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      Long−Term Follow−Up of a Pseudohypoparathyroidism Type 1A Patient with Missense Mutation (Pro115Ser) in Exon 5

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          Abstract

          Pseudohypoparathyroidism (PHP) refers to end−organ resistance that primarily impairs the renal actions of parathyroid hormone (PTH). The patients with PHP type Ia (PHP−Ia), one of the 4 types of PHP, show resistance to other peptide hormones as well as clinical features of Albright hereditary osteodystrophy (AHO), a constellation of short stature, obesity, brachydactyly, ectopic ossifications, and/or mental retardation. Here we report clinical follow−up for a long−term period in a PHP−Ia case who had a missense mutation leading to the substitution of proline by serine (Prol115Ser) in exon 5 which has been reported previously in only two patients. An 11−year−old boy applied for hand spasm to our hospital. On physical examination, he had short stature, round−shaped face and brachydactly. Laboratory evaluation revealed PTH and TSH resistance. Molecular genetic analysis of the GNAS gene revealed a P115S substitution. The patient was followed up for 13 years. Normocalcaemia was achieved with reduced doses of calcitriol (0.25 μg/day) and calcium supplements (40 mg/kg/day). Daily requirement for levothyroxine supplementation was still high (2.3 μg/kg) to achieve euthyroidism. His pubertal development was Tanner stage V and he has no gonadotropin resistance. To our knowledge, this is the first report concerning long−term follow−up of this rare mutation. We believe that despite the genetic heterogeneity of AHO, phenotype/genotype correlations of this kind of rare mutations may help to understand progress of the disease.

          Conflict of interest:None declared.

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          Most cited references15

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          Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance.

          Albright hereditary osteodystrophy (AHO) is a genetic disorder caused by heterozygous inactivating mutations in GNAS1, the gene encoding the alpha-chain of G(s), and is associated with short stature, obesity, brachydactyly, and sc ossifications. AHO patients with GNAS1 mutations on maternally inherited alleles also manifest resistance to multiple hormones (e.g. PTH, TSH, LH, FSH), a variant termed pseudohypoparathyroidism (PHP) type 1a, due to paternal imprinting of G alpha(s) transcripts in specific tissues. Recent evidence has shown that G alpha(s) transcripts are also imprinted in the pituitary somatotrophs that secrete GH. Because this imprinting could influence GHRH-dependent stimulation of somatotrophs, we hypothesized that maternally inherited GNAS1 mutations would impair GH secretion. We studied GH status in 13 subjects with PHP type 1a. GH responses to arginine/L-dopa and arginine/GHRH were deficient in nine subjects, all of whom were obese and had low serum concentrations of IGF-I. By contrast, none of the four GH-sufficient subjects were obese, and all had normal IGF-I levels. Our data indicate that GH deficiency is common (69%) in PHP type 1a and may contribute to the obesity and short stature typical of AHO. We propose that GH status be evaluated in all patients with PHP type 1a.
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            Analysis of the GNAS1 gene in Albright's hereditary osteodystrophy.

            Albright's hereditary osteodystrophy (AHO) is characterized by phenotypic signs that typically include brachydactyly and sc calcifications occurring with or without hormone resistance toward PTH or other hormones such as thyroid hormone or gonadotropins. Different inactivating mutations of the gene GNAS1 encoding Gsalpha lead to a reduced Gsalpha protein activity in patients with AHO and pseudohypoparathyroidism type Ia or without resistance to PTH (pseudopseudohypoparathyroidism). We investigated 29 unrelated patients with AHO and pseudohypoparathyroidism type Ia or pseudopseudohypoparathyroidism and their affected family members performing functional and molecular genetic analysis of Gsalpha. In vitro determination of Gsalpha protein activity in erythrocyte membranes was followed by the investigation of the whole coding region of the GNAS1 gene using PCR, nonisotopic single strand conformation analysis, and direct sequencing of the PCR products. All patients showed a reduced Gsalpha protein activity (mean 59% compared with healthy controls). In 21/29 (72%) patients, 15 different mutations in GNAS1 including 11 novel mutations were detected. In addition we add five unrelated patients with a previously described 4 bp deletion in exon 7 (Delta GACT, codon 189/190), confirming the presence of a hot spot for loss of function mutations in GNAS1. In eight patients, no molecular abnormality was found in the GNAS1 gene despite a functional defect of Gsalpha. We conclude that biochemical and molecular analysis of Gsalpha and its gene GNAS1 can be valuable tools to confirm the diagnosis of AHO. However, in some patients with reduced activity of Gsalpha, the molecular defect cannot be detected in the exons encoding the common form of Gsalpha.
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              GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance.

              We conducted clinical and biological studies including screening for mutations in the gene encoding the alpha subunit of G(s) (GNAS1) in 30 subjects (21 unrelated families) with Albright's hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP); and decreased erythrocyte G(s) activity (PHP-Ia; n = 19); AHO and decreased erythrocyte G(s) activity (isolated AHO; n = 10); or AHO, hormonal resistance, and normal erythrocyte G(s) activity (PHP-Ic; n = 1). A heterozygous GNAS1 gene lesion was found in 14 of 17 PHP-Ia index cases (82%), including 11 new mutations and a mutational hot-spot involving codons 189-190 (21%). These lesions lead to a truncated protein in all but three cases with missense mutations R280K, V159M, and D156N. In the patient diagnosed with PHP-Ic, G(s)alpha protein was shortened by just four amino acids, a finding consistent with the conservation of G(s) activity in erythrocytes and the loss of receptor contact. No GNAS1 lesions were found in individuals with isolated AHO that were not relatives to PHP-Ia patients (n = 5). Intrafamilial segregation analyses of the mutated GNAS1 allele in nine PHP-Ia patients established that the mutation had either occurred de novo on the maternal allele (n = 4) or had been transmitted by a mother with a mild phenotype (n = 5). This finding is consistent with an imprinting of GNAS1 playing a role in the clinical phenotype of loss of function mutations and with a functional maternal GNAS1 allele having a predominant role in preventing the hormonal resistance of PHP-Ia.
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                Author and article information

                Journal
                J Clin Res Pediatr Endocrinol
                JCRPE
                Journal of Clinical Research in Pediatric Endocrinology
                Galenos Publishing
                1308-5727
                1308-5735
                June 2010
                7 May 2010
                : 2
                : 2
                : 85-88
                Affiliations
                [1 ] Ankara University School of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Ankara, Turkey
                [2 ] Kırıkkale University School of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Ankara, Turkey
                [3 ] University of Lubeck, Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Lubeck, Germany
                +90 312 595 67 91 senaysavas@ 123456yahoo.com Ankara University School of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Ankara, Turkey
                Article
                60
                10.4274/jcrpe.v2i2.85
                3005667
                21274345
                96151e02-929c-4ea7-abcc-e800e5041e18
                © Journal of Clinical Research in Pediatric Endocrinology, Published by Galenos Publishing.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 6 February 2010
                : 12 April 2010
                Categories
                Case Reports

                Pediatrics
                pseudohypoparathyroidism type ia,albright’s hereditary osteodystrophy,mutation

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