Context: G to A transition at position 6664 (G6664A) in human GH-1 results in the substitution of arginine by histidine at position 183 (R183H) of the GH molecule and causes familial IGHD II.

Objectives: 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.

Design and Patients: Sixty-six subjects from two core families were included. The G6664A mutation among family members was determined by RFLP.

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 SDS, p < 0.0001) and had significantly lower IGF-I serum levels (-1.9 vs. -0.5 SDS, p < 0.0001) compared to 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 (> -2SDS). 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, GV, BA, 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 GHD 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 GHD and the indications for GH therapy.