Rapid Skeletal Turnover in a Radiographic Mimic of Osteopetrosis

Whyte, Michael P.; Madson, Katherine L.; Mumm, Steven; McAlister, William H.; Novack, Deborah V.; Blair, Jo; Helliwell, T. R.; Stolina, Marina; Abernethy, Laurence; Shaw, Nicholas

doi:10.1002/jbmr.2289

Cited by 12 publications

(14 citation statements)

References 52 publications

(139 reference statements)

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“…To the Editor: I n their article "Rapid Skeletal Turnover in a Radiographic Mimic of Osteopetrosis," Whyte and colleagues (1) accurately describe the case of unknown etiology and pathogenesis of an 11-year-old boy with a syndrome that radiographically mimics osteopetrosis, but features rapid skeletal turnover. In similar cases the presence of systemic mastocytosis (SM) should be taken into account.…”

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confidence: 99%

A Rapid Skeletal Turnover in Radiographic Mimic of Osteopetrosis Might Be Secondary to Systemic Mastocytosis

Rossini

Viapiana

Adami

et al. 2015

Journal of Bone and Mineral Research

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confidence: 99%

A Rapid Skeletal Turnover in Radiographic Mimic of Osteopetrosis Might Be Secondary to Systemic Mastocytosis

Rossini

Viapiana

Adami

et al. 2015

Journal of Bone and Mineral Research

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“…In some ultra‐rare situations of rapid skeletal remodeling, OPT can be mimicked radiographically. For example, in 2014, we reported radiographic OPT in an 11‐year‐old boy with a parasellar giant cell granuloma whose bone turnover markers and histopathological findings instead revealed accelerated bone turnover. In 2016, we reported a neonate with radiographic OPT and discovered the first mutation involving the five‐member NF‐κB complex (a heterozygous loss‐of‐function missense defect in RELA encoding p65) .…”

Section: Discussionmentioning

confidence: 99%

“…NF‐κB is a key transcription factor for osteoclastogenesis as well as OC activation and function, including when the vitamin D receptor is activated by 1,25(OH) 2 D binding . Hence, a gain‐of‐function mutation in NOD2 that activates NF‐κB would not be expected to cause OPT but perhaps instead cause rapid skeletal remodeling that still could resemble OPT radiographically . Whether modifying genes, infections, or environmental factors condition the process is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…(1) Hence, a gainof-function mutation in NOD2 that activates NF-kB would not be expected to cause OPT but perhaps instead cause rapid skeletal remodeling that still could resemble OPT radiographically. (43)(44)(45) Whether modifying genes, infections, or environmental factors condition the process is unknown. We anticipate, based upon her metaphyseal changes and active bone remodeling, that our patient's histopathological findings of OPT will fully resolve.…”

Section: Nod2 Pathophysiologymentioning

confidence: 99%

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Unique Variant of NOD2 Pediatric Granulomatous Arthritis With Severe 1,25-Dihydroxyvitamin D-Mediated Hypercalcemia and Generalized Osteosclerosis

Whyte

Lim

McAlister

et al. 2018

Journal of Bone and Mineral Research

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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.

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“…(2-6) Other relatively common etiologies include marrow-centric disorders like myelofibrosis or mastocytosis. (1,3,5) Hematologic, metabolic, and infectious disorders are further possibilities. (1,3,7) …”

Section: Ii) Introductionmentioning

confidence: 99%

Idiopathic Acquired Osteosclerosis in a Middle-Aged Woman With Systemic Lupus Erythematosus

Guañabens

Mumm

Gifre

et al. 2016

Journal of Bone and Mineral Research

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Widely distributed osteosclerosis is an unusual radiographic finding with multiple causes. A 42-year-old premenopausal Spanish woman gradually acquired dense bone diffusely affecting her axial skeleton and focally affecting her proximal long bones. Systemic lupus erythematosus (SLE) diagnosed in adolescence had been well controlled. She had not fractured or received antiresorptive therapy, and she was hepatitis C virus antibody negative. Family members had low bone mass. Lumbar spine bone mineral density (BMD) measured by dual-photon absorptiometry (DPA) at age 17 years, while receiving glucocorticoids, was 79% the average value of age-matched controls. From ages 30 to 37 years, dual-energy X-ray absorptiometry (DXA) BMD Z-scores steadily increased in her lumbar spine from þ3.8 to þ7.9, and in her femoral neck from -1.4 to -0.7. Serum calcium and phosphorus levels were consistently normal, 25-hydroxyvitamin D (25OHD) <20 ng/mL, and parathyroid hormone (PTH) sometimes slightly increased. Her reduced estimated glomerular filtration rate (eGFR) was 38 to 55 mL/min. Hypocalciuria likely reflected positive mineral balance. During increasing BMD, turnover markers (serum bone-specific alkaline phosphatase [ALP], procollagen type 1 N propeptide [P1NP], osteocalcin [OCN], and carboxy-terminal cross-linking telopeptide of type 1 collagen [CTx], and urinary amino-terminal cross-linking telopeptide of type 1 collagen [NTx and CTx]) were 1.6-to 2.8-fold above the reference limits. Those of bone formation seemed increased more than those of resorption. FGF-23 was slightly elevated, perhaps from kidney disease. Serum osteoprotegerin (OPG) and TGFb1 levels were normal, but sclerostin (SOST) and receptor activator of nuclear factor kappa-B ligand (RANKL) were elevated. Serum multiplex biomarker profiling confirmed a high level of SOST and RANKL, whereas Dickkopf-1 (DKK-1) seemed low. Matrix metalloproteinases-3 (MMP-3) and -7 (MMP-7) were elevated. Iliac crest biopsy revealed tetracycline labels, no distinction between thick trabeculae and cortical bone, absence of peritrabecular fibrosis, few osteoclasts, and no mastocytosis. Then, for the past 3 years, BMD Z-scores steadily decreased. Skeletal fluorosis, mastocytosis, myelofibrosis, hepatitis C-associated osteosclerosis, multiple myeloma, and aberrant phosphate homeostasis did not explain her osteosclerosis. Mutation analysis of the LRP5, LRP4, SOST, and osteopetrosis genes was negative. Microarray showed no notable copy number variation. Perhaps her osteosclerosis reflected an interval of autoimmune-mediated resistance to SOST and/or RANKL.

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Rapid Skeletal Turnover in a Radiographic Mimic of Osteopetrosis

Cited by 12 publications

References 52 publications

A Rapid Skeletal Turnover in Radiographic Mimic of Osteopetrosis Might Be Secondary to Systemic Mastocytosis

A Rapid Skeletal Turnover in Radiographic Mimic of Osteopetrosis Might Be Secondary to Systemic Mastocytosis

Unique Variant of NOD2 Pediatric Granulomatous Arthritis With Severe 1,25-Dihydroxyvitamin D-Mediated Hypercalcemia and Generalized Osteosclerosis

Idiopathic Acquired Osteosclerosis in a Middle-Aged Woman With Systemic Lupus Erythematosus

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