Heterozygous STAT5b Gene Mutations: Impact on Clinical Phenotype.

OV FOFANOVA-GAMBETTI; V HWA; AAL JORGE; CA TONELLI; JM WIT; MJE WALENKAMP; H DOMENE; HG JASPER; A MARTINEZ; M BERBEROGLU; G OCAL; A BELGOROSKY; R MARINO; M MIRAS; RG ROSENFELD

Congreso; 92nd Annual Meeting of The Endocrine Society; 2010

Background/Aims. In humans, the impact of homozygous and/or compound heterozygous defects in the STAT5b, GHR, IGFI, IGF1R, and ALS genes on short stature is well described. The possibility that heterozygous defects in these same genes may also modulate growth has become of increasing interest. Recently, a clinically significant impact of approximately 1.0 SD height loss was shown for heterozygous IGFALS and IGF1 mutations. The present study was, therefore, undertaken to evaluate the impact of heterozygous expression of STAT5b mutations on height.Patients/Methods. To date, a total of 7 novel mutations of the STAT5b gene in 10 patients from 8 non-related families have been identified. Patients who carry homozygous STAT5b mutations (n=10) and family members, who were heterozygous carriers for STAT5b mutations (n=16) were analyzed. Three wild type siblings were not analyzed due to unavailability of height data. Height at diagnosis was expressed as SDS (HSDS) for US references. Within each family in whom height data of two or more heterozygous carriers was available, the effect on stature of two mutant alleles versus one was calculated. The differences in HSDS were then pooled for all the families, and evaluated in the entire cohort. Results. The cohort of patients with STAT5b mutations represented high divergency in ethnicity; 50% families came from Argentina. Out of 8 families, 3 (37.5%) were consanguineous, and 3 (37.5%) were non-consanguineous; in 2 families the probands were adopted. All reported STAT5b mutations were homozygous. According to the type of mutation, 3 (38%) were missense, 2 (25%) insertion, 2 (25%) deletion, and 1 (12%) a nonsense mutation. In the whole cohort, mean ± SD height SDS in patients was -5.68 ± 1.60 (below -5 SDS in 70%); in heterozygous carriers -0.98 ± 0.99 (below 0 SDS in 81%, below -2 SDS in 2 parents (14%) from the same family). The difference in mean HSDS between patients and heterozygous carriers was -4.47 ± 1.48 (n=8, 6 families). Conclusions. Homozygosity for STAT5b mutations results in approximately 4.5 SD height loss in comparison with heterozygosity. To avoid ascertainment bias issues in further “genotype: phenotype” studies, the family analysis approach should include, as much as possible, wild type and heterozygous carriers of first degree relatives in families of patients harboring STAT5b mutations.