Background: GH insensitivity (GHI) presents with growth failure, IGF-1 deficiency and normal/elevated GH (basal >5 μg/l and/or peak >10 μg/l). GHI encompasses a spectrum of clinical and biochemical abnormalities. Associations between phenotypic characteristics and genetic defects remain obscure.
Objective: Identify phenotypic predictors of underlying genetic defects in GHI.
Methods: In total of 102 children (62M) median age 6.2 yr with short stature and suspected GHI (mean height −4.5 SDS; mean IGF-1 −2.6 SDS, mean peak GH levels 29.6 mcg/l) underwent genetic analysis (including candidate gene and whole exome sequencing). Phenotypic evaluation was performed at referring centres. Subjects with genetic diagnosis were compared with those with no diagnosis using an unpaired t-test and univariate/multivariate logistic regression analysis to assess age, sex, height SDS, IGF-1 SDS, consanguinity, ethnicity and peak GH levels.
Results: Genetic sequencing identified likely causative variants in 49/102 (48%) patients (GHR , IGFALS , OBSL1 , CUL7 , CCDC8 , PTPN11 , SOS1 , H19 hypomethylation  and MatUPD7 ). Mean height SDS was significantly lower in those with a genetic diagnosis (−5.2 vs −3.8, P=0.0005; 95% CI 0.62). There was no difference in age, sex and IGF-1 SDS between the two groups. Significant univariate phenotypic predictors for underlying genetic defects were lower height SDS (P=0.001; 95%CI 0.470.83, OR 0.62), consanguinity (P=0.0001; 95% CI 5.344.1, OR 15.27), non-Caucasian ethnic heritage (P=0.0001; 95%CI 3.426.2, OR 9.5) and higher peak GH levels (P=0.009; 95%CI 1.0081.058, OR 1.03). In the multivariate model, lower height SDS and consanguinity remained statistically significant.
Conclusion: Lower height SDS, consanguinity and non-Caucasian ethnicity were the strongest predictors for finding a genetic defect in GHI. IGF-1 level was not a helpful predictor and may reflect the wide inter- and intra-assay variation between centres. These findings highlight the importance of careful phenotyping to guide genetic investigations.
23 - 25 Nov 2016
British Society for Paediatric Endocrinology and Diabetes