Aim We report the effective use of the synthetic parathyroid hormone (PTH) teriparatide to treat a 4 year old boy with autosomal dominant hypocalcaemia.
Background Autosomal Dominant hypocalcaemia is characterised by hypocalcaemia with a lack of parathyroid hormone (PTH) response and inappropriately high urinary calcium excretion. It is caused by gain-of-function mutations in the extracellular calcium sensing receptor which then “over-reads” the extracellular fluid concentration of calcium resulting in suppression of PTH secretion. This then reduces PTH-mediated calcium reabsorption in the distal nephron. Treatment of hypocalcaemia with vitamin D analogues and calcium supplements results in further increases in urinary calcium concentrations, frequently causing nephrocalcinosis and progressive renal damage.
Our four year old male patient presented in the neonatal period with seizures secondary to hypocalcaemia and low PTH levels. He suffered repeated seizures with associated tetany. Treatment with alfaclacidol and calcium supplements was able to provide seizure control, however episodes of tetany continued. A heterozygous, activating mutation of the extracellular calcium sensing receptor (c.2528C>A; p.Ala843Glu) was confirmed at age 2. The treatment caused significant hypercalciuria and nephrocalcinosis with a reduction in GFR to 73 ml/mim/m.2 Continuing this therapy would have resulted in end stage kidney disease requiring dialysis/transplantation. The decision was made to try treatment with PTH in order to raise the plasma calcium concentration while minimising the increase in urinary calcium excretion.
Funding for treatment was approved by specialised commissioning and treatment was commenced at a dose of 0.4 microg/kg BD.
Administration Teriparatide is only available in a prefilled pen (Forsteo®) delivering 20 microg in 80 microlitre per dose. Following discussions with the pharmacy team at Great Ormond Street Hospital for Sick Children a protocol was developed to allow these set doses to be diluted prior to administration. By diluting the 20 microg dose to 0.5 ml in a 1 ml syringe a solution containing 40 microg/ml was obtained.
Outcome Treatment was started at 3.66 years of age. Pre-treatment adjusted plasma calcium concentration was 1.96 mmol/L and the urinary calcium excretion was 0.11 mmol/kg/day (normal<0.1). After 5 days of treatment the patient felt very much better and had more energy. The adjusted plasma calcium concentration had risen to 2.09 mmol/L and the urinary calcium excretion had fallen to 0.045 mmol/kg/day.
Over the following 9 months the dose of alfacalcidol was reduced from 600 nanograms per day to 300 nanograms per day and calcium supplements were reduced from 16 mmol four times per day to zero. The teriparatide dose was increased from an initial dose of 2 microgram twice daily to 6 microgram twice daily. The plasma calcium has remained above 2 mmol/L apart from a period where further weaning of the alfacalcidol dose was attempted.
Rather to our surprise, the patient did not experience symptoms of hypercalcaemia with plasma calcium concentrations within the normal range. His muscle power and tone has increased.
We conclude that teriparatide is a useful agent for treating patients with gain-of-function mutations of the calcium-sensing receptor/autosomal dominant hypocalcaemia