Section of Pediatric Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Horm Res Paediatr. 2012;78(1):59-66. doi: 10.1159/000337249. Epub 2012 Jul 20.
BACKGROUND/AIMS: Insulin-like growth factor (IGF)-I is critical for normal human growth. Extremely rare homozygous mutations of the IGF1 gene severely impair intrauterine growth, intellectual development and postnatal growth. CASE/METHOD: A young male presented with postnatal growth retardation (-4.0 height SDS). His serum IGF-I concentration was low (115 µg/l, -2.21 SDS) and increased minimally to 130 µg/l (-1.82 SDS) on GH therapy, and he was analyzed for defect(s) in the GH-IGF-I axis. Severe short stature could be traced back several generations.
From the proband and 4 other severely short-statured family members, two novel, heterozygous, variants were identified in the IGF1 gene: c.207G>A in exon 3 and c.402+1G>C in the donor splice site of intron 4. The IGF1 gene was normal in 11 normal stature family members, and, interestingly, in 5 other short-statured family members. Study of IGF1 mRNA indicated c.402+1G>A induced splicing out of exon 4, leading to a predicted frameshift and protein truncation.
A novel heterozygous IGF1 splicing variant is associated with familial short stature in an extended family. Although it remains unclear whether this heterozygous mutation is the cause of the growth failure, the extreme rarity of IGF1 gene defects makes these cases of considerable interest.
背景/目的：胰岛素样生长因子（IGF）-I 对于正常的人类生长至关重要。IGF1 基因的极其罕见的纯合突变严重损害宫内生长、智力发育和出生后生长。
病例/方法：一名年轻男性因出生后生长迟缓（-4.0 身高 SDS）就诊。他的血清 IGF-I 浓度较低（115 µg/l，-2.21 SDS），GH 治疗后仅轻度增加至 130 µg/l（-1.82 SDS），并对 GH-IGF-I 轴的缺陷进行了分析。严重的身材矮小可以追溯到几代人。
从先证者和另外 4 名严重身材矮小的家族成员中，在 IGF1 基因中鉴定出 2 个新的杂合变异：c.207G>A 在第 3 外显子和 c.402+1G>C 在第 4 内含子供体位点。11 名正常身高的家族成员和 5 名其他身材矮小的家族成员中 IGF1 基因正常。IGF1 mRNA 的研究表明，c.402+1G>A 诱导外显子 4 的剪接缺失，导致预测的移码和蛋白截断。
一种新的杂合 IGF1 剪接变异与一个大家庭中的家族性身材矮小有关。尽管尚不清楚这种杂合突变是否是生长失败的原因，但 IGF1 基因突变的极其罕见性使这些病例具有相当大的研究意义。
