Elamin and de Buyl Journal of Medical Case Reports 2010, 4:349 http://www.jmedicalcasereports.com/content/4/1/349 (CKD), and low vitamin D level. Because two of her children had hypercalcemia and hypocalciuria as well, we carried out DNA sequencing in the CaSR gene in the patient and three of her children. Case presentation An 80-year-old Irish woman was admitted to our hos- pital after the onset of a dense right hemiplegia and dysphasia. She had been seen in our hospital pre- viously after an episode of collapse and was diagnosed with hypertension, atrial fibrillation, congestive heart failure, epilepsy, and hypercalcemia. She had a past history of cholecystectomy 33 years earlier. No history of constipation, anorexia, vomiting, bone pains, poly- uria or polydypsia, or psychiatric or cognitive distur- bance was noted. Her hypercalcemia had been quite severe, ranging between 3.22 and 3.47 mmol/L, with albumin levels of 40 g/L on both occasions; the mag- nesium level was 0.90 mmol/L (normal, 0.70 to 1.00). PTH levels in those instances had been measured between 170 and 235 ng/L (normal, 10 to 55 ng/L). She was taking no medication at the time of sampling. Her urine analysis was negative on three occasions. Arterial blood gases showed no evidence of an acid- base disturbance. Bicarbonate was 25 mmol/L, and chloride was 101 mmol/L. A myeloma screen was negative. Her full blood count was entirely normal. ESR was 12 mm/h. 25-OH Vitamin D level was shown to be low at 33 nmol/L (normal, 53 to 150). An X-ray showing the kidney, ureter, and bladder did not show any kidney stones or abnormal calcification. A bone-density scan was not performed. A parathyr- oid sestamibi scan was normal. She was offered para- thyroidectomy in another hospital; she declined. She remained at home for a period of two years without any obvious symptoms of hypercalcemia. During this admis- sion, she was shown to have had a total left anterior cir- culation stroke, most probably embolic. She also had an embolism in her leg and eventually died of aspiration pneumonia. One of her sons (son 1), reported that he was recently found to have hypercalcemia. His own past medical his- tory included gastroesophageal reflux disease (GERD), Barrett esophagus, duodenal polyps with gastric heteroto- pia, asthma, allergy to shellfish, and hypercholesterolemia. He informed us that he had seven brothers and no sister. Three of them had died: one at the age of six months of unknown cause; one at the age 26 years of an epileptic sei- zure; and one at the age of 36 years of pneumonia. Two were living abroad. The remaining two brothers were available for investigations. One of them (son 2), aged 37 years, was affected with hypercholesterolemia, hyperurice- mia, and abnormal liver-function tests attributed to exces- sive alcohol intake. He also had hypercalcemia. His other Page 2 of 5 brother (son 3), aged 50 years, had white-coat hyperten- sion, hypercholesterolemia, and normocalcemia. Their results are presented in Table 1. The findings of a familial hypercalcemia with relative hypocalciuria were strongly suggestive of a diagnosis of familial hypocalciuric hypercalcemia (FHH). We there- fore decided to analyze the calcium-sensing receptor (CaSR) gene. Direct DNA sequencing showed that the proband was heterozygous for a point mutation in the fourth exon of the CaSR gene (GCA®GAA), leading to a substitution from alanine to glutamate at position 213 (A213E) (Figure 1). Son 1 and son 2, both with hyper- calcemia, were also heterozygous for the same mutation (Figure 2). Son 3, who was normocalcemic, did not carry the mutation (Figure 3). The proband, her deceased husband, and their offspring were all from the southwest of Ireland. Discussion This 80-year-old woman was noted to have hypercalce- mia, relative hypocalciuria, and an elevated PTH level. Possible explanations for this include the milk-alkali syn- drome, the use of lithium or thiazide diuretics, primary hyperparathyroidism (PHPT) associated with vitamin D deficiency with or without low calcium intake [11], FHH, and the combination of FHH with secondary hyperpar- athyroidism (SHPT) and CKD. The first two possibilities are ruled out by the normal acid/base status and by the negative history of drug intake. The possibility of primary hyperparathyroidism with vitamin D deficiency exists, but the sestamibi scan was negative, and she did not appear to have any of the symptoms of hyperparathyroid- ism except for the hypertension and the CKD stage 3. The combination of FHH with SHPT could explain the fairly high calcium and PTH observed [12]. Two of the three sons we investigated were hypercal- cemic and did carry the same GCA® GAA mutation in the CaSR gene as their mother, whereas the normocal- cemic son did not, strongly suggesting that the mutation was the cause of the hypercalcemia and the diagnosis of FHH. We did not test the biologic activity of this mutated receptor. This missense mutation leads to the A213E (alanine®glutamate) change in the extracellular domain of the protein, in close proximity to one of the calcium-binding sites [13]. Glutamate (acidic side chain) and alanine (nonpolar) belong to different classes of amino acids. This change is therefore likely to affect the conformation of the extracellular domain of the receptor and of its affinity for calcium. Predictive testing by using PolyPhen-2 [14] concluded that the mutation was prob- ably damaging, with a score of 0.982 (sensitivity, 0.66; specificity, 0.94). The phenotype of FHH in the elderly is bound to be obscured by coexisting common disorders of calcium