Genetic characterisation of a cohort of children clinically labelled as GH or IGF1 insensitive: diagnostic value of serum IGF1 and height at presentation

Abstract

Objective and designGH insensitivity (GHI) encompasses growth failure, low serum IGF1 and normal/elevated serum GH. By contrast, IGF1 insensitivity results in pre- and postnatal growth failure associated with relatively high IGF1 levels. From 2008 to 2013, 72 patients from 68 families (45M), mean age 7.1 years (0.4–17.0) with short stature (mean height SDS −3.9; range −9.4 to −1.5), were referred for sequencing.MethodsAs a genetics referral centre, we have sequenced appropriate candidate genes (GHR, including its pseudoexon (6Ψ),STAT5B,IGFALS,IGF1,IGF1R,OBSL1,CUL7andCCDC8) in subjects referred with suspected GHI (n=69) or IGF1 insensitivity (n=3).ResultsMean serum IGF1 SDS was −2.7 (range −0.9 to −8.2) in GHI patients and 2.0, 3.7 and 4.4 in patients with suspected IGF1 insensitivity. Out of 69 GHI patients, 16 (23%) (19% families) had mutations in GH–IGF1 axis genes: homozygousGHR(n=13; 6 6Ψ, two novel IVS5ds+1 G to A) and homozygousIGFALS(n=3; one novel c.1291delT). In the GHI groups, two homozygousOBSL1mutations were also identified (height SDS −4.9 and −5.7) and two patients had hypomethylation in imprinting control region 1 in 11p15 or mUPD7 consistent with Silver–Russell syndrome (SRS) (height SDS −3.7 and −4.3). A novel heterozygousIGF1R(c.112G>A) mutation was identified in one out of three (33%) IGF1-insensitive subjects.ConclusionGenotyping contributed to the diagnosis of children with suspected GHI and IGF1 insensitivity, particularly in the GHI subjects with low serum IGF1 SDS (<−2.0) and height SDS (<−2.5). Diagnoses with similar phenotypes included SRS and 3-M syndrome. In 71% patients, no diagnosis was defined justifying further genetic investigation.