IGF1 Defects (OMIM 608747)
IGF- 1 deficiency was first described in humans in 1996, in a patient with severe intrauterine and postnatal growth failure, microcephaly, sensorineural deafness, intellectual deficit and severe reduction in vertebral bone mass who had a homozygous partial deletion in the IGF1 gene. His basal GH and his peak after stimulation with clonidine were elevated, and IGFBP- 3 and ALS were normal.
Since then, seven other index cases with IGF1 variants were described, three of them with homozygous variants, inherited as an autosomal recessive trait. Besides the characteristics described in the first patient, they can also present with insulin resistance (secondary to GH excess), partial gonadal dysfunction, or obesity. One of the homozygous patients had a bioinactive IGF- 1 (see next) and another had partial IGF- 1 deficiency, presenting with pre- and postnatal growth retardation and microcephaly but with mild developmental delay and normal hearing. Heterozygous parents of homozygous patients have a height SDS below the population mean, with some of them presenting with a height SDS lower than - 2, compatible with a dose- dependent effect. Patients harbouring heterozygous mutations, inherited in an autosomal dominant manner, have a milder clinical presentation, with significant short stature but with variable presence of cognitive delay or hearing impairment.
IGF2 Defects (OMIM 616489)
In 2015, Begemann et al. described the first IGF2 gene variant associated with growth restriction in humans. Four members from one family presented with severe intrauterine (birth length SDS – 4.2 to – 4.9) and variable postnatal growth restriction. They also had clinical signs compatible with Silver- Russell syndrome (OMIM 180860), such as normal head circumference at birth, triangular face and micrognathia, and delayed psychomotor development. The IGF- 2 level was low and IGF- 1, IGFBP- 3, and GH levels were normal to elevated. A heterozygous stop- gain variant, which intro duces a premature termination codon, was found in the IGF2 gene in seven family members, but only those who inherited the variant through paternal transmission were affected, a finding consistent with the maternal imprinting of the IGF2 gene.
In 2018, Habib et al investigated a population of 192 patients with intrauterine growth retardation, suspected of Silver- Russell syn drome for whom a genetic or epigenetic diagnosis was not found. They found two de novo heterozygous variants in the IGF2 gene, two heterozygous variants in HMGA2 gene (one de novo and the other probably paternally inherited) and two heterozygous variants in PLAG1 gene (one sporadic and one familiar case). PLAG1 and HMGA2 are oncogenes; PLAG1 activates IGF2 through a promoter and HMGA2 is an upstream regulator of PLAG1. Both were associated with growth in mice models and in genome- wide association studies (GWAS) meta- analysis studies in humans.
