Endocrine Abstracts

Objective: To evaluate the prevalence of the RET mutation and the genotype–phenotype relation in Saudi patients (families) with multiple endocrine neoplasia type 2A (MEN2A) or familial medullary thyroid carcinoma (FMTC).

Design: Cross-sectional study.

Patients and methods: A total of ten unrelated Saudi families with germline mutation of the RET protooncogene and/or immunohistochemistry diagnosis of MTC were identified. Before undergoing genetic testing, all patients and their at risk family members had given their written informed consent in accordance with institutional ethic guidelines and national regulations. The presence of pheochromocytoma (PHEO) or hyperparathyroidism (HPT) was excluded by extensive testing of all affected individuals and their at risk family. Seventy-eight family members were evaluated by medical history, physical examination and biochemical measurements of fasting serum calcium, basal plasma calcitonin (CT) levels, plasma parathyroid hormone (1–84) (PTH), 24-h urinary excretion of catecholamines and metabolites, and DNA analysis. Genomic DNA was isolated from peripheral blood leucocytes using standard procedure. Exons 10, 11, 13, 14 and 16 of the RET proto-oncogene were analyzed by single strand conformation polymorphism analysis, direct DNA sequencing and/or restriction enzyme analysis.

Results: Among the 78 individuals, a total of 46 individuals with hereditary MTC were enrolled in this study. Thirty (aged 12–65 years), were patients previously thyroidectomized for MTC. In addition; molecular screening identified another 16 individuals without clinical evidence of disease but at risk because of an affected relative. From this MTC group ten patients had been operated on for PHEO and four for HPT. The diagnosis of MTC, PHEO and parathyroid hyperplasia was confirmed by pathological examination after operation. Of the ten families with hereditary MTC analyzed, five were diagnosed with MEN2A and five with FMTC. In two of five MEN2A family’s mutation was located at codon 618 in exon 10. The incidence of medullary thyroid carcinoma (MTC), pheochromocytoma (PCC) and hyperparathyroidism (HPT) in the 25 MEN2A patients was 100%, 52 and 16%, respectively; the onset of MTC in MEN2A patients was earlier than that of PCC and HPT. In our series, the most frequent phenotype was the MEN2A syndrome with codon 618 mutations (46.6%), followed by 634 mutation 44.2%. In 1 of 10 families, screening of exons 10, 11, 13, 14 and 16 was negative for RET mutations. Of the five families classified as MEN2A, three had a mutation at codon 634, exon 11 while the other tow families presented the syndrome of MEN2A had a mutation at codon 618.

Discussion: Mutations that cause activation of RET have been well characterized and several groups have studied the disease phenotype–genotype. Differences in the frequency of specific RET mutations in MEN2A phenotypes have been found in series from different countries, suggesting that the occurrence of these mutations may be influenced by genetic background. We analyzed the RET proto-oncogene from 79 patients from 10 unrelated Saudi families. A total of 46 individuals with hereditary MTC were enrolled in this study. It is interesting to report that the nature of the mutations in our MEN2A families was different from the results of the International RET mutation consortium analysis which showed that 634 mutation was found in 86% of all cases of MEN2A.

Although the small number of our families is not sufficient for statistical analysis, the high frequency of 618 mutation may reflect different hereditary factors in our population.

Conclusion: We showed the frequency profile of RET proto-oncogene mutations in a sample of 10 unrelated Saudi’s families with hereditary MTC. The most frequent RET proto-oncogene mutations in Saudi’s families with MEN2A and familial medullary thyroid carcinoma (FMTC) is mutation in codon 618.