Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA.
Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA.
J Bone Miner Res. 2018 Nov;33(11):2071-2080. doi: 10.1002/jbmr.3532. Epub 2018 Jul 30.
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) 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) 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.1001G>A, p.Arg334Gln). Thus, radiological and histological findings of OPT and severe hypercalcemia from apparent extrarenal production of 1,25(OH) 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.
儿科肉芽肿性关节炎（PGA）是指两种以前独立的实体：常染色体显性 Blau 综合征（BS）及其散发性表型早发性结节病（EOS）。2001 年 BS 和 2005 年 EOS 的发病机制是由编码核苷酸结合寡聚化结构域蛋白 2（NOD2）的基因中的杂合突变引起的，该基因也称为半胱氨酸天冬氨酸蛋白酶募集域蛋白 15（CARD15）。NOD2 是白细胞胞质中的微生物传感器，可激活和调节炎症。PGA 的特征是儿童早期出现三联征的自身炎症性疾病（皮炎、葡萄膜炎和关节炎），这表明 NOD2/CARD15 突变是激活缺陷的原因。当 NOD2 突变分析变得普遍可用时，PGA 的其他并发症才被识别出来。然而，在 PGA 中，高钙血症仅被简要提及，并且没有报道全身性骨质硬化症，尽管 NOD2 调节 NF-κB 信号通路对破骨细胞生成和破骨细胞功能至关重要。在此，我们报告了一名 4 岁女孩，她患有独特的 PGA，伴有严重的 1,25（OH）D 介导的高钙血症、肾钙沉着症和肾功能受损，以及骨硬化症（OPT）的影像学和组织病理学特征。尽管存在关节疼痛和止痛步态，伴有手腕、膝盖和脚踝肿胀以及手部、膝盖和脚部的非触痛性软性肿块，但经典的 PGA 并发症三联征缺失。MRI 显示手部腱鞘炎和髌上囊积液。滑膜活检显示反应性滑膜炎而无肉芽肿。干骺端骨质硬化症自发消退，而生化标志物则提示活跃的骨转换。抗炎药物抑制了循环中的 1,25（OH）D，纠正了高钙血症，改善了肾功能、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 型和已知形式的 OPT，并在 NOD2 中发现了与 PGA 常见的杂合种系错义突变（c.1001G>A，p.Arg334Gln）。因此，明显的肾外 1,25（OH）D 产生可导致 OPT 和严重高钙血症的影像学和组织学发现可使 NOD2 相关的 PGA 复杂化。尽管骨骼发现似乎无关紧要，但治疗高钙血症对于保护肾脏至关重要。© 2018 美国骨骼矿物质研究学会。
