title: Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in GNAS.
abstract: BACKGROUND
  Loss-of-function GNAS mutations lead to hormone resistance and Albright's hereditary osteodystrophy (AHO) when maternally inherited, i.e. pseudohypoparathyroidism-Ia (PHPIa), but cause AHO alone when located on the paternal allele, i.e. pseudoPHP (PPHP).
  
  
  OBJECTIVE
  We aimed to establish the molecular diagnosis in a patient with AHO and evidence of hormone resistance.
  
  
  METHODS
  The patient is a female who presented at the age of 13.5years with short stature and multiple AHO features. No evidence for TSH or gonadotropin-resistance was present. Serum calcium and vitamin D levels were normal. However, serum PTH was elevated on multiple occasions (64-178pg/mL, normal: 9-52) and growth hormone response to clonidine or L-DOPA was blunted, suggesting hormone resistance and PHP-Ia. The patient had diminished erythrocyte Gsα activity and a novel heterozygous GNAS mutation (c.328 G>C; p.A109P). The mother lacked the mutation, and the father's DNA was not available. Hence, a diagnosis of PPHP also appeared possible, supported by low birth weight and a lack of AHO features associated predominantly with PHP-Ia, i.e. obesity and cognitive impairment. To determine the parental origin of the mutation, we amplified the paternally expressed A/B and biallelically expressed Gsα transcripts from the patient's peripheral blood RNA. While both wild-type and mutant nucleotides were detected in the Gsα amplicon, only the mutant nucleotide was present in the A/B amplicon, indicating that the mutation was paternal.
  
  
  CONCLUSIONS
  These findings suggest that PTH and other hormone resistance may not be an exclusive feature of PHP-Ia and could also be observed in patients with PPHP.
authors.affiliation: Marmara University, Department of Pediatric Endocrinology, Istanbul, Turkey. Electronic address: serap.turan@marmara.edu.tr.
authors.forename: Serap
authors.initials: S
authors.lastname: Turan
authors.affiliation: Division of Experimental Paediatric Endocrinology and Diabetes, University of Luebeck, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Thiele
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
authors.forename: Olta
authors.initials: O
authors.lastname: Tafaj
authors.affiliation: Division of Experimental Paediatric Endocrinology and Diabetes, University of Luebeck, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Brix
authors.affiliation: Marmara University, Department of Pediatric Endocrinology, Istanbul, Turkey.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Atay
authors.affiliation: Marmara University, Department of Pediatric Endocrinology, Istanbul, Turkey.
authors.forename: Saygin
authors.initials: S
authors.lastname: Abali
authors.affiliation: Marmara University, Department of Pediatric Endocrinology, Istanbul, Turkey.
authors.forename: Belma
authors.initials: B
authors.lastname: Haliloglu
authors.affiliation: Marmara University, Department of Pediatric Endocrinology, Istanbul, Turkey.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Bereket
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, USA. Electronic address: bastepe@helix.mgh.harvard.edu.
authors.forename: Murat
authors.initials: M
authors.lastname: Bastepe
mesh_terms: D000293:Adolescent; D000483:Alleles; D002118:Calcium / Q000097:blood; D002864:Chromogranins; D004252:DNA Mutational Analysis; D005220:Fathers; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D010281:Parathyroid Hormone / Q000097:blood; D011556:Pseudopseudohypoparathyroidism / Q000097:blood / Q000235:genetics*; D014807:Vitamin D / Q000097:blood
chemical_list: D002864:Chromogranins; D010281:Parathyroid Hormone; D014807:Vitamin D; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D002118:Calcium
keywords: GNAS; Hormone resistance; Pseudohypoparathyroidism; Pseudopseudohypoparathyroidism