title: HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype.
abstract: Mutations in the transcription factor HESX1 can cause isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD) with or without septo-optic dysplasia (SOD). So far there is no clear genotype-phenotype correlation.
  
  
  
  We report four different recessive loss-of-function mutations in three unrelated families with CPHD and no midline defects or SOD. A homozygous p.R160C mutation was found by Sanger sequencing in two siblings from a consanguineous family. These patients presented with ACTH, TSH and GH deficiencies, severe anterior pituitary hypoplasia (APH) or pituitary aplasia (PA) and normal posterior pituitary. The p.R160C mutation was previously reported in a case with SOD, CPHD and ectopic posterior pituitary (EPP). Using exome sequencing, a homozygous p.I26T mutation was found in a Brazilian patient born to consanguineous parents. This patient had evolving CPHD, normal ACTH, APH and normal posterior pituitary (NPP). A previously reported patient homozygous for p.I26T had evolving CPHD and EPP. Finally, we identified compound heterozygous mutations in HESX1, p.[R159W];[R160H], in a patient with PA and CPHD. We showed that both of these mutations abrogate the ability of HESX1 to repress PROP1-mediated transcriptional activation. A patient homozygous for p.R160H was previously reported in a patient with CPHD, EPP, APH.
  
  
  
  These three examples demonstrate that HESX1 mutations cause variable clinical features in patients, which suggests an influence of modifier genes or environmental factors on the phenotype.
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Division of Endocrinology, Unit of Endocrinology and Development, Laboratory of Hormones and Molecular Genetics, Clinical Hospital of the Faculty of Medicine of the University of São Paulo, São Paulo, Brazil.
authors.forename: Anna Flavia Figueredo
authors.initials: AF
authors.lastname: Benedetti
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Qianyi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Developmental Endocrinology Research Group, Section of Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, University College London, Institute of Child Health, London, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Gregory
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Jun Z
authors.initials: JZ
authors.lastname: Li
authors.affiliation: Developmental Endocrinology Research Group, Section of Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, University College London, Institute of Child Health, London, UK.
authors.forename: Mehul
authors.initials: M
authors.lastname: Dattani
authors.affiliation: Division of Pediatric Endocrinology, Floating Hospital for Children at Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Abdollah
authors.initials: A
authors.lastname: Sadeghi-Nejad
authors.affiliation: Division of Endocrinology, Unit of Endocrinology and Development, Laboratory of Hormones and Molecular Genetics, Clinical Hospital of the Faculty of Medicine of the University of São Paulo, São Paulo, Brazil.
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
authors.affiliation: Division of Endocrinology, Unit of Endocrinology and Development, Laboratory of Hormones and Molecular Genetics, Clinical Hospital of the Faculty of Medicine of the University of São Paulo, São Paulo, Brazil.
authors.forename: Berenice Bilharinho
authors.initials: BB
authors.lastname: Mendonca
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Camper
authors.affiliation: Division of Endocrinology, Unit of Endocrinology and Development, Laboratory of Hormones and Molecular Genetics, Clinical Hospital of the Faculty of Medicine of the University of São Paulo, São Paulo, Brazil.
authors.forename: Luciani R
authors.initials: LR
authors.lastname: Carvalho
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D001938:Brazil; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007018:Hypopituitarism / Q000175:diagnosis / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D008877:Middle East; D009154:Mutation; D010375:Pedigree
chemical_list: C489736:HESX1 protein, human; D018398:Homeodomain Proteins