ESPE Abstracts

Background: IGF1 receptor (IGF1R) mutations are associated with pre- and post-natal growth retardation. We describe two monozygotic twins, one of them born small for gestational age (SGA), referred at the age 4 years and 2 months for short stature.

Case presentation: The twins were born from non-consanguineous parents at 37-weeks gestational age by caesarean delivery. At birth: patient 1 had weight 2.076 kg (−2.4 SDS), length 43 cm (−2.7 SDS) and head circumference 32 cm (-1.2 SDS); patient 2: weight 2.320 Kg (-1.9 SDS), length 48 cm (-0.63 SDS) and head circumference 33 cm (-0.9 SDS). There was no family history of congenital anomalies or other relevant disease. Mid-parental height was 173.5 cm (25th percentile). Growth retardation was noticed since the first years of life. At first evaluation, they presented with mild short stature (height -2.2 SDS). At physical examination, some facial dysmorphisms like frontal bossing, micrognathia, thin upper lip, small and low set ears were observed. The patients showed a normal GH peak response to GHRH plus arginine stimulation test. IGF1 and IGFBP3 concentrations were normal. Bone age was 3 years and 6 months at 4 years and 2 months of chronological age. At the age of 7.6 years their height was -2.63 SDS and growth deceleration was observed (3.2 cm/year). rhGH therapy was initiated at the dose of 0.03 mg/kg/day. During the first year of therapy the height gain was +1.23 SDS and growth velocity was 7.2 cm/yr, respectively. Karyotype and SNP-array were normal. Next generation sequencing analysis showed a novel heterozygous variant c.3001A>T (p.Met1001Leu) of IGF1R gene, inherited from the father; this variant is considered like a variants of uncertain significance and could affect thyrosine kinase domain of IGF1R. We performed functional validation study to investigate the pathogenicity of this variant. Plasmids containing wild-type and mutant IGF1R were transfected into HEK293 cells. Immunoblot analyses indicated that the variant caused significant decreases phosphorylation of IGF1R with concomitant poor response to IGF-I stimulation (P< 0.01), thus supporting the pathogenic role of the variant.

Conclusions: Molecular characterization and functional analysis of two twins with short stature have led to the identification of a novel pathogenic variant of IGF1R gene, which can differently affect pre- and post-natal growth as well as phenotype in different individuals. Gene redundancy and epigenetic effects may play role in the phenotypic expression of the variant.