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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.

SUMMARY.A relationship between serum concentrations of ionized calcium and parathyroid hormone (PTH) in persons without parathyroid over activity was defined by performing an oral calcium load test. As a result, a serum PTH concentration greater than 2· 6 pmol/L in a hypercalcaemic patient was regarded as suggestive of hyperparathyroidism. Fasting serum PTH concentrations in 58 patients with surgically and histologically proven primary hyperparathyroidism (PHPD were all above 2· 7 pmol/L (range 3' 2-84' 5). Thirteen of 20 patients with familial benign hypercalcaemia (FBH) had fasting serum PTH concentrations greater than 2· 6 pmollL (range 1'6-6'1). There was a significant correlation between serum PTH and age in the FBH patients only. Fasting urine calcium excretion (CaE) ranged from 14 to 222 p.mol/L of glomerular filtrate in PHPT and 3-34 p.mol/L of glomerular filtrate in FBH. The best biochemical discriminant between patients with PHPT and FBH was a plot of fasting serum PTH against CaE' A plot of post-calcium load PTH against post-load CaE showed no further significant advantage in discriminating between the two conditions. Additional key phrases: hypercalcaemia; calcium excretion; differential diagnosisMost patients with biochemical evidence of primary hyperparathyroidism (PHPT) are referred to a parathyroid surgeon, even if symptoms are mild or absent.t-' The advent of technology enabling measurement of the intact PTH molecule in serum has improved our ability to diagnose PHPT biochemically.v' but the lower limit of serum PTH concentration in patients with proven PHPT has not been established. The inherited condition familial benign hypercalcaemia (FBH) is recognized as one which can be difficult to distinguish from PHPT biochemically. 5 FBH is characterized by asymptomatic hypercalcaemia beginning early in life. It is inherited in an autosomal dominant pattern with high penetrance. Patients with FBH should not be advised to undergo parathyroid surgery. The condition probably accounts for around 10070 of cases of unsuccessful parathyroid explorations.' We have studied a number of blood and urine measurements to try to achieve Correspondence: Dr Ian R Gunn. 52clear distinction among patients without parathyroid pathology, patients with PHPT and those with FBH. SUBJECTS AND METHODSHealthy volunteers comprised 38 laboratory workers (19 women, 19 men, age range 18-60).Fifty-eight patients (43 females, 15 males, age range 24-90) had histologically proven PH PT. Fifty had a single adenoma, and the remaining eight had two or three enlarged overactive glands. None had diffuse hyperplasia of all four glands. Three of the eight with more than one enlarged gland developed post-operative hypocalcaemia which required treatment with vitamin D. In two cases, the diagnosis of PHPT had been confirmed at post-mortem examination, but in the other 53 cases stable normocalcaemia was achieved postoperatively without calcium or vitamin D therapy.Twenty patients (12 females, 8 males, age range 9-69) from four different families ...

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1. 65Cu/63Cu stable-isotope ratios have been measured in blood serum after oral administration of the stable isotope 65Cu. The incorporation of the isotope into the plasma protein pool was followed at various times for up to 3 days. The resulting patterns of enrichment in healthy control subjects, in Wilson's disease patients and in heterozygotes for the Wilson's disease gene, were similar in appearance to those found by others using copper radioactive isotopes. After an initially high enrichment at 2 h after dosage, the Wilson's disease cases, in contrast to the control subjects, did not show a secondary rise in isotope enrichment of the plasma pool after 72 h, demonstrating a failure to incorporate copper into caeruloplasmin. The Wilson's disease heterozygotes had variable degrees of impairment of isotope incorporation, not always distinguished from those of control subjects. 2. The stability of the isotope also permits the copper tracer to be followed for a longer period. Ten healthy subjects were studied for over 40 days, allowing the biological half-time of an oral dose of copper to be determined (median 18.5 days, 95% confidence interval 14-26 days). Known heterozygotes for the Wilson's disease gene were found to have a significantly increased biological half-time for removal of copper from the plasma pool (median 43 days, 95% confidence interval 32-77 days). 3. The incorporation of 65 Cu in patients with diseases of the liver (other than Wilson's disease) was found to be similar to that in control subjects, aiding differential diagnosis.