A few inborn errors

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A few inborn errors

• Bruce R. Wall, MD, FACP
• October 10, 2005

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Contents

• Von Hippel-Landau disease
• Alports syndrome (hereditary nephritis)
• Fabrys disease
• Sturge Weber disease
• Tuberous sclerosis
• AD-PCKD
• Too much
• Brief mystery case

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Baseball season famous quotes

• It aint about the heat, its the humility
• He hits from both sides of the plate. Hes
  amphibious.
• Baseball is 90 mental. The other half is
  physical.
• Yogi Berra

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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 youre
  left holding the pail Hank Aaron,
  retirement party 1976

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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??

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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

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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

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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

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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

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Hemangioblastoma

• Most common lesion 60-85 of VHL pts mean
  diagnosis _at_ 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

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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 gt 70 (except optic nerve)
• XRT may have a role for salvage VEGF receptor
  inhibitors are being studied

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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

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Renal sparing approach

• Improved imaging modalities CT, MRI, US
• Solid renal tumors lt 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

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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

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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

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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

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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

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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 lt 50)
• Counseling VHL family Alliance (www.vhl.org)

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Surveillance protocols

• Infants and children lt age 11 annual retinal
  exam and plasma catecholamines
• Adolescents gt 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

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Genetics of PCKD nice gene

• Occurring in 1 in every 400 to 1000 births
• lt 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

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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)

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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

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Mystery case

• 18 yo WF noted to have minimal proteinuria and
  microscopic hematuria _at_ 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, Wegeners, and VHL
• Diagnostic test was performed
  

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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

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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 (alports)
• Rarely may lead to progressive CKD (?FSGN)