A few inborn errors

1. A few inborn errors Bruce R. Wall, MD, FACP October 10, 2005

2. Contents: • Von Hippel-Landau disease • Alport’s syndrome (hereditary nephritis) • Fabry’s disease • Sturge Weber disease • Tuberous sclerosis • AD-PCKD • Too much… • Brief mystery case

3. Baseball season: famous quotes • “It ain’t about the heat, it’s the humility” • “He hits from both sides of the plate. He’s amphibious.” • “Baseball is 90% mental. The other half is physical.” Yogi Berra

4. More baseball quotes • “I never questioned the integrity of an umpire… their eyesight, yes…” Leo Durocher • “About the only problem with success is that is does not teach you how to deal with failure” Tommy Lasorda • “I think the good Lord is a Yankee” Mariano Rivera • “You can only milk a cow so long, then you’re left holding the pail” Hank Aaron, retirement party 1976

5. Recent admission • 60 yo WM with known von Hippel Landau • Previous native nephrectomy for RCC • Progressive CKD related to diabetes • Previous CNS screen (CT scan) negative for hemangioblastoma • No sign of episodic hypertension/pheo • No recent imaging of remaining kidney • Does he need bilateral nephrectomy??

6. History • 1894: Von Hippel, German opthalmologist, recognized familial nature of retinal hemangioblastoma • 1896: Arvid Landau, Swedish opthalmologist, added cerebellar and retinal hemorrhages – “angiomatosis of the central nervous system” • (noted renal and pancreatic involvement) • 1964: landmark paper from Melmon and Rose codified term VHL disease

7. Clinical features of VHL • Inherited autosomal dominant syndrome with a variety of benign and malignant tumors • 1 in 36,000 newborns • Hemangioblastomas, including retinal angiomas • Clear cell renal cell carcinomas (RCCs) • Pheochromocytoma • Endolymphatic sac tumor of the middle ear • Serous cystadenomas/neuroendocrine tumor of pancreas • Papillary cystadenomas of epididymis/broad ligament • Median actuarial survival was 49yrs; death from RCCs • Type I do not develop pheochromocytoma • Type II do have pheochromocytoma, +/- RCCs

8. Molecular pathogenesis of VHL • “Two hit model” with germline mutation that inactivates one copy of VHL gene in all cells • Gene whose normal function is regulate cell growth • Disease occurs with loss of expression of the second (normal allele) from either somatic mutation or hypermethylation of its promoter • VHL gene has been mapped to chromosome 3p25 and cloned • Gene product, pVHL, functions as tumor suppressor protein

9. Improving survival in VHL • Improved understanding of natural history of VHL-associated tumors • Surveillance strategies have led to detection of small asymptomatic tumors, prior to metastatic disease • Renal-sparing surgery in RCC decreases ESRD

10. Hemangioblastoma • Most common lesion; 60-85% of VHL pts; mean diagnosis @ 29yrs of age • Conversely - among pts with HemangioB - 25% have VHL and 75% cases are sporadic • Well-circumscribed, capillary rich benign neoplasm cause pressure via hemorrhage • Opthalmoscopy + fluorescein angiograpy (not CT) • In VHL pts, HemangioB tend to be infratentorial and multiple (160pts: total of 655 tumors, including spinal cord, cerebellum and brain stem) • Management: can be dormant, unpredictable, +/- phases of accelerated growth • Stereotactic radiosurgery plus conventional radiation play a role in lesions not accessible to surgery

11. Retinal angiomas • Hemangioblastomas that develop in the retina or optic nerve • Affect 60% of VHL patients, often multifocal, and bilateral • Untreated causes hemorrhage, detachment, and loss of vision • VHL pts are younger (age 18), average 4 tumors • Laser photocoagulation and cryotherapy are effective > 70% (except optic nerve) • XRT may have a role for salvage; VEGF receptor inhibitors are being studied

12. Renal cell carcinoma • 60% VHL pts develop multiple cysts & RCC • All VHL RCC are clear cell tumors (not papillary, chromophobe, or oncocytic histology) • Mean age of onset 44 years; 70% of patients surviving to age 60 • Multicentric, bilateral, not restricted to cysts • Therapeutic approach to VHL-associated RCC has shifted from radical nephrectomy to renal sparing surgery

13. Renal sparing approach • Improved imaging modalities: CT, MRI, US • Solid renal tumors < 3cm have low metastatic potential, and can be monitored • Partial nephrectomy as effective as total nephrectomy for early RCC • Laparoscopic cryoablation or radioablation in patients with mulitple or bilateral tumors • 85% develop new renal tumors by 10yrs (LC) • Transplantation in VHL post bilat nephrectomy is ok; no increased ‘tumorogenesis’ despite meds

14. Pheochromocytoma • Pheo can be sporadic in VHL, MEN 2, neurofibromatosis 1, succinate DeHYase Def • For VHL type II is subdivided based upon risk of RCC: Type IIA and IIB : low and high% of RCC • Type IIC have pheochromocytoma without RCC • Pheochromocytoma in VHL occur in younger pts, mulitple, extraadrenal, less sxs, difficult to Dx • NIH study: 64pts = 106 tumors; 12% extraadrenal • Mayo : 109pts = 20 tumors; 15% extraadrenal 33% failed evidence of catecholamine production

