Phenotype and phenocopy: the relationship between genotype and clinical phenotype in a single large family with multiple endocrine neoplasia type 1 (MEN 1)

BACKGROUND The majority of reports describing the natural history and progn osis of multiple endocrine neoplasia type 1 (MEN 1) utilize phenotypic rath er than molecular genetic criteria to establish a diagnosis of MEN 1. OBJECTIVES AND PATIENTS We sought to determine the spectrum of endocrine ab normality amongst 152 members (64 gene carriers and 88 noncarriers) of a ta rge MEN 1 family in whom a determination of MEN 1 status had previously bee n made by phenotype screening. The predictive utility of both clinical and molecular screening techniques are described, RESULTS A novel IVS2-3 (C-G) MEN1 mutation was identified in affected membe rs of this family. Seven (10%) of 71 individuals satisfying clinical diagno stic criteria for MEN 1 were found to be genetically negative (excluded by mutation analysis and haplotyping) for MEN 1, These cases of MEN 1 phenocop y comprised four cases of primary hyperparathyroidism, two 'nonsecretory' p ituitary adenoma and one case of coincident prolactinoma and hyperparathyro idism. Three of the patients with hyperparathyroidism had previously requir ed parathyroidectomy and each had achieved normocalcaemia following parathy roid resection. Predictive genetic testing prospectively identified three c hildren with the MEN 1 genotype, Serum calcium was normal at the time of th eir initial molecular genetic diagnosis. In each case hyperparathyroidism s ubsequently developed during adolescence. CONCLUSION Multiple endocrine neoplasia type 1 phenocopy is an important di fferential diagnosis in patients exhibiting an multiple endocrine neoplasia type 1 phenotype. This is a relevant consideration, particularly when the diagnosis of multiple endocrine neoplasia type 1 is made using sensitive, b ut nonspecific, criteria such as mild hyperparathyroidism, pituitary micoad enoma, and hyperprolactinaemia, Confirmatory genetic testing should be unde rtaken to confirm clinical diagnoses of multiple endocrine neoplasia type 1 .