ESPE Abstracts

Introduction: The insulin-like growth factor 1 receptor (IGF1R) gene, located on chromosome 15q26.3, encodes the 1367 aa tyrosine kinase receptor IGF1R which is involved in many processes, including growth. Few heterozygous mutations and deletions of IGF1R leading to IGF-I resistance have been described in patients with intrauterine and postnatal growth retardation, microcephaly and variable learning difficulties. We report a not yet previously described IGF1R nonsense variant in a child with normal birth weight, only mild short stature, and microcephaly.

Case: A 9-year-old male presented at 5.4 years with mild short stature (Height -2.1 SDS) low BMI (-2.6 SD) and microcephaly (Head circumference -3.9 SDS). His height velocity was 6–7 cm/year increasing his height to -1.75 SD. Birth weight was normal (1.38 kg at 31+6 weeks (-1.25 SDS). He also has a squint, delayed developmental milestones, behavioural difficulties and requires learning support. There was no significant family history. Maternal height was -1.39 SDS; paternal height -0.89 SDS.

Results: IGF1 was consistently mildly raised [aged 5.4 years, 228 mg/l (15.6-216.4), aged 6.6 years, 338 mg/l (18-307)]; IGFBP-3 was around the upper normal range [ 4.1 and 5.4 mg/l (1.9-5.2) ] with raised random GH concentration (8.7 mg/l), in line with IGF1 resistance. Bone age was normal. Spine X ray showed mild scoliosis and brain MRI reduced white matter. CGH array was normal. Sanger sequencing of IGF1R showed a nonsense variant (c.1237C>T, p.Gln413*), generating a premature stop codon. This variant has not been reported in control databases (dbSNP,1000 Genomes, ExAC and gnomAD, Human Gene Mutation Database, ClinVar and LOVD). and has been classified as pathogenic using ACMG criteria and bioinformatic predictors (SIFT, PolyPhen-2, Mutation Taster). The truncated IGF1R lacks the beta-chain and will be unable to signal. The mother had normal IGF1 and IGFBP3 concentration and did not carry the IGF1R variant. Paternal DNA was not available.

Discussion: In conclusion, the novel heterozygous nonsense IGF1R variant c.1237C>T (P.Gln413*) results in mild impairment of IGF1R signalling with mild GH and IGF1 overproduction, and a phenotype of mild short stature without SGA but with significant microcephaly. Our patient fulfils 3 of the 4 previously proposed criteria for IGF1 resistance. The phenotype is in line with a milder phenotype of IGF1 resistance and suggests that IGF1R should be investigated in patients with biochemical evidence of IGF1 resistance even in the absence of short stature or SGA.