Familial hypocalciuric hypercalcaemia – a case report and review of the literature
S Samarasinghe, M Martineau, West Middlesex University Hospital
Familial hypocalciuric hypercalcaemia (FHH) is characterised by mild to moderate hypercalcaemia in the setting of relative hypocalciuria and an inappropriately normal or marginally elevated parathyroid hormone (PTH) level. It is a relatively benign condition with no long-term sequelae in the majority of patients and is inherited in an autosomal dominant pattern. In most cases, FHH results from heterozygous inactivating mutations of the calcium-sensing receptor (CaSR) gene. It can be difficult to distinguish FHH from primary hyperparathyroidism (PHPT) in the clinical context but this is important to prevent unnecessary surgical interventions. Currently, FHH is differentiated from PHPT by clinical features (decreased bone density, symptomatic hypercalcaemia, nephrolithiasis) and biochemical factors (calcium creatinine clearance ratio (CCCR) < 0.01 is suggestive of FHH and level 0.02 or higher suggests PHPT). The presence of symptoms is therefore more suggestive of PHPT. Approximately 80% of PHPT patients in western countries are now identified by routine screening of serum calcium levels in asymptomatic patients.
We present the case of a 64-year-old woman referred to the endocrinology team with asymptomatic hypercalcaemia. She has a past medical history of type 2 diabetes mellitus, diabetic retinopathy, stroke and dyslipidemia. The patient was initially reviewed in 2005 for poorly controlled diabetes and routine bloods at the time showed hypercalcaemia (adjusted calcium 2.82 mmol/L) with a parathyroid hormone (PTH) 0.846 pmol/L and normal parathyroid ultrasound scan. On each admission to hospital, incidental hypercalcaemia was noted and she was referred for specialist advice. She has remained asymptomatic with no evidence of skeletal or renal involvement. A repeat PTH on her most recent admission was normal with a CCCR 0.0038. The patient has a suspended diagnosis of FHH.
Current guidelines have set the CCCR cut off value of <0.01 for diagnosis of FHH and >0.02 for PHPT with a sensitivity of 85% and a specificity of 88%. This is important as FHH is a benign condition which rarely requires intervention. A Danish study reported the cut-off value of <0.0115 as optimal for diagnosis of FHH with a specificity of 0.88 and a sensitivity of 0.80. If there is strong suspicion for FHH, the presence of the CaSR gene mutation can be detected using polymerase chain reaction techniques. This genetic test provides diagnostic security when the CCCR is indicative of FHH. There are currently no international guidelines on when genetic testing should be undertaken in patients with suspected FHH. One group proposed using a 2-step screening process with CCCR as the initial screen and genetic testing for the CaSR gene reserved for patients with a CCCR <0.02. The most effective screening strategy is yet to be clearly defined but would ideally take into consideration the relative prevalence of FHH and PHPT, the costs of genetic testing vs misdiagnosis resulting in unnecessary/non-curative surgery.