title: Madelung-like deformity in pseudohypoparathyroidism type 1b.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Analyses included clinical examination, assessment of mineral metabolism, thyroid function, skeletal radiography, and analysis of the GNAS and STX16 genes.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Division of Pediatric Endocrinology, MCCD 3044A, D820, 1601 NW 12th Avenue, Miami, Florida 33136. jsanchez@med.miami.edu.
authors.forename: Janine
authors.initials: J
authors.lastname: Sanchez
authors.forename: Erasmo
authors.initials: E
authors.lastname: Perera
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jan de Beur
authors.forename: Changlin
authors.initials: C
authors.lastname: Ding
authors.forename: Anna
authors.initials: A
authors.lastname: Dang
authors.forename: Gary D
authors.initials: GD
authors.lastname: Berkovitz
authors.forename: Michael A
authors.initials: MA
authors.lastname: Levine
mesh_terms: D000328:Adult; D000483:Alleles; D002864:Chromogranins; D019175:DNA Methylation; D005260:Female; D005532:Foot Deformities, Congenital / Q000150:complications / Q000235:genetics*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D008040:Genetic Linkage; D018392:Genomic Imprinting; D006228:Hand Deformities, Congenital / Q000150:complications / Q000235:genetics*; D006801:Humans; D008069:Lipomatosis, Multiple Symmetrical / Q000150:complications / Q000235:genetics*; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011547:Pseudohypoparathyroidism / Q000150:complications / Q000235:genetics*
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs