Endocrine Abstracts

Introduction: A syndrome of MEN2A and Hirschsprung’s disease described in Israeli Jews of Moroccan descent is caused by Cys 618 Arg mutation, one of the less common causes of MEN2A. We aimed to define the clinical characteristics of a large cohort with this mutation from a multi-center Israeli registry.

Methods: The Israeli MTC registry including 8 centers was searched retrospectively for results of RET mutational analysis. Patients with a Cys 618 Arg mutation belonging to a single large extended family were included in the study, as were their first-degree family members with MTC without available genetic test results. Clinical, laboratory and pathological data, as well as long-term surveillance data were retrieved.

Results: Of the 274 patients in the Israeli registry, 53 (19.3%) had documented RET mutations, and 29/53 (54.7%) had the Cys 618 Arg mutation. Through development of a family tree spanning five generations, a familial connection was determined for 28/29 patients, descendants of one large family of Moroccan Jewish descent. Another 4 patients from the MTC registry without available genetic test results belonged to this extended family. Clinical and pathological data pertaining to these 32 patients was analyzed. Nineteen patients (59%) were female; mean age at surgery was 26.6 ±12.8 years. Tumor size was 10.8 ±9.3 mm. Extrathyroidal extension was described in 4/19 (21.0%); vascular invasion in 5/18 (27.8%); multifocality in 17/21 (81.0%) and bilateral lesions in 17/22 (77.3%). Ki67 was mentioned for only one patient and was 3%. Lymph nodes were removed in 8 patients, and metastases found in 3. Extranodal extension was found in 1 case. Three patients had distant metastases at diagnosis. Of 22 patients with one-year follow-up, 11 were cured, 10 had persistent disease and 1 suffered disease-related mortality. Of those with persistent disease, 6 were biochemical, 2 structural and 2 unknown. Surveillance duration was 9.3 ±12.9 years. Recurrence occurred in 4/19 patients (21.2%), 3 with distant metastases. Seven patients had additional therapy: 4 surgery, 2 radiotherapy and 1 tyrosine kinase inhibitors. One more patient died during follow-up; whether his death was disease-related is unclear. Comorbidities included pheochromocytoma in 2 patients, Hirschsprung disease in 2 and primary hyperparathyroidism in 1 patient.

Conclusion: The prevalent RET mutation in Israel is Cys 618 Arg, and almost all cases are linked to one large family of Moroccan Jewish descent. Genotype-phenotype correlation are similar to that described previously with cases of pheochomocytoma and hyperparathyroidism, rendering screening for these conditions essential.