A few inborn errorsA few inborn errors

Bruce R. Wall, MD, FACPBruce R. Wall, MD, FACP

October 10, 2005October 10, 2005

Contents:Contents:

Von Hippel-Landau diseaseVon Hippel-Landau disease Alport’s syndrome (hereditary nephritis)Alport’s syndrome (hereditary nephritis) Fabry’s diseaseFabry’s disease Sturge Weber diseaseSturge Weber disease Tuberous sclerosisTuberous sclerosis AD-PCKDAD-PCKD

Too much…Too much… Brief mystery caseBrief mystery case

Baseball season: famous quotesBaseball season: famous quotes

““It ain’t about the heat, it’s the humility”It ain’t about the heat, it’s the humility” ““He hits from both sides of the plate. He’s He hits from both sides of the plate. He’s

amphibious.”amphibious.” ““Baseball is 90% mental. The other half is Baseball is 90% mental. The other half is

physical.”physical.”

Yogi BerraYogi Berra

More baseball quotesMore baseball quotes ““I never questioned the integrity of an umpire… I never questioned the integrity of an umpire…

their eyesight, yes…” their eyesight, yes…” Leo DurocherLeo Durocher

““About the only problem with success is that is About the only problem with success is that is does not teach you how to deal with failure” does not teach you how to deal with failure”

Tommy LasordaTommy Lasorda ““I think the good Lord is a Yankee”I think the good Lord is a Yankee”

Mariano RiveraMariano Rivera ““You can only milk a cow so long, then you’re left You can only milk a cow so long, then you’re left

holding the pail” holding the pail” Hank Aaron, retirement party Hank Aaron, retirement party

19761976

Recent admissionRecent admission

60 yo WM with known von Hippel Landau60 yo WM with known von Hippel Landau Previous native nephrectomy for RCCPrevious native nephrectomy for RCC Progressive CKD related to diabetesProgressive CKD related to diabetes Previous CNS screen (CT scan) negative Previous CNS screen (CT scan) negative

for hemangioblastomafor hemangioblastoma No sign of episodic hypertension/pheoNo sign of episodic hypertension/pheo No recent imaging of remaining kidneyNo recent imaging of remaining kidney Does he need bilateral nephrectomy??Does he need bilateral nephrectomy??

HistoryHistory

1894: Von Hippel, German opthalmologist, 1894: Von Hippel, German opthalmologist, recognized familial nature of retinal recognized familial nature of retinal

hemangioblastomahemangioblastoma 1896: Arvid Landau, Swedish opthalmologist, 1896: Arvid Landau, Swedish opthalmologist,

added cerebellar and retinal hemorrhages – added cerebellar and retinal hemorrhages – “angiomatosis of the central nervous system”“angiomatosis of the central nervous system”

(noted renal and pancreatic involvement)(noted renal and pancreatic involvement) 1964: landmark paper from Melmon and Rose 1964: landmark paper from Melmon and Rose

codified term VHL diseasecodified term VHL disease

Clinical features of VHLClinical features of VHL Inherited autosomal dominant syndrome with a variety Inherited autosomal dominant syndrome with a variety

of benign and malignant tumorsof benign and malignant tumors 1 in 36,000 newborns1 in 36,000 newborns Hemangioblastomas, including retinal angiomasHemangioblastomas, including retinal angiomas Clear cell renal cell carcinomas (RCCs)Clear cell renal cell carcinomas (RCCs) PheochromocytomaPheochromocytoma Endolymphatic sac tumor of the middle earEndolymphatic sac tumor of the middle ear Serous cystadenomas/neuroendocrine tumor of Serous cystadenomas/neuroendocrine tumor of

pancreaspancreas Papillary cystadenomas of epididymis/broad ligamentPapillary cystadenomas of epididymis/broad ligament Median actuarial survival was 49yrs; death from RCCsMedian actuarial survival was 49yrs; death from RCCs Type I do not develop pheochromocytomaType I do not develop pheochromocytoma Type II do have pheochromocytoma, +/- RCCsType II do have pheochromocytoma, +/- RCCs

Molecular pathogenesis of VHLMolecular pathogenesis of VHL

““Two hit model” with germline mutation that Two hit model” with germline mutation that inactivates one copy of VHL gene in all cellsinactivates one copy of VHL gene in all cells

Gene whose normal function is regulate cell Gene whose normal function is regulate cell growthgrowth

Disease occurs with loss of expression of the Disease occurs with loss of expression of the second (normal allele) from either somatic second (normal allele) from either somatic mutation or hypermethylation of its promotermutation or hypermethylation of its promoter

VHL gene has been mapped to chromosome 3p25 VHL gene has been mapped to chromosome 3p25 and clonedand cloned

Gene product, pVHL, functions as tumor Gene product, pVHL, functions as tumor suppressor proteinsuppressor protein

