Clinical Correlates of A Large Israeli Cohort of Cys 618 Arg RET Mutation

Introduction:
A MEN2A syndrome with Hirschsprung`s disease described in Israeli Jews of Moroccan descent is caused by Cys 618 Arg mutation. We aimed to define characteristics of a large cohort with this mutation from a multi-center Israeli registry.

Methods:
The Israeli multi-center MTC registry was searched for patients with Cys 618 Arg mutations.

Results:
Fifty-three patients (19.3%) had documented RET mutations; 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 family of Moroccan Jewish descent. Another 4 patients from the MTC registry without available genetic test results belonged to this family. Clinical data of these 32 patients was analyzed.

Nineteen patients (59%) were female. Age at surgery was 26.6 ±12.8 years. Tumor size was 10.8 ±9.3mm. 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%). Lymph node metastases were found in 3; distant metastases in 3.

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. Two patients died during follow-up; one death was disease-related. Two patients had pheochromocytoma, 2 had Hirschsprung disease and 1 had primary hyperparathyroidism.

Conclusion:
The prevalent RET mutation in Israel is Cys 618 Arg; almost all cases were linked to one large family of Moroccan descent. Comorbidities included pheochromocytoma and hyperparathyroidism, rendering screening essential.