MEN2A DUE TO C609S: A LARGE FAMILY DESCRIPTION

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Mian C1, Zambonin L.1, De Piccoli N.2, Pelizzo M.R.2, Bernante P.2, Nacamulli D.1, Mantero F.1, Girelli M.E.1, Opocher G.1
1 Endocrinogy Unit; 2Surgical Special Pathology, Department of Medical and Surgical Sciences, University of Padua, Italy
Point mutations of RET codon 609 are rare and belong to an intermediate risk category to develop aggressive medullary thyroid carcinoma (MTC). Our study describes the MTC phenotype of a MEN2A kindred, spanning five generations, with a RET mutation determining a cysteine to serine substitution at codon 609: only two families with such mutation have been previously reported.

Patient and methods: The index patient presented a thyroid node at 36 years of age, with an indeterminate cytology and a high serum Calcitonin (Ct). Subsequent thyroidectomy revealed a MTC, staged as T1 NO. Family history revealed 2 family members (20 and 28 years of age) with an isolated MTC; 3 family members (38, 59 and 62 years of age) with MTC and node metastases, one of whom with distant metastases (62 years of age).Two family members (20 and 62 years of age) had a pheochromocytoma. RET analysis revealed a C609S mutation in the index case. Screening 32 family members, we identified 9 gene carriers who underwent further evaluations with :basal and pentagrastin-stimulated serum Ct (Pg-test); thyroid ultrasonography (US); measurement of urinary metanephrines and adrenal imaging, calcium and PTH measurements.

Results: no gene carrier showed an evident thyroid node at US (> 10 mm); 2/9 (62 and 86 years of age) had a high basal Ct; 4/9 (16; 17; 41 and 47 years of age) showed a positive or 61 borderline Pg-test; no gene carriers showed biochemical or radiological signs consistent with pheochromocytoma. One gene carrier presented primary hyperparathyroidism as the first sign of MEN2A. Five gene carriers underwent thyroidectomy: 4 (17, 41, 74 and 62 years of age) had an isolated MTC and 1 (16 years of age) a C cell hyperplasia.

Conclusions: the C609S RET mutation is associated with a MEN2A syndrome characterized by: 1) not aggressive MTC: no MTC development under 17 years of age; no lymph node metastases under 30 years of age; no distant metastases under 60 years of age; a 86 year old gene carrier, who did not undergo surgery; 2) low penetrance (13%) of pheochromocytoma.

Kinlaw WB, Scott SM, Maue RA, Memoli VA, Harris RO, Daniels GH, Porter OM, Belloni DR, Spooner ET, Ernesti MM, Noll Ww. Multiple endocrine neoplasia 2A due to a unique C609S RET mutation presents with pheochromocytoma and reduced penetrance of medullary thyroid carcinoma. Clin Endocrinol (Oxf), 63(6), 67682,2005.
Igaz P, Pat6cs A, Racz K, Klein I, Varadi A, Esik O. Occurrence of pheochromocytoma in a MEN2A family with codon 609 mutation of the RET proto-oncogene. J Clin Endocrinol Metab, 87(6), 2994, 2002.