15. Endolymphatic sac tumors of the middle ear • Papillary cystadenomas are highly vascular lesion within middle ear • Occur at younger age; often bilateral • Common symptoms: hearing loss, tinnitus, vertigo, and facial muscle weakness • Generally slow growth rate; primary therapy is surgical • Radiosurgery may have a role

16. Pancreatic tumors • Common in pts with VHL • Multicenter study of 158 pts: 77% pancreatic lesions – cysts, adenomas, neuroendocrine tumors • Mostly asymptomatic, rarely pancreatitis • Neuroendocrine tumors can metastasize and produce secreted peptides (VIP,insulin) • Surgery is primary form of therapy

17. Papillary cystadenomas of epididymis or broad ligament • Single epididymal cyst is common in general population (does not mean pt has VHL) • Bilateral epididymal cysts are almost pathognomonic of VHL • No treatment is required • In women, symptoms may include pain and menorrhagia

18. Diagnosis: autosomal dominant disease • Clinical Dx based on finding TWO VHL-associated tumors • Genetic testing (DNA sequencing and quantitative Southern blot of VHL gene): 100% sensitive and specific • Germline mutations in VHL gene can be inherited or present de novo (20% of VHL kindreds) • Somatic mosaics: mutation occurs during embryonic development after fertilization; pt may present with classic VHL, yet mutation may not be detectable in peripheral blood (risk of transmission to children < 50%) • Counseling: VHL family Alliance (www.vhl.org)

19. Surveillance protocols: • Infants and children < age 11: annual retinal exam and plasma catecholamines • Adolescents > age 11: Plasma catecholamines and abd CT with contrast plus retinal exam plus MRI brain and spine with gadolinium • Adults: catecholamines, abd CT, retinal exam, MRI of CNS, MRI of kidneys, baseline ENT exam with audiometry

20. Genetics of PCKD: “nice gene” • Occurring in 1 in every 400 to 1000 births • < 50% will be diagnosed (clinically silent) • Most families abnormal chromosome 16 (called PKD1 locus) • Other gene is on chromosome 4 (PKD2 locus) • PKD1 96% of North America; 85% of Europe • Both encode proteins AKA “polycystin I & II” • PKD1 gene is adjacent to gene of Tuberous sclerosis (TSC2), associated with cyst formation (angiomyolipoma) • Genotype/phenotype correlation with PKD1 & 2 “unclear”

21. Polycystin 1 • Localized in renal tubular epithelia, hepatic ductules, pancreatic ducts (all sites in PCKD) • Integral membrane protein • Less abundant in adult than fetal epithelia • Overexpressed in most cysts in kidney from PCKD patients • Cause abnormalities in renal cilia • Induce cell cycle arrest • Why is there variable phenotypic expression? • Defect is present in 100% of cells, yet only 10% of tubules form cysts… (second hit hypothesis?) • Therefore – mechanism of cyst formation and growth is unclear (abnormal differentiation or cell maturation)

22. Diagnosis and screening for PCKD • Easy diagnosis in overt disease: flank pain, positive family history, CRI, large kidneys with multiple bilateral cysts on CT or sono • Cysts in liver, pancreas, and spleen • What do you do with otherwise unexplained CRI, hematuria, with negative family hx? • Acquired cystic disease of the kidney

23. Mystery case • 18 yo WF noted to have minimal proteinuria and microscopic hematuria @ 3rd trimester • Abnormal urinalysis persisted post delivery • 24 hour urine protein 800mg per day; GFR estimation of 90ml/hr • During 2nd pregnancy at age 25 yrs: abn UA with 1200mg proteinuria with creatinine clearance of 82ml/hr • Negative serology for hepatitis B, lues, SLE, myeloma, Wegener’s, and VHL… • Diagnostic test was performed

24. Thin basement membrane diseaese • Benign familial hematuria – relatively common (autosomal dominant inheritance) • GBM decreased to 150-225nM vs 400nM • Along with IGA – common cause of asymptomatic hematuria • Heterozygous defect in COL4A3 or A4 (alpha-4 chains of type IV collagen) • Discovered via work up of microscopic hematuria (normal urine protein, BP, GFR) • Rare episodes of gross hematuria and flank pain from hypercalciuria or hyperuricosuria rather than GBM changes • Since GFR is usually normal, renal biopsy not done

25. Thin basement membrane disease • Hematuria represents and exaggeration of the normal process of naturally occurring leaks in the GBM • No extra renal manifestations: hearing loss, ocular abnormalities • Early renal biopsy difficult to distinguish from hereditary nephritis • Screen first degree relatives (autos dominant inheritance) – look for father to son inheritance, which is not seen in X linked nephritis (alport’s) • Rarely may lead to progressive CKD (?FSGN)