ESPE Abstracts (2021) 94 FC6.2

1Department of Paediatric Endocrinology, Barts Health NHS Trust, Royal London Children’s Hospital, London, United Kingdom.;2Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.;3Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.;4Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, United Kingdom.;5Royal Surrey County Hospital, Guildford, United Kingdom.;6Department of Endocrinology, Barts Health NSH Trust, London, United Kingdom.;7Surrey and Sussex Healthcare NHS Trust-East Surrey Hospital, Surrey, United Kingdom.;8East Suffolk and North Essex NHS Foundation Trust - Ipswich Hospital, Ipswich, United Kingdom.;9Department of Endocrinology and Diabetes WISDEM Centre, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom.;10Department of Paediatric Endocrinology, Great Ormond Street Hospital, London, United Kingdom

Background: Patients with autosomal dominant hypocalcemia type 1 (ADH1), due to germline gain-of-function calcium-sensing receptor (CASR) mutations, have hypocalcemia and seizures, hyperphosphatemia, hypercalciuria and inappropriately low parathyroid hormone (PTH) concentrations. Treatment for ADH1 comprises calcium and vitamin D analogs, however, their use predisposes to nephrocalcinosis and renal impairment. In contrast, recombinant human PTH(1-34) may increase serum calcium, without causing hypercalciuric renal disease, in ADH1 patients. We evaluated the effectiveness of continuous subcutaneous PTH(1-34) infusion (CSPI) in a retrospective cohort of six patients with severe forms ADH1 characterised by recurrent seizures in childhood.

Methods: Retrospective observational study of six ADH1 patients (age 5weeks-22years) treated with CSPI (mean duration = 3.2±0.6 years). All patients had recurrent hypocalcemic seizures requiring hospital admission and/or prolonged hospitalization despite treatment with calcium and vitamin D and/or bolus PTH injections. Effects on serum and urinary mineral concentrations, seizure frequency, and hospital admissions was assessed. CASR sequence analysis was undertaken, and the signalling responses of ADH1 mutants were assessed in HEK293cells.

Results: All patients had germline heterozygous CaSR gain-of-function mutations, with three being constitutively active mutations that had arisen de novo and showed diminished signaling responses to the calcilytic, NPS-2143. CSPI treatment over a period of 0.8-5.5 years, significantly increased serum adjusted-calcium concentrations from 1.79±0.06 to 2.10±0.04 mmol/L (P < 0.01), and reduced serum phosphate concentrations from 3.06±0.24 to 2.15±0.20 mmol/L(P < 0.001) without causing hypercalciuria in all the six studied patients. CSPI was also associated with decreased mean calcium-phosphate product from 5.45±0.33mmol2/L2 to 4.46±0.39 mmol2/L2 (P < 0.01) in 5 patients, and increased mean serum magnesium by 0.09mmol/L (95%CI, 0.03 to 0.14) in 4 patients. CSPI dramatically decreased frequency of hypocalcemic seizures per month from 2.0±1.4 to 0.01±0.005 (P < 0.05), that led to fewer hospital admissions per month from 9.9±4.7 to 0.8±0.4 in 5 patients. Serious adverse effects were not observed during the treatment with CSPI. Bone mineral apparent density was measured in three of the patients, and remained normal. One patient who was suspected to develop tachyphylaxis to PTH(1-34), sustained a unilateral slipped upper femoral epiphysis. CSPI did not worsen nephrocalcinosis or increase calcium excretion, which was reduced in three patients.

Conclusion: CSPI is well tolerated and represents a long-term therapy for children and young adults with ADH1, increasing serum calcium, ameliorating seizures and reducing hospital admissions. A prospective study is required to confirm these findings.

Volume 94

59th Annual ESPE (ESPE 2021 Online)

22 Sep 2021 - 26 Sep 2021

European Society for Paediatric Endocrinology 

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