Management of autosomal dominant hypocalcemia type 1: Literature review and clinical practice recommendations

Abstract

Purpose: Autosomal Dominant Hypocalcemia type 1 (ADH1), caused by gain-of-function variants in the calcium-sensing receptor (CASR), is characterized by a variable degree of hypocalcemia and hypercalciuria with inappropriately low PTH. The clinical spectrum is broad, ranging from being asymptomatic to presenting with severe clinical features of hypocalcemia and end-organ damage such as nephrolithiasis and intracerebral calcifications. Although the underlying pathophysiology is different, ADH1 patients are often managed as patients with 'classical' primary hypoparathyroidism, possibly leading to (exacerbation of) hypercalciuria. New treatments such as PTH analogues and calcilytics directly targeting the CASR are in the pipeline. Specific clinical guidance for treatment and monitoring of ADH1 patients is lacking. The purpose of this study is to provide a literature review on management of ADH1, including new therapies, and to formulate practice recommendations.

Methods: We searched for articles and ongoing clinical trials regarding management of ADH1.

Results: Forty articles were included. First we review the conventional treatment of ADH1, focusing on active vitamin D, calcium supplements, thiazide diuretics, phosphorus binders and dietary recommendations. In a second part we give an overview of studies with emerging treatments in ADH1: PTH analogues (PTH1-34, rhPTH1-84, TransCon PTH and others) and calcilytics (preclinical studies and clinical trials). In a third part we discuss literature findings regarding monitoring of ADH1 patients. Finally, we formulate clinical practice recommendations.

Conclusion: We provide an overview of conventional and new treatments for ADH1 patients. Based on these data, we propose practical recommendations to assist clinicians in the management of ADH1 patients.

Keywords: Autosomal Dominant Hypocalcemia type 1; Calcilytics; Calcium sensing receptor; Parathyroid hormone analogues; Practice recommendations.

Fig. 1

PRISMA Flow diagram of the study selection process. ADH1: Autosomal Dominant Hypocalcemia type 1; CASR: calcium sensing receptor; hypoPT: hypoparathyroidism; QoL: quality of life

Fig. 2

Treatment options for Autosomal Dominant Hypocalcemia type 1. A: calcium supplements; B: active vitamin D; C: thiazide diuretics; D: calcilytics; E: PTH analogues. Solid arrows indicate stimulation, dashed lines indicate inhibition. CASR: calcium sensing receptor; PTH1R: PTH1 receptor; VDR: vitamin D receptor Images: Flaticon.com

Fig. 3

Management of Autosomal Dominant Hypocalcemia type 1.⁽¹⁾ Severe hypocalcemia is defined as the presence of significant neurologic, cardiac or respiratory symptoms or serum calcium < 1.75mmol/L ⁽²⁾ Mild neuromuscular symptoms, central nervous system calcifications, nephrocalcinosis, kidney stones, impaired renal function, posterior subcapsular cataract ⁽³⁾ Hypercalciuria is defined as > 6.25mmol/24 h urine for females, > 7.5mmol/24 h urine for males (or a urinary calcium/creatinine ratio > 0.6 when a reliable urine collection is not possible) ⁽⁴⁾ Add calcium carbonate if daily calcium dietary intake is < 1000 mg or if hyperphosphatemia is present despite dietary recommendations ⁽⁵⁾ Follow-up as determined in clinical trial protocol ⁽⁶⁾ Therapy directed towards target: symptom relief and serum [Ca²⁺] between 1.8–2.1 mmol/L. We advise a 25(OH)D₃ concentration between 20–50 ng/mL using ergocalciferol or cholecalciferol if required ⁽⁷⁾ Follow-up includes a brain CT and slit lamp examination every 10 years independently of signs and symptoms of hypocalcemia or presence of hypercalciuria ⁽⁸⁾ Renal ultrasonography should be repeated when patients experience symptoms of nephrolithiasis or when renal function declines, regardless of time intervals. IV: intravenous; m: month; RUS: renal ultrasonography; SB: serum biochemistry, including calcium, albumin, phosphate, magnesium, potassium, sodium, PTH, creatinine, 25(OH)D₃; UB: urine biochemistry including calcium, sodium and creatinine; y: year