FaCD Online Syndrome Fact Sheet

Last updated: 03 Apr 2009

Co-authors of this topic: Frederik Hes, MD PhD, dept of Clinical Genetics, Leiden University Medical Center, the Netherlands

Name: von Hippel-Lindau disease

Synonym: VHL

Mode of Inheritance: AD

OMIM number: 193300

Genes

VHL, mapped to 3p25-p26

Tumor features

adnexal papillary cystadenoma of probable mesonephric origin (APMO)
bone hemangioma
brain hemangioblastoma
cerebellar hemangioblastoma
choroid plexus papilloma
endolymphatic sac tumor
epididymis, cystadenoma of
hepatic cystadenoma
hepatic hemangioma
lung cystadenoma
lung hemangioma
medullar/spinal hemangioblastoma
pancreatic adenoma
pancreatic cystadenoma
pancreatic endocrine tumor
pancreatic hemangioma
paraganglioma, chromaffin (extra-adrenal pheochromocytoma)
pheochromocytoma
renal cell cancer, clear-cell (Grawitz tumor)
renal cystadenoma
retinal hemangioblastoma (hemangioma / angioma)
splenic cystadenoma

Tumor features (possible)

astrocytoma
bile duct carcinoid
chondrosarcoma
meningioma
pancreatic adenocarcinoma
renal oncocytoma

Non-tumor features

pancreatic cysts
renal cysts

Non-tumor features (possible)

developmental delay/mental deficiency/mental retardation
hyperparathyroidism
microcephaly

Comment

This disorder is characterized by retinal and central nervous system (in particular cerebellar) hemangioblastomas, clear cell renal cell cancer, pheochromocytomas and germline mutations in the VHL gene[1-3,37,39,41,51].
In approximately 40 % of cases, the retinal tumors are the first manifestation of VHL and apparently sporadic retinal angioma patients should be checked for other VHL symptoms and/or germline VHL mutations[4].

Approximately 9-20% of apparently sporadic pheochromocytoma patients carry germline VHL mutations, and childhood-onset pheochromocytoma is typically associated with germline VHL mutations[5,31-33]. In rare cases, the pheochromocytomas, or paragangliomas, may occur at extra-adrenal sites in VHL patients[6-8,30,50]. VHL-associated pheochromocytomas detected by screening are usually smaller and less functional than sporadic pheochromocytomas[9].

Compared to sporadic renal cell cancer, VHL associated renal cell cancer occurs earlier, is associated with renal cysts, and more often bilateral/multifocal, showing a cystic organization and low grade clear cell histology and lower metastatic potential[10-14]. However, more aggressive renal tumors have been reported[36]. A rare case of multifocal renal oncocytoma in VHL has been reported[35].

Pancreatic tumors (multicentric cysts) are common in VHL, predominantly neuroendocrine tumors (PNET), often nonsecretory islet cell tumors which can become malignant)[28]. However, adenocarcinoma and pancreatic intraductal papillary mucinous neoplasms have been reported in rare cases as well[15,26,46]. Most endocrine pancreatic tumors in VHL patients appear to be somatostatin receptor scintigraphy-positive and malignant, without correlation with the VHL genotype[47]. Cysts in the adnexal tissue, including the broad ligaments, may be found in VHL. These cysts are more appropriately referred to as adnexal papillary cystadenoma of probable mesonephric origin (APMO). Endolymphatic sac tumors (slow-growing low-grade papillary adenocarcinoma), frequently bilateral, are another complication of VHL[16-21,38]. Epididymal lesions are commonly reported as cystadenomas. Detailed analysis has revealed two distinctive steps: maldevelopment of VHL-deficient mesonephric cells, followed by neoplastic papillary proliferation[48,49]

Maher et al.[22] calculated cumulative risks: from birth until age 50 years risk for pheochromocytoma was 60 % (associated with missense mutations in the VHL gene) or 9 % (associated with mutations leading to truncated VHL protein), cerebellar hemangioblastoma 65-75 %, retinal hemangioblastoma 64-72 % and renal cell cancer 60-64 %. Other tumors have been reported as well: malignant pancreatic paraganglioma[23], carotid paraganglioma[8], astrocytoma[24], chondrosarcoma[27], biled duct carcinoid[28] and meningioma[43-45]. A boy with developmental delay, micocephaly, signs of VHL and an apparently de novo missense VLH mutation has been reported[40]. Hyperparathyroidism is rare[42].

Families with a full or partial deletion of the VHL gene have a low risk of pheochromocytomas and a preponderance of central nervous system hemangioblastoma[25]. Risks of retinal angiomas and renal cell cancer are higher in individuals with a nonsense or frameshift mutation than in those with deletions or pathogenic missense mutations[34].

Clinical diagnostic criteria[2]:
A) In the presence of a family history of VHL:

-single retinal hemangioblastoma, or
-single cerebellar hemangioblastoma, or
-renal cell cancer (only clear cell type ?), or
-pheochromocytoma
(-or multiple pancreatic cysts ?)

B) In the absence of a family history of VHL:

-2 or more retinal or cerebellar hemangioblastomas, or
- single retinal or cerebellar hemangioblastoma + 1 typical VHL associated visceral tumor (pheochromocytoma, renal cell carcinoma or multiple pancreatic cysts).

Links

The VHL Family Alliance 24 1 08

References