Familial hypocalciuric hypercalcaemia

Familial hypocalciuric hypercalcaemia (FHH) is caused by pathogenic variants in the calcium sensing receptor (CASR) gene or, more rarely, other genes such as GNA11 or AP2S1. It results in lifelong elevated calcium levels, and is generally asymptomatic.

• FHH is most commonly caused by a pathogenic variant in the CASR gene.
• FHH results in lifelong elevated serum calcium levels, typically with normal or mildly elevated parathyroid hormone levels (occasionally more marked elevations are seen), coupled with relative hypocalciuria.
• FHH is generally asymptomatic. Rarely, affected individuals develop pancreatitis and chondrocalcinosis.
• Individuals with FHH do not benefit from surgical management (parathyroidectomy), which is in contrast to individuals with primary hyperparathyroidism (PHPT). For this reason, the two conditions should be differentiated.
• In a vitamin D-replete individual, FHH and PHPT are typically differentiated by the presence or absence of hypocalciuria (a low urinary-calcium-clearance-to-creatinine-clearance ratio (UCCCR) of less than 0.02 is observed in FHH). In a minority of patients, overlaps in urinary phenotype may be observed (such as FHH patients with a UCCCR above the typical threshold).

CASR, GNA11 and AP2S1

• FHH is most commonly caused by heterozygous constitutional (germline) pathogenic variants in the CASR gene (this presents as FHH type 1).
• CASR encodes the calcium-sensing receptor protein, which is a G-protein coupled receptor.
• Pathogenic variants found in CASR comprise missense (over 80%) and loss-of-function (such as nonsense, frameshift or splice site) variants. They can result in an impaired calcium-sensing function of the receptor protein, which in turn results in a higher set point for serum calcium.

GNA11 and AP2S1

• Pathogenic variants in the GNA11 and AP2S1 genes cause FHH types 2 and 3 respectively.
• GNA11 encodes an accessory G-protein (Gα11), which forms part of a heterotrimeric G-protein complex required for CASR signalling.
• AP2S1 encodes an adaptor protein implicated in receptor endocytosis. The overwhelming majority of FHH type 3-associated APS21 pathogenic variants are missense variants affecting the Arg15 residue.

For information about genomic testing, see Presentation: Patient with possible familial hyperparathyroidism.

FHH is inherited in an autosomal dominant pattern. This means that there is a one-in-two (50%) chance that the child of an affected individual will inherit the condition.

• Individuals with FHH do not require surgical management of hyperparathyroidism.
• In rare cases associated with symptoms or more severe hypercalcaemia, treatment with cinacalcet may improve biochemical features; however, it is not currently licensed for this use in the UK.
• An awareness of the diagnosis of FHH in prospective parents may be important, as the offspring of affected parents may experience atypical calcium homeostasis in the neonatal period dependent on the clinical context (that is, depending on whether the affected parent is the mother or the father, and whether the neonate has inherited the associated variant). Specialist advice should be sought in these instances.
• In individuals identified as having FHH, similarly affected family members can be identified by checking serum calcium levels.

For clinicians

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels resource
• NHS England: National Genomic Test Directory

References:

• Lee JY and Shoback DM. ‘Familial hypocalciuric hypercalcemia and related disorders‘. Best Practice & Research Clinical Endocrinology & Metabolism 2018: volume 32, issue 5, pages 609–619. DOI: 10.1016/j.beem.2018.05.004
• Vannucci L and Brandi ML. ‘Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism‘. Frontiers of Hormone Research 2019: volume 51, pages 52–62. DOI: 10.1159/000491038

For patients

• Genetic and Rare Diseases Information Center: Familial hypocalciuric hypercalcemia