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Variable Phenotypes in Familial Isolated Growth Hormone Deficiency Caused by a G6664A Mutation in the GH-1 Gene

Faculty of Sciences (O.H.), Bar Ilan University, Ramat Gan 52900, Israel; Genetic Institute (O.H., Y.H., S.A.-S.), and Pediatric Endocrine Unit (Y.T.-R.), Ha’ Emek Medical Center, 18101 Afula, Israel; Pfizer Inc. (M.P.W.), New York, New York 10017; Technion Faculty of Medicine (S.A.-S., Y.T.-R.), Haifa 31096, Israel; Pediatric Endocrine Unit (Z.Z.), Kaplan Medical Center, Rehovot and the Hebrew University of Jerusalem, Jerusalem, 76100, Israel; and Department of Community Health and Epidemiology (I.L.), Carmel Medical Center, Haifa 34362, Israel

Address all correspondence and requests for reprints to: Yardena Tenenbaum-Rakover, Director, Pediatric Endocrine Unit, Ha’ Emek Medical Center, Afula 18101, Israel. E-mail: rakover_y{at}clalit.org.il.

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 isolated GH deficiency type II (IGHD II).

Objectives: 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.

Design and Patients: 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.