Endocrine Abstracts

Background: GH resistance or primary IGF1 deficiency (PIGFD) presents with growth failure, low serum IGF1 and normal/elevated serum GH. PIGFD comprises a spectrum of phenotypic and biochemical abnormalities for which genetic GH–IGF1 axis defects may be causative.

Objective: Genotyping of PIGFD patients referred for sequencing of candidate genes.

Methods: From 2008 to 2013, 62 patients (42 males and 20 females), median age 6.9 years (range 0.4–17.0) with short stature (mean height SDS −3.4; range −9.4 to −1.1) were referred for genotyping. Depending on the phenotype, coding exons/intron boundaries of GHR, the GHR pseudoexon, STAT5B, IGFALS, IGF1 and OBSL1 were amplified by PCR from genomic DNA and the products purified and sequenced on an automated DNA sequencer (ABI 3700).

Results: Median serum IGF1 levels were 32.9 ng/ml (range 1.4–95.0; below the normal IGF1 range for age), with 15 patient samples being below the lower limit of the assay. GH secretion was normal or elevated: median peak GH 19.0 μg/l (range 6.0–119.0). Seven patients did not have GH provocation tests, basal GH being elevated (median 45.0 μg/l; range 12.3–398.0). Seventeen patients (27%) had mutations in GH–IGF1 axis genes: homozygous GHR (n=13; including six pseudoexon and two novel IVS5ds+1 G to A), homozygous IGFALS (n=3; 1 novel c.1291delT) and a novel heterozygous STAT5B (n=1; p.A478V). Heights in these subjects were −6.9 to −2.0 SDS. Two homozygous mutations were identified in the OBSL1 gene (height SDS −4.9 and −5.7). Two other patients had hypomethylation in imprinting control region one in 11p15 or maternal UPD for chromosome seven consistent with Silver–Russell syndrome (SRS) (height SDS −3.7 and −4.3).

Conclusions: Genotyping is advised in short children with PIGFD. In 27% of PIGFD patients, all with heights <−2.0 SDS, a genetic abnormality demonstrated a major contribution to pathogenesis. Diagnoses with similar phenotypes included SRS and 3M syndrome. In 65% (n=41) of patients no diagnosis was defined justifying further genetic investigation.