Inherited
pheochromocytomas are often part of familial syndromes, especially
multiple endocrine neoplasia type 2 (
MEN 2),
retinal cerebellar hemangioblastomatosis [von Hippel-Lindau (vHL) disease] or
neurofibromatosis type 1. It is not clear whether isolated
familial pheochromocytoma exists as a separate clinical entity. In a family with
pheochromocytomas in three generations and with at least seven affected members, we investigated by clinical and genetic analyses the presence or absence of associated conditions. The clinical investigations included ophthalmological and radiological studies for
von Hippel-Lindau disease (magnetic resonance imaging of the brain, computed tomography of the abdomen, and direct ophthalmoscopy after
mydriasis) and annual
calcitonin stimulation tests for C cell disease in five members who agreed to regular follow-up. Besides the
pheochromocytomas (so far, these have been multiple in five of seven individuals) no definite second associated condition was found. Genetic analysis did not identify any MEN 2-specific RET protooncogene point mutations (which are present in 97% of
MEN 2a families). However, despite the complete absence of other clinical manifestations of the vHL disease (besides
pheochromocytomas), a previously undescribed germline missense mutation in the vHL tumor suppressor gene was found (C775G transversion with a predicted substitution of a
leucine by a
valine at
codon 259 in the putative vHL
protein). We conclude that in this family the sole occurrence of
pheochromocytoma is a variant of vHL disease.