Pre- and postnatal growth failure with microcephaly due to two novel heterozygous IGF1R mutations and response to growth hormone treatment

Aim To explore the phenotype and response to growth hormone in patients with heterozygous mutations in the insulin-like growth factor I receptor gene (IGF1R). Methods Children with short stature, microcephaly, born SGA combined with biochemical sign of IGF-I insensitivity were analysed forIGF1Rmutations or deletions using Sanger sequencing and Multiple ligation-dependent probe amplification analysis. Results In two families, a novel heterozygous non-synonymous missenseIGF1Rvariant was identified. In family 1, c.3364G > T, p.(Gly1122Cys) was found in the proband and co-segregated perfectly with the phenotype in three generations. In family 2, a de novo variant c.3530G > A, p.(Arg1177His) was detected. Both variants were rare, not present in the GnomAD database. Three individuals carryingIGF1Rmutations have received rhGH treatment. The average gain in height SDS during treatment was 0.42 (range: 0.26-0.60) and 0.64 (range: 0.32-0.86) after 1 and 2 years of treatment, respectively. Conclusion Our study presents two heterozygousIGF1Rmutations causing pre- and postnatal growth failure and microcephaly and also indicates that individuals with heterozygousIGF1Rmutations can respond to rhGH treatment. The findings highlight that sequencing of theIGF1Rshould be considered in children with microcephaly and short stature due to pre- and postnatal growth failure.