Improving survival in VHLImproving survival in VHL

Improved understanding of natural history of Improved understanding of natural history of VHL-associated tumorsVHL-associated tumors

Surveillance strategies have led to detection Surveillance strategies have led to detection of small asymptomatic tumors, prior to of small asymptomatic tumors, prior to metastatic diseasemetastatic disease

Renal-sparing surgery in RCC decreases Renal-sparing surgery in RCC decreases ESRDESRD

HemangioblastomaHemangioblastoma Most common lesion; 60-85% of VHL pts; mean Most common lesion; 60-85% of VHL pts; mean

diagnosis @ 29yrs of agediagnosis @ 29yrs of age Conversely - among pts with HemangioB - 25% Conversely - among pts with HemangioB - 25%

have VHL and 75% cases are sporadichave VHL and 75% cases are sporadic Well-circumscribed, capillary rich benign neoplasm Well-circumscribed, capillary rich benign neoplasm

cause pressure via hemorrhagecause pressure via hemorrhage Opthalmoscopy + fluorescein angiograpy (not CT)Opthalmoscopy + fluorescein angiograpy (not CT) In VHL pts, HemangioB tend to be infratentorial and In VHL pts, HemangioB tend to be infratentorial and

multiple (160pts: total of 655 tumors, including spinal multiple (160pts: total of 655 tumors, including spinal cord, cerebellum and brain stem)cord, cerebellum and brain stem)

Management: can be dormant, unpredictable, +/- Management: can be dormant, unpredictable, +/- phases of accelerated growthphases of accelerated growth

Stereotactic radiosurgery plus conventional radiation Stereotactic radiosurgery plus conventional radiation play a role in lesions not accessible to surgery play a role in lesions not accessible to surgery

Retinal angiomasRetinal angiomas

Hemangioblastomas that develop in the retina or Hemangioblastomas that develop in the retina or optic nerveoptic nerve

Affect 60% of VHL patients, often multifocal, and Affect 60% of VHL patients, often multifocal, and bilateralbilateral

Untreated causes hemorrhage, detachment, and Untreated causes hemorrhage, detachment, and loss of visionloss of vision

VHL pts are younger (age 18), average 4 tumorsVHL pts are younger (age 18), average 4 tumors Laser photocoagulation and cryotherapy are Laser photocoagulation and cryotherapy are

effective > 70% (except optic nerve)effective > 70% (except optic nerve) XRT may have a role for salvage; VEGF receptor XRT may have a role for salvage; VEGF receptor

inhibitors are being studiedinhibitors are being studied

Renal cell carcinomaRenal cell carcinoma

60% VHL pts develop multiple cysts & RCC60% VHL pts develop multiple cysts & RCC All VHL RCC are clear cell tumors (not All VHL RCC are clear cell tumors (not

papillary, chromophobe, or oncocytic papillary, chromophobe, or oncocytic histology)histology)

Mean age of onset 44 years; 70% of Mean age of onset 44 years; 70% of patients surviving to age 60patients surviving to age 60

Multicentric, bilateral, not restricted to cystsMulticentric, bilateral, not restricted to cysts Therapeutic approach to VHL-associated Therapeutic approach to VHL-associated

RCC has shifted from radical nephrectomy RCC has shifted from radical nephrectomy to renal sparing surgeryto renal sparing surgery

Renal sparing approachRenal sparing approach

Improved imaging modalities: CT, MRI, USImproved imaging modalities: CT, MRI, US Solid renal tumors < 3cm have low metastatic Solid renal tumors < 3cm have low metastatic

potential, and can be monitoredpotential, and can be monitored Partial nephrectomy as effective as total Partial nephrectomy as effective as total

nephrectomy for early RCCnephrectomy for early RCC Laparoscopic cryoablation or radioablation in Laparoscopic cryoablation or radioablation in

patients with mulitple or bilateral tumorspatients with mulitple or bilateral tumors 85% develop new renal tumors by 10yrs (LC)85% develop new renal tumors by 10yrs (LC) Transplantation in VHL post bilat nephrectomy is Transplantation in VHL post bilat nephrectomy is

ok; no increased ‘tumorogenesis’ despite medsok; no increased ‘tumorogenesis’ despite meds

PheochromocytomaPheochromocytoma Pheo can be sporadic in VHL, MEN 2, Pheo can be sporadic in VHL, MEN 2,

neurofibromatosis 1, succinate DeHYase Defneurofibromatosis 1, succinate DeHYase Def For VHL type II is subdivided based upon risk of For VHL type II is subdivided based upon risk of

