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Pre and postnatal growth failure with microcephaly due to two novel heterozygous IGF1R mutations and response to growth hormone treatment
Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institute and University Hospital, Stockholm, Sweden.
Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institute and University Hospital, Stockholm, Sweden.
Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, Sweden.
Department of Pediatrics, Sunderby Hospital, Sunderby, Sweden.
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2020 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227Article in journal (Refereed) Epub ahead of print
Abstract [en]

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 analyzed 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.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2020.
Keywords [en]
IGF1R, GH treatment, IGF-I, IGFBP-3, Idiopathic short stature
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:oru:diva-79930DOI: 10.1111/apa.15218PubMedID: 32037650OAI: oai:DiVA.org:oru-79930DiVA, id: diva2:1394801
Available from: 2020-02-20 Created: 2020-02-20 Last updated: 2020-02-20Bibliographically approved

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