Endocrine Abstracts

Familial hypocalciuric hypercalcaemia type 1 (FHH1) is mainly caused by loss-of-function missense mutations of the extracellular calcium-sensing receptor (CaSR), which is a parathyroid- and kidney-expressed G-protein coupled receptor that plays a pivotal role in mineral metabolism. Here, we report the unusual occurrence of a novel heterozygous in-frame CASR exon 4 deletion, c.(492+1_493-1)_(1377+1_1378-1)del, in a family with FHH1. This mutation is predicted...

Background: Kidney stone disease (KSD) has been linked to obesity, metabolic syndrome and higher serum calcium concentration (SCa). The mechanisms underlying these associations are uncertain. Using conventional and genetic epidemiological techniques, we aimed to investigate the effects of adiposity on KSD.Methods: Observational associations between adiposity and incident KSD in 479, 405 people from the UK Biobank were assessed. Genome-wide association st...

Marshall-Smith syndrome (MSS) is a congenital disorder characterised by developmental delay, short stature, respiratory difficulties, distinctive facial features, skeletal abnormalities (such as kyphoscoliosis, dysostosis and osteopenia) and delayed neural development, and is due to heterozygous mutations that are clustered in exons 6–10 of the transcription factor nuclear factor I/X (NFIX) gene. These frameshift and splice-site NFIX variants result in t...

Neuroendocrine tumours (NETs) presenting as metastatic cancer of unknown primary site (CUP) are suspected to confer poorer prognosis compared to metastatic NETs of known primary site. We performed a retrospective, single centre study to determine the prognostic indicators in CUP-NETs compared to metastatic small intestinal NET (SiNET), before and after adjusting for factors known to affect overall survival. Subjects were selected from a departmental database of 1050 NET patien...

The modulation of pancreatic islet mass represents a novel therapeutic approach for the management of diabetes mellitus. G-protein coupled receptors (GPCRs) regulate beta-cell expansion and proliferation, and the objective of this study was to assess whether the calcium-sensing receptor (CaSR), which is an abundantly expressed beta-cell GPCR, may influence islet mass and systemic glucose homeostasis, and thus represent an exploitable drug target in some forms of diabetes. We c...

Renal calcification (nephrocalcinosis), which has a multi-factorial etiology involving environmental and genetic determinants, affects ~8% of adults by 70 years. Nephrocalcinosis may occur as a familial disorder in ~65% of patients, and in 70% of patients, nephrocalcinosis may be associated with endocrine and metabolic disorders that include primary hyperparathyroidism, renal tubular acidosis, hypercalciuria, cystinuria, and hyperoxaluria. Investigations of families with hered...

Pancreatic neuroendocrine tumours (NETs) are reported to show frequent mutations in chromatin remodelling genes, while pituitary NETS have alterations in histone modification. Histone modifications, and specifically acetylated residues on histone tails are recognised by members of the bromo and extra terminal (BET) protein family, via their bromodomains, causing alterations in the transcription of growth stimulating genes. BET bromodomain inhibitors have been demonstrated to s...

Cushing’s syndrome, which is characterised by excessive circulating glucocorticoid (GC) concentrations, may be due to ACTH-dependent or -independent causes that include anterior pituitary and adrenal cortical tumours, respectively. In the course of our phenotype-driven screens of mouse mutants induced by the chemical mutagen N-ethyl-N-nitrosourea (ENU), we observed a mutant mouse with obesity, hyperglycaemia and low bone mineral density, features that ar...

Familial hypocalciuric hypercalcaemia (FHH) is an autosomal dominant disorder characterized by lifelong elevation of serum calcium concentrations with inappropriately low urinary calcium excretion. Three types referred to as FHH1, FHH2 and FHH3 and located on chromosomes 3q21.1, 19p and 19q13.3, respectively, have been reported. FHH1, caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), accounts for >65% of FHH patients. To identify the gen...

Pituitary non-functioning adenomas (NFAs), arising mostly from gonadotroph cells, represent the second most common type of pituitary tumour, after prolactinomas. NFAs are monoclonal in origin, but mutations of genes associated with hereditary pituitary syndromes (e.g. MEN1, AIP, CDKN1B, and PRKAR1A), classic oncogenes or tumour suppressor genes are rarely found. We therefore performed whole-exome sequence analysis to determine the tumourigenic events in pituitary NFAs using DN...