Family Survey And Mutation Analysis Of VHL Gene In A Chinese Family With Nonsyndromic Pheochromocytoma

Pheochromocytomas are neuroendocrine tumors stemmed from the sympathetic nervous system. It is also a major cause of endocrine hypertension. Familial pheochromocytoma is a special type which displays autosomal dominant inheritance. Patients with a familial history are usually diagnosed at an early onset age. Because these tumors often have a bilateral and multifocal presentation,and the paroxysmal hypertension is severe,it is difficult for treatment and prognosis. The pathogenesy of pheochromocytoma is not clear yet.But for patients with familial and genetic susceptibility,the genetic pathogenesy can be recognized by detection of some susceptibility genes. Familial pheochromocytomas are usually accompanied with some genetic syndromes,such as VHLD,MEN2,and NF1,which have been confirmed to be related with some pheochromocytoma-susceptibility genes ,including VHL gene,RET gene,and NF1 gene. Another special type of familial pheochromocytomas only has a presentation of adrenal tumors. The molecular genetics of this cluster is still vague to be related to one specific gene. But the recognition of such cluster of pheochromocytomas is valuable in clinical treatment. Genetic analysis of some candidate genes can not only identify the pathogeny of pheochromocytoma patients,but also achieve the purpose of early diagnosis of susceptible family members.VHL gene is a tumor suppressor gene,which encodes a protein (pVHL) that is expressed in most tissues and has been implicated in a variety of functions,in particular,the regulation of cell cycle,stability of mRNA,and expression of hypoxia-inducible genes. VHL gene mutation is related to VHLD,and one of it's special types(VHLD2C)has an only performance of adrenal pheochromocytoma,which is also be called nonsyndromic pheochromocytoma. Therefore,VHL gene is usually taken as a preferred screening gene of pheochromocytoma. However there are no domestic molecular genetics reports about familial pheochromocytomas. Last year we found a typical three-generation nonsyndromic familial pheochromocytoma.We first had a pedigree of the family and performed clinical analysis,then we detected the VHL gene mutation in the family members in order to explore the association between the prevalence of the family and VHL gene mutation. The studies are as follows:Objective: To study the clinical characteristics of nonsyndromic familial pheochromocytomas and to detect the VHL gene mutation in a Chinese family with nonsyndromic pheochromocytoma. Methods: A nonsyndromic pheochromocytoma family was investigated. Then a dendrogram was drawn and a genetic analysis was performed. The following study was to detect VHL gene mutation in this family.Five patients and sixteen relatives were involved in this study.Peripheral blood was collected and total genomic DNA was prepared for polymerase chain reaction(PCR).PCR products of all the three exons of VHL gene were purified and a direct gene sequence analysis was performed.The DNA sequence was BLAST in GenBank.If a novel gene mutation was found,TaqMan PCR method would be used to detect the mutation in the crowd.Results: There are seven members with pheochromocytoma in the big family that includes fifty-six members. Two patients were clinically suspected and five patients were confirmed by operation. The tumors were planted on the adrenal body only. Six patients were found bilateral and multifocal tumors and three of them were recurred on the opposite side after unilateral operation. The pathological examinations were benign tomors and the symptoms were disappeared after operation. All the patients were followed up for six months to twenty-three years. There was no recurrence on the sick side. All the five patients present a codon 125 from histidine(H)to proline (P) change at nucleotide 587 (A→C) in the second exon. Seven members of sixteen relatives are carriers with the same VHL gene mutation. Two carriers were detected differently with bilateral adrenal tumors and right renal cyst by ultrasonic inspection. None of the 100 normal controls was found this mutation. The novel mutation was confirmed as a point mutation but not a SNP. It was first report that this point mutation be found in VHL gene.We bankited this novel mutation to GenBank,and the accession number is EF507247.Conclusions: The characteristics of the kindred are according with what autosomal dominant inheritance diseases have. The novel VHL gene mutation detected in the kindred may be the causative gene. The nonsyndromic familial pheochromocytomas present symptoms at a younger onset age. The tumors are usually bilateral and multifocal,and the clinical presentation can be successive. The tumors are planted on adrenal body only. Most tumors have a lower malignant pathology and a better prognosis. All the patients after unilateral operation should be followed up regularly.