Endocrine Abstracts

An 18-year-old male, presenting with unexplained weight loss, was found to have asymptomatic hypocalcaemia (adjusted 1.72 mmol/l, range 2.2-2.6 mmol/l) and hyperphosphataemia (2.05 mmol/l, range 0.8-1.5 mmol/l). He had a background of repaired perimembranous VSD, mild learning difficulties and developmental delay. Parathyroid hormone (PTH) was found to be undetectable and 25-OH Vitamin D insufficient (43 nmol/l). Urine calcium/creatinine ratio was elevated (0.81 mmol/mmol). There was no evidence of autoimmune endocrinopathy: no mucocutaneous candidiasis and both thyroid function and 9 am cortisol were normal. Parathyroid autoantibodies were negative. There was no family history, although the patient and his mother were both noted to have short stature and possible facial anomalies. Genetic testing established a heterozygous c.2488G>A activating variant of the calcium sensing receptor gene (CaSR) resulting in amino acid substitution p.(Gly830Ser), which has previously been described in the literature. This confirmed the diagnosis of autosomal dominant hypocalcaemia. It was challenging to achieve normocalcaemia at presentation, requiring multiple intravenous calcium infusions and uptitration to 2 mg alfacidol and 10 Calcichew tablets daily. Calcium then fell to 1.88 mmol/l at clinic follow-up and alfacalcidol was switched to calcitriol 500 ng twice daily. The patient became intolerant of multiple calcium formulations and resulted to consuming up to five pints of milk a day to maintain normocalcaemia. Calcitriol was increased further to 1500 ng daily, but calcium rose to 2.46 mmol/l and so was reduced to 1250 ng and the patient advised to lower dairy intake. The patient has subsequently presented with chronic daily headache and CT imaging demonstrated ectopic intracerebral calcifications. Ultrasound to assess for nephrocalcinosis is awaited. Renal function is maintained with eGFR>60 and calcium/creatinine ratio is in the normal range (0.43 mmol/mmol). CaSR expression is highest in parathyroid and kidney. Gain-of-function leads to reduced PTH secretion, and consequently reduced calcium release from bone, Vitamin D activation and renal calcium reabsorption. As CaSR is also expressed in the kidney this compounds the effect on calcium reabsorption. Treatment with activated Vitamin D and calcium supplementation increases filtered calcium load, worsening hypercalciuria and leading to nephrocalcinosis and intracerebral calcifications. Paradoxically in this patient calciuria improved with treatment. It is recommended calcium is maintained in the bottom or just below the normal range and thiazide diuretics can be used to reduce calciuria. Future treatment avenues in research trials include calcilytics and long-acting PTH analogues.