ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 65 P86 | DOI: 10.1530/endoabs.65.P86

Effect of vitamin D analogue therapy in a patient with autosomal dominant hypocalcaemia type 2 (ADH2) due to GNA11 p.Arg60Leu mutation

Catriona Farrell1, Fadil Hannan2, Jacob George3, Emma Robinson4, Joanne McLean5, Hannah Boon6, Treena Cranston6, David Goudie5, Rajesh Thakker7 & Paul Newey1

1Division of Molecular and Clinical Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK; 2Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK; 3Ninewells Hospital & Medical School, University of Dundee, Dundee, UK; 4University Hospitals of Derby & Burton NHS foundation Trust, Derby, UK; 5Clinical Genetics, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK; 6Oxford Medical Genetics Laboratory, Oxford University Hospitals NHS Foundatiion Trust, Oxford, UK; 7Radcliffe Department of Medicine, University of Oxford, Oxford, UK

Background: Autosomal dominant hypocalcaemia (ADH) is most commonly due to activating mutations in the Calcium Sensing Receptor (ADH Type 1), in which treatment with vitamin D analogues is frequently associated with hypercalciuria. More recently, activating mutations in the alpha-subunit of the G-protein α-11 (Gα11), encoded by GNA11, have been identified in a small number of ADH kindreds (ADH Type 2). The impact of vitamin D analogue treatment in ADH2 patients has not been evaluated.

Case Report: The proband, a 46-year-old female, was incidentally found to be hypocalcaemic. Clinical assessment revealed that she was experiencing intermittent paresthesia and cramping of the digits. Baseline biochemical testing confirmed a reduced serum corrected calcium (1.79 mmol/l; NR 2.1–2.55 mmol/l), raised serum phosphate (2.05; NR 0.8–1.5 mmol/l), low plasma PTH (1.0 pmol/l; NR 1.5–7.6 pmol/l), and low urine calcium:creatinine (U.Ca:Creat) ratio (0.2; NR 0.3–0.7). Her father had been on long-term calcium supplementation raising the possibility of a dominantly inherited hypocalcaemic disorder. Subsequent gene-panel testing revealed a pathogenic GNA11 variant (c.179G>T; p.Arg60Leu) establishing the diagnosis of ADH2. The patient was treated with calcitriol (with ≥1000 mg dietary/oral calcium/day) to relieve hypocalcaemic symptoms and has been monitored for >21 months with serum and urine calcium measurements. The calcitriol dose was progressively increased from 250 ng daily to 1000 ng daily, which improved symptoms, and increased her serum calcium in a dose-dependent manner from 1.79 to 2.09 mmol/l. This was not associated with consistent alterations in serum phosphate or PTH. However, treatment with calcitriol 1000 ng daily increased her U.Ca:Creat ratio to 0.5 and was associated with hypercalciuria (24 hour urine calcium >0.1 mmol/kg per 24 h), despite failing to normalise serum calcium concentration.

Conclusions: Although vitamin D analogue therapy may alleviate symptoms and improve hypocalcaemia in patients with ADH2, caution is required as hypercalciuria may occur, even when serum calcium is below the reference range.