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首页> 外文期刊>Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research >Unique Variant of NOD2 NOD2 Pediatric Granulomatous Arthritis With Severe 1,25‐Dihydroxyvitamin D‐Mediated Hypercalcemia and Generalized Osteosclerosis
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Unique Variant of NOD2 NOD2 Pediatric Granulomatous Arthritis With Severe 1,25‐Dihydroxyvitamin D‐Mediated Hypercalcemia and Generalized Osteosclerosis

机译：Nod2 Nod2小儿肉芽肿性关节炎的独特变体，具有严重的1,25-二羟基维生素D型介导的高钙血症和广义骨静脉病

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ABSTRACT Pediatric granulomatous arthritis (PGA) refers to two formerly separate entities: autosomal dominant Blau syndrome (BS) and its sporadic phenocopy early‐onset sarcoidosis (EOS). In 2001 BS and in 2005 EOS became explained by heterozygous mutations within the gene that encodes nucleotide‐binding oligomerization domain‐containing protein 2 (NOD2), also called caspase recruitment domain‐containing protein 15 (CARD15). NOD2 is a microbe sensor in leukocyte cytosol that activates and regulates inflammation. PGA is characterized by a triad of autoinflammatory problems (dermatitis, uveitis, and arthritis) in early childhood, which suggests the causal NOD2 / CARD15 mutations are activating defects. Additional complications of PGA were recognized especially when NOD2 mutation analysis became generally available. However, in PGA, hypercalcemia is only briefly mentioned, and generalized osteosclerosis is not reported, although NOD2 regulates NF‐κB signaling essential for osteoclastogenesis and osteoclast function. Herein, we report a 4‐year‐old girl with PGA uniquely complicated by severe 1,25(OH) 2 D‐mediated hypercalcemia, nephrocalcinosis, and compromised renal function together with radiological and histopathological features of osteopetrosis (OPT). The classic triad of PGA complications was absent, although joint pain and an antalgic gait accompanied wrist, knee, and ankle swelling and soft non‐tender masses over her hands, knees, and feet. MRI revealed tenosynovitis in her hands and suprapatellar effusions. Synovial biopsy demonstrated reactive synovitis without granulomas. Spontaneous resolution of metaphyseal osteosclerosis occurred while biochemical markers indicated active bone turnover. Anti‐inflammatory medications suppressed circulating 1,25(OH) 2 D, corrected the hypercalcemia, and improved her renal function, joint pain and swelling, and gait. Mutation analysis excluded idiopathic infantile hypercalcemia, type 1, and known forms of OPT, and identified a heterozygous germline missense mutation in NOD2 common in PGA (c.1001GA, p.Arg334Gln). Thus, radiological and histological findings of OPT and severe hypercalcemia from apparent extrarenal production of 1,25(OH) 2 D can complicate NOD2‐associated PGA. Although the skeletal findings seem inconsequential, treatment of the hypercalcemia is crucial to protect the kidneys. ? 2018 American Society for Bone and Mineral Research.
机译：摘要儿科肉芽肿性关节炎（PGA）是指两名以前单独的实体：常染色体占优势Blau综合征（BS）及其散发性的异发明早期开始（EOS）。在2001年，BS和2005年，EOS通过基因内的杂合突变进行了解释，所述杂合子突变编码含核苷酸结合的寡聚化结构域蛋白2（NOD2），也称为含胱天冬酶募集结构域的蛋白15（CARD15）。 NOD2是在白细胞细胞溶胶中的微生物传感器，其激活和调节炎症。 PGA的特征在于儿童早期的自身炎症问题（皮炎，葡萄球炎和关节炎）的特征，这表明原因NOD2 / CARD15突变正在激活缺陷。特别是当NOD2突变分析通常可用时，特别识别PGA的额外并发症。然而，在PGA中，只有简要介绍，高钙血症仅提及，并且尚未报道广泛化的骨静脉，尽管NOD2调节骨酸骨细胞发生和破骨细胞功能必需的NF-κB信号。在此，我们向一名4岁的女孩通过严重的1,25（OH）2 d介导的高钙血症，肾功能术和肾功能造成的PGA唯一复杂，肾功能愈合，以及骨质病症的放射学和组织病理学特征（OPT）。 PGA并发症的经典三合会缺席，尽管关节疼痛和抗抗凝手腕，膝盖和踝关节肿胀，柔软的非温柔的群体，膝盖和脚。 MRI在她手中揭示了Tenosynovitis和suprapatellar的积液。滑膜活检表明没有肉芽肿的反应性滑膜炎。发生的自发分辨率的结骨粥样硬化，而生物化学标志物表明活跃的骨质周转。抗炎药物抑制循环1,25（OH）2 D，纠正高钙血症，改善肾功能，关节疼痛和肿胀，以及步态。突变分析排除了特发性婴儿高钙血症，1型和已知的选择形式的选择，并鉴定在PGA中常见的NOD2中的杂合种种系义突变（C.1001G＆GT; A，P.Arg334GlN）。因此，来自表观外肠杆菌的OPT和严重高钙血症的放射性和组织学发现来自1,25（OH）2d的表观外侧型产生可以使NOD2相关的PGA复杂化。虽然骨骼发现似乎无关紧要，但对高钙血症的治疗对于保护肾脏至关重要。还2018年美国骨骼和矿物学研究。

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