Von Hippel-Lindau syndrome (VHL) is an autosomal dominant multisystem disorder characterized by hemangioblastomas of the central nervous system (CNS), clear cell renal cell carcinoma (kidney cancer), pheochromocytomas (a type of non-cancerous tumor), islet cell tumors of the pancreas, endolymphatic sac tumors, cysts (renal, pancreatic, and epididymal), and a predisposition to bilateral and multicentric retinal angiomas. The disease has a prevalence rate of 1 in 36000 birth.
Retinal angiomas may be the initial manifestation of VHL syndrome and can cause vision loss, while CNS hemangioblastoma (Lindau tumor) is the most commonly recognized finding of VHL syndrome that occurs in 40% of patients. Renal cell carcinoma occurs also in about 40% of the patients and it is the main cause of mortality. Endolymphatic sac tumors occur in 10% of the cases and can cause hearing loss. The incidence of VHL syndrome is thought to be about one in 36,000 live births. Both genders are equally affected, and about 20% of the cases are familial.
The classification of VHL syndrome phenotypes depends on the risk of developing pheochromocytoma or renal cell carcinoma. VHL type 1 has a low risk for pheochromocytoma, whereas VHL type 2 has a high risk for pheochromocytoma. VHL type 2 is further subdivided into: type 2A (with low risk of renal cell carcinoma), type 2B (with high risk of renal carcinoma), and type 2C (has risk for pheochromocytoma only). A new VHL phenotype is identified to have a low risk for both renal cell carcinoma and pheochromocytoma.
Von Hippel-Lindau syndrome is associated with mutations in Von Hippel-Lindau tumor suppressor (VHL) gene. Cyclin D1 gene (CCND1) variants are also known to contribute to the phenotype by acting as a modifier.
Grexa and Elizabeth (1998) described the abdominal manifestations in 13 members of a Kuwaiti family affected with Von Hippel-Lindau disease. [Grexa, Elizabeth. Abdominal manifestation of von Hippel-Lindom disease in a Kuwaiti family. Kuwait Med. J. 1998; 30 (3): 246-249.]
AlFadhli et al. (2004) identified a novel germline mutation in the splice donor site of the first intron (IVS+1 G>T) in the VHL gene in an extended Arabic (Kuwaiti)-Persian family with Arab parentage, of which one member was clinically diagnosed with VHL disease. The origin of the mutation was found from the Arabic side of the family.
Athyal et al. (2007) reported the first case that represented an occurrence of urinary bladder paraganglioma in von Hippel-Lindau patients. The case represented a 33 year old woman diagnosed with von Hippel-Lindau disease at Al-Amiri Hospital in Kuwait. The subject suffered from hematuria and was found to have urinary bladder paraganglioma which was revealed through CT and MRI scans. Athyal et al. (2007) suggested considering the diagnosis of vesical paraganglioma in subjects with von Hippel-Lindau disease demonstrating macroscopic hematuria.
AlFadhli et al. (2008) carried a molecular study in another multigenerational extended Kuwaiti family with Arabian and Persian genetic admixture. Thirteen members of this family had been clinically diagnosed as having VHL and had gone through several surgeries abroad. The clinical history of all patients revealed multiple hemangioblastomas in various organs and renal cell carcinoma without pheochromocytomas. Only one affected member of the family had been diagnosed as having a bladder tumor, considered rare in VHL cases, and a brain tumor. Of the thirteen patients, eight had expired at early ages between 35 and 45 years and four patients are receiving a very intensive medical care. The rest of the family members were physically healthy and were confirmed by molecular analysis not to carry the mutated VHL gene. The index patient in this family presented with a history of VHL syndrome and multiple hemangioblastomas. This patient had undergone multiple surgeries because of tumors involving the cerebellum, cervical spine, lumbar spine, multiple abdominal and pelvic organs and the retina. The tumor had been demonstrated on angiography as very extensive and vascular. The patient had had a partial nephrectomy, adrenalectomy, distal pancreatomy for involvement of the tail of the pancreas with a hemangioblastoma and a left salpingoophorectomy. Most recently, the patient was found to have a metastatic renal cell cancer to L5 that developed into a progressively enlarging tumor destroying the left L5 vertebral body with progressive left-sided L5 and S1 radiculopathy. The tumor was described as being very necrotic and very highly vascular and therefore, was devascularized prior to surgery. The bone surrounding the tumor was not invaded but was mainly eroded by the tumor mass. Because the patient did not have any known history of hypertension and the right adrenal had been removed, it was concluded the VHL disease was not associated with a pheochromocytoma. At the molecular level, a heterozygous missense c.G563T (p.Trp117Cys)mutation in exon 2 of the VHL gene was found in the index patients as well as all relatives with clinical diagnoses but in none of the healthy members or in 55 healthy control subjects.
Medlej-Hashim et al. (2004) studied two affected Lebanese families with von Hippel-Lindau syndrome with hemangioblastomas of the central nervous system. The propositus in the first family, 64-years-old, was operated several times since he was 37-years-old. Family history indicated that his father died at 39 years of age because of a cerebral hemangioblastomas. The propositus in the second family, 44-years-old, was also operated at 33 years because of medullary hemangioblastomas. His son, 18-years-old, was also operated because of two cerebral hemangioblastomas. Additionally, the mother of the propositus had previous consecutive interventions due to development of cerebral tumors. She died at 36 years. A brother also died at 23 years one year after being operated. Medlej-Hashim et al. (2004) conducted molecular analysis in the two families and identified two different mutations of the VHL gene, S65W and F76S, respectively; confirming the clinical diagnosis of the patients. Molecular diagnosis was then performed for at risk members of these families.