Selective Deficiency of 1,25-Dihydroxycholecalciferol: A Cause of Isolated Skeletal Resistance to Parathyroid Hormone

To investigate the role of vitamin D metabolites in the pathogenesis of pseudohypoparathyroidism, we studied an elderly man with a unique variant of the disease, which was characterized by hypocalcemia, elevated serum parathyroid hormone (513±13 pg per milliliter, mean ± S.E.M., normal, <450) but normal renal responses (phosphate and cyclic AMP) to exogenous parathyroid extract. Treatment with parathyroid extract did not produce a calcemic effect, suggesting an isolated skeletal hyporesponsiveness to parathyroid hormone. Although 25-hydroxyvitamin D levels were not reduced, levels of 1,25-dihydroxycholecalciferol were extremely low (0.52 ng per deciliter; normal, 3.3 ±0.6, S.D.). Treatment with 1,25-dihydroxycholecalciferol (1 μg by mouth per day for four days) increased circulating levels to normal (4.60 ng per deciliter) and restored to normal the calcemic response to parathyroid (change in calcium, 3.0 mg per deciliter). These data suggest that 1,25-dihydroxycholecalciferol deficiency may explain the skeletal resistance, but not the renal resistance, often present in classic pseudohypoparathyroidism. (N Engl J Med 297:1084–1090, 1977) Pseudohypoparathyroidism is a heterogeneous group of disorders characterized by resistance to parathyroid hormone, with or without typical somatic anomalies (Albright's osteodystrophy).¹ Since deficient renal responses to parathyroid hormone are virtually always demonstrable, the diagnostic sine qua non has been a subnormal increase in urinary cyclic AMP or phosphate (or both) in response to infused parathyroid extract. Deficient responsiveness of bone (as demonstrated by an inadequate calcemic increment after parathyroid extract) may or may not be present; in the cases in which bone responds normally, chronic exposure to elevated parathyroid hormone levels may even lead to osteitis fibrosa.² No patient has.