The metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) cleaves insulin-like growth factor (IGF) binding proteins 3 and 5 to release bioactive IGF-I from its ternary complex. Patients with mutations in PAPP-A2 have growth failure and low free IGF-I despite elevated total IGF-I. We describe five-year treatment response to recombinant human IGF-1 (rhIGF-1) in a patient with PAPP-A2 deficiency, and the phenotype of PAPP-A2 deficiency in three siblings. 金属蛋白酶妊娠相关血浆蛋白A2（PAPP-A2）切割类胰岛素生长因子（IGF）结合蛋白3和5以释放生物活性IGF-I，从其三元复合物中释放生物活性IGF-I。患有PAPP-A2突变的患者具有生长障碍和低自由IGF-I，尽管总IGF-I升高。我们描述了一个PAPP-A2缺陷患者对重组人类IGF-1（rhIGF-1）的五年治疗反应，以及三个兄弟姐妹的PAPP-A2缺陷表型。 Two siblings (P2, P3) with PAPP-A2 deficiency were recruited for rhIGF-1 therapy at 120 mcg/kg subcutaneous twice daily, along with a third sibling (P1) for phenotyping. We evaluated efficacy and safety of rhIGF-1 therapy, including effect on metabolic measures and bone mineral density (BMD). 招募PAPP-A2缺陷的两个兄弟姐妹（P2、P3）接受120毫克/公斤皮下注射两次/天的rhIGF-1治疗，还有一个第三个兄弟姐妹（P1）用于表型分析。我们评估了rhIGF-1治疗的疗效和安全性，包括对代谢指标和骨密度（BMD）的影响。 Treatment with rhIGF-1 was started in 10.4y (P3) and 14.5y (P2) old brothers. P2 discontinued therapy due to pseudotumor cerebri. P3 continued rhIGF-1 for 5 years; HV increased (3.0 cm/y at baseline; 5.0-7.6 cm/y thereafter) as did height SDS (+0.6). P3's pubertal onset was at 12.4y. BMD height-adjusted-Z-score modestly improved for lumbar spine (+0.4), and decreased in forearm (-0.2) and hip (-0.3). All siblings had hyperinsulinemia. Impaired glucose tolerance (IGT) resolved in P1. P2 showed worsening glucose tolerance (2-hr glucose: 225 mg/dL). Impaired fasting glucose and hyperinsulinemia initially resolved for P3, but IGT (2-hr glucose: 152 mg/dL) developed during puberty. 治疗以rhIGF-1开始在现年10.4岁（P3）和14.5岁（P2）的兄弟身上进行。 P2因假性脑膜瘤而停止治疗。 P3接受了5年的rhIGF-1治疗； HV增加（基线为3.0厘米/年；此后为5.0-7.6厘米/年），身高SDS也增加（+0.6）。 P3的青春期始于12.4岁。躯干脊柱骨密度（BMD）高度调整Z得分小幅改善（+0.4），前臂（-0.2）和髋部（-0.3）BMD降低。所有兄弟姐妹都有高胰岛素血症。 P1的糖耐量受损（IGT）得到改善。 P2的糖耐量恶化（2小时血糖：225毫克/分升）。 起初，P3的空腹血糖和高胰岛素血症得到改善，但在青春期期间发生了IGT（2小时血糖：152毫克/分升）。 治疗rhIGF-1在PAPPA-2缺陷患者中适度改善了一个患者的线性生长，但没有真正追赶上。治疗与一名兄弟姐妹出现假性脑膜瘤有关。 rhIGF-1的初始骨密度和血糖模式改善在青春期期间没有保持。S. Karger AG，巴塞尔。

The metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) cleaves insulin-like growth factor (IGF) binding proteins 3 and 5 to release bioactive IGF-I from its ternary complex. Patients with mutations in PAPP-A2 have growth failure and low free IGF-I despite elevated total IGF-I. We describe five-year treatment response to recombinant human IGF-1 (rhIGF-1) in a patient with PAPP-A2 deficiency, and the phenotype of PAPP-A2 deficiency in three siblings.Two siblings (P2, P3) with PAPP-A2 deficiency were recruited for rhIGF-1 therapy at 120 mcg/kg subcutaneous twice daily, along with a third sibling (P1) for phenotyping. We evaluated efficacy and safety of rhIGF-1 therapy, including effect on metabolic measures and bone mineral density (BMD).Treatment with rhIGF-1 was started in 10.4y (P3) and 14.5y (P2) old brothers. P2 discontinued therapy due to pseudotumor cerebri. P3 continued rhIGF-1 for 5 years; HV increased (3.0 cm/y at baseline; 5.0-7.6 cm/y thereafter) as did height SDS (+0.6). P3's pubertal onset was at 12.4y. BMD height-adjusted-Z-score modestly improved for lumbar spine (+0.4), and decreased in forearm (-0.2) and hip (-0.3). All siblings had hyperinsulinemia. Impaired glucose tolerance (IGT) resolved in P1. P2 showed worsening glucose tolerance (2-hr glucose: 225 mg/dL). Impaired fasting glucose and hyperinsulinemia initially resolved for P3, but IGT (2-hr glucose: 152 mg/dL) developed during puberty.Therapy with rhIGF-1 modestly improved linear growth in one patient with PAPPA-2 deficiency, but without true catch-up. Therapy was associated with pseudotumor cerebri in a sibling. Initial improvement in BMD and glycemic pattern on rhIGF-1 was not sustained during puberty.S. Karger AG, Basel.