Activating mutations in the calcium-sensing receptor: genetic and clinical spectrum in 25 patients with autosomal dominant hypocalcaemia - a German survey

• Published in: Clinical endocrinology (Oxford) Vol. 75; no. 6; pp. 760 - 765
• Main Authors: Raue, Friedhelm, Pichl, Josef, Dörr, Helmuth-G., Schnabel, Dirk, Heidemann, Peter, Hammersen, Gerhard, Jaursch-Hancke, Cornelia, Santen, Reinhard, Schöfl, Christof, Wabitsch, Martin, Haag, Christine, Schulze, Egbert, Frank-Raue, Karin
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-12-2011; Blackwell; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Age; Basal ganglia; Biological and medical sciences; Calcification; Calcification (ectopic); Calcinosis; Calcitriol; Calcium (blood); Calcium-sensing receptors; Child; Child, Preschool; Cohort Studies; Data Collection; DNA Mutational Analysis; Endocrinopathies; Female; Fundamental and applied biological sciences. Psychology; Genes, Dominant; Germany - epidemiology; Humans; Hypercalciuria; Hypocalcemia - epidemiology; Hypocalcemia - genetics; Hypoparathyroidism; Infant; Infant, Newborn; Kidney; Kidney diseases; Male; Medical sciences; Middle Aged; Missense mutation; Mutation - physiology; Parathyroid hormone; Phenotype; Receptors, Calcium-Sensing - chemistry; Receptors, Calcium-Sensing - genetics; Retrospective Studies; Vertebrates: endocrinology; Vitamin D; Young Adult; Europe; Germany; Human; Hydroelectrolytic balance disorder; Calcium; Patient; German; Inorganic element; Metabolic disorder; Survey; Surveillance; Autosomal character; Genetics; Inheritance(genetics); Mutation; Calcium-sensing receptor; Endocrinology; Hypocalcemia
• ISSN: 0300-0664; 1365-2265
• DOI: 10.1111/j.1365-2265.2011.04142.x

Summary
Objective  Autosomal dominant hypocalcaemia or hypoparathyroidism is caused by activating mutations of the calcium‐sensing receptor (CaSR). Treatment with calcium and vitamin D often worsens hypercalciuria and nephrocalcinosis, and renal impairment can result. Our aim was to describe the phenotypic variance of this rare disorder in a large series and to evaluate the outcome after long‐term treatment.
Design  Nationwide retrospective collaborative study.
Patients  We describe 25 patients (14 men and 11 women), 20 belonging to 11 families and five single cases.
Measurements  Activating CaSR mutations and clinical and biochemical findings were evaluated.
Results  Nine different missense mutations of the CaSR, including one novel variant (M734T), were found. Twelve patients (50%) were symptomatic, 9 (36%) had basal ganglia calcifications and 3 (12%) had nephrocalcinosis. Serum calcium was decreased (1·87 ± 0·13 mm), and PTH was decreased (n = 19) or inappropriately low (n = 4). The occurrence of hypocalcaemic symptoms at diagnosis was related to the degree of hypocalcaemia. The occurrence of features like calcification of basal ganglia or kidney calcification did not correlate with the severity of hypocalcaemia or the age at diagnosis. The most common treatment was calcitriol (median dosage 0·6 μg/day), and the mean duration of therapy was 7·1 years (max. 26 years). Hypercalcaemic episodes rarely occurred, and the rate of kidney calcifications was remarkably low (12%).
Conclusion  This series increases the limited knowledge of mutations and phenotypes of this rare disorder. Mutation analysis of the CaSR gene facilitates patient and family management. Low dosages of calcitriol resulted in less frequent renal calcifications.