ISOLATED FAMILIAL PHEOCHROMOCYTOMA AS A VARIANT OF VON HIPPEL-LINDAU DISEASE

Inherited pheochromocytomas are often part of familial syndromes, espe cially multiple endocrine neoplasia type 2 (MEN 2), retinal cerebellar hemangioblastomatosis [von Hippel-Lindau (vHL) disease] or neurofibro matosis type 1. It is not clear whether isolated familial pheochromocy toma exists as a separate clinical entity. In a family with pheochromo cytomas in three generations and with at least seven affected members, we investigated by clinical and genetic analyses the presence or abse nce of associated conditions. The clinical investigations included oph thalmological and radiological studies for von Hippel-Lindau disease ( magnetic resonance imaging of the brain, computed tomography of the ab domen, and direct ophthalmoscopy after mydriasis) and annual calcitoni n stimulation tests for C cell disease in five members who agreed to r egular follow-up. Besides the pheochromocytomas (so far, these have be en multiple in five of seven individuals) no definite second associate d condition was found. Genetic analysis did not identify any MEN 2-spe cific RET protooncogene point mutations (which are present in 97% of M EN 2a families). However, despite the complete absence of other clinic al manifestations of the vHL disease (besides pheochromocytomas), a pr eviously undescribed germline missense mutation in the vHL tumor suppr essor gene was found (C775G transversion with a predicted substitution of a leucine by a valine at codon 259 in the putative vHL protein). W e conclude that in this family the sole occurrence of pheochromocytoma is a variant of vHL disease.