SFEBES2014 Poster Presentations Bone (30 abstracts)
Clinical studies of adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 reveal genotype–phenotype correlations and effectiveness of cinacalcet
Fadil Hannan 1 , Angela Rogers 1 , Sarah Howles 1 , Treena Cranston 2 , Malachi McKenna 3 , Tristan Richardson 4 , Valerie Babinsky 1 , Anita Reed 1 , Clare Thakker 1 , Detlef Bockenhauer 5 , Rosalind Brown 6 , Jacqueline Cook 7 , Ken Darzy 8 , Sarah Ehtisham 9 , Una Graham 10 , Tony Hulse 11 , Steven Hunter 10 , Dhavendra Kumar 12 , John McKnight 13 , Patrick Morrison 14 , Zulf Mughal 9 , Simon Pearce 15 , Isabelle Scheers 16 , Timothy Wang 17 , Michael Whyte 18 , M Andrew Nesbit 1 & Rajesh Thakker 1
1University of Oxford, Oxford, UK; 2Churchill Hospital, Oxford, UK; 3St. Vincent’s University Hospital, Dublin, Ireland; 4Royal Bournemouth Hospital, Bournemouth, UK; 5UCL Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; 6Boston Children’s Hospital, Boston, Massachusetts, USA; 7Sheffield Children’s Hospital, Sheffield, UK; 8Queen Elizabeth II Hospital, Welwyn Garden City, UK; 9Royal Manchester Children’s Hospital, Manchester, UK; 10Royal Victoria Hospital, Belfast, UK; 11St Thomas’ Hospital, London, UK; 12University Hospital of Wales, Cardiff, UK; 13Western General Hospital, Edinburgh, UK; 14Queen’s University Belfast, Belfast, UK; 15Newcastle University, Newcastle Upon Tyne, UK; 16Cliniques universitaires Saint-Luc, Brussels, Belgium; 17Frimley Park Hospital, Surrey, UK; 18Shriners Hospital for Children, St. Louis, Missouri, USA.
Familial hypocalciuric hypercalcaemia (FHH) comprises three types: FHH1, FHH2, and FHH3, which are due to mutations of the calcium-sensing receptor (CaSR), G-protein α 11 subunit (Gα11), and adaptor protein-2 sigma subunit (AP2σ), respectively. The aims of this study were: to assess for genotype–phenotype correlations among the three reported FHH3-causing AP2σ mutations, which all involve the Arg15 residue, and comprise Arg15Cys, Arg15His, and Arg15Leu; to compare the calcium-related phenotypes between FHH3 and FHH1; and to assess the effectiveness of cinacalcet, a CaSR-targeted agonist, to lower the hypercalcaemia in FHH3 individuals. An analysis of genotype–phenotype correlations in the FHH3 probands (n=23) harbouring either the Arg15Cys (n=7), Arg15His (n=7) or Arg15Leu (n=9) AP2σ mutations, revealed Arg15Leu to be associated with marked hypercalcaemia (mean±S.E.M serum adjusted-calcium=3.08±0.05 mmol/l for Arg15Leu, 2.83±0.04 mmol/l for Arg15Cys, and 2.79±0.05 mmol/l for Arg15His, P<0.01). A comparison of the biochemical phenotypes of FHH1 individuals (n=43) and FHH3 individuals (n=48), revealed FHH3 to be associated with significantly higher serum adjusted-calcium concentrations (2.87±0.02 mmol/l for FHH3 vs 2.76±0.02 mmol/l for FHH1, P=0.001) and significantly lower urinary calcium-to-creatinine clearance ratios (0.004±0.001 for FHH3 vs 0.007±0.001 for FHH1, P<0.001). There were no significant differences in serum concentrations of phosphate, alkaline phosphatase activity, or parathyroid hormone (PTH) between FHH3 and FHH1 subjects. Administration of cinacalcet (30–60 mg daily for >6 months) in three unrelated symptomatic FHH3 individuals, each with a Arg15Cys, Arg15His, or Arg15Leu mutation and with serum calcium concentrations ≥3.0 mmol/l, corrected the values to within the normal range, and also lowered serum PTH concentrations, which remained within the normal range. These findings indicate a genotype–phenotype correlation in FHH3 individuals, with the Arg15Leu AP2σ mutation resulting in the most severe FHH phenotype, and demonstrate the effectiveness of cinacalcet in correcting the hypercalcaemia of FHH3 individuals.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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