title: Novel Lethal Form of Congenital Hypopituitarism Associated With the First Recessive LHX4 Mutation.
abstract: BACKGROUND
  LHX4 encodes a member of the LIM-homeodomain family of transcription factors that is required for normal development of the pituitary gland. To date, only incompletely penetrant heterozygous mutations in LHX4 have been described in patients with variable combined pituitary hormone deficiencies.
  
  
  OBJECTIVE
  To report a unique family with a novel recessive variant in LHX4 associated with a lethal form of congenital hypopituitarism that was identified through screening a total of 97 patients.
  
  
  METHODS
  We screened 97 unrelated patients with combined pituitary hormone deficiency, including 65% with an ectopic posterior pituitary, for variants in the LHX4 gene using Sanger sequencing. Control databases (1000 Genomes, dbSNP, Exome Variant Server, ExAC Browser) were consulted upon identification of variants.
  
  
  RESULTS
  We identified the first novel homozygous missense variant (c.377C>T, p.T126M) in two deceased male patients of Pakistani origin with severe panhypopituitarism associated with anterior pituitary aplasia and posterior pituitary ectopia. Both were born small for gestational age with a small phallus, undescended testes, and mid-facial hypoplasia. The parents' first-born child was a female with mid-facial hypoplasia (DNA was unavailable). Despite rapid commencement of hydrocortisone and T4 in the brothers, all three children died within the first week of life. The LHX4(p.T126M) variant is located within the LIM2 domain, in a highly conserved location. The absence of homozygosity for the variant in over 65 000 controls suggests that it is likely to be responsible for the phenotype.
  
  
  CONCLUSIONS
  We report, for the first time to our knowledge, a novel homozygous mutation in LHX4 associated with a lethal phenotype, implying that recessive mutations in LHX4 may be incompatible with life.
authors: Developmental Endocrinology Research Group (L.C.G., J.P.G.T., M.J.M., M.T.D.), Genetics and Epigenetics in Health and Disease Unit, Genetic and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, United Kingdom; Department of Pediatrics and Child Health (K.N.H.), Aga Khan University, Karachi 74800, Pakistan; and Department of Biology (S.J.R.), Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202.
authors: L C
authors: LC
authors: Gregory
authors: Developmental Endocrinology Research Group (L.C.G., J.P.G.T., M.J.M., M.T.D.), Genetics and Epigenetics in Health and Disease Unit, Genetic and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, United Kingdom; Department of Pediatrics and Child Health (K.N.H.), Aga Khan University, Karachi 74800, Pakistan; and Department of Biology (S.J.R.), Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202.
authors: K N
authors: KN
authors: Humayun
authors: Developmental Endocrinology Research Group (L.C.G., J.P.G.T., M.J.M., M.T.D.), Genetics and Epigenetics in Health and Disease Unit, Genetic and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, United Kingdom; Department of Pediatrics and Child Health (K.N.H.), Aga Khan University, Karachi 74800, Pakistan; and Department of Biology (S.J.R.), Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202.
authors: J P G
authors: JP
authors: Turton
authors: Developmental Endocrinology Research Group (L.C.G., J.P.G.T., M.J.M., M.T.D.), Genetics and Epigenetics in Health and Disease Unit, Genetic and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, United Kingdom; Department of Pediatrics and Child Health (K.N.H.), Aga Khan University, Karachi 74800, Pakistan; and Department of Biology (S.J.R.), Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202.
authors: M J
authors: MJ
authors: McCabe
authors: Developmental Endocrinology Research Group (L.C.G., J.P.G.T., M.J.M., M.T.D.), Genetics and Epigenetics in Health and Disease Unit, Genetic and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, United Kingdom; Department of Pediatrics and Child Health (K.N.H.), Aga Khan University, Karachi 74800, Pakistan; and Department of Biology (S.J.R.), Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202.
authors: S J
authors: SJ
authors: Rhodes
authors: Developmental Endocrinology Research Group (L.C.G., J.P.G.T., M.J.M., M.T.D.), Genetics and Epigenetics in Health and Disease Unit, Genetic and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, United Kingdom; Department of Pediatrics and Child Health (K.N.H.), Aga Khan University, Karachi 74800, Pakistan; and Department of Biology (S.J.R.), Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202.
authors: M T
authors: MT
authors: Dattani
mesh_terms: D001483:Base Sequence; D005260:Female; D005804:Genes, Lethal; D005808:Genes, Recessive; D057809:HEK293 Cells; D006801:Humans; D007018:Hypopituitarism / Q000151:congenital* / Q000235:genetics*; D007231:Infant, Newborn; D060850:LIM-Homeodomain Proteins / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D066087:Perinatal Death; D035781:Siblings; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*
chemical_list: C486362:LHX4 protein, human; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors