Multiple Endocrine Neoplasia Type 4 via the CDKN1B Gene

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder distinguished by tumors of the parathyroid glands, pancreatic islet cells, and anterior pituitary gland (Pannett and Thakker Endocrine-Related Cancer 6:449-473, 1999). Some patients with MEN1 may also develop adrenal cortical tumors, carcinoid tumors, facial angiofibromas, collagenomas, or lipomas. Neoplasia of endocrine glands typically leads to excessive hormone production. As a result, the clinical manifestations of MEN are directly related to the sites of the tumors. For example, ~95% of patients exhibit hypercalcemia, nephrolithiasis, or osteitis fibrosa cystica due to parathyroid tumors; ~40% have recurrent peptic ulcers, hypoglycemia, or hyperglucagonaemia due to pancreatic tumors; and ~30% have hyperprolactinaemia, hypercorticism (i.e. Cushing’s syndrome), or acromegaly due to anterior pituitary tumors. Approximately 30% of patients with a MEN1 phenotype test negative for variants in the MEN1 gene (Ozawa et al. J Clin Endocrinol Metab 92(5):1948-51, 2007). Multiple endocrine neoplasia was identified in a rodent model (MENX), and this helped identify variants in the human homolog CDKN1B. Patients with a MEN1-like phenotype who are positive for CDKN1B variants have been deemed to have multiple endocrine neoplasia type IV (MEN4). The clinical features of MEN4 are not clearly defined due to the limited number of patients reported. However, pituitary and parathyroid cancers as well as other malignancies have been identified (Marinoni and Pellegata. Neuroendocrinology 93:19–28, 2011).

Heterozygous germline variants in the CDKN1B gene predispose individuals to multiple endocrine neoplasia type 4 (Pellegata et al. PNAS 103:15558-15563, 2006; Marinoni and Pellegata. Neuroendocrinology 93:19–28, 2011). CDKN1B encodes the cyclin-dependent kinase inhibitor 1B (p27, Kip1), which acts as a tumor suppressor by binding to cyclin/Cdk complexes and inhibiting cell cycle progression (Sherr & Roberts, Genes Dev 13:1501-1512, 1999). Variants to date include missense variants, a regulatory variant, a small insertion, and a small deletion (Human Gene Mutation Database).

Analytical sensitivity for variants in CDKN1B should be high because variants reported to date include missense variants, a regulatory variant, a small insertion, and a small deletion (Human Gene Mutation Database). This test is predicted to detect a causative variant in ~3% of MEN1 patients without a detectable variant in MEN1 (Georgitsi et al. J Clin Endocrinol Metab 92(8): 3321-5, 2007).

Clinical sensitivity for gross deletions/duplications is currently unknown.

This test provides full coverage of all coding exons of the CDKN1B gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.