Diagnostic challenges due to phenocopies: lessons from Multiple Endocrine Neoplasia type1 (MEN1)

Abstract

Phenocopies may confound the clinical diagnoses of hereditary disorders. We report phenocopies in Multiple Endocrine Neoplasia type 1 (MEN1), an autosomal dominant disorder, characterised by the combined occurrence of parathyroid, pituitary and pancreatic tumours. We studied 261 affected individuals from 74 families referred with a clinical diagnosis of MEN1 and sought inconsistencies between the mutational and clinical data. We identified four patients from unrelated families with phenocopies. Patients 1 and 2 from families with MEN1, developed prolactinomas as the sole endocrinopathy but they did not harbour the germline MEN1 mutation present in their affected relatives. Patient 3, had acromegaly and recurrent hypercalcaemia following parathyroidectomy, whilst patient 4 had parathyroid tumours and a microprolactinoma. Patients 3 and 4 and their relatives did not have MEN1 mutations, but instead had familial hypocalciuric hypercalcaemia (FHH) due to a calcium-sensing receptor mutation (p.Arg680Cys), and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome due to a hyperparathyroidism type 2 deletional-frameshift mutation (c.1239delA), respectively. Phenocopies may mimic MEN1 either by occurrence of a single sporadic endocrine tumour in a patient with familial MEN1, or occurrence of two endocrine abnormalities associated with different aetiologies. Phenocopies arose in >5% of MEN1 families, and awareness of them is important in the clinical management of MEN1 and other hereditary disorders.

Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'étude des Tumeurs Endocrines

“…Moreover, regularly updated recommendations for screening and diagnosis are available on the GTE website in order to help physicians to follow the same rules in all of the centers (http://sfendocrino.org/IMG/pdf/livret_ NEM1_2006-2.pdf). Nevertheless, despite the apparent clarity of the diagnosis criteria, some uncertainties may remain regarding MEN1 diagnosis in routine practice (24,25). Such uncertain patients were analyzed carefully using complementary criteria before their inclusion in the database when genetic analyses were negative (18).…”

CDC73-related hereditary hyperparathyroidism: five new mutations and the clinical spectrum

“…Therefore, MEN1 gene analysis should be completed first in suspected hereditary HPT; if MEN1 mutation analysis is negative, CDC73 analysis should be considered. In 5-10% of cases, MEN1 phenocopies may be present and it is important to be aware of their presence in the clinical setting of hereditary HPT (22). Some of these cases have been attributed to mutations in the cyclin-dependent kinase inhibitor genes (23).…”

A Patient with Persistent Lactation and Recurrent Hypercalcemia

“…A diagnosis of MEN1 is established by the occurrence of 2 or more primary MEN1-associated endocrine tumors, the occurrence of MEN1-associated tumors in a first-degree relative of a patient with a clinical diagnosis of MEN1, or identification of a germline MEN1 mutation in an asymptomatic individual who has not yet developed serum biochemical or radiological abnormalities indicative of tumor development (2,6 ). The diagnosis of MEN1 is often delayed.…”

“…The diagnosis of MEN1 is often delayed. The interval between the appearance of symptoms and the diagnosis of MEN1 varies from several to dozens of years (6 ). Failure to recognize multiple clinical manifestations of MEN1 is a common reason for the delayed diagnosis.…”