Seropositive rheumatoid arthritis in osteogenesis imperfecta type XI (FKBP10 mutation): First case report and literature review

Seropositive rheumatoid arthritis in osteogenesis imperfecta type XI (FKBP10 mutation): First case report and literature review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Seropositive rheumatoid arthritis in osteogenesis imperfecta type XI (FKBP10 mutation): First case report and literature review Anas Manhal, Jamal Abdallah, Mahmoud M Qouqas, Ahmad Waleed, Layth Al-Karaja, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6950688/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Jan, 2026 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 6 You are reading this latest preprint version Abstract Background: Osteogenesis imperfecta (OI) is a rare genetic disorder primarily caused by mutations in genes involved in type I collagen production. We report a 27-year-old female with genetically confirmed OI type XI (OI-XI) who experienced a delayed diagnosis of seropositive rheumatoid arthritis (RA), resulting in irreversible deformities. Case Presentation: The patient had multiple congenital contractures and became wheelchair-dependent in early childhood. She received only one course of bone protection therapy in her lifetime. Two years prior to presentation, she developed bilateral hand pain, stiffness, and progressive deformities. The diagnosis of RA was confirmed based on clinical features, imaging, and high titers of anti-cyclic citrullinated peptide (anti-CCP) antibodies. Genetic analysis revealed a homozygous FKBP10 mutation (c.391 + 4A > T), confirming OI-XI. Treatment with methotrexate, folic acid, and vitamin D led to symptom improvement and stabilization of deformities. Conclusions: This is the first reported case of RA in a patient with genetically confirmed OI-XI. The case underscores the importance of early detection and treatment of RA in individuals with OI to prevent irreversible joint damage. Osteogenesis imperfecta rheumatoid arthritis FKBP10 rare disease case report bone fragility autoimmune disease Figures Figure 1 Figure 2 Introduction Osteogenesis imperfecta (OI) is a rare skeletal dysplasia that occurs in approximately 1 in every 15,000 to 20,000 individuals [ 1 ]. OI is a heterogeneous disorder primarily caused by mutations in genes involved in the production of type I collagen and is characterized by bone fragility resulting in fractures, bone deformities, and growth retardation [ 2 ]. OI can also lead to extra-skeletal manifestations such as blue sclera, dentinogenesis imperfecta (DI), joint hypermobility, hearing loss, cardiovascular and respiratory complications [ 3 ]. Osteogenesis imperfecta type XI (OI-XI) is a rare sub-type that is inherited as an autosomal recessive disorder and is caused by a bi-allelic mutation of FKBP10 gene that results in a defect of FKBP65 protein production that leads to a delayed type I procollagen secretion and accumulation in the endoplasmic reticulum [ 4 ]. OI-XI is characterized by contractures affecting major joints and progressive kyphoscoliosis, interestingly, these patients rarely have blue sclera, DI or hearing loss [ 4 ],[ 5 ]. Rheumatoid arthritis (RA) is a common chronic inflammatory disorder marked by inflammation of the synovial membrane within the joints. This persistent inflammation ultimately if untreated leads to the destruction of joint components, including cartilage and bone, resulting in significant damage to the articular structures over time [ 6 ]. RA affects approximately 1% of the global population, with an annual incidence rate of about 3 per 10,000 adults. The condition is two to three times more prevalent in women than men. About one-third of RA patients develop disabilities, depending on several factors including the disease's initial severity, time of diagnosis and commitment to treatment and follow up. Although the exact cause of RA remains unclear, genetic factors contribute up to 30% of disease susceptibility. Key genetic links include HLA-DR4 and DR1, which share specific regions that increase the risk of developing RA. Various infectious agents have also been proposed as potential triggers [ 7 ]. The coexistence of osteogenesis imperfecta and inflammatory arthritis is rare, but systemic inflammation has been found in osteogenesis imperfecta. Mutations in COL1A1 can affect collagen synthesis and interactions with the extracellular matrix, including ligands involved in rheumatoid arthritis [ 8 ]. In this case report, we describe what we believe to be the first documented instance of RA in a patient with genetically confirmed OI-XI—highlighting the diagnostic