Familial benign hypocalciuric hypercalcaemia

Familial benign hypocalciuric hypercalcaemia (FBHH) is a benign autosomal dominant condition characterized by elevated serum calcium, normal or slightly elevated parathyroid hormone (PTH) and low urine calcium. Serum magnesium is also frequently elevated. It can be confused with primary hyperparathyroidism (PHP), which can have similar serum biochemistry. Various terms have been used for this condition which was first described in 1972 by Foley et al. ¹ who used the term familial benign hypercalcaemia. This term fell out of favour and was replaced by familial hypocalciuric hypercalcaemia (FHH). More recently, the term FBHH has become popular and, rather confusingly, the terms FHH and FBHH are both in common usage at present. Two separate studies estimate the prevalence of FBHH in the West of Scotland to be between 1 in 16,000 ² and 1 in 77.000. ³

In about two-thirds of kindreds studied, FBHH can be shown to be due to inactivating mutations (sometimes referred to as loss-of-function mutations) in the calcium sensing receptor (CASR), which result in a receptor that is less sensitive to calcium. In a few cases, the mutant receptor appears to function normally but the number of receptors present is reduced. This finding has helped to clarify, to some extent at least, the role of the CASR in calcium metabolism and has led to a greater understanding of the FBHH phenotype. The cause of FBHH in the third of kindreds where no CASR mutation can be detected is not clear, but one theory is that these cases are due to mutations in the cell signal transduction pathway downstream of the CASR. In the kindreds where FBHH has been shown to be due to a CASR mutation, although over 70 mutations have been described, very few FBHH kindreds have the same mutation (see website casrdb.mcgill.ca). In other words, to date, most mutations are unique to their kindred. Two novel mutations in kindreds of Scottish descent, one of which was shared by two apparently unrelated kindreds, were recently reported. This raises the possibility that the two apparently unrelated kindreds could be descended from a common ancestor. ⁴

The wild-type CASR is a 1078 amino acid G-protein-coupled receptor, which is expressed in several tissues including parathyroid cells, kidney, bone marrow, osteoclasts, thyroid C-cells and intestine. Its main role is in the regulation of calcium metabolism via parathyroid and renal function.^5,6 PTH secretion is under the control of the CASR and varies inversely with serum calcium concentration. A low serum calcium will therefore increase serum PTH and this acts to raise serum calcium by increasing bone resorption and calcitriol formation as well as decreasing renal calcium excretion. Calcitriol, in turn, raises serum calcium by increasing its absorption from the gut and its resorption from bone. In FBHH, inactivating mutations make the CASR less sensitive, which means that a higher than normal serum calcium level is needed to suppress the release of PTH ⁷ , so that serum PTH is inappropriately high. In the kidney, the altered CASR function leads to an increase in calcium and magnesium resorption. ⁸ The result is elevated serum calcium and magnesium, normal or slightly elevated PTH and low urine calcium – the observed phenotype in FBHH.

The degree of hypercalcaemia is dependent on the amount of mutant CASR present (the ‘gene dose’).^9,10 The FBHH patients are heterozygotes for the mutation and the mutant CASR does not normally effect the functioning of the normal CASR, so that calcium levels are only moderately raised. Patients who are homozygotes for inactivating mutations are much more severely affected and present with neonatal severe hyperparathyroidism^9-11 which is characterized by severe hypercalcaemia and early death.

FBHH is generally accepted, as the name suggests, as a benign disease. This is intriguing. Patients do not exhibit the usual signs and symptoms of hypercalcaemia (e.g. psychiatric symptoms, polyuria, constipation,). It may be, therefore, that it requires both a relatively high PTH and hypercalcaemia (as seen in PHP) to cause such symptoms. Similarly, it may be that the altered function of the CASR seen in FBHH, protects in some way against these symptoms – or to put it another way, the CASR may have a role in the generation of symptoms in PHP. It is also worth noting that FBHH patients do not appear to suffer from the bone disease seen in PHP and it is possible that the relatively low levels of PTH which accompany hypercalcaemia in FBHH (as compared with PHP) have no major effect on bone turnover. However, there are reports of patients with FBHH developing nephrolithiasis or pancreatitis.^12–14 It is not clear whether these are coincidental occurrences or whether the pancreatitis and nephrolithiasis are caused by FBHH. A recent report of cases of pancreatitis in an FBHH kindred, has shed some light on this. Felderbauer et al. ¹⁵ showed that only individuals with FBHH and a mutation in the pancreatic secretory trypsin inhibitory gene (SPINK 1), developed pancreatitis.

Hypercalcaemia with a high normal or slightly elevated PTH can occur in PHP – a more common cause of hypercalcaemia than FBHH. The prevalence of PHP may be as high as 1 in 47 in women aged 55–75 years. This would equate to one in 333 of the general population.^16,17 FBHH is much less common as discussed above.^2,3 Due the benign nature of FBHH, patients should not be subjected to parathyroidectomy as may be warranted in PHP. Indeed, hypercalcaemia does not respond to subtotal parathyroidectomy carried out in FBHH patients.^18-20 It is important, therefore, to be able to differentiate between the two conditions. Mutation detection in FBHH offers a definitive form of diagnosis, but it should be borne in mind that, although the presence of a mutation is strong evidence in favour of the FBHH, the absence of a mutation cannot confirm absence of FBHH. In kindreds with no detectable mutation, more traditional diagnostic methods need to be employed. Unfortunately, serum and urinary biochemical estimations have been shown to be poor discriminators of FBHH and PHP. There is considerable overlap between plasma calcium, chloride, magnesium and PTH in the two conditions. Similarly, urinary parameters such as 24 hour urinary calcium, cAMP and hydroxyproline/creatinine ratio are of limited value, while calcium/creatinine clearance ratio and CaE (fasting urine calcium excretion), which require both serum and urinary measurements, though probably more reliable, are neither sensitive nor specific enough for diagnostic purposes. ²¹ Imaging studies (ultrasonography and sestamibi scanning) can be useful in the localization of parathyroid adenomas in PHP. However, even in experienced hands, negative imaging studies are unavoidable in PHP, ²² so that the absence of an adenoma on imaging does not rule out PHP. Such studies are therefore of limited value in the diagnosis of FBHH. The following findings will help to differentiate PHP from FBHH. In FBHH, the kindred (including young children) will show an autosomal dominant pattern of inheritance for hypercalcaemia and hypocalciuria. Penetrance is extremely high, so family screening is often the most reliable method of diagnosis. The proband has often been extensively investigated for possible causes of hypercalcaemia, but no case is found. Similarly, symptoms of hypercalcaemia (psychiatric symptoms, polyuria, constipation, nephrolithiasis) are absent as are complications of other causes of hypercalcaemia (osteopenia, osteitis fibrosa). Where family studies are not possible but FBHH is suspected, other causes of low urinary calcium excretion (such as a low calcium diet or vitamin D deficiency) should be considered before ruling out PHP.