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Abstract：
Juvenile Paget\'s disease (JPD) became in 1974 the commonly used name for ultra-rare heritable occurrences of rapid bone remodeling throughout of the skeleton that present in infancy or early childhood as fractures and deformity hallmarked biochemically by marked elevation of serum alkaline phosphatase (ALP) activity (hyperphosphatasemia). Untreated, JPD can kill during childhood or young adult life. In 2002, we reported that homozygous deletion of the gene called tumor necrosis factor receptor superfamily, member 11B (TNFRSF11B) encoding osteoprotegerin (OPG) explained JPD in Navajos. Soon after, other bi-allelic loss-of-function TNFRSF11B defects were identified in JPD worldwide. OPG inhibits osteoclastogenesis and osteoclast activity by decoying receptor activator of nuclear factor κ-B (RANK) ligand (RANKL) away from its receptor RANK. Then, in 2014, we reported JPD in a Bolivian girl caused by a heterozygous activating duplication within TNFRSF11A encoding RANK. Herein, we identify mutation of a third gene underlying JPD. An infant girl began atraumatic fracturing of her lower extremity long-bones. Skull deformity and mild hearing loss followed. Our single investigation of the patient, when she was 15 years-of-age, showed generalized osteosclerosis and hyperostosis. DXA revealed a Z-score of +5.1 at her lumbar spine and T-score of +3.3 at her non-dominant wrist. Biochemical studies were consistent with positive mineral balance and several markers of bone turnover were elevated and included striking hyperphosphatasemia. Iliac crest histopathology was consistent with rapid skeletal remodeling. Measles virus transcripts, common in classic Paget\'s disease of bone, were not detected in circulating mononuclear cells. Then, reportedly, she responded to several months of alendronate therapy with less skeletal pain and correction of hyperphosphatasemia but had been lost to our follow-up. After we detected no defect in TNFRSF11A or B, trio exome sequencing revealed a de novo heterozygous missense mutation (c.926C>G; p.S309W) within SP7 encoding the osteoblast transcription factor osterix (specificity protein 7, transcription factor SP7). Thus, mutation of SP7 represents a third genetic cause of JPD.
摘要：
幼年Paget病（JPD）于1974年成为整个骨骼快速骨重建的超罕见遗传性事件的常用名称，该名称在婴儿期或幼儿期表现为骨折和畸形，其生化特征是血清碱性磷酸酶（ALP）活性（高磷酸盐血症）的显着升高。未治疗,JPD可以在童年或年轻的成人生活中杀人。2002年，我们报道了肿瘤坏死因子受体超家族基因的纯合缺失，编码骨保护素（OPG）的11B成员（TNFRSF11B）解释了纳瓦霍斯的JPD。不久之后,在全世界的JPD中发现了其他双等位基因功能丧失TNFRSF11B缺陷.OPG通过诱骗核因子κ-B（RANK）配体（RANKL）的受体激活剂远离其受体RANK来抑制破骨细胞生成和破骨细胞活性。然后，2014年,我们报道了一名玻利维亚女孩的JPD,该女孩是由编码RANK的TNFRSF11A内的杂合激活复制引起的.在这里，我们确定了JPD基础的第三个基因的突变。一名女婴开始对她的下肢长骨进行无创伤骨折。随后出现颅骨畸形和轻度听力损失。我们对病人的单一调查，当她15岁的时候,表现为全身性骨硬化和骨增生。DXA显示腰椎的Z评分为5.1，非优势腕部的T评分为3.3。生化研究与矿物质平衡阳性一致，骨转换的几种标志物升高，包括明显的高磷酸盐血症。Ilic的组织病理学与快速骨骼重塑一致。麻疹病毒转录本,常见于经典的佩吉特骨病，在循环单核细胞中未检测到。然后，据报道,在阿仑膦酸钠治疗几个月后,她的骨骼疼痛减轻,高磷酸盐血症得到纠正,但在我们的随访中失传.在我们检测到TNFRSF11A或B没有缺陷后，三外显子组测序显示SP7内编码成骨细胞转录因子osterix（特异性蛋白7，转录因子SP7）的从头杂合错义突变（c.926C>G；p.S309W）。因此，SP7的突变代表了JPD的第三个遗传原因。
