CONTEXT Short stature in children is a common reason for referral to pediatric endocrinologists. The underlying cause of short stature remains unclear in many cases and patients often receive unsatisfactory, descriptive diagnoses. While textbooks underline the rarity of genetic causes of growth hormone (GH) insensitivity and the severity of its associated growth failure, increased genetic testing in patients with short stature of unclear origin has revealed gene defects in the GH/insulin-like growth factor (IGF-I) axis associated with milder phenotypes. As such, heterozygous IGF1 gene defects have been reported as a cause of mild and severe short stature. Here, we aimed to describe the clinical and hormonal profile of children with IGF1 haploinsufficiency and their short-term response to growth hormone treatment (GHT). CASE DESCRIPTIONS We describe five patients presenting with short stature, microcephaly, and in four out of five born small for gestational age diagnosed with IGF1 haploinsufficiency. The phenotype of these patients resembles that of previously described cases with similar gene defects. In our series, segregation of the short stature with the IGF1 deletion is evident from the pedigrees and our data suggests a modest response to GHT. CONCLUSIONS This study is the first case series of complete heterozygous IGF1 deletions in children. The specific genetic defects provide a clear image of the phenotype of IGF1 haploinsufficiency - unbiased by heterozygous mutations with possible dominant negative effects on IGF-I function. We increase the evidence for IGF1 haploinsufficiency as a cause of short stature, microcephaly, and SGA.

中文翻译：

---

身材矮小儿童的 IGF1 单倍体不足：病例系列。

背景 儿童身材矮小是转诊给儿科内分泌科医生的常见原因。在许多情况下，身材矮小的根本原因仍不清楚，患者经常接受不令人满意的描述性诊断。虽然教科书强调了导致生长激素 (GH) 不敏感的罕见遗传原因及其相关生长失败的严重性，但增加对来源不明的矮身高患者的基因检测揭示了 GH/胰岛素样生长因子 (IGF) 的基因缺陷-I) 轴与较温和的表型相关。因此，据报道，杂合 IGF1 基因缺陷是轻度和重度身材矮小的原因。在这里，我们旨在描述 IGF1 单倍体不足儿童的临床和激素特征及其对生长激素治疗 (GHT) 的短期反应。病例描述 我们描述了五名身材矮小、小头畸形的患者，五分之四的出生小于胎龄的患者被诊断为 IGF1 单倍体不足。这些患者的表型类似于先前描述的具有相似基因缺陷的病例。在我们的系列中，从谱系中可以明显看出身材矮小与 IGF1 缺失的分离，我们的数据表明对 GHT 的反应适度。结论 本研究是儿童 IGF1 完全杂合缺失的第一个病例系列。特定的遗传缺陷提供了 IGF1 单倍体不足表型的清晰图像 - 不受杂合突变的影响，可能对 IGF-I 功能产生显性负面影响。我们增加了将 IGF1 单倍体不足作为身材矮小、小头畸形和 SGA 的原因的证据。