Roderick Clifton-Bligh, Head of Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District and Faculty of Medicine and Health, University of Sydney.
Blood calcium concentrations are regulated through the co-ordinate actions of parathyroid hormone (promoting renal calcium reabsorption, renal 1-alpha hydroxylation and bone resorption), 1,25-dihydroxyvitamin D (promoting intestinal calcium absorption), and calcium itself (acting on the calcium sensing receptor in parathyroid glands and kidney). Genetic disorders in each of these components lead to either hypercalcaemia or hypocalcaemia; each classified most readily into PTH-dependent and -independent forms, and thereafter into syndromic and non-syndromic categories.
Genetic disorders causing PTH-dependent hypercalcaemia include the Multiple Endocrine Neoplasia (MEN) syndromes 1-5 (arising from pathogenic variants in MEN1, RET, CDKN1B and MAX, respectively), Familial Isolated Hyperparathyroidism (MEN1, CASR or GCM2), Hyperparathyroidism-Jaw Tumour syndrome (CDC73), and Familial Hypocalciuric Hypercalcaemia (CASR, AP2S1, GNA11).
PTH-independent hypercalcaemia can be associated with pathogenic variants in CYP24A1 (causing hypervitaminosis D), ALPL (hypophosphatasia) or SLC34A1 (infantile hypercalcaemia).
Genetic disorders causing PTH-dependent hypocalcaemia include Familial Isolated Hypoparathyroidism (PTH, GCM2), Di George syndrome (TBX1, NEBL), Hypoparathyroidism-deafness-renal syndrome (GATA3), Kenny-Caffey syndrome (TBCE, FAM111A), Kearns Sayre (mitochondrial), Autoimmune Polyendocrinopathy-candidiasis-ectodermal dystrophy (AIRE) and Autosomal Dominant Hypocalcaemia (CASR, GNA11).
Conditions causing PTH-independent hypocalcaemia include Pseudohypoparathyroidism (GNAS1) and Hereditary vitamin D resistant rickets (VDR, CYP27B1).
Genetic causes of PTH-dependent hypercalcaemia should be considered in the presence of multiglandular parathyroid disease, MEN or HPT-JT features, parathyroid carcinoma (or absent parafibromin immunostaining in a parathyroid neoplasm), hypocalciuria or family history of hypercalcaemia; or in any patient younger than 40 y. Genetic causes of PTH-independent hypercalcaemia should be considered when acquired causes have been excluded. Similarly, genetic causes of hypocalcaemia should be considered in any patient if there is no clear acquired cause.