Molecular-genetic diagnosis of a Bulgarian family with multiple endocrine neoplasia, type IIA

Abstract

INTRODUCTION : Multiple Endocrine Neoplasia (MEN) is a rare autosomal dominant disease with frequency 1:30 000 and it is classified in 3 subtypes: MEN 2A (Sipple syndrome), familial medullary thyroid carcinoma (FMTC), MEN 2B. The MEN 2A subtype constitutes approximately 70%-80% of cases of MEN 2. The onset age of the MEN 2A is prior to age 35 years. MEN 2A has an increased risk for parathyroid hyperplasia or adenoma. The clinical diagnosis is suspected when at least 2 specific endocrine tumors are detected in one patient or close relatives (MTC, pheochromocytoma, parathyroid adenomas). MTC is suspected in case of increased serum levels of calcitonin. The biochemical phenotype of MTC is revealed between age 5 and 25 (mean age 15 years). The tumor formation in the neck area is between age of 15 and 20 (2). Although there is controversy surrounding the definition of CCH, its utility to identify or confirm MEN 2 has been essentially replaced by RET (REarranged during Transfection) protooncogene testing. This allows the early surgery interventions, proper genetic counseling and prenatal diagnostics. MATERIAL AND METHODS : We report on a Caucasian male with complains of general weakness and weight loss (10 kg for 2 month). The patient`s mother has been diagnosed at 47 as bilateral pheochromocytomas and struma nodosa and died at age of 51. In the index patient abdominal ultrasound examination with biopsy of adrenal glands and histological analysis revealed pheochromocytoma on the right side; elevated plasma calcitonin concentration and US scan with biopsy of thyroid tissue detected medular thyroid cancer. The index patient has two elder brothers - it turned out that one of them had been surgically treated for medular thyroid cancer in the past; bilateral pheocromocytomas were detected in the family screening process. RESULTS AND CONCLUSION : MEN 2A diagnosis was suspected and we performed sequencing of RET protooncogene. The genetic analysis of the family affected members revealed c.1902C>G, p.Cys634Trp heterozygous mutation. Unfortunately, two kids in the families of 2 of the brothers have also inherited the mutation. All adult family members were offered genetic counseling. The standard therapy and the prophylactic thyroidectomy include the surgical removal of the thyroid gland, followed by parathyroid gland autotransplantation. In case codon 634 mutation the surgery is recommended before age of 5 years. All affected relatives are going through monitoring for residual disease. The screening protocol includes plasma levels of calcitonin. The stimulation tests are more sensitive than calcitonin measurements alone so they are recommended.