Familial hypocalciuric hypercalcaemia

Familial hypocalciuric hypercalcaemia (FHH) is a usually benign disorder of calcium homeostasis, characterised by mildly elevated serum calcium with inappropriately normal or elevated parathyroid hormone (PTH). Reduced activity of the calcium-sensing receptor facilitates renal calcium and magnesium reabsorption, producing hypercalcaemia together with low urinary calcium excretion. Most affected individuals are asymptomatic, and the biochemical abnormality is present from birth. The principal clinical challenge, particularly in children, adolescents and young adults, is to distinguish FHH from primary hyperparathyroidism and so avoid unnecessary parathyroidectomy. A severe neonatal form of hyperparathyroidism, associated with high morbidity, lies at the opposite end of the disease spectrum.

The estimated prevalence is 1/100,000 to 1/10,000, though it may be underestimated.

FHH results from germline loss-of-function variants that reduce signalling through the calcium-sensing receptor pathway. Heterozygous pathogenic variants in CASR cause the most frequent form, FHH type 1; variants in AP2S1 cause FHH type 3, the second most common form; and variants in GNA11 cause the extremely rare FHH type 2. Reduced receptor activity facilitates renal calcium and magnesium reabsorption and sustains PTH secretion despite mildly elevated serum calcium, producing hypocalciuria.

FHH is inherited in an autosomal dominant manner. An affected parent has a 50% chance of transmitting the pathogenic variant to each child. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis combines biochemical and molecular findings. A low urinary calcium-to-creatinine clearance ratio, usually below 0.01, accompanies mildly elevated serum calcium and inappropriately normal or elevated PTH. Because this biochemical picture overlaps with primary hyperparathyroidism, molecular testing of CASR, GNA11 and AP2S1 is required to establish the diagnosis.

Main differential diagnoses include:

• Primary hyperparathyroidism: the principal distinction; hypercalcaemia with inappropriately normal or raised PTH but a urinary calcium-to-creatinine clearance ratio usually above 0.02 (versus below 0.01 in FHH) and frequently hypercalciuria; hereditary forms involve MEN1, RET or CDC73
• : life-threatening hypercalcaemia in infancy caused by biallelic CASR loss-of-function variants, in contrast to the heterozygous variants underlying FHH, and often requiring urgent parathyroidectomy
• Vitamin D or vitamin A toxicity: hypercalcaemia with suppressed PTH and a relevant intake history
• Drug-induced hypercalcaemia: thiazide diuretics and lithium can raise serum calcium and biochemically mimic FHH
• Malignancy-associated hypercalcaemia: typically suppressed PTH, often with raised parathyroid-hormone-related peptide

• Establishing the diagnosis: identification of the underlying germline pathogenic variant confirms the diagnosis at the molecular level.
• Clinical management: identification of the pathogenic variant supports condition-specific management decisions made by the treating physicians in consultation with the affected individual.
• Testing of family members: once the familial pathogenic variant is known, at-risk relatives can be offered predictive testing to clarify their variant status.

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