title: Similar clinical and laboratory findings in patients with symptomatic autosomal dominant and sporadic pseudohypoparathyroidism type Ib despite different epigenetic changes at the GNAS locus.
abstract: OBJECTIVE
  Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) carry an identical maternally inherited 3-kb microdeletion up-stream of GNAS (STX16del4-6(mat)), which is associated with a methylation loss restricted to exon A/B. STX16del4-6(mat) is not found in sporadic PHP-Ib (sporPHP-Ib) patients, who show broad GNAS methylation changes. Because of the epigenetic differences between both groups, we searched for clinical and/or laboratory differences.
  
  
  METHODS
  Age at diagnosis, calcium, phosphorus and PTH were analysed in 43 patients with AD-PHP-Ib due to STX16del4-6(mat) and in 22 patients with sporPHP-Ib.
  
  
  RESULTS
  All AD-PHP-Ib patients with STX16del4-6(mat) showed only loss of exon A/B methylation. Of the 43 individuals, 26 were symptomatic when diagnosis was established at age 12.1 +/- 1.34 years (mean +/- SEM); laboratory findings at presentation were calcium 1.69 +/- 0.06 mmol/l, phosphorus 2.25 +/- 0.12 mmol/l and PTH 442 +/- 54.1 pg/ml. The remaining 17 individuals with STX16del4-6(mat) were asymptomatic when diagnosed at age 23.5 +/- 3.93 years (calcium 2.18 +/- 0.05 mmol/l, phosphorus 1.63 +/- 0.10 mmol/l, PTH 222 +/- 40.3 pg/ml). Patients with sporPHP-Ib showed methylation changes at two or more GNAS exons, presented at age 10.0 +/- 1.01 years and had, as a group, similar laboratory findings as patients with symptomatic AD-PHP-Ib (calcium 1.51 +/- 0.06 mmol/l, phosphorus 2.65 +/- 0.10 mmol/l, PTH 634 +/- 162.1 pg/ml). However, sporPHP-Ib females appeared to be more severely affected.
  
  
  CONCLUSIONS
  Patients with symptomatic AD-PHP-Ib due to STX16del4-6(mat) and sporPHP-Ib have similar changes in calcium, phosphate and PTH. STX16del4-6(mat) often leads to asymptomatic disease and screening of all siblings of affected individuals is therefore advised. The cause of the apparent sexual dimorphism in patients with sporPHP-Ib remains uncertain.
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Agnès
authors.initials: A
authors.lastname: Linglart
authors.forename: Murat
authors.initials: M
authors.lastname: Bastepe
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
mesh_terms: D000328:Adult; D017668:Age of Onset; D002118:Calcium / Q000097:blood; D002864:Chromogranins; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D008297:Male; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood; D011547:Pseudohypoparathyroidism / Q000097:blood* / Q000235:genetics*
chemical_list: D002864:Chromogranins; D010281:Parathyroid Hormone; D010758:Phosphorus; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D002118:Calcium