitrypsin levels 5. Mitral valve prolapse

42. Sweat Test Reference Ranges • For infants up to and including 6 months of age, a chloride level of: • Equal to or less than 29 mmol/L = CF is very unlikely • 30 – 59 mmol/L = intermediate means that CF is possible • Greater than or equal to 60 mmol/L = CF is likely to be diagnosed • For people older than 6 months of age, a chloride level of: • Equal to or less than 39 mmol/L = CF is very unlikely • 40 – 59 mmol/L = intermediate means that CF is possible • Greater than or equal to 60 mmol/L = CF is likely to be diagnosed

43. Autosomal Recessive Dz’s • PKU • Genetics and Cell Level: • Defect in phenylalanine hydroxylase which converts Phenylalanine to Tyrosine

44. Autosomal Recessive Dz’s • PKU • Clinical Presentation: The mother's body is able to break down phenylalanine during pregnancy, infants with PKU are normal at birth • Mental retardation & seizures, • Albinism • “musty odor” to urine and sweat • Misc: • Very treatable diet low in Phe and high in Tyr • Newborn screening is Mandatory!

45. END PART II