title: Auxological and endocrine phenotype in a population-based cohort of patients with PROP1 gene defects.
abstract: OBJECTIVE
  Multiple pituitary hormone deficiency (MPHD) may result from defects of transcription factors that govern early pituitary development. We aimed to establish the prevalence of HESX1, PROP1, and POU1F1 gene defects in a population-based cohort of patients with MPHD and to analyse the phenotype of affected individuals.
  
  
  METHODS
  Genomic analysis was carried out on 74 children and adults with MPHD from the Czech Republic (including four sibling pairs). Phenotypic data were collected from medical records and referring physicians.
  
  
  RESULTS
  One patient carried a heterozygous mutation of POU1F1 (71C > T), and 18 patients (including three sibling pairs) had a PROP1 mutation (genotypes 150delA/301delGA/9/, 301delGA/301-delGA/8/, or 301delGA/349T > A/1/). A detailed longitudinal phenotypic analysis was performed for patients with PROP1 mutations (n = 17). The mean ( +/-s.d.) birth length SDS of these patients (0.12 +/- 0.76) was lower than expected based on their mean ( +/-s.d.) birth weight SDS (0.63 +/- 1.27; P = 0.01). Parental heights were normal. The patients' mean ( +/-s.d.) height SDS declined to -1.5 +/- 0.9, -3.6 +/- 1.3 and -4.1 +/- 1.2 at 1.5, 3 and 5 years of age, respectively. GH therapy, initiated at 6.8 +/- 3.2 years of age (mean dose: 0.022 mg/kg per day), led to substantial growth acceleration in all patients. Mean adult height (n = 7) was normal when adjusted for mid-parental height. ACTH deficiency developed in two out of seven young adult patients.
  
  
  CONCLUSIONS
  PROP1 defects are a prevalent cause of MPHD. We suggest that testing for PROP1 mutations in patients with MPHD might become standard practice in order to predict risk of additional pituitary hormone deficiencies.
authors.affiliation: Department of Paediatrics, 3 Faculty of Medicine, Charles University Parague, Czech Republic. lebl@fnkv.cz
authors.forename: Jan
authors.initials: J
authors.lastname: Lebl
authors.forename: Jan
authors.initials: J
authors.lastname: Vosáhlo
authors.forename: Roland W
authors.initials: RW
authors.lastname: Pfaeffle
authors.forename: Heike
authors.initials: H
authors.lastname: Stobbe
authors.forename: Jana
authors.initials: J
authors.lastname: Cerná
authors.forename: Dana
authors.initials: D
authors.lastname: Novotná
authors.forename: Jirina
authors.initials: J
authors.lastname: Zapletalová
authors.forename: Bozena
authors.initials: B
authors.lastname: Kalvachová
authors.forename: Václav
authors.initials: V
authors.lastname: Hána
authors.forename: Vladimír
authors.initials: V
authors.lastname: Weiss
authors.forename: Werner F
authors.initials: WF
authors.lastname: Blum
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001827:Body Height / Q000502:physiology; D002648:Child; D015331:Cohort Studies; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation; D010641:Phenotype; D010900:Pituitary Diseases / Q000235:genetics*; D010907:Pituitary Hormones / Q000172:deficiency*; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C489736:HESX1 protein, human; D018398:Homeodomain Proteins; C494187:POU1F1 protein, human; D010907:Pituitary Hormones; C102134:Prophet of Pit-1 protein; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; D004247:DNA