title: New N-terminal located mutation (Q4ter) within the POU1F1-gene (PIT-1) causes recessive combined pituitary hormone deficiency and variable phenotype.
abstract: OBJECTIVE
  Growth is an inherent property of life. About 10% of the congenital forms of growth retardation and short stature are genetically caused. Beside the gene involved in direct GH-production, there are different candidate genes important for appropriate pituitary development causing combined pituitary hormone deficiency (CPHD). However, severe growth retardation and failure to thrive remain the leading reason for medical assessment in these patients.
  
  
  METHODS
  We report two siblings of a healthy but consanguineous Malaysian family presenting with severe short stature caused by CPHD with a variable phenotype. Importantly, at the beginning the girl presented with isolated GHD, whereas the boy was hypothyroid. As the most common gene alterations responsible for CPHD are within either the PROP-1- or the POU1F1- (PIT-1)-gene these two genes were further studied.
  
  
  RESULTS
  Subsequent sequencing of the six exons of the POU1F1-gene allowed the identification of a new N-terminal mutation (Q4ter) in these two children. A substitution of C to T induced a change from a glutamine (CAA) to a stop codon (TAA) in exon 1 of the PIT-1 protein. Both affected children were homozygous for the mutation, whereas the mother and father were heterozygous.
  
  
  CONCLUSIONS
  We describe two children with autosomal recessive inherited CPHD caused by a new N-terminal located mutation within the PUO1F1-gene. The clinical history of these two children underline the phenotypic variability and support the fact that children with any isolated and/or combined PHD need to be closely followed as at an any time other hormonal deficiencies may occur. In addition, molecular analysis of the possible genes involved might be most helpful for the future follow-up.
authors.affiliation: University Children's Hospital, Paediatric Endocrinology, Inselspital, Bern CH-3010, Switzerland.
authors.forename: Souzan
authors.initials: S
authors.lastname: Salemi
authors.forename: Amélie
authors.initials: A
authors.lastname: Besson
authors.forename: Andrée
authors.initials: A
authors.lastname: Eblé
authors.forename: Sabina
authors.initials: S
authors.lastname: Gallati
authors.forename: Roland W
authors.initials: RW
authors.lastname: Pfäffle
authors.forename: Primus E
authors.initials: PE
authors.lastname: Mullis
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006130:Growth Disorders / Q000235:genetics* / Q000473:pathology; D019382:Human Growth Hormone / Q000172:deficiency; D006801:Humans; D008296:Malaysia; D008297:Male; D008969:Molecular Sequence Data; D010641:Phenotype; D010907:Pituitary Hormones / Q000172:deficiency*; D017354:Point Mutation; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C494187:POU1F1 protein, human; D010907:Pituitary Hormones; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; D019382:Human Growth Hormone