Gkourogianni Alexandra, Andrade Anenisia C, Jonsson Björn-Anders, Segerlund Emma, Werner-Sperker Antje, Horemuzova Eva, Dahlgren Jovanna, Burstedt Magnus, Nilsson Ola
Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden.
Center for Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden.
Acta Paediatr. 2020 Oct;109(10):2067-2074. doi: 10.1111/apa.15218. Epub 2020 Mar 6.
To explore the phenotype and response to growth hormone in patients with heterozygous mutations in the insulin-like growth factor I receptor gene (IGF1R).
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.
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.
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.
探讨胰岛素样生长因子I受体基因（IGF1R）杂合突变患者的表型及对生长激素的反应。
对身材矮小、小头畸形、出生时小于胎龄儿且伴有IGF-I不敏感生化指标的儿童，采用桑格测序和多重连接依赖探针扩增分析检测IGF1R突变或缺失。
在两个家系中，鉴定出一种新的杂合非同义错义IGF1R变异。在家族1中，先证者中发现c.3364G>T，p.(Gly1122Cys)，并在三代人中与表型完全共分离。在家族2中，检测到一个新发变异c.3530G>A，p.(Arg1177His)。这两种变异均罕见，未见于GnomAD数据库。3名携带IGF1R突变的个体接受了重组人生长激素（rhGH）治疗。治疗1年和2年后身高标准差积分（SDS）的平均增加分别为0.42（范围：0.26 - 0.60）和0.64（范围：0.32 - 0.86）。
我们的研究呈现了两个导致产前和产后生长发育迟缓及小头畸形的杂合IGF1R突变，同时表明携带IGF1R杂合突变的个体对rhGH治疗有反应。这些发现强调，对于因产前和产后生长发育迟缓导致小头畸形和身材矮小的儿童，应考虑对IGF1R进行测序。
