A patient with isolated adrenocorticotropin deficiency presenting with repetitive oesophageal ulcer and stenosis.

Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a potentially fatal condition that is difficult to diagnose. The authors diagnosed IAD in a patient who presented with recurrent oesophageal ulceration resulting in oesophageal stenosis. The recurrent oesophageal ulcers were due to frequent nausea and vomiting that were the presenting digestive symptoms of adrenal insufficiency. Severe hypoglycaemia during this patient's course suggested the diagnosis of adrenal insufficiency. This case is educational because digestive symptoms are the most common symptoms in patients with adrenal insufficiency, but the diagnosis of adrenal insufficiency in such patients is not easy.

A family of autosomal dominant hypocalcemia with an activating mutation of calcium-sensing receptor gene.

Autosomal dominant hypocalcemia (ADH) caused by activating mutations of calcium-sensing receptor (CaSR) is characterized by hypocalcemia with inappropriately low concentration of PTH and relative hypercalciuria. Active vitamin D treatment often leads to nephrolithiasis and renal impairment in patients with ADH. However, differential diagnosis between ADH and idiopathic hypoparathyroidism is sometimes very difficult. Here, we report a mutation of CaSR and its functional property found in three generations of a Japanese family. The proband developed seizures at 7 days of age. His mother and elder sister were discovered to have hypoparathyroidism by family survey, but his father was normocalcemic. His grandfather developed heart failure and was found to have hypoparathyroidism. All affected members had been treated with active vitamin D3 and bilateral nephrolithiasis were detected in three of them. DNA sequencing revealed that all affected patients had a heterozygous mutation in CaSR gene that causes proline to leucine substitution at codon 221 (P221L). In vitro functional analysis of the mutant CaSR by measuring inositol 1,4,5-trisphosphate production in response to changes of extracellular Ca indicated that this mutation is an activating one and responsible for ADH in this family. Therefore, careful monitoring of urinary Ca excretion before and during treatment of PTH-deficient hypoparathyroidism is very important, and screening of CaSR mutation should be considered in patients with relative hypercalciuria or with a family history of hypocalcemia.

Clonal endothelial cells produce humoral factors that inhibit osteoclast-like cell formation in vitro.

Angiogenesis and bone remodeling are closely associated, and vascular endothelial cells may have potential roles for osteoclastic bone resorption. We examined whether clonal endothelial cells established from bone, aorta and brain of Balb/c mice influenced osteoclast-like cell formation in vitro. As low as 1% conditioned media of those endothelial cells inhibited osteoclast-like cell formation in bone marrow cultures induced by 1,25-dihydroxyvitamin D3, and did so in spleen cell cultures in the presence of soluble receptor activator of nuclear factor-kappaB ligand (RANKL), M-CSF and prostaglandin E2. The level of osteoprotegerin (OPG), a decoy receptor for RANKL, secreted by endothelial cells was not high enough to inhibit osteoclastogenesis. These observations suggest that endothelial cells derived from various tissues secrete factor(s) that inhibits precursors to differentiate into osteoclasts even in the presence of optimal stimulators for osteoclastogenesis. Hence, endothelial cells in bone may inhibit recruitment of fresh osteoclasts, and those in tissues other than bone may be involved in prohibiting ectopic osteoclastogenesis.

Association between activating mutations of calcium-sensing receptor and Bartter's syndrome.

Bartter's syndrome is a heterogeneous disorder characterised by deficient renal reabsorption of sodium and chloride, and hypokalaemic metabolic alkalosis with hyper-reninaemia and hyperaldosteronaemia. Mutations in several ion transporters and channels have been associated with the pathogenesis of Bartter's syndrome. We describe two hypocalcaemic patients with deficient parathyroid hormone secretion who also showed characteristics of Bartter's syndrome. We found activating mutations of the gene for the calcium-sensing receptor (CASR) in both patients. Activation of this calcium-sensing receptor inhibits the activity of a renal outer-medullary potassium channel that is mutated in type 2 Bartter's syndrome. We therefore suggest that some activating mutations of CASR could provide new mechanisms for the development of Bartter's syndrome.

A family of autosomal dominant hypocalcemia with a positive correlation between serum calcium and magnesium: identification of a novel gain of function mutation (Ser(820)Phe) in the calcium-sensing receptor.

To date about 20 activating mutations in the calcium-sensing receptor (CaR) gene have been identified to cause autosomal dominant hypocalcemia (ADH) or sporadic hypoparathyroidism. We report a novel activating mutation in the CaR gene in a Japanese family with ADH. The proband, a 15-yr-old boy, and 5 other patients in 3 generations were asymptomatic, except for the proband's grandmother who had a history of seizures. They showed mild hypocalcemia (1.68-1.98 mmol/liter) with normal urinary calcium excretion and low normal serum PTH levels. Their serum magnesium concentrations were below normal in 3 adults and within the normal range in 3 teenagers. There was a significant positive correlation (r = 0.90; P < 0.05) between the serum calcium and magnesium concentrations of 6 affected members. Nucleotide sequencing revealed that the proband had a known polymorphism (Gly(990)Arg) and a novel heterozygous mutation substituting phenylalanine for serine at codon 820 (Ser(820)Phe) in the sixth transmembrane helix of the CaR. In other family members, the Ser(820)Phe mutation cosegregated with hypocalcemia. The mutation was not detected in 50 control subjects. The Gly(990)Arg polymorphism was observed in 8 of 9 family members with or without hypocalcemia and in 36 of 50 controls. The sensitivity of the Ser(820)Phe mutant CaR to calcium was assessed using transiently transfected HEK293 cells and measuring the increases in intracellular Ca(2+) concentrations in response to the changes in extracellular Ca(2+). The concentration-response curve of the mutant receptor was left-shifted, and its EC(50) (2.5 mM) was significantly (P < 0.05) lower than that of the wild-type CaR (3.3 mM). We conclude that the Ser(820)Phe mutation in the CaR caused ADH in this family. The positive correlation between serum calcium and magnesium levels observed in this family may support the concept that renal CaR acts as a magnesium sensor as well as a calcium sensor.