Transcript A few inborn errors

A few inborn errors
Bruce R. Wall, MD, FACP
October 10, 2005
Contents:
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Von Hippel-Landau disease
Alport’s syndrome (hereditary nephritis)
Fabry’s disease
Sturge Weber disease
Tuberous sclerosis
AD-PCKD
 Too much…
 Brief mystery case
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
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
Recent admission
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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??
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
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
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
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
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
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
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
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
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
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
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
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
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)
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
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”
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)
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
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
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
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)