title: Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD).
abstract: OBJECTIVE
  Mutations within the pituitary-specific paired-like homeobox gene PROP1 have been described in 50-100% of patients with familial combined pituitary hormone deficiency (CPHD). We screened a cohort of sporadic (n = 189) and familial (n = 44) patients with hypopituitarism (153 CPHD and 80 isolated hormone deficiencies) for mutations within the coding sequence of PROP1.
  
  
  METHODS
  Patients with congenital hypopituitarism were recruited from the London Centre for Paediatric Endocrinology as well as several national and international centres. The pituitary phenotype ranged from isolated growth hormone deficiency (IGHD) to panhypopituitarism. Clinical data, including endocrine and neuro-radiological studies were obtained from patient records, and DNA was collected and screened for mutations within PROP1 using PCR and single-stranded conformation polymorphism (SSCP) analysis. Positive results on SSCP were sequenced directly.
  
  
  RESULTS
  The prevalence of PROP1 mutations in unselected sporadic cases of hypopituitarism was lower (1.1%) than in familial cases (29.5%). PROP1 mutations can be associated with a highly variable phenotype, and both pituitary hypoplasia and pituitary hyperplasia. We describe the waxing and waning of a pituitary mass over 20 months in association with a PROP1 mutation that is predicted to lead to complete loss of function. Additionally, we have identified a possible founder mutation in CPHD patients from the Indian subcontinent.
  
  
  CONCLUSIONS
  PROP1 mutations are rare in sporadic cases of CPHD, although the prevalence rises if there is a positive family history or if the patients are carefully selected with respect to the endocrine and neuroradiological phenotype. There is considerable phenotypic variability in families with the same mutation, indicating the role of other genetic or environmental factors on phenotypic expression. Finally, the pituitary enlargement that is observed in patients with PROP1 mutations can wax and wane in size before eventual involution.
authors.affiliation: Biochemistry, Endocrinology and Metabolism Unit, University College London, UK.
authors.forename: James P G
authors.initials: JP
authors.lastname: Turton
authors.forename: Ameeta
authors.initials: A
authors.lastname: Mehta
authors.forename: Jamal
authors.initials: J
authors.lastname: Raza
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Woods
authors.forename: Anatoly
authors.initials: A
authors.lastname: Tiulpakov
authors.forename: Joseph
authors.initials: J
authors.lastname: Cassar
authors.forename: Kling
authors.initials: K
authors.lastname: Chong
authors.forename: Paul Q
authors.initials: PQ
authors.lastname: Thomas
authors.forename: Marumudi
authors.initials: M
authors.lastname: Eunice
authors.forename: Ariachery C
authors.initials: AC
authors.lastname: Ammini
authors.forename: Pierre M
authors.initials: PM
authors.lastname: Bouloux
authors.forename: Jerzy
authors.initials: J
authors.lastname: Starzyk
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hindmarsh
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005192:Family Health; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics* / Q000473:pathology; D007030:Hypothalamo-Hypophyseal System / Q000473:pathology; D007223:Infant; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D010913:Pituitary-Adrenal System / Q000473:pathology; D011110:Polymorphism, Genetic; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C102134:Prophet of Pit-1 protein; D014157:Transcription Factors