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 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 @ 3 rd trimester  Abnormal urinalysis persisted post delivery  24 hour urine protein 800mg per day; GFR estimation of 90ml/hr  During 2 nd 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)