title: Familial growth hormone deficiency with mutated GHRH receptor gene: clinical and hormonal findings in homozygous and heterozygous individuals from Itabaianinha.
abstract: OBJECTIVE
  To characterize clinically and hormonally the syndrome of autosomal recessive familial growth hormone deficiency (FGHD) recently identified in Itabaianinha, Sergipe, Brazil, caused by a novel mutation (mt) that inactivates the growth hormone-releasing hormone receptor (GHRH-R) gene.
  
  
  METHODS
  Clinical and hormonal evaluations were performed in 21 FGHD individuals (mt/mt group) aged 8 to 63 years, 13 heterozygotes for the GHRH-R mutation (wt/mt group) and 5 homozygotes for the wild type (wt) allele (wt/wt group), identified by genotyping of peripheral blood leukocyte DNA.
  
  
  METHODS
  Clinical and hormonal characterization included physical examination and measurement of GH, IGF-I, IGF binding protein-3 (IGFBP-3), cortisol, prolactin, LH, FSH, and free thyroxine (FT4).
  
  
  RESULTS
  Clinical features were consistent with isolated growth hormone deficiency. Height was significantly reduced in the mt/mt group compared with the wt/mt group (mean height standard deviation score (SDS) +/- s.d.: -7.35+/-1.37 vs -1.84+/-1.44 respectively, P<0. 0001), and the wt/wt group (-1.85 +/- 0.81, P=0.0007). The height of the 13 wt/mt subjects did not differ from the 5wt/wt individuals. Serum GH, IGF-I, IGF-I SDS, IGFBP-3 and IGFBP-3 SDS were all significantly lower in the mt/mt group than in the wt/mt and wt/wt groups. Two affected children treated with GH for 1 year showed a normal growth response. Serum IGF-I and IGF-I SDS were lower in wt/mt compared with wt/wt group, but did not reach statistical significance. IGF-I and IGF-I SDS correlated inversely with age in wt/mt group.
  
  
  CONCLUSIONS
  FGHD due to an autosomal recessive GHRH-R gene mutation leads to marked dwarfism, phenotypically and hormonally indistinguishable from other forms of isolated GH deficiency. Heterozygotes for the GHRH-R mutation appear to have a partial defect in the GH/IGF axis, with no apparent height impairment.
authors.affiliation: Endocrine-Genetics Unit/LIM 25, Endocrine Division, Department of Medicine, São Paulo University School of Medicine, 01246-903, São Paulo, Brazil.
authors.forename: C Y
authors.initials: CY
authors.lastname: Hayashida
authors.forename: R G
authors.initials: RG
authors.lastname: Gondo
authors.forename: C
authors.initials: C
authors.lastname: Ferrari
authors.forename: S P
authors.initials: SP
authors.lastname: Toledo
authors.forename: R
authors.initials: R
authors.lastname: Salvatori
authors.forename: M A
authors.initials: MA
authors.lastname: Levine
authors.forename: M C
authors.initials: MC
authors.lastname: Ezabella
authors.forename: N
authors.initials: N
authors.lastname: Abelin
authors.forename: D
authors.initials: D
authors.lastname: Gianella-Neto
authors.forename: B L
authors.initials: BL
authors.lastname: Wajchenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001938:Brazil; D002648:Child; D004392:Dwarfism / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D013006:Growth Hormone / Q000172:deficiency*; D006579:Heterozygote; D006720:Homozygote; D006728:Hormones / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D018013:Receptors, Neuropeptide / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics*
chemical_list: D006728:Hormones; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D013006:Growth Hormone; C048250:somatotropin releasing hormone receptor