Safety and efficacy of continuous subcutaneous PTH (1-34) infusion therapy (CSPI) for severe autosomal dominant hypocalcaemia type 1 (ADH1) in Children and Young People (CYP)

Aikaterini Perogiannaki; Alattar Mohammad Meshari; Kishore Baske; Rebecca J. Gorrigan; Oladimeji Smith; Debbie Pullen; Sailesh Sankaranarayanan; Jeremy Allgrove; Evelien Gevers

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ESPE Abstracts (2024) 98 P1-220

ESPE2024 Poster Category 1 Bone, Growth Plate and Mineral Metabolism 3 (10 abstracts)

Safety and efficacy of continuous subcutaneous PTH (1-34) infusion therapy (CSPI) for severe autosomal dominant hypocalcaemia type 1 (ADH1) in Children and Young People (CYP)

Aikaterini Perogiannaki* ¹ , Mohammad Meshari Alattar* ¹ , Kishore Baske ¹ , Rebecca J. Gorrigan ² , Oladimeji Smith ³ , Debbie Pullen ⁴ , Sailesh Sankaranarayanan ⁵ , Jeremy Allgrove ⁶ & Evelien Gevers ^7,1

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¹Barts Health NHS Trust, Royal London Hospital, Department of Paediatric Endocrinology, London, United Kingdom. ²Barts Health NHS Trust, Royal London Hospital, Department of Endocrinology, London, United Kingdom. ³East Kent Hospitals University NHS Foundation Trust, William Harvey Hospital, Ashford, United Kingdom. ⁴Surrey and Sussex Healthcare NHS Trust, East Surrey Hospital, Redhill, United Kingdom. ⁵University Hospitals Coventry and Warwickshire Coventry, Coventry, United Kingdom. ⁶Great Ormond Street Hospital for Children London, London, United Kingdom. ⁷Queen Mary University of London, Barts and the London Medical School, William Harvey Research Institute, Centre for Endocrinology, London, United Kingdom

*Aikaterini Perogiannaki and Mohammad Meshari Alattar are joint first authors of this work.

Introduction: ADH1 is caused by Calcium Sensing Receptor (CaSR) gain of function (GoF) variants, leading to hypoparathyroidism, hypocalcaemia, seizures, hyperphosphatemia, hypomagnesaemia and severe hypercalciuria. Conventional treatment (Alphacalcidol, Calcium) predisposes to nephrocalcinosis and renal impairment and may not reduce seizures. We previously reported that CSPI by insulin pump effectively increased serum calcium concentrations and reduced seizures, hospital admissions and calcium excretion in six patients with severe ADH1 (mean CSPI duratio n = 3.2±0.6 years). We now report longer-term data on the CSPI safety and efficacy.

Methods: Retrospective observational study of five ADH1 patients (age 6-30 years) treated with CSPI (mean duratio n = 8.22±1.26years). The sixth had renal and parathyroid transplantation and stopped CSPI. All had GoF CASR variants and recurrent hypocalcaemic seizures requiring hospital admission on conventional treatment or PTH injections prior to CSPI. Effects on seizure frequency, growth, bone mineral density and hospital admissions were assessed. Six-monthly serum and urine mineral concentrations were collected from the end of the previous collection period (Jan 2018) and mean and SD are presented.

Results: Effect of CSPI treatment over 5.99-9.01 years is shown in the table below.

NR: Normal range *Latest value **Data expressed as: Mean±SD (Minimum, Maximum)


Patient(P)	P1	P2	P3	P4	P5
CASR Variant	p.F821L	p.T828N	p.T828N	p.Y829C	p.A843E
Current Age(Years)	8.77	9.43	30.86	9.15	6.23
CSPI Duration(Years)	8.67	8.58	8.86	9.01	5.99
CSPI Dose[mcg/kg/day]*	0.63	0.28	0.6	0.29	0.56
Adjusted Calcium[mmol/L](NR:2.2-2.6)**	1.98±0.31(1.55,2.71)	1.94±0.36(1.49,2.57)	1.90±0.20(1.7,2.35)	2.06±0.28(1.41,2.48)	2.27±0.22(1.89,2.6)
Calcium-Phosphate Product**	3.50±0.51(2.57,4.30)	3.91±0.41(3.13,4.27)	2.34±0.33(1.91,2.91)	4.18±0.58(3.27,5.45)	4.48±0.56(3.73,5.52)
Urine Calcium/Creatinine Ratio**	1.12±0.61(0.48,2.50)	0.74±0.29(0.27,1.19)	0.58±0.23(0.21,0.87)	0.49±0.21(0.13,0.74)	0.45±0.31(0.14, 1.00)
24-hour Urinary Calcium[mmol/day](NR:2.5-7.5)**	4.5±1.06(3.1,5.6)	2.0±1.85(1.4,2.6)	2.82±0.88(2.2,3.44)	1.7±0.95(0.8,2.7)	NA
Admissions for Hypocalcaemia(Days)	21	3	7	0	3
Hypocalcaemic Seizures	0	1	1	0	0
Height(SDS)*	126.6(-0.73)	132.9(-0.41)	145.1(-3.06)	134.6(0.09)	124.9(1.67)
BMD L1-L4 Z Score*	-1.4	-0.5	NA	0.3	0.3
Nephrocalcinosis	Early nephrocalcinosis	Stable	Stable	None	None
Treatment Emergent Adverse Events	Autoimmune Hypothyroidism	Frequent Vomiting	Anxiety and depression		Dental issues, Central Precocious puberty
None of the patients that started CSPI before the age of 1 year had a learning disability.

Conclusion: CSPI remains a safe long-term option for CYP with ADH1, maintaining serum calcium, ameliorating seizures and reducing hospital admissions. Importantly, calcium excretion and BMD remains normal, and only one patient developed new mild nephrocalcinosis. It is currently not known whether the TEAEs are related to CSPI. In conclusion, these data suggest that, without other effective treatments, CSPI is a safe and effective option for severe ADH1.