FMTC is diagnosed in families with medullary thyroid carcinoma in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. RET mutations in exons 10, 11, 13, and 14 account for most cases. (See Table 2.)
Table 2. Clinical Features of MEN 2 Syndromes
|MEN 2 Subtype
||Medullary Thyroid Carcinoma
||20% to 30%
A germline activating mutation in the RET oncogene (a receptor tyrosine kinase) on chromosome 10q11.2 is responsible for the uncontrolled growth of cells in medullary thyroid carcinoma associated with MEN 2A and MEN 2B syndromes.[10,11,12] The management of medullary thyroid cancer in children from families having the MEN 2 syndromes relies on presymptomatic detection of the RET proto-oncogene mutation responsible for the disease. For children with MEN 2A, thyroidectomy is commonly performed by approximately age 5 years or older if that is when a mutation is identified. [12,13,14,15,16,17] Relatives of patients with MEN 2A should undergo genetic testing in early childhood, before the age of 5 years. Carriers should undergo total thyroidectomy as described above with autotransplantation of one parathyroid gland by a certain age.[17,18,19,20] Because of the increased virulence of medullary thyroid carcinoma in children with MEN 2B and in those with mutations in codons 883, 918, and 922, it is recommended that these children undergo prophylactic thyroidectomy in infancy.[9,14,21]; [Level of evidence: 3iiiDii] Complete removal of the thyroid gland is the recommended procedure for surgical management of medullary thyroid cancer in children, since there is a high incidence of bilateral disease.
Hirschsprung disease has been associated in a small percentage of cases with the development of neuroendocrine tumors such as medullary thyroid carcinoma. RET germline inactivating mutations have been detected in up to 50% of patients with familial Hirschsprung disease and less often in the sporadic form.[23,24,25] Cosegregation of Hirschsprung disease and medullary thyroid carcinoma phenotype is infrequently reported, but these individuals usually have a mutation in RET exon 10. It has been recommended that patients with Hirschsprung disease be screened for mutations in RET exon 10 and consideration be given to prophylactic thyroidectomy if such a mutation is discovered.[25,26,27]
The Carney complex is an autosomal dominant syndrome caused by mutations in the PPKAR1A gene, located in chromosome 17. The syndrome is characterized by cardiac and cutaneous myxomas, pale brown to brown lentigines, blue nevi, primary pigmented nodular adrenocortical disease causing Cushing syndrome, and a variety of endocrine and nonendocrine tumors, including pituitary adenomas, thyroid tumors, and large cell calcifying Sertoli cell tumor of the testis.[28,29,30] There are guidelines that may be followed for screening patients with Carney complex.