HUMAN MUTATION Mutation in Brief #150 (1997) Online

Variable Penetrance of FamilialPheochromocytoma associated with the von HippelLindau gene mutation, S68W

Roger Martin, Athel Hockey, Ian Walpole, Jack Goldblatt

Genetic Services of Western Australia, Princess Margaret Hospital, GPO Box D184, Perth 6000,Australia.

Communicated by Henrik Dahl

Key Words: von Hippel-Lindau; VHL; pheochromocytoma; S68W

Received 7 July 1997; Accepted 6 November 1997

Von Hippel-Lindau disease (VHL) is an autosomal dominantly inherited disorder, characterised by thedevelopment of clear cell renal carcinomas, CNS hemangioblastomas, retinal angiomas, pancreatictumors, pheochromocytomas and hepatic cysts. Recently a number of families with dominant familialpheochromocytoma as the only clinical manifestation have been reported to carry mutations in the VHLgene. We describe a family in which a novel VHL S68W mutation was segregating and carrierindividuals manifested with variable penetrance of isolated pheochromocytomas. Investigation of thiskindred confirmed that a mutation in the VHL gene could produce isolated pheochromocytomas as theonly clinical feature and was variably penetrant. © 1997 Wiley-Liss, Inc.

Article

Introduction

About 10% of pheochromocytomas are inherited in an autosomal dominant manner and occur in multipleendocrine neoplasia type 2 (MEN2), neurofibromatosis 1 (NF1) and the von Hippel-Lindau (VHL;OMIM: 193300) syndrome (Anderson and Lynch 1993). Recent studies have described a number offamilies with familial pheochromocytoma who carry missense mutations in the VHL gene (Crossey et al

http://journals.wiley.com/1059-7794/html/mutation/marttext.htm (1 of 3) [10/1/1999 11:06:26 AM]

1995, Ritter et al 1996, Walther and Linehan1996). Affected individuals had no other clinical signs ofVHL indicating that in some families this may be the only manifestation of a mutation in the VHL gene.In this study, we have investigated a kindred with familial isolated unilateral pheochromocytoma inwhich a novel mutation of variable penetrance was ascertained in the VHL gene. Previous clinical andendocrinological assessment had excluded the diagnoses of MEN2 and NF1.

Discussion

The family was screened for mutations in the VHL gene as previously reported (Martin et al 1996) andthe S68W mutation in exon 1 was identified in 5 family members (Fig. 1). This mutation was notdetected on 100 control chromosomes. The oldest surviving member of the family, I:2 tested negative forthe mutation (Fig. 1). Her husband, who may be presumed to have carried the mutation died, age 78,showing no signs of pheochromocytoma or any other endocrine disorder. Of the couples two survivingchildren, both carry the S68W mutation. II:2 had her pheochromocytoma removed at age 24. By contrastsib II:4 has remained asymptomatic and is presently 63 years of age. Of II:2's three children, two carrythe S68W mutation. III:2 presented with symptoms of pheochromocytoma at age 12, whilst III:1 at age35 has remained asymptomatic. III:1's only endocrine problem was thyroiditis at age 24. Of II:4's sixchildren, four have been tested to date. III:4 carries the S68W mutation and was diagnosed withpheochromocytoma at the age of 23. None of the untested sibs have presented with symptoms ofpheochromocytoma and carrier individuals have not had any other clinical features or endocrineabnormalities to suggest an associated genetic syndromic disorder. In addition, clinical monitoring of theindividuals carrying the S68W mutation, which includes ophthalmological examinations, has notrevealed symptoms indicative of VHL or any other genetic syndromic disorders.

This report supports the few previous accounts of isolated familial pheochromocytoma occurring inindividuals shown to carry mutations in the VHL gene (Crossey et al 1995, Walther and Linehan 1996,Ritter et al 1996). In contrast to the other reported mutations, the S68W mutation appears to present withvariable penetrance of isolated pheochromocytoma. However, the use of DNA based testing has helpedclarify at risk status in family members irrespective of their clinical situation.

Summary

The role of mutation screening in isolated pheochromocytomas to ascertain possible germ-line mutationsin the VHL gene needs further consideration, unfortunately no consensus defects have yet been reportedto simplify this approach.

Figure 1

Pedigree of the familial pheochromocytoma kindred. Affected members are shown in black.Asymptomatic members who carry the S68W mutation are shown with a cross. N=DNA tested normal.

Mutations in Brief 1997: Martin et al.

http://journals.wiley.com/1059-7794/html/mutation/marttext.htm (2 of 3) [10/1/1999 11:06:26 AM]

References

Anderson RJ. Lynch HT. Familial risk for neuroendocrine tumors. Current Opinion in Oncology.5(1):75-84, 1993.

Crossey PA. Eng C. Ginalska-Malinowska M. Lennard TW. Wheeler DC. Ponder BA. Maher ER.Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma. Journal ofMedical Genetics. 32(11):885-6, 1995.

Martin RL. Walpole I. Goldblatt J. Identification of two sporadically derived mutations in the VonHippel-Lindau gene. Human Mutation. 7(2):185, 1996.

Ritter MM. Frilling A. Crossey PA. Hoppner W. Maher ER. Mulligan L. Ponder BA. EngelhardtD.Isolated familial pheochromocytoma as a variant of von Hippel-Lindau disease. Journal of ClinicalEndocrinology & Metabolism. 81(3):1035-7, 1996.

Walther MM. Linehan WM. Von Hippel-Lindau disease and pheochromocytoma JAMA.275(11):839-40, 1996.

Correspondence to

Roger MartinGenetic Services of Western AustraliaPrincess Margaret HospitalGPO Box D184Perth 6000Australia

Mutations in Brief 1997: Martin et al.

http://journals.wiley.com/1059-7794/html/mutation/marttext.htm (3 of 3) [10/1/1999 11:06:26 AM]