title: Variable phenotypes in familial isolated growth hormone deficiency caused by a G6664A mutation in the GH-1 gene.
abstract: BACKGROUND
  G to A transition at position 6,664 (G6664A) in human GH-1 results in the substitution of arginine by histidine at position 183 (R183H) of the GH molecule and causes familial isolated GH deficiency type II (IGHD II).
  
  
  OBJECTIVE
  The objective of the study was to assess the phenotype-genotype correlation of subjects affected with IGHD II caused by a G6664A mutation in 34 affected members of two large families.
  
  
  METHODS
  Sixty-six subjects from two core families were included. The G6664A mutation among family members was determined by restriction fragment length polymorphism.
  
  
  RESULTS
  Twenty-four of the 52 members from family 1 and 10 of 14 from family 2 carried the same G6664A mutation in a heterozygous state. The affected subjects in family 1 were significantly shorter [-2.6 vs. -0.1 sd score (SDS), P < 0.0001] and had significantly lower IGF-I serum levels (-1.9 vs. -0.5 SDS, P < 0.0001), compared with normal-genotype family members. The affected adults exhibited great variability in their stature, ranging from -4.5 to -1.0 (mean -2.8 SDS), with five members being of normal height (>-2 SDS). Twelve children were diagnosed with IGHD. Two affected children had normal peak GH levels, although one of these subsequently demonstrated GH insufficiency (6.5 and 3.7 ng/ml). The affected children from both families exhibited large variability in their height, growth velocity, delay in bone age (chronological age - bone age), age at diagnosis, peak GH response, and IGF-I levels.
  
  
  CONCLUSIONS
  These detailed phenotypic analyses show the variable expressivity of patients bearing a G6664A mutation, reflecting the spectrum of GH deficiency in affected patients, even within families, and the presence of additional genes modifying height determination. Our findings raise a new dilemma in the guidelines for the diagnosis of GH deficiency and the indications for GH therapy.
authors.affiliation: Faculty of Sciences, Bar Ilan University, Ramat Gan 52900, Israel.
authors.forename: Ora
authors.initials: O
authors.lastname: Hess
authors.forename: Yasir
authors.initials: Y
authors.lastname: Hujeirat
authors.forename: Michael P
authors.initials: MP
authors.lastname: Wajnrajch
authors.forename: Stavit
authors.initials: S
authors.lastname: Allon-Shalev
authors.forename: Zvi
authors.initials: Z
authors.lastname: Zadik
authors.forename: Idit
authors.initials: I
authors.lastname: Lavi
authors.forename: Yardena
authors.initials: Y
authors.lastname: Tenenbaum-Rakover
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018912:Arabs; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D019382:Human Growth Hormone / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007223:Infant; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007585:Jews; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics* / Q000502:physiology*; D010375:Pedigree; D010641:Phenotype; D014427:Twins