Endocrine Abstracts

VHL is an autosomal dominant familial cancer syndrome with renal, CNS and pancreato-biliary manifestations in addition to phaeochromocytoma (PC)/paraganglioma (PGL). Importantly, there is a partial genotype–phenotype correlation, with kindreds harboring deletions and mutations of the VHL gene leading to premature termination/truncation not manifesting PC/PGL. As genetic testing in PC/PGL moves from a research-focus into clinical service, knowledge and understanding of transmission and genotype–phenotype correlations are likely to develop. We present a kindred with VHL associated with a novel partial deletion of the VHL gene, presenting with PC/PGL. In addition, the kindred demonstrates transmission of VHL through paternal mosaicism.

The index case presented at 21 years with hypertension in the context of a twin pregnancy. Urine catecholamine and metanephrine excretion were elevated and imaging confirmed a right adrenal tumour consistent with PC. Subsequent laparoscopic adrenalectomy 6 weeks post delivery was uneventful. The female sib of the index case presented with symptoms of a pheochromocytoma at age 19. A 3.8 cm left adrenal tumour was removed laproscopically following pre-operative alpha-blockade. There was no additional family history of endocrine disease or associated manifestation of inherited/syndromic PC/PGL.

Genetic testing in both sibs was negative for SDHB, SDHD and RET germ line mutations but positive for the same novel in-frame exon 3 deletion within the VHL gene: c.796_798delCAG (p.Gln195del). Genetic testing of the father of the index case revealed him to be a mosaic for the same mutation. Transmission and inheritance of VHL through this mechanism is extremely unusual. Subsequent extended screening of both sibs for other manifestations of VHL has revealed a single retinal angioma in the younger of the pair to date. The father has no phenotypic manifestations. The kindred remains under regular surveillance.

This case highlights the importance of a systematic cascade of genetic testing in the context of early onset PC/PGL, even in apparently isolated disease. The novel VHL mutation we describe extends the phenotype–genotype correlation in VHL and the importance of thorough surveillance for non-endocrine manifestations over the natural history of the condition.