In 2016 a new syndrome with postnatal short stature and low IGF1 bioavailability caused by biallelic loss-of-function mutations in the gene encoding the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) was described in two families. Here we report two siblings of a third family from Saudi Arabia with postnatal growth retardation and decreased IGF1 availability due to a new homozygous nonsense mutation (p.Glu886* in exon 7) in PAPPA2. The two affected males showed progressively severe short stature starting around 8 years of age, moderate microcephaly, decreased bone mineral density, and high circulating levels of total IGF1, IGFBP3, and the IGF acid-labile subunit (IGFALS), with decreased free IGF1 concentrations. Interestingly, circulating IGF2 and IGFBP5 were not increased. An increase in growth velocity and height was seen in the prepuberal patient in response to rhIGF1. These patients contribute to the confirmation of the clinical picture associated with PAPP-A2 deficiency and that the PAPPA2 gene should be studied in all patients with short stature with this characteristic phenotype. Hence, pediatric endocrinologists should measure circulating PAPP-A2 levels in the study of short stature as very low or undetectable levels of this protein can help to focus the diagnosis and treatment.

中文翻译：

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沙特家庭因妊娠相关血浆蛋白 A2 缺乏导致身材矮小，胰岛素样生长因子 1 可用性低

2016 年，在两个家族中描述了一种由编码金属蛋白酶妊娠相关血浆蛋白 A2 (PAPP-A2) 的基因中的双等位基因功能丧失突变引起的产后身材矮小和 IGF1 生物利用度低的新综合征。在这里，我们报告了来自沙特阿拉伯的第三个家庭的两个兄弟姐妹，由于 PAPPA2 中的新纯合无义突变（外显子 7 中的 p.Glu886*）导致出生后生长迟缓和 IGF1 可用性降低. 两名受影响的男性在 8 岁左右开始出现逐渐严重的身材矮小，中度小头畸形，骨矿物质密度降低，总 IGF1、IGFBP3 和 IGF 酸不稳定亚基 (IGFALS) 的循环水平高，游离 IGF1 浓度降低. 有趣的是，循环 IGF2 和 IGFBP5 没有增加。青春期前患者对 rhIGF1 的反应可见生长速度和身高的增加。这些患者有助于确认与 PAPP-A2 缺乏相关的临床表现以及PAPPA2应在所有具有这种特征表型的身材矮小患者中研究该基因。因此，儿科内分泌学家应该在身材矮小的研究中测量循环 PAPP-A2 水平，因为这种蛋白质的非常低或无法检测到的水平有助于集中诊断和治疗。