1/161. Effectiveness of 1,25-dihydroxyvitamin D supplementation on blood pressure reduction in a pseudohypoparathyroidism patient with high renin activity. A 42-year-old man had biochemical and somatic abnormalities compatible with pseudohypoparathyroidism type I (PsHP) and also had high plasma renin activity (PRA). After 1,25-dihydroxyvitamin D (calcitriol) supplementation the systolic/diastolic blood pressure, assessed by 24-hour non-invasive ambulatory blood pressure monitoring, was reduced from 145/96 mm Hg to 128/85 mm Hg with normalization of the serum calcium level and its related hormones, as well as decreased PRA. calcitriol supplementation successfully reduced the blood pressure in this patient with PsHP and a high PRA, suggesting that calcium-related hormones and/or the renin-angiotensin system were involved in lowering the blood pressure. ( info) |
2/161. Stimulatory guanine nucleotide binding protein subunit 1 mutation in two siblings with pseudohypoparathyroidism type 1a and mother with pseudopseudohypoparathyroidism. Pseudohypoparathyroidism (PHP) type la is characterized by multihormone resistance and a constellation of somatic features referred to as Albright hereditary osteodystrophy. Several mutations in the gene coding for the Gs alpha subunit (GNAS1) have been described. Clinical symptoms are heterogeneous and initially laboratory parameters may be normal. We identified a 4 base pair deletion within GNAS1 in two affected siblings with PHP type la and their mother with presumed pseudo PHP. The female proband was diagnosed after an episode of apnoea and seizures. The younger brother was asymptomatic during infancy and had normal plasma parameters. PHP was diagnosed at the age of 4.4 years. Regular check-ups of siblings in families with index cases are therefore important. Molecular genetic analyses or biochemical screening for stimulatory guanine nucleotide binding protein defects should be performed. CONCLUSION: Different symptoms may be seen in patients with the same mutation causing pseudohypoparathyroidism or pseudopseudohypoparathyroidism. Therefore, clinical and biochemical investigations should be performed in all family members with an index patient. ( info) |
3/161. osteoma cutis in pseudohypoparathyroidism. Pseudohypoparathyroidism (PHP) is a hereditary disorder characterized by an end-organ resistance for parathormone. PHP can be classified into different types by biochemical and phenotypic characteristics and the level of the defect in the hormone-receptor complex. PHP is described as Albright's hereditary osteodystrophy (AHO) when a specific phenotype is present. We report a case of osteoma cutis in a 30-year-old woman with AHO. Successful treatment was obtained by debriding the lesion followed by split-thickness skin grafting. ( info) |
4/161. Pseudohypoparathyroidism type 1b in pregnancy. calcium-regulating hormones were serially measured during the second pregnancy in a woman with pseudohypoparathyroidism type 1b. calcium levels corrected for serum albumin were maintained almost normal during her second pregnancy with 1alpha-hydroxycalciferol (2.0 microg daily) though they were slightly decreased in late pregnancy. 1,25-Dihydroxyvitamin D levels were higher in early and mid-pregnancy, but not in late pregnancy compared to those after delivery. parathyroid hormone levels were higher in late pregnancy than after delivery. ( info) |
5/161. Identification of two novel deletion mutations within the Gs alpha gene (GNAS1) in Albright hereditary osteodystrophy. Albright hereditary osteodystrophy (AHO) is a genetic disorder characterized by short stature, skeletal defects, and obesity. Within AHO kindreds, some affected family members have only the somatic features of AHO [pseudopseudohypoparathyroidism (PPHP)], whereas others have these features in association with resistance to multiple hormones that stimulate adenylyl cyclase within their target tissues [pseudohypoparathyroidism type Ia (PHP Ia)]. Affected members of most AHO kindreds (both those with PPHP and those with PHP Ia) have a partial deficiency of Gs alpha, the alpha-subunit of the G protein that couples receptors to adenylyl cyclase stimulation, and in a number of cases heterozygous loss of function mutations within the Gs alpha gene (GNAS1) have been identified. Using PCR with the attachment of a high melting domain (GC-clamp) and temperature gradient gel electrophoresis, two novel heterozygous frameshift mutations within GNAS1 were found in two AHO kindreds. In one kindred all affected members (both PHP Ia and PPHP) had a heterozygous 2-bp deletion in exon 8, whereas in the second kindred a heterozygous 2-bp deletion in exon 4 was identified in all affected members examined. In both cases the frameshift encoded a premature termination codon several codons downstream of the deletion. In the latter kindred affected members were previously shown to have decreased levels of GNAS1 messenger ribonucleic acid expression. These results further underscore the genetic heterogeneity of AHO and provides further evidence that PHP Ia and PPHP are two clinical presentations of a common genetic defect. Serial measurements of thyroid function in members of kindred 1 indicate that TSH resistance progresses with age and becomes more evident after the first year of life. ( info) |
