Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation.

Defects in the human Ca(2+)-sensing receptor gene have recently been shown to cause familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism. We now demonstrate that a missense mutation (Glu128Ala) in this gene causes familial hypocalcaemia in affected members of one family. Xenopus oocytes expressing the mutant receptor exhibit a larger increase in inositol 1,4,5-triphosphate in response to Ca2+ than oocytes expressing the wild-type receptor. We conclude that this extracellular domain mutation increases the receptor's activity at low Ca2+ concentrations, causing hypocalcaemia in patients heterozygous for such a mutation.

Bilateral carpal tunnel syndrome caused by Graves' disease.

We observed three patients in whom carpal tunnel syndrome (CTS) developed in association with hyperthyroidism (Graves' disease). The course of one of these patients was marked by resolution of symptoms and electrophysiologic measures of CTS that paralleled the remission of Graves' disease after treatment with radioactive iodine. No other treatment of CTS was required or given. There may be a causal relationship between Graves' disease and CTS.

Effect of chronic adrenocorticotropin stimulation on the excretion of 18-hydroxycortisol and 18-oxocortisol.

The human adrenal gland can metabolize cortisol to yield steroids oxygenated at the 18 position in a series of reactions similar to those by which corticosterone is converted to 18-hydroxycorticosterone and aldosterone and perhaps catalyzed by the same enzyme. These analog steroids, 18-hydroxycortisol and 18-oxocortisol, are produced in small quantities normally, but can be produced in excess by aldosterone-producing adrenal adenomas and in glucocorticoid-suppressible aldosteronism. Chronic ACTH administration has been reported to produce a transient increase in aldosterone production. We studied the effect of chronic ACTH administration on the excretion of aldosterone-18-oxoglucuronide and its relationship to the excretion of 18-hydroxycortisol and 18-oxocortisol. Five normal men collected 24-h urine samples for 3 control days and 5 days while receiving ACTH (40 U, im, twice daily). Urinary excretion of tetrahydrocortisol, tetrahydrocortisone, aldosterone 18-oxo-glucuronide, 18-hydroxycortisol, and 18-oxo-cortisol was measured by RIA. Urinary tetrahydrocortisol and tetrahydrocortisone excretion increased 7- to 10-fold during ACTH administration. Urinary aldosterone 18-oxoglucuronide excretion increased to a peak on the second day (6-fold increase) and decreased to basal levels by the fifth day of continuous ACTH administration. The excretion of 18-hydroxycortisol increased about 6-fold and remained elevated throughout the period of ACTH administration. The excretion of 18-oxocortisol increased from an average of 3.7 nmol/day to a peak of 176.7 nmol/day (a 47-fold increase) on the third day and decreased to 107.9 nmol/day on the fifth day of ACTH administration. These results are consistent with the hypothesis that the decrease in aldosterone production after 2 days of ACTH administration is the result of induction of 17-hydroxylase by ACTH, resulting in the biosynthesis of cortisol in these cells. Since the cells have the cytochrome P-450-dependent corticosterone methyl oxidase enzyme, cortisol becomes its predominant substrate, resulting in the increase in 18-hydroxycortisol and 18-oxocortisol production. We have called these cells transitional cells because they have enzymatic systems of the zona glomerulosa and the zona fasciculata.

Reversible avascular necrosis of the femoral head in tumor-induced osteomalacia.

OBJECTIVE: To document the course and reversal of avascular necrosis of the femoral heads (ANFH) in a 27-year-old woman with tumor-induced osteomalacia (TIO). METHODS: We describe clinical, biochemical, and magnetic resonance imaging changes in a patient who sought medical assistance because of pain in her back, hips, and knees and an enlarging mass on her right thigh. RESULTS: The patient proved to have TIO, an unusual condition characterized by humorally controlled renal phosphate wasting, low to undetectable levels of 1,25-dihydroxyvitamin D(3), and osteomalacia. Eleven months after removal of a small spindle cell tumor of the right thigh and without other treatment, complete clinical and biochemical remission was observed, and the magnetic resonance images revealed resolution of the ANFH. CONCLUSION: Prompt treatment of ANFH in TIO can lead to complete radiologic and clinical remission.

Case report: reversible mitral regurgitation and congestive heart failure complicating thyrotoxicosis.

Congestive heart failure is a relatively uncommon manifestation of thyrotoxic heart disease, and different mechanisms have been proposed. The authors present a possible explanation of congestive heart failure in some cases of thyrotoxicosis. A 39 year-old woman with Graves' disease was hypermetabolic, in atrial fibrillation, and had signs of congestive heart failure. She had a loud murmur of mitral regurgitation, clinical cardiomegaly, accentuated pulmonic sound, and peripheral edema. Propranolol reduced the heart rate to 60 beats per minute, but the loud mitral regurgitation murmur persisted. Echocardiographic and angiographic data were consistent with moderate to severe mitral regurgitation, serious enough to consider mitral valve replacement. As the patient's hyperthyroid state came under control, weight increased and the cardiac murmur resolved. After radioactive iodine treatment and the return to a eumetabolic state, an echocardiogram revealed only trace mitral regurgitation, with near normal left ventricular function and pulmonary arterial systolic pressures. These findings were confirmed by subsequent cardiac catheterization. The authors believe that mitral regurgitation, perhaps secondary to intrinsic papillary muscle dysfunction from hyperthyroidism, was the major cause of reversible congestive heart failure in this case. Valvular disease may play a more substantive role in thyrotoxic heart disease than previously recognized.

Serum alkaline phosphatase in diabetes mellitus.

Elevation of serum alkaline phosphatase concentration in patients with diabetes mellitus has been observed for several years, but the source and reasons are unknown. We report our experience with 39 diabetics, 38% of whom had an unexplained elevation of serum alkaline phosphatase. Isoenzyme determinations revealed bone fraction as the predominant species. Mean fasting serum glucose was significantly higher in the group with elevated alkaline phosphatase, supporting an association between the severity of diabetes and diabetic bone disease.

Theophylline-induced hypercalcemia.

Sixty patients with theophylline toxicity were hospitalized during a 2-year period. Eleven patients had hypercalcemia; their calcium levels returned to normal as theophylline levels fell to therapeutic or subtherapeutic levels. Serum calcium levels also fell significantly in three additional patients with theophylline toxicity, although the initial serum calcium concentration was not outside normal limits. A significant increase in serum calcium levels associated with therapeutic levels of theophylline in normal volunteers was reversed by propranolol. It appears that theophylline causes elevation of serum calcium by a system subject to beta-adrenergic regulation.

Inadequate parathyroid response in acute pancreatitis.

We studied nine consecutive hypocalcemic patients with acute pancreatitis to elucidate the mechanism of hypocalcemia. Mean serum ionized calcium, 0.97 mM, was below the normal mean of 1.16 mM (P less than 0.001). Seven of eight patients tested had normal parathyroid hormone levels. All responded to parenteral parathyroid extract by increasing serum ionized calcium and urinary cyclic AMP, indicating parathyroid-hormone-responsive target organs. Calcitonin and glucagon concentrations were increased above normal in some patients, but there was no relation with serum ionized calcium. Parenteral glucagon had no significant effect on serum ionized calcium or calcitonin concentrations. These findings suggest that neither glucagon nor calcitonin was primarily responsible for the hypocalcemia, which did not produce expected increases in serum parathyroid hormone concentrations. Relative parathyroid insufficiency may account for the persistent hypocalcemia frequently observed in patients with acute pancreatitis.