Carriers of Mutation Responsible for Multiple Endocrine Neoplasia Can Face Difficult Choices

The authors of a case study presented at the 21st Annual Congress of the American Association of Clinical Endocrinologists noted that multiple endocrine neoplasia (MEN) type 2 is “a syndrome of familial cancers with autosomal dominant inheritance basically characterized by Medullary Thyroid Cancer (MTC).” The MEN 2A subtype, which makes up around 90% of cases of MEN, is caused by mutations in the RET protooncogene, most commonly resulting in “the substitution of one of six cysteine residues in exon 10 and 11;” MEN 2A is “most frequently caused by activating mutations of the extracellular codon 34.”

Patients with MEN 2A often develop cutaneous lichen amyloidosis, primary hyperparathyroidism (about 15-30% of cases), pheochromocytoma (about 50%), and MTC (about 95%). MEN 2A may be indicated when patients develop bilateral or multifocal MTC, or when MTC presents at an early age (younger than 3-5 years). Diagnosis relies on clinical findings, family history, and genetic testing of the RET gene.

In “Multiple Endocrine Neoplasia Type 2A: Study of a Family of Three Generations with Pedigree Analysis of the RET Protooncogene,” Galesanu and colleagues reported on the results of genetic screening of the RET protooncogene for mutation exons 10 and 11, codons 609, 611, 618, 629, 630, and 634, in three generations of a family in which the first patient (proband) presented with “bilateral pheochromocytoma associated with MTC.”

Out of nine family members screened, six (proband, three daughters, and two male grandchildren) were found to have the RET protooncogene mutation codon 634 (Cys 634 Trp) in exon 11. The proband and one daughter had bilateral pheochromocytoma and MTC, two daughters had unilateral pheochromocytoma (one with confirmed MTC, one with nodular goiter and increased serum calcitonin), and one of the male grandchildren also has increased serum calcitonin.

The authors noted that risk-reducing thyroidectomy is a preventive option for all subtypes of MEN, and is recommended in many cases by the American Thyroid Association. The case findings presented here confirm that “genetic screening for germline RET protooncogene mutation in hereditary medullary thyroid cancer is accurate,” enabling patients who are carriers of the mutation to opt for early prophylactic surgery. However, this can be a difficult decision for parents of young children to make—in this case study, although the two grandchildren carry the RET mutation, their parents opted against total thyroidectomy, underscoring the need for further study of “the psychosocial impact of genetic testing for MEN 2” and the challenges of accepting surgical treatment and lifelong follow-up surveillance.