Absence of MMP2 Mutations in Idiopathic Multicentric Osteolysis w/Nephropathy in 2 American Boys

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Title:

Absence of MMP2 Mutations in Idiopathic Multicentric Osteolysis with Nephropathy in 2 American Boys

Category:

12. Pediatric rheumatology — pathogenesis and genetics

Author(s):

Deborah Wenkert1, Mumm2, Stefanie M. Wiegand2, H. McAlister3, P. Whyte1. 1Cntr Metab Bone Dis and Mol Res, Shriners Hospt Children, St. Louis, MO; 2Div Bone Miner Dis, Wash Univ Sch Med, St. Louis, MO; 3Mallinckrodt Inst Radiol, Wash Univ Sch Med, St. Louis, MO

Presentation Number:

754

Poster Board Number:

56

Early in the clinical presentation of osteolysis syndromes, patients can be diagnosed with juvenile idiopathic arthritis (JIA). Often, only after anti-inflammatory agents have failed and disappearance of bones becomes noted on x-ray is an osteolysis syndrome recognized.

In 2001, Saudi Arabians with “multicentric osteolysis and arthritis syndrome” were found to have mutations of the gene encoding matrix metalloproteinase 2 (MMP2) (Nat Genet, 2001, 28:261-5). They suffered crippling arthritis, subcutaneous nodules, and osteoporosis with carpal-tarsal destruction. This entity has also been called Nodulosis-Arthropathy-Osteolysis Syndrome (NAO) (OMIM #605156).

We report 2 unrelated boys with idiopathic multicentric osteolysis (IMO) with characteristic nephropathy in whom no MMP2 mutation was identified. Elsewhere, each had initially been diagnosed with Juvenile Rheumatoid Arthritis (JRA) (although ANA, RF and ESR were unremarkable) and had received NSAIDs, prednisone, gold, and methotrexate with minimal effect.

Patient 1: A Caucasian boy, crawled on knees and elbows at 1 yr of age. X-rays showed "delayed bone age". Flares of pain and limited motion of feet, wrists, elbows, and perhaps knees persisted despite JRA treatment. After IMO was diagnosed, pamidronate was administered for 1 yr. Upon referral at age 8, keloids involved his skin at a subclavian port and a shin (previous site of eczema-poison ivy). Mild proteinuria developed over the next 1/2 yr. Osteolysis was treated with oral alendronate.

Patient 2: A Caucasian boy, referred at age 7, had developed a worsening limp at age 2.5 yrs. Pain and swelling of an ankle had preceded progressive involvement of wrists and ankles. Myopathy, from disuse atrophy, led to a negative workup for muscle disease, and a presumptive diagnosis of JRA was made at age 3. IMO was diagnosed at age 5 after he developed elbow, knee, and shoulder involvement with contractures and bony erosions. Proteinuria discovered at referral and progressive renal disease led to kidney transplantation at age 17.

All 13 exons and adjacent mRNA splice sites of the MMP2 gene were amplified by PCR, using genomic DNA isolated from blood leukocytes. Amplicons were sequenced in both directions, using the same PCR primers. Sequencing chromatograms were inspected and sequences aligned using VectorNTI AlignX software. No MMP2 mutations were detected.

Each of our patients had originally been diagnosed with JIA. Early clinical clues to IMO included aggressive symmetric involvement of wrists and ankles prior to the involvement of other joints, x-ray reading of “delayed bone age”, and negative serologies. DNA-based diagnosis of IMO would help the early identification of IMO patients. However, our experience, supports the clinical impression that IMO represents a disease distinct from NAO.

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