Multiple Endocrine Neoplasia Type 4

Excerpt

Clinical characteristics: Multiple endocrine neoplasia type 4 (MEN4) is characterized by the development of endocrine tumors, especially those involving the parathyroid and/or pituitary gland. Parathyroid adenomas and parathyroid hyperplasia manifest as hypercalcemia (primary hyperparathyroidism) as a result of the overproduction of parathyroid hormone. Anterior pituitary adenomas can secrete adrenocorticotrophic hormone (ACTH), growth hormone (GH), prolactin, or are nonfunctional (nonsecreting) adenomas. Well-differentiated endocrine tumors of the gastroenteropancreatic tract, carcinoid tumors, and adrenocortical tumors can also occur.

Diagnosis/testing: The diagnosis of MEN4 is established in a proband with a germline heterozygous pathogenic variant in CDKN1B identified by molecular genetic testing.

Management: Treatment of manifestations: Parathyroidectomy for primary hyperparathyroidism; cinacalcet may be considered in those with symptomatic hypercalcemia who are not surgical candidates; surgical resection for pituitary adenomas that secrete ACTH or GH; cabergoline for prolactin-secreting tumors; surgical resection for neuroendocrine and carcinoid tumors if possible; some individuals may be treated with somatostatin analogs; proton pump inhibitors for individuals with gastrin-secreting tumors.

Surveillance: Biennial serum calcium and gastrin starting at age 25 years; IGF-1 and prolactin every three to five years or as symptoms indicate, starting at age 25 years; pituitary MRI every five years starting at age 25 years; abdominal MRI or CT every five years starting at age 25 years and increasing frequency to every 2.5 years starting at age 40 years.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the CDKN1B pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of surveillance and treatment.

Genetic counseling: MEN4 is inherited in an autosomal dominant manner. Most individuals diagnosed with MEN4 have an affected parent; some individuals diagnosed with MEN4 may have the disorder as the result of a de novo CDKN1B pathogenic variant. Each child of an individual with MEN4 has a 50% chance of inheriting the CDKN1B pathogenic variant. Once the CDKN1B pathogenic variant has been identified in an affected family member, testing of at-risk asymptomatic family members (strongly recommended for all first-degree relatives of an affected person with an identified CDKN1B pathogenic variant) and prenatal and preimplantation genetic testing are possible.