6/161. Increased urinary phosphate excretion in pseudohypoparathyroidism type II with long-term treatment with phosphodiesterase inhibitor. A 58-year-old woman was diagnosed to have pseudohypoparathyroidism (PHP) type II because of the absence of an increase of urinary phosphate secretion, despite a marked increase in urinary cAMP excretion on the Ellsworth-Howard test. We treated the patient with a cyclic-nucleotide phosphodiesterase inhibitor, theophylline, resulting in increased urinary phosphate and cAMP excretions. Dibutyl cAMP administration induced the increase in the urinary phosphate excretion. In this case, the unresponsiveness of the urinary phosphate secretion to cAMP was recovered by a high dose of cAMP or long-term administration of a phosphodiesterase inhibitor. These data imply that cAMP responsiveness to renal tubular phosphate reabsorption should be more strictly elucidated in the patient with PHP type II. ( info) |
7/161. Corrected QT interval (QTc) prolongation and syncope associated with pseudohypoparathyroidism and hypocalcemia. An adolescent presented with exercise-associated syncope and electrocardiographic corrected QT interval (QTc) prolongation. Pseudohypoparathyroidism-induced hypocalcemia was diagnosed. The QTc (485 to 505 milliseconds) shortened during normalization of calcium levels, and syncope has not reoccurred. ( info) |
8/161. Pseudohypoparathyroidism--another monogenic obesity syndrome. obesity is a common feature of pseudohypoparathyroidism (PHP) type 1a, but is usually associated with short stature. We describe two children referred because of hyperphagia and excessive weight gain from early infancy. Tall stature in both children initially confounded the diagnosis of PHP, but on follow-up both children developed the typical hormonal abnormalities and Case 2 developed typical skeletal features of Albright hereditary osteodystrophy. PHP type 1a is caused by germline loss of function mutations in the alpha subunit of GS, the ubiquitously expressed G protein that couples many hormone receptors to the adenylate cyclase second messenger system. Recent evidence suggest that the hypothalamic GS protein coupled melanocortin-4 receptor (MC4R) may mediate the central effects of leptin on inhibition of satiety. Similar patterns of infancy onset hyperphagia, excessive weight gain and tall stature are seen in subjects with congenital leptin deficiency and in subjects with MC4R mutations. We suggest that the genetic mutations in GSalpha which underlie PHP type 1a may also directly result in severe obesity. This diagnosis should be considered in any child with a history of hyperphagia and early onset morbid obesity. ( info) |
9/161. Pseudohypoparathyroidism-Albright hereditary osteodystrophy. A 13 year old girl with short stature, and retarded mental growth with coarse facies and deranged thyroid function test was initially suspected as a case of hypothyroidism and was started on thyroxine. Lack of response to treatment and on further investigations it was diagnosed as a case of pseudohypoparathyroidism. High index of suspicion and careful evaluation is important to diagnose such an entity. ( info) |
10/161. Pseudohypoparathyroidism 1b: exclusion of parathyroid hormone and its receptors as candidate disease genes. Pseudohypoparathyroidism 1b (PHP 1b) is characterized by specific resistance of target tissues to PTH, but no mutations in the PTH/PTH-related peptide (PTHrP) receptor gene have been identified. To investigate the basis for defective PTH signaling, we used polymorphic markers in or near the genes encoding PTH and its receptors to perform linkage analysis between these loci and PHP 1b. Two multiplex PHP 1b families (families M and K) were informative for an intragenic polymorphism in exon 13 of the PTH/PTHrP receptor gene detected by PCR amplification and resolved by denaturing gradient gel electrophoresis. Linkage analysis revealed discordance of the PTH/PTHrP receptor with PHP1b. One PHP 1b kindred (family M) was informative for a intragenic polymorphism in exon 3 of the PTH gene detected by PCR amplification and resolved by denaturing gradient gel electrophoresis. The PTH gene polymorphism segregation was discordant with PHP 1b. Probands from each family had normal PTH genes by direct sequence analysis. In three PHP 1b kindreds, we analyzed simple sequence polymorphisms in three microsatellite markers flanking the PTH type 2 receptor locus located at 2q33. Linkage analysis demonstrated no linkage. In conclusion, neither the PTH gene nor the PTH receptor genes (type 1 and 2) are linked to PHP 1b. ( info) |