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.1001G>A, 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.