The certified gene for this condition is RET. According to GeneReviews, MEN2 subtypes, including FMTC, are inherited in an autosomal dominant manner, and the diagnosis is established with a heterozygous germline gain-of-function pathogenic variant in RET. By definition, individuals with FMTC have multiple affected family members. A ClinGen validity classification for RET is not supplied in this packet.

Genotype-phenotype and penetrance: The review reports that pathogenic variants in cysteine codons 609, 611, 618, and 620 in exon 10 of RET are associated with MEN2A, FMTC, and Hirschsprung disease, and are detected in more than 50% of families with FMTC; these variants are described as having low transforming activity. Variants at codons 790 or 804 may be associated with papillary thyroid carcinoma in addition to MTC. Disease expression of codon 804 variants is described as highly variable, even within the same family: some individuals with the same variant had MTC at age five years and fatal metastatic MTC at age 12 years, whereas others had normal thyroid histology at age 27 years, normal biochemical screening at age 40 years, and no clinical evidence of MTC at age 86 years. The review also states that penetrance of some RET variants is incomplete, and that the incidence of MTC, pheochromocytoma, and parathyroid disease varies by MEN2 phenotype.

According to GeneReviews, FMTC is suspected in families with more than one individual diagnosed with MTC in the absence of pheochromocytoma or parathyroid adenoma or hyperplasia, and is diagnosed clinically in families with two or more individuals with MTC in the absence of those findings. The review describes establishing the diagnosis through a clinical diagnosis or through identification of a heterozygous germline gain-of-function pathogenic or likely pathogenic variant in RET, and notes that a RET variant of uncertain significance neither establishes nor rules out the diagnosis.

Molecular testing approaches described include single-gene sequence analysis of RET, deletion and duplication analysis, select-exon testing for suspected MEN2A or FMTC, and multigene cancer predisposition panels. Biochemical findings described include an elevated plasma calcitonin concentration, which the review calls a sensitive and specific marker for MTC and C-cell hyperplasia; provocative testing measures calcitonin before and after intravenous calcium, and other secretagogues such as pentagastrin are also used. Histologically, MTC arises from calcitonin-producing C cells, and immunohistochemistry for calcitonin may serve as an adjunct. Pentagastrin carries an orphan drug designation as an aid in diagnosing medullary thyroid carcinoma; a designation is not a marketing approval.

The review's differential diagnosis discusses sporadic MTC, in which a somatic RET variant is found in 40-50% of tumors, and notes that about 20-30% of all individuals with MTC have a germline RET pathogenic variant. No newborn screening information is certified for this condition.

No foundational therapies or FDA-approved treatments are listed in this packet, and no orphan drug record in the packet is an approved treatment for this condition. The following describes the GeneReviews account of MEN2 management, which includes FMTC.

Surgery: The review describes prophylactic thyroidectomy as the primary preventive measure for individuals with an identified germline RET pathogenic variant, and states that its timing is considered controversial and can be guided by the RET codon position according to American Thyroid Association consensus. It lists surgical removal of the thyroid with lymph node dissection as standard treatment for MTC, with external beam radiation therapy mentioned for incomplete resection or extrathyroidal extension with positive margins. Thyroid hormone replacement is described for hypothyroidism after thyroidectomy. The review also describes evaluating for pheochromocytoma before any surgery.

Systemic therapy: For metastatic MTC, the review describes multikinase inhibitors, RET-selective inhibitors, and, for certain tumors with high mutational burden, an anti-PD-1 antibody. It states that kinase inhibitors have improved progression-free survival in some persons.

Surveillance and care team: Surveillance described in the review includes serum calcitonin and carcinoembryonic antigen measurement after thyroidectomy, and biochemical screening for pheochromocytoma and parathyroid disease, with intervals that depend on the RET variant risk category. Supportive care is described as multidisciplinary, involving endocrinology, endocrine surgery, and medical genetics. Surveillance for complications is distinct from treatment of active manifestations.

A natural history field is not certified in this packet. According to the GeneReviews clinical description of MEN2, all individuals with an MTC-predisposing RET variant who have not undergone prophylactic thyroidectomy demonstrate biochemical evidence of MTC by age 35 years, and approximately 50% of individuals with MTC who have undergone total thyroidectomy and neck nodal dissection have recurrent disease. The review also states that thyroid glands removed from individuals with a germline RET variant and normal plasma calcitonin have been found to contain MTC, and that diarrhea with a high plasma calcitonin concentration implies a poor prognosis. Expression varies widely between individuals, including within families, as described under codon 804 variants. These statements describe published group-level observations for MEN2 and do not predict the course for any individual.

Certified active trial records are present in the packet, and several are listed for this condition. Examples include NCT07383246, "CTR-FAPI-guided Precision Surgery for Newly Diagnosed MTC" (Phase 3, recruiting; Cancer Institute and Hospital, Chinese Academy of Medical Sciences); NCT07006727, a Phase 1 study of [225Ac]Ac-ETN029 in advanced DLL3-expressing solid tumors (recruiting; Novartis Pharmaceuticals); and NCT03583528, "DOTATOC PET/CT for Imaging NET Patients" (active, not recruiting; British Columbia Cancer Agency). Trial titles do not establish that an intervention is effective for this condition. GeneReviews also describes clinical trials of multikinase inhibitors and immune checkpoint inhibitors as under way for MTC. Active clinical trials for this condition are listed on ClinicalTrials.gov.