RCC: Type IIA and IIB : low and high% of RCCRCC: Type IIA and IIB : low and high% of RCC Type IIC have pheochromocytoma without RCCType IIC have pheochromocytoma without RCC Pheochromocytoma in VHL occur in younger pts, Pheochromocytoma in VHL occur in younger pts,

mulitple, extraadrenal, less sxs, difficult to Dxmulitple, extraadrenal, less sxs, difficult to Dx NIH study: 64pts = 106 tumors; 12% extraadrenalNIH study: 64pts = 106 tumors; 12% extraadrenal Mayo : 109pts = 20 tumors; 15% extraadrenal 33% Mayo : 109pts = 20 tumors; 15% extraadrenal 33%

failed evidence of catecholamine productionfailed evidence of catecholamine production

Endolymphatic sac tumors of the Endolymphatic sac tumors of the middle earmiddle ear

Papillary cystadenomas are highly vascular Papillary cystadenomas are highly vascular lesion within middle earlesion within middle ear

Occur at younger age; often bilateralOccur at younger age; often bilateral Common symptoms: hearing loss, tinnitus, Common symptoms: hearing loss, tinnitus,

vertigo, and facial muscle weaknessvertigo, and facial muscle weakness Generally slow growth rate; primary therapy Generally slow growth rate; primary therapy

is surgicalis surgical Radiosurgery may have a roleRadiosurgery may have a role

Pancreatic tumorsPancreatic tumors

Common in pts with VHLCommon in pts with VHL Multicenter study of 158 pts: 77% pancreatic Multicenter study of 158 pts: 77% pancreatic

lesions – cysts, adenomas, neuroendocrine lesions – cysts, adenomas, neuroendocrine tumorstumors

Mostly asymptomatic, rarely pancreatitisMostly asymptomatic, rarely pancreatitis Neuroendocrine tumors can metastasize Neuroendocrine tumors can metastasize

and produce secreted peptides (VIP,insulin)and produce secreted peptides (VIP,insulin) Surgery is primary form of therapySurgery is primary form of therapy

Papillary cystadenomas of Papillary cystadenomas of epididymis or broad ligamentepididymis or broad ligament

Single epididymal cyst is common in general Single epididymal cyst is common in general population (does not mean pt has VHL)population (does not mean pt has VHL)

Bilateral epididymal cysts are almost Bilateral epididymal cysts are almost pathognomonic of VHLpathognomonic of VHL

No treatment is requiredNo treatment is required In women, symptoms may include pain and In women, symptoms may include pain and

menorrhagiamenorrhagia

Diagnosis: autosomal dominant Diagnosis: autosomal dominant diseasedisease

Clinical Dx based on finding TWO VHL-associated Clinical Dx based on finding TWO VHL-associated tumorstumors

Genetic testing (DNA sequencing and quantitative Genetic testing (DNA sequencing and quantitative Southern blot of VHL gene): 100% sensitive and Southern blot of VHL gene): 100% sensitive and specificspecific

Germline mutations in VHL gene can be inherited Germline mutations in VHL gene can be inherited or present de novo (20% of VHL kindreds)or present de novo (20% of VHL kindreds)

Somatic mosaics: mutation occurs during Somatic mosaics: mutation occurs during embryonic development after fertilization; pt may embryonic development after fertilization; pt may present with classic VHL, yet mutation may not be present with classic VHL, yet mutation may not be detectable in peripheral blood (risk of transmission detectable in peripheral blood (risk of transmission to children < 50%)to children < 50%)

Counseling: VHL family Alliance (www.vhl.org)Counseling: VHL family Alliance (www.vhl.org)

Surveillance protocols:Surveillance protocols:

Infants and children < age 11: annual retinal Infants and children < age 11: annual retinal exam and plasma catecholaminesexam and plasma catecholamines

Adolescents > age 11: Plasma Adolescents > age 11: Plasma catecholamines and abd CT with contrast catecholamines and abd CT with contrast plus retinal exam plus MRI brain and spine plus retinal exam plus MRI brain and spine with gadoliniumwith gadolinium

Adults: catecholamines, abd CT, retinal Adults: catecholamines, abd CT, retinal exam, MRI of CNS, MRI of kidneys, exam, MRI of CNS, MRI of kidneys, baseline ENT exam with audiometrybaseline ENT exam with audiometry

Genetics of PCKD: “nice gene”Genetics of PCKD: “nice gene”

Occurring in 1 in every 400 to 1000 birthsOccurring in 1 in every 400 to 1000 births < 50% will be diagnosed (clinically silent)< 50% will be diagnosed (clinically silent) Most families abnormal chromosome 16 (called Most families abnormal chromosome 16 (called

PKD1 locus) PKD1 locus) Other gene is on chromosome 4 (PKD2 locus)Other gene is on chromosome 4 (PKD2 locus) PKD1 96% of North America; 85% of EuropePKD1 96% of North America; 85% of Europe Both encode proteins AKA “polycystin I & II”Both encode proteins AKA “polycystin I & II” PKD1 gene is adjacent to gene of Tuberous PKD1 gene is adjacent to gene of Tuberous

sclerosis (TSC2), associated with cyst formation sclerosis (TSC2), associated with cyst formation (angiomyolipoma)(angiomyolipoma)

