Hypoparathyroidism

Chronic hypoparathyroidism presents with low serum calcium, elevated serum phosphorus, and low or inappropriately normal serum parathyroid hormone (PTH) concentrations. Clinical manifestations include neuromuscular irritability (tetany, paraesthesia, seizures) and cardiac repolarisation abnormalities such as prolonged QT interval. Recognised long-term complications encompass hypercalciuria, nephrocalcinosis, kidney stones, chronic kidney disease, low bone turnover, cardiac and vascular calcifications, basal-ganglia calcifications, cataracts, neuropsychiatric manifestations, possible increased susceptibility to infections, and complications during pregnancy.

Both syndromic and non-syndromic genetic forms are clinically relevant: syndromic entities present with extra-endocrine features (cardiac, immunological, otological, or renal), while isolated familial forms manifest with biochemical hypoparathyroidism alone. Age of onset ranges from neonatal or congenital presentation in chromosomal and severe monogenic forms to childhood or adult onset in autoimmune and milder familial forms.

Several genes have been associated with hypoparathyroidism. Genetic forms are broadly classified as isolated (non-syndromic) familial hypoparathyroidism or syndromic hypoparathyroidism. Frequently recognised isolated forms include GCM2-related familial isolated hypoparathyroidism, caused by defects in a key parathyroid-cell transcription factor, and PTH-related familial isolated hypoparathyroidism, resulting from impaired parathyroid hormone biosynthesis).

Other important isolated genetic causes include autosomal dominant hypocalcaemia due to activating variants in CASR or GNA11. Syndromic forms include 22q11.2 deletion syndrome, characterised by developmental hypoplasia of the thymus and parathyroid glands, and autoimmune polyendocrine syndrome type 1 (APS-1/), characterised by autoimmune endocrinopathy and chronic mucocutaneous candidiasis.