Domené Horacio M, Scaglia Paula A, Lteif Aida, Mahmud Farid H, Kirmani Salman, Frystyk Jan, Bedecarrás Patricia, Gutiérrez Mariana, Jasper Héctor G
Centro de Investigaciones Endocrinológicas, Hospital de Niños "R. Gutiérrez," Gallo 1330, 1425 Buenos Aires, Argentina.
J Clin Endocrinol Metab. 2007 Nov;92(11):4444-50. doi: 10.1210/jc.2007-1152. Epub 2007 Aug 28.
IGF-I deficiency may result from impairment of GH secretion or action, or from defects in IGF-I synthesis, transport, or action. Complete deficiency of the acid-labile subunit (ALS), previously described in two male patients, the only known inherited alteration in IGF-I transport, is characterized by severe circulating IGF-I and IGF binding protein (IGFBP)-3 deficiency with only mild growth retardation.
Our objective was to study the characterization, at biochemical and molecular levels, of the cause for severe circulating IGF-I and IGFBP-3 deficiency in a male patient with mild growth retardation.
We report an adolescent male with delayed growth and pubertal development (Tanner stage I, -2.00 sd score for height at the age of 15.3 yr), profound circulating IGF-I and IGFBP-3 deficiency, and poor response to GH treatment.
The index case, as well as one of his brothers, and his sister were found to be compound heterozygotes for two novel IGFALS gene mutations: C540R, a missense point mutation; and S195_197Rdup, a 9-bp duplication. The parents and youngest brother were found to be carriers for one of these two mutations. The three affected siblings had marked reduction of IGF-I and IGFBP-3 levels, undetectable serum levels of ALS, inability to form ternary complexes, and moderate insulin resistance. All of them attained a normal near-adult height (between -1.0 and -0.5 sd score), which was nonetheless lower than that of their heterozygous brother. The IGF system was only modestly affected in the heterozygous carriers.
This study confirms the critical role of ALS in forming ternary complexes and the maintenance of normal levels of IGF-I and IGFBP-3. Insulin resistance, pubertal delay in male patients, and poor GH responsiveness seem to be frequent findings in ALS deficiency. However, haploinsufficiency of the IGFALS gene has no discernible clinical effects with only modest impact on the IGF system.
胰岛素样生长因子 -I（IGF-I）缺乏可能源于生长激素（GH）分泌或作用受损，或IGF-I合成、转运或作用缺陷。酸不稳定亚基（ALS）完全缺乏，此前在两名男性患者中被描述，这是唯一已知的IGF-I转运方面的遗传性改变，其特征是循环中IGF-I和IGF结合蛋白（IGFBP）-3严重缺乏，仅有轻度生长迟缓。
我们的目的是从生化和分子水平研究一名轻度生长迟缓男性患者循环中IGF-I和IGFBP-3严重缺乏的原因。
我们报告一名青春期男性，生长和青春期发育延迟（坦纳分期I期，15.3岁时身高标准差评分为 -2.00），循环中IGF-I和IGFBP-3严重缺乏，对GH治疗反应不佳。
索引病例及其一名兄弟和妹妹被发现是两个新的IGFALS基因突变的复合杂合子：C540R，一个错义点突变；以及S195_197Rdup，一个9个碱基对的重复。父母和最小的兄弟被发现是这两个突变之一的携带者。三名受影响的兄弟姐妹IGF-I和IGFBP-3水平显著降低，血清ALS水平检测不到，无法形成三元复合物，且有中度胰岛素抵抗。他们都达到了接近成人的正常身高（标准差评分在 -1.0至 -0.5之间），但仍低于其杂合子兄弟的身高。IGF系统在杂合子携带者中仅受到轻微影响。
本研究证实了ALS在形成三元复合物以及维持IGF-I和IGFBP-3正常水平方面的关键作用。胰岛素抵抗、男性患者青春期延迟和GH反应不佳似乎是ALS缺乏时常见的表现。然而，IGFALS基因的单倍剂量不足没有明显的临床影响，对IGF系统仅有轻微影响。
