Department of Pediatric Endocrinology, Hacettepe University Faculty of Medicine, 06100, Ankara, Turkey.
Department of Medical Genetics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
J Endocrinol Invest. 2020 Dec;43(12):1739-1748. doi: 10.1007/s40618-020-01264-y. Epub 2020 Apr 30.
We aimed to identify the phenotypic variability of IGF1R defects in a cohort of short children with normal GH secretion gathered through the last decade.
Fifty children (25 girls) with short stature and a basal/stimulated growth hormone (GH) over 10 ng/ml having either a low birth weight or microcephaly were enrolled. MLPA and then Sanger sequence analysis were performed to detect IGF1R defects. The auxological and metabolic evaluation were carried out in index cases and their first degree family members whenever available.
A total of seven (14%) IGF1R defects were detected. Two IGF1R deletions and five heterozygous variants (one frameshift, four missense) were identified. Three (likely) pathogenic, one VUS and one likely benign were classified by using ACMG. All children with IGF1R defects had a height < - 2.5SDS, birth weight < - 1.4SDS, and head circumference < - 1.36SDS. IGF-1 ranged from - 2.44 to 2.13 SDS. One child with a 15q terminal deletion had a normal phenotype and intelligence, whereas low IQ is a finding in a case with missense variant. Two parents who carried IGF1R mutations had diabetes mellitus, hypertension and hyperlipidemia, one of whom also had hypergonadotropic hypogonadism.
We found a deletion or variant in IGF1R in 14% of short children. Birth weight, head circumference, intelligence, dysmorphic features, IGF-1 levels and even height are not consistent among patients. Additionally, metabolic and gonadal complications may appear during adulthood, suggesting that patients should be followed into adulthood to monitor for these late complications.
我们旨在确定过去十年中通过收集的具有正常 GH 分泌的矮小儿童中 IGF1R 缺陷的表型变异性。
共纳入 50 名身材矮小且基础/刺激生长激素（GH）超过 10ng/ml 的儿童（25 名女孩），他们要么出生体重低，要么头围小。进行 MLPA 后，进行 Sanger 序列分析以检测 IGF1R 缺陷。在有索引病例及其一级亲属的情况下，进行了人体测量和代谢评估。
共发现 7 例（14%）IGF1R 缺陷。鉴定出 2 例 IGF1R 缺失和 5 例杂合变体（1 例移码，4 例错义）。使用 ACMG 对所有儿童进行分类，其中 3 例（可能）致病性、1 例 VUS 和 1 例可能良性。所有 IGF1R 缺陷的儿童身高均<-2.5SDS，出生体重<-1.4SDS，头围<-1.36SDS。IGF-1 范围从-2.44 到 2.13 SDS。15q 末端缺失的患儿具有正常的表型和智力，而错义变异的患儿存在低智商。携带 IGF1R 突变的 2 位父母患有糖尿病、高血压和高血脂，其中 1 位还患有高促性腺激素性性腺功能减退症。
我们在 14%的矮小儿童中发现 IGF1R 缺失或变体。出生体重、头围、智力、畸形特征、IGF-1 水平甚至身高在患者之间并不一致。此外，成年后可能会出现代谢和性腺并发症，这表明患者应随访至成年期，以监测这些晚期并发症。
