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Pre- and postnatal growth failure with microcephaly due to two novel heterozygous IGF1R mutations and response to
Alexandra Gkourogianni1,2, Anenisia C Andrade1,2, Björn-Anders Jonsson3
1Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
Insights
Two novel heterozygous insulin-like growth factor I receptor gene (IGF1R) mutations cause growth failure. Patients with these IGF1R mutations showed positive response to recombinant human growth hormone (rhGH) therapy.
Area of Science:
- Genetics
- Endocrinology
- Pediatrics
Background:
- Insulin-like growth factor I receptor (IGF1R) plays a crucial role in growth and development.
- Mutations in IGF1R can lead to growth disorders, including short stature and microcephaly.
- Understanding the genetic basis of growth failure is essential for effective treatment strategies.
Purpose of the Study:
- To investigate the phenotype and response to growth hormone therapy in patients with heterozygous IGF1R mutations.
- To identify novel mutations in the IGF1R gene associated with growth impairment.
- To evaluate the efficacy of recombinant human growth hormone (rhGH) in individuals with IGF1R mutations.
Main Methods:
- Genetic analysis of children with short stature, microcephaly, and signs of IGF-I insensitivity.
- Sanger sequencing and Multiple Ligation-dependent Probe Amplification (MLPA) were used to detect IGF1R mutations or deletions.
- Phenotypic evaluation and growth monitoring during rhGH treatment.
Main Results:
- Two novel heterozygous missense IGF1R variants (p.Gly1122Cys and p.Arg1177His) were identified in two families, co-segregating with the phenotype.
- These variants were rare and not found in the GnomAD database.
- Three individuals with IGF1R mutations showed an average height increase of 0.42 SDS after 1 year and 0.64 SDS after 2 years of rhGH treatment.
Conclusions:
- Heterozygous IGF1R mutations can cause pre- and postnatal growth failure and microcephaly.
- Individuals with heterozygous IGF1R mutations may respond positively to rhGH treatment.
- Sequencing of the IGF1R gene should be considered in children presenting with microcephaly and short stature due to growth failure.
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 for IGF1R mutations or deletions using Sanger sequencing and Multiple ligation-dependent probe amplification analysis.
Results:
In two families, a novel heterozygous non-synonymous missense IGF1R variant 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 carrying IGF1R mutations 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 heterozygous IGF1R mutations causing pre- and postnatal growth failure and microcephaly and also indicates that individuals with heterozygous IGF1R mutations can respond to rhGH treatment. The findings highlight that sequencing of the IGF1R should be considered in children with microcephaly and short stature due to pre- and postnatal growth failure.
