Endocrine Abstracts

Familial hypocalciuric hypercalcaemia (FHH) is a rare but highly penetrant autosomal dominant condition, which is characterised by lifelong mild-to-moderate hypercalcaemia in association with normal or mildly raised serum parathyroid hormone (PTH) concentrations. FHH is considered to be a benign and asymptomatic condition, which in general requires no specific treatment. However, as this disorder has a similar serum biochemical phenotype to primary hyperparathyroidism (PHPT), FHH patients have been misdiagnosed as having PHPT, and undergone parathyroidectomy, which generally fails to normalize the hypercalcaemia. In clinical practice, FHH is distinguished from PHPT by measurement of the 24-hour calcium to creatinine clearance ratio (CCCR), which is <0.01 in 95% of FHH patients. However, around 10% of PHPT patients may also have a CCCR of <0.01, and therefore the CCCR test may not always reliably differentiate FHH from PHPT. Thus, additional investigations may be required, and these include measurement of serum calcium concentrations in first-degree relatives and DNA sequence analysis of the genes known to cause FHH. Recent studies have shown FHH to comprise three genetically distinct conditions, designated as FHH types 1–3, which are due to germline loss-of-function mutations affecting the CASR, GNA11 and AP2S1 genes, respectively. Mutations of the CASR have been reported in ~65% of FHH cases; whereas GNA11 and AP2S1 mutations account for <5% and ~10% of FHH cases, respectively. FHH types 1 and 2 are in general asymptomatic disorders; however, FHH type 3 may be associated with symptomatic hypercalcaemia, low bone mineral densities and cognitive dysfunction. This presentation will outline the clinical challenges in diagnosing FHH and also describe the different genetic variants of this disorder.