Hypoparathyroidism is characterized by insufficient secretion of parathyroid hormone (PTH) leading to hypocalcemia, and is diagnosed on biochemical grounds. Low calcium concentrations with concurrent inappropriately low serum PTH concentration are the hallmarks of the disease. There may also be hyperphosphataemia and hypercalciuria.

Hypoparathyroidism in children can have many different etiologies. In adults, hypoparathyroidism is most commonly related to surgery for thyroidectomy, but in children most causes of hypoparathyroidism are related to underlying genetic or immune abnormalities. The hypoparathyroidism can be isolated, as in familial isolated hypoparathyroidism due to GCM2 or PTH gene variants, or autosomal dominant hypocalcaemia (ADH), or part of a syndrome such as DiGeorge Syndrome, CHARGE syndrome, Sanjad-Sankati syndrome, or genetic immune disorders such as APACED syndrome.

ADH1 is caused by Calcium Sensing Receptor (CaSR) gain-of-function (GoF) variants, leading to hypoparathyroidism, hypocalcaemia, seizures, hyperphosphatemia, hypomagnesaemia and severe hypercalciuria, and can lead to isolated hypoparathyroidism. It may have additional features, such as Bartter syndrome.

Many children with hypoparathyroidism present with seizures due to hypocalcaemia.

Conventional treatment of hypoparathyroidism is with Alphacalcidol and Calcium, while ensuring vitamin D concentrations are normal using Cholecalciferol supplementation. This treatment is usually sufficient to stop seizures and normalize hypocalcaemia, but predisposes to hypercalciuria, resulting in nephrocalcinosis and renal impairment. However, this treatment may not be sufficient to stop seizures or symptoms of hypocalcaemia in children with severe hypoparathyroidism.

Treatment with PTH is more physiological, and can improve treatment outcomes. PTH 1-34 has a short half-life, whereas PTH 1-84 has a longer half-life. PTH 1-34 is licenced for the treatment of osteoporosis in adults. Treatment of severe hypoparathyroidism with multiple daily injections of PTH may be effective, but can still lead to inadequate control of symptoms due to its short half-life. PTH 1-84 required less frequent injections, but has been withdrawn from the market.

Continuous subcutaneous infusion of PTH (CSPI) is an option for treatment of severe hypoparathyroidism, and is delivered using insulin pumps. It has been used successfully for severe forms of hypoparathyroidism, but mostly for short periods of time. I will discuss how long-term treatment in a small cohort of patients with ADH1. CSPI by insulin pump effectively increases serum calcium concentrations and reduces seizures, hospital admissions and calcium excretion (mean CSPI duration=3.2±0.6 years), and I will present longerterm data on the safety and efficacy of CSPI in this cohort.

Other treatments, in the form of long acting PTH or inhibition of CaSR activity in ADH1, are potential effective alternatives for refractory or severe hypoparathyroidism. I will discuss new long-acting forms of PTH, their mode of action and the results of recent trials. I will also discuss Encaleret, which inhibits CaSR activity, its mode of action and efficacy in ADH.