Arnold S. Brickman

Pseudohypoparathyroidism type Ia from maternal but not paternal transmission of a Gsα gene mutation

While loss-of-function mutations in Gsalpha are invariably associated with the short stature and brachydactyly of Albright hereditary osteodystrophy (AHO), the association with hormone resistance (to parathyroid hormone and thyrotropin) typical of pseudohypoparathyroidism type Ia (PHP-Ia) is much more variable. Observational studies and DNA polymorphism analysis suggest that maternal transmission of the Gsalpha mutation may be required for full expression of clinical hormone resistance. To test this hypothesis, we studied transmission of a frameshift mutation in Gsalpha through three generations of a pedigree affected by AHO and PHP-Ia. While all family members carrying this loss-of-function mutation in one Gsalpha allele had AHO, neither the presence of the mutation nor the degree of reduction of erythrocyte Gsalpha bioactivity allowed prediction of phenotype (AHO alone versus AHO and PHP-Ia). Paternal transmission of the mutation (from the patriarch of the first generation to three members of the second generation) was not associated with concurrent PHP-Ia, but maternal transmission (from two women in the second generation to four children in the third generation) was invariably associated with PHP-Ia. No expansion of an upstream short CCG nucleotide repeat region was detected, nor was there evidence of uniparental disomy by polymorphism analysis. This report, the first to document the effects across three generations of both paternal and maternal transmission of a specific Gsalpha mutation, strongly supports the hypothesis that a maternal factor determines full expression of Gsalpha dysfunction as PHP-Ia.

Hypertension in pseudohypoparathyroidism type I

PURPOSE There is increasing evidence of a central role for the calcium ion in blood pressure regulation. By studying blood pressure control in disorders of calcium homeostasis, a better understanding of the role of the calcium ion and certain calcitrophic hormones in modulating arterial pressure in humans may be gained. Our goal was to examine levels of blood pressure in a group of patients with either type Ia or type Ib pseudohypoparathyroidism (PsHP), a disorder characterized by target organ resistance to parathyroid hormone. PATIENTS AND METHODS Forty-six patients with type I PsHP were recruited for the study (28 with type Ia and 18 with type Ib). Blood pressure was measured and the degree of obesity was assessed in all patients. Detailed measurements of hormones involved in blood pressure regulation were made in nine hypertensive patients with PsHP. RESULTS Elevated arterial pressure was present in 18 of the 46 patients with PsHP, which comprised 53 percent (18 of 34) of the adult subjects. Prevalence of hypertension was similar in PsHP type Ia (nine of 21) and type Ib (nine of 13; p not significant) and was not related to coexisting hypothyroidism or degree of hypocalcemia. However, hypertension in PsHP was strongly linked to severe obesity. Mean body weights of normotensive and hypertensive patients with PsHP were 64 +/- 2.8 (SEM) kg (125 +/- 6 percent ideal body weight) and 96 +/- 4.7 kg (172 +/- 10 percent ideal body weight), respectively. Compared with obese hypertensive non-PsHP persons, hypertensive subjects with PsHP had reduced basal and posture-stimulated renin activity (basal, 1.68 +/- 0.36 [n = 9] versus 3.97 +/- 0.61 ng/ml/hour [n = 9] [p less than 0.05]; upright posture, 2.11 +/- 0.42 versus 7.13 ng/ml/hour [p less than 0.05]; and lower basal and posture-stimulated plasma norepinephrine levels (basal, 236 +/- 52 versus 426 +/- 37 pg/ml [p less than 0.05]; upright posture, 424 +/- 62 versus 707 +/- 64 pg/ml [p less than 0.05]). CONCLUSION Our data suggest that hypertension is common in PsHP types Ia and Ib. This newly identified form of endocrine hypertension is strongly linked to excessive body weight but is associated with alterations in the renin-aldosterone and sympathetic nervous systems that are distinct from those encountered in obesity-related hypertension in the general population. The pathophysiologic basis for hypertension in these two distinctly different forms of PsHP remains to be determined.

Current status of the use of newer analogs of vitamin D in the management of renal osteodystrophy.

In this discussion, the term renal osteodystrophy is used to denote a clinical syndrome observed in azotemic patients with a variety of skeletal lesions including osteitis fibrosa, osteomalacia, osteosclerosis, osteoporosis, and retardation of growth. The pathophysiologic alteration in advanced renal failure include hypocalcemia, hyperphosphatemia, hypermagnesemia, soft tissue calcification, and impaired intestinal calcium absorption. Secondary hyperparathyroidism is a major feature, and it is believed to have its onset early in the course of renal insufficiency. Parathyroid hyperplasia is thought to arise as a consequence of hypocalcemia produced in part by 1) phosphate retention and hyperphosphatemia, 2) from impaired renal conversion of 25-hydroxy-vitamin D3 [25(OH)D3] to 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3], and 3) reduced skeletal responsiveness to the calcemic action of PTH. Knowledge that the kidney is the sole organ capable of producing 1,25(OH)2D3, the most active known form of vitamin D, from 25(OH)D3 (1) suggests a major pathogenic role of altered vitamin D metabolism in causing renal osteodystrophy. The observations that plasma levels of 1,25(OH)2D3 are low (2), the failure of conversion of radio-labeled 25(OH)D3 to 1,25(OH)2D3 (3) and the restoration of intestinal Ca absorption to normal following treatment with 1,25(OH)2D3 (4,5) in patients with end-stage uremia support the concept that renal production of 1,25(OH)2D3 is impaired in advanced renal failure. Moreover, such observations have prompted numerous clinical trials employing newer vitamin D analogs to uremic patients with bone disease. It is our purpose to briefly review the present state of knowledge on the usefulness of these analogs in renal osteodystrophy.