Endocrine Abstracts (2019) 65 P140 | DOI: 10.1530/endoabs.65.P140

A cyclin dependent kinase inhibitor 1B missense mutation (Pro69Leu) is associated with familial hypomagnesaemia, but not multiple endocrine neoplasia type 4 (MEN4)

Mark Stevenson1, Eric Olinger2,3, Huguette Debaix2, Bruno Vogt3, Olivier Devuyst2 & Rajesh Thakker1


1University of Oxford, Oxford, UK; 2University of Zurich, Zurich, Switzerland; 3Bern University Hospital, Bern, Switzerland


Mutations in cyclin dependent kinase inhibitor 1B (CDKN1B) are associated with multiple endocrine neoplasia type 4 (MEN4), in which patients typically develop parathyroid and anterior pituitary tumours, and occasionally tumours of the pancreas, adrenals, kidneys and reproductive organs. Here, we report a family with a missense mutation of CDKN1B (p.Pro69Leu) that did not have MEN4-associated tumours, but instead had hypomagnesaemia. The proband, presented with fatigue, cramps, thirst, hypomagnesaemia, and Hashimoto’s thyroiditis, and subsequently also developed uterine fibromas and episodic frontal alopecia. The proband, mother and stepsister had hypomagnesaemia, due to renal magnesium wasting, and Hashimoto’s thyroiditis; but none of them had primary hyperparathyroidism, pituitary tumours, pancreatic neuroendocrine tumours or phaeochromocytoma; a maternal aunt had Hashimoto’s thyroiditis only. Hypomagnesaemia, which occurs in ˜30% of hospitalised patients, can result from gastrointestinal and renal loss, and may also occur as: part of a hereditary syndromic disorder (e.g. autosomal dominant hypocalcaemia or Bartter syndrome type V); or an isolated non-syndromic familial disease. Owing to the large number of genes encoding transporter proteins involved in magnesium homeostasis that could be responsible, whole exome sequencing was undertaken in the three family members with hypomagnesaemia after obtaining informed consent. No mutations were identified in known magnesiotropic genes, but a heterozygous c.206C>T CDKN1B variant, that predicted a missense mutation p.Pro69Leu of an evolutionarily conserved amino acid, was identified. The CDKN1B Pro69Leu mutation co-segregated with hypomagnesaemia, but not Hashimoto’s thyroiditis, among six family members (three with renal magnesium wasting and Hashimoto’s thyroiditis, one with Hashimoto’s thyroiditis only, and two unaffected members). The Pro69Leu missense CDKN1B mutation, which has been previously reported in MEN4 patients, results in rapid proteosomal degradation and reduced binding to cyclin dependent kinase 2 (CDK2). Thus, our studies expand the spectrum of clinical features associated with CDKN1B mutations, to include renal magnesium wasting.

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