title: Autosomal recessive form of isolated growth hormone deficiency is more frequent than the autosomal dominant form in a Brazilian cohort.
abstract: BACKGROUND
  In most studies, the autosomal dominant (type II) form of isolated growth hormone deficiency (IGHD) has been more frequent than the autosomal recessive (type I) form. Our aim was to assess defects in the GH1 in short Brazilian children with different GH secretion status.
  
  
  METHODS
  We selected 135 children with postnatal short stature and classified according to the highest GH peak at stimulation tests in: severe IGHD (peak GH≤3.3 μg/L, n=38, all with normal pituitary magnetic resonance imaging); GH peak between 3.3 and 10 μg/L (n=76); and GH peak >10 μg/L (n=21). The entire coding region of GH1 was sequenced and complete GH1 deletions were assessed by Multiplex Ligation Dependent Probe Amplification and restriction enzyme digestion.
  
  
  RESULTS
  Patients with severe IGHD had a higher frequency of consanguinity, were shorter, had lower levels of IGF-1 and IGFBP-3, and despite treatment with lower GH doses had a greater growth response than patients with GH peak ≥3.3 μg/L. Mutations were found only in patients with severe IGHD (GH peak<3.3 μg/L). Eight patients had autosomal recessive IGHD: Seven patients were homozygous for GH1 deletions and one patient was compound heterozygous for a GH1 deletion and the novel c.171+5G>C point mutation in intron 2, predicted to abolish the donor splice site. Only one patient, who was heterozygous for the c.291+1G>T mutation located at the universal donor splice site of intron 3 and predicts exon 3 skipping, had an autosomal dominant form.
  
  
  CONCLUSIONS
  Analysis of GH1 in a cohort of Brazilian patients revealed that the autosomal recessive form of IGHD was more common than the dominant one, and both were found only in severe IGHD.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42 do Hospital das Clinicas, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Unidade de Endocrinologia Genetica, Laboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, 01246-903 Sao Paulo, Brazil.
authors.forename: Andria C V
authors.initials: AC
authors.lastname: Lido
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42 do Hospital das Clinicas, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil.
authors.forename: Marcela M
authors.initials: MM
authors.lastname: França
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42 do Hospital das Clinicas, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil.
authors.forename: Fernanda A
authors.initials: FA
authors.lastname: Correa
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42 do Hospital das Clinicas, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil.
authors.forename: Aline P
authors.initials: AP
authors.lastname: Otto
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42 do Hospital das Clinicas, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil.
authors.forename: Luciani R
authors.initials: LR
authors.lastname: Carvalho
authors.affiliation: Unidade de Endocrinologia Genetica, Laboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, 01246-903 Sao Paulo, Brazil.
authors.forename: Elisangela P S
authors.initials: EP
authors.lastname: Quedas
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42 do Hospital das Clinicas, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil.
authors.forename: Mirian Y
authors.initials: MY
authors.lastname: Nishi
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42 do Hospital das Clinicas, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil.
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42 do Hospital das Clinicas, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil.
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
authors.affiliation: Unidade de Endocrinologia Genetica, Laboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, 01246-903 Sao Paulo, Brazil. Electronic address: alexj@usp.br.
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
mesh_terms: D000293:Adolescent; D001938:Brazil / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004393:Dwarfism, Pituitary / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005799:Genes, Dominant; D005808:Genes, Recessive; D019382:Human Growth Hormone / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D008297:Male
chemical_list: D019382:Human Growth Hormone
keywords: Brazilian children; Growth hormone (GH) secretion status; Isolated GH deficiency (IGHD); Mutation in Growth hormone 1 gene (GH1); Short stature