Clinical and laboratory features of calcium-sensing receptor disorders: a systematic review

Abstract

Mutations in the calcium-sensing receptor gene (CaSR) may result in disorders of calcium homeostasis manifesting as familial benign hypocalciuric hypercalcaemia (FBHH), neonatal severe hyperparathyroidism (NSHPT) or autosomal dominant hypocalcaemia with hypercalciuria (ADHH). FBHH may have a population prevalence as high as one in 16 000, and ADHH one in 70 000. NSHPT is very rare.The FBHH condition is usually asymptomatic. Parathyroidectomy does not result in normal serum calcium, and no active treatment is indicated. To differentiate FBHH from primary hyperparathyroidism (PHPT), a guideline which includes measurement of serum calcium, intact parathyroid hormone (PTH), magnesium and fasting urinary calcium excretion is proposed. Screening of family members for hypercalcaemia, and occasionally a search for mutations in the CaSR gene, may be required.The NSHPT condition may manifest with hypercalcaemia, (usually) very elevated serum PTH concentration, subperiosteal erosions and fractures. Milder cases may be managed medically, but respiratory failure, extreme hypercalcaemia and failure to thrive are indications for early parathyroidectomy.The ADHH condition may result in asymptomatic hypocalcaemia, but some affected family members have minor symptoms, and a minority experience seizures in infancy which can recur into adulthood. A significant proportion of cases previously reported as idiopathic hypoparathyroidism (IHP) may in fact be due to mutations in the CaSR gene. In a moderately hypocalcaemic patient with no other clearly discernible cause, an elevated urine calcium:creatinine ratio is suggestive of ADHH, as is the presence of a first-degree relative with hypocalcaemia. If treatment with vitamin D analogues is undertaken, serum and urine calcium should be monitored, advice which applies equally to ADHH and IHP.

24-Hour Urinary Calcium in Primary Hyperparathyroidism

“…4,5,14,17,18 The Ca/Cr clearance ratio is also used as a marker of hypercalciuria, where hypercalciuria cannot be excluded if the urinary creatinine concentration exceeds 40 mg/100 mL. 19,20 In the evaluation of PHPT, it is recommended that FHH be ruled out, even though this condition is very rare. Currently, if there is a strong suspicion for FHH, the presence of the CaSR gene mutation can be detected using readily available polymerase chain reaction techniques.…”

“…However, this should be reserved for cases in which treatment would be significantly altered based on the diagnosis. 5,7,14,15,19 Hypercalcemia increases eGFR; however, tubular resorption of calcium is altered by many other factors such as age, medications, and hormones. While the volume of urine collected can affect the urinary creatinine and calcium levels and could be affected by diuretic use, we did not specifically analyze these factors.…”

Four cases of autosomal dominant hypocalcaemia with hypercalciuria including two with novel mutations in the calcium-sensing receptor gene

“…10,11 Since mutational analysis of the CaSR gene became available, many individuals with hypocalcaemia have had their diagnosis revised. Lienhardt et al 12 reported a 42% prevalence of activating CaSR mutations in unrelated individuals with isolated hypoparathyroidism and Gunn and Gaffney 13 estimated the population prevalence of this condition to be one in 70,000.…”

Plasma 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and parathyroid hormone in familial hypocalciuric hypercalcemia and primary hyperparathyroidism

“…In the clinical setting, the separation between FHH and PHPT is often based on the CCCR (20,41,42). We recommend a two-step diagnostic procedure in hypercalcemic patients with clinical suspicion of PHPT or FHH.…”