Genotype/phenotype correlation with PKD1 & 2 Genotype/phenotype correlation with PKD1 & 2 “unclear”“unclear”

Polycystin 1Polycystin 1 Localized in renal tubular epithelia, hepatic ductules, Localized in renal tubular epithelia, hepatic ductules,

pancreatic ducts (all sites in PCKD)pancreatic ducts (all sites in PCKD) Integral membrane proteinIntegral membrane protein Less abundant in adult than fetal epitheliaLess abundant in adult than fetal epithelia Overexpressed in most cysts in kidney from PCKD Overexpressed in most cysts in kidney from PCKD

patientspatients Cause abnormalities in renal ciliaCause abnormalities in renal cilia Induce cell cycle arrestInduce cell cycle arrest Why is there variable phenotypic expression?Why is there variable phenotypic expression? Defect is present in 100% of cells, yet only 10% of Defect is present in 100% of cells, yet only 10% of

tubules form cysts… (second hit hypothesis?)tubules form cysts… (second hit hypothesis?) Therefore – mechanism of cyst formation and growth Therefore – mechanism of cyst formation and growth

is unclear (abnormal differentiation or cell maturation)is unclear (abnormal differentiation or cell maturation)

Diagnosis and screening for PCKDDiagnosis and screening for PCKD

Easy diagnosis in overt disease: flank pain, Easy diagnosis in overt disease: flank pain, positive family history, CRI, large kidneys positive family history, CRI, large kidneys with multiple bilateral cysts on CT or sonowith multiple bilateral cysts on CT or sono

Cysts in liver, pancreas, and spleenCysts in liver, pancreas, and spleen What do you do with otherwise unexplained What do you do with otherwise unexplained

CRI, hematuria, with negative family hx?CRI, hematuria, with negative family hx? Acquired cystic disease of the kidneyAcquired cystic disease of the kidney

Mystery caseMystery case

18 yo WF noted to have minimal proteinuria and 18 yo WF noted to have minimal proteinuria and microscopic hematuria @ 3microscopic hematuria @ 3rdrd trimester trimester

Abnormal urinalysis persisted post deliveryAbnormal urinalysis persisted post delivery 24 hour urine protein 800mg per day; GFR 24 hour urine protein 800mg per day; GFR

estimation of 90ml/hrestimation of 90ml/hr During 2During 2ndnd pregnancy at age 25 yrs: abn UA with pregnancy at age 25 yrs: abn UA with

1200mg proteinuria with creatinine clearance of 1200mg proteinuria with creatinine clearance of 82ml/hr82ml/hr

Negative serology for hepatitis B, lues, SLE, Negative serology for hepatitis B, lues, SLE, myeloma, Wegener’s, and VHL… myeloma, Wegener’s, and VHL…

Diagnostic test was performed Diagnostic test was performed

Thin basement membrane diseaeseThin basement membrane diseaese Benign familial hematuria – relatively common Benign familial hematuria – relatively common

(autosomal dominant inheritance)(autosomal dominant inheritance) GBM decreased to 150-225nM vs 400nMGBM decreased to 150-225nM vs 400nM Along with IGA – common cause of asymptomatic Along with IGA – common cause of asymptomatic

hematuriahematuria Heterozygous defect in COL4A3 or A4 (alpha-4 Heterozygous defect in COL4A3 or A4 (alpha-4

chains of type IV collagen)chains of type IV collagen) Discovered via work up of microscopic hematuria Discovered via work up of microscopic hematuria

(normal urine protein, BP, GFR)(normal urine protein, BP, GFR) Rare episodes of gross hematuria and flank pain Rare episodes of gross hematuria and flank pain

from hypercalciuria or hyperuricosuria rather than from hypercalciuria or hyperuricosuria rather than GBM changesGBM changes

Since GFR is usually normal, renal biopsy not doneSince GFR is usually normal, renal biopsy not done

Thin basement membrane diseaseThin basement membrane disease

Hematuria represents and exaggeration of the Hematuria represents and exaggeration of the normal process of naturally occurring leaks in the normal process of naturally occurring leaks in the GBMGBM

No extra renal manifestations: hearing loss, ocular No extra renal manifestations: hearing loss, ocular abnormalitiesabnormalities

Early renal biopsy difficult to distinguish from Early renal biopsy difficult to distinguish from hereditary nephritishereditary nephritis

Screen first degree relatives (autos dominant Screen first degree relatives (autos dominant inheritance) – look for father to son inheritance, inheritance) – look for father to son inheritance, which is not seen in X linked nephritis (alport’s)which is not seen in X linked nephritis (alport’s)

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