CONTEXT: Pseudohypoparathyroidism (PHP) types 1a and 1b are distinguished by clinical, biochemical, and molecular features. We report extended kindred with PHP 1b in which many affected members also had growth plate defects, including brachydactyly and a Madelung-like deformity. DESIGN: Analyses included clinical examination, assessment of mineral metabolism, thyroid function, skeletal radiography, and analysis of the GNAS and STX16 genes. SETTING: Patients were studied in an academic medical center. RESULTS: We studied 37 members of a family in which PHP 1b occurred in 23 individuals. Ten of 17 affected patients who were examined had brachydactyly E, including two subjects with Madelung-like defects. Five of 16 subjects had subclinical hypothyroidism; no subject showed sc ossification or short stature. None of the unaffected members had brachydactyly or an elevated serum level of PTH or TSH. Levels of immunoactive erythrocyte Gα(s) were normal in two affected subjects tested. Linkage analysis indicated linkage between PTH resistance and the GNAS gene locus; however, no mutations were identified in GNAS exons 1-13. Methylation analysis of genomic DNA from affected subjects showed loss of maternal epigenotype in exon 1A with normal methylation of the differentially methylated regions for XLGαs and NESP55, and PCR demonstrated heterozygosity for a 3.0-kb deletion in the STX16 gene. CONCLUSION: The segregation of brachydactyly with PHP 1b in this family indicates that an imprinting defect in GNAS can lead to growth plate defects, including brachydactyly and Madelung deformity. These features suggest that GNAS signaling plays a more extensive role in chondrocyte maturation than previously thought.
CONTEXT: Pseudohypoparathyroidism (PHP) types 1a and 1b are distinguished by clinical, biochemical, and molecular features. We report extended kindred with PHP 1b in which many affected members also had growth plate defects, including brachydactyly and a Madelung-like deformity. DESIGN: Analyses included clinical examination, assessment of mineral metabolism, thyroid function, skeletal radiography, and analysis of the GNAS and STX16 genes. SETTING:Patients were studied in an academic medical center. RESULTS: We studied 37 members of a family in which PHP 1b occurred in 23 individuals. Ten of 17 affected patients who were examined had brachydactyly E, including two subjects with Madelung-like defects. Five of 16 subjects had subclinical hypothyroidism; no subject showed sc ossification or short stature. None of the unaffected members had brachydactyly or an elevated serum level of PTH or TSH. Levels of immunoactive erythrocyte Gα(s) were normal in two affected subjects tested. Linkage analysis indicated linkage between PTH resistance and the GNAS gene locus; however, no mutations were identified in GNAS exons 1-13. Methylation analysis of genomic DNA from affected subjects showed loss of maternal epigenotype in exon 1A with normal methylation of the differentially methylated regions for XLGαs and NESP55, and PCR demonstrated heterozygosity for a 3.0-kb deletion in the STX16 gene. CONCLUSION: The segregation of brachydactyly with PHP 1b in this family indicates that an imprinting defect in GNAS can lead to growth plate defects, including brachydactyly and Madelung deformity. These features suggest that GNAS signaling plays a more extensive role in chondrocyte maturation than previously thought.
Authors: B Lanske; A C Karaplis; K Lee; A Luz; A Vortkamp; A Pirro; M Karperien; L H Defize; C Ho; R C Mulligan; A B Abou-Samra; H Jüppner; G V Segre; H M Kronenberg Journal: Science Date: 1996-08-02 Impact factor: 47.728
Authors: Giovanna Mantovani; Sara Bondioni; Marco Locatelli; Cecilia Pedroni; Andrea G Lania; Emanuele Ferrante; Marcello Filopanti; Paolo Beck-Peccoz; Anna Spada Journal: J Clin Endocrinol Metab Date: 2004-12 Impact factor: 5.958
Authors: Murat Bastepe; Leopold F Fröhlich; Geoffrey N Hendy; Olafur S Indridason; Robert G Josse; Hiroyuki Koshiyama; Jarmo Körkkö; Jon M Nakamoto; Arlan L Rosenbloom; Arnold H Slyper; Toshitsugu Sugimoto; Agathocles Tsatsoulis; John D Crawford; Harald Jüppner Journal: J Clin Invest Date: 2003-10 Impact factor: 14.808
Authors: A C Karaplis; A Luz; J Glowacki; R T Bronson; V L Tybulewicz; H M Kronenberg; R C Mulligan Journal: Genes Dev Date: 1994-02-01 Impact factor: 11.361
Authors: Suzanne M Jan De Beur; Jeffery R O'Connell; Rita Peila; Justin Cho; Zhichao Deng; Stephen Kam; Michael A Levine Journal: J Bone Miner Res Date: 2003-03 Impact factor: 6.741
Authors: Sihoon Lee; Michael Mannstadt; Jun Guo; Seul Min Kim; Hyon-Seung Yi; Ashok Khatri; Thomas Dean; Makoto Okazaki; Thomas J Gardella; Harald Jüppner Journal: J Bone Miner Res Date: 2015-06-08 Impact factor: 6.741
Authors: Serap Turan; Jaakko Ignatius; Jukka S Moilanen; Outi Kuismin; Helen Stewart; Nicholas P Mann; Agnès Linglart; Murat Bastepe; Harald Jüppner Journal: J Clin Endocrinol Metab Date: 2012-10-18 Impact factor: 5.958
Authors: Bart L Clarke; Edward M Brown; Michael T Collins; Harald Jüppner; Peter Lakatos; Michael A Levine; Michael M Mannstadt; John P Bilezikian; Anatoly F Romanischen; Rajesh V Thakker Journal: J Clin Endocrinol Metab Date: 2016-03-04 Impact factor: 5.958