Multicentric Carpotarsal Osteolysis Syndrome in a Mother and Daughter with a <b><i>MAFB</i></b> Missense Variant and Natural History of the Disease

Abstract

Multicentric carpotarsal osteolysis syndrome (MCTO; MIM #166300) is a rare skeletal disorder characterized by osteolysis affecting particularly the carpal, metacarpal, and tarsal bones, although other bones might be involved. MCTO is an autosomal dominant disease caused by heterozygous variants in the &lt;i&gt;MAFB&lt;/i&gt; gene, frequently misdiagnosed as juvenile rheumatoid arthritis due to similar clinical manifestations. This study reports the first Brazilian family diagnosed with MCTO with progressive osteolysis of the carpal and tarsal bones, presenting a c.161C&amp;#x3e;T (p.Ser54Leu) heterozygous variant in the &lt;i&gt;MAFB&lt;/i&gt; gene, describing the clinical, radiological, and molecular findings, compared with literature data, and discussing the different clinical and molecular diagnosis, as well as the natural history of the disease. Since MCTO is a disorder with progressive symptoms, an early diagnosis is important to avoid unnecessary investigations and treatments and to provide the proper follow-up.

An unusual manifestation in a pediatric patient with MAFB mutation: Sacroiliitis in multicentric carpotarsal osteolysis syndrome

“…To date, 54 MCTO cases with MAFB mutations were reported in the literature. Most of them resembled JIA; however, treatment could not prevent disease progression and bone loss 2,4–12,14–18 . Similarly, although pain did improve with anti‐tumor necrosis factor medications in our patient, osteolysis could not be avoided.…”

“…Most of them resembled JIA; however, treatment could not prevent disease progression and bone loss. 2,[4][5][6][7][8][9][10][11][12][14][15][16][17][18] Similarly, although pain did improve with anti-tumor necrosis factor medications in our patient, osteolysis could not be avoided. The main problem in MCTO was suggested to be increased RANKL activation and excessive osteoclastic activity, but the cause of the selection of distinctive bones remains unclear.…”

“…MCTO is caused by monoallelic mutations in the MAFB gene and although several patients had de-novo mutations without affected individuals in their families, some cases are familial. 5,8,11 Pathognomonic features of the disease include progressive loss of carpal and tarsal bones, resulting in abnormal deviation of hands and feet. Facial appearance, including triangular face, micrognathia, and exophthalmos, may also be suggestive of the disease.…”

“…2 Interestingly, the early phases of the disease usually resemble juvenile idiopathic arthritis (JIA) with inflammatory pain and synovial effusions, thus the majority of the MCTO patients have been treated with methotrexate and even biological agents until the recognition of the complete disappearance of the bones and confirmation of MCTO diagnosis. [4][5][6][7][8][9][10][11] Similarly, our patient was diagnosed as having JIA in early childhood and had persistent proteinuria and complete loss of carpal and tarsal bones. Further, she also suffered from inflammatory back pain during follow-up and magnetic resonance imaging (MRI) revealed sacroiliitis, which had a favorable response to adalimumab treatment.…”

Multicentric Carpotarsal Osteolysis Syndrome Associated Nephropathy: Novel Variants of MAFB Gene and Literature Review

“…In 2012, Zankl et al [ 1 ] for the first time identified missense mutations clustering within a 51 base pair region of the single exon of MAFB in five unrelated simplex cases of MCTO. After that, 57 cases with genetic diagnosis were reported in the literature [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. All cases showed a large phenotypical heterogeneity, even among patients presenting the same variant [ 4 ].…”