and clinical challenges involved. Methods (Case Description) Patient Information The patient is a 27-year-old woman born with multiple congenital contractures involving her knees, ankles, and—less severely—her elbows and hands. She achieved independent ambulation with a tiptoe gait by age one and underwent several tendon lengthening procedures early in life. At the age of four, she sustained her first low-trauma femoral fracture, which was managed with bilateral intramedullary rodding. At age seven, she sustained a tibial fracture that was treated with external fixation. She received a single infusion of pamidronate at age 12, but later suffered another femoral fracture, requiring further surgery. Following her last major surgery, she remained fracture-free but reported intermittent hip pain. Despite developing progressive kyphoscoliosis, she did not experience hearing, dental, or speech issues. She maintained independence in her daily activities, even though she required a wheelchair. A strong family history of OI, combined with genetic testing, confirmed a homozygous FKBP10 mutation (c.391 + 4A > T), leading to a definitive diagnosis of OI-XI. Diagnostic Assessment The patient reported normal hand and arm function until the age of 25. Over the two years prior to presentation, she began to experience bilateral hand pain, prolonged morning stiffness lasting over an hour, and progressive deformities. Initially attributing these symptoms to her underlying OI, she delayed seeking medical advice. However, her hand function continued to decline, eventually affecting her independence. On examination, she measured 1.20 meters in height and weighed 23 kilograms. She had mild blue sclerae and severe kyphoscoliosis. Examination of her hands revealed classical signs of inflammatory arthritis, including ulnar deviation and swan-neck deformities (Fig. 1 ), tenderness of the MCP and PIP joints, and a limited range of motion. Musculoskeletal ultrasound demonstrated joint effusions and erosions, particularly in the second MCP joints bilaterally (Fig. 2 ). Laboratory studies showed high titers of anti-CCP antibodies (596.7 U/mL), a positive rheumatoid factor (RF), an elevated CRP of 48 mg/L, and an ESR of 33 mm/h. All other laboratory values—including CBC, renal and liver function tests, and bone metabolism markers—were within normal limits, except for a low vitamin D level. Laboratory findings are summarized in Table 1 . A DXA scan revealed severe osteoporosis with a lumbar spine BMD T-score of − 8.5 SD. Due to surgical implants, femoral measurements were not interpretable. The patient’s Disease Activity Score 28 for RA with ESR (DAS28-ESR) was 5, indicating moderate disease activity. Interventions The patient was started on vitamin D3 (cholecalciferol) supplementation in preparation for bone-directed therapy. Based on her clinical presentation, laboratory findings, and imaging, she was diagnosed with seropositive RA. Methotrexate (20 mg/week orally) was initiated in line with international treatment recommendations. Folic acid was added, and NSAIDs were used briefly before being substituted with glucocorticoids. Outcomes The patient responded well to treatment. Over a 10-month follow-up period, her symptoms improved significantly, and further joint deformities were halted. Repeat musculoskeletal ultrasound showed resolution of joint effusions. Her ESR decreased to 7 mm/h, and her DAS28-ESR improved from 5 to 2.3, indicating disease remission. Results The clinical course, diagnostic evaluations, and treatment outcomes are outlined above. For comparison, Table 2 summarizes previously published cases of RA in patients with other types of OI. Discussion Osteogenesis imperfecta (OI) patients commonly experience joint pain, stiffness, and instability, particularly in the weight-bearing joints of the lower extremities, the occurrence of symptomatic inflammatory joint disease alongside OI is rare. A study by McKiernan et al. revealed that almost half of 111 type 1 OI patients reported a diagnosis of "noninflammatory arthritis," typically osteoarthritis. In contrast, only 4% of patients had inflammatory arthritis, such as psoriatic or rheumatoid arthritis. To date, only four cases of rheumatoid arthritis associated with OI have been reported [ 9 ]. In these patients, the time between the onset of RA symptoms and diagnosis was delayed ranging from 6 months to 13 years. Our patient suffered for two years from inflammatory joint pain until she was seen at our clinic where her evaluation revealed the seropositive rheumatoid arthritis diagnosis. The presence of her OI-XI disease has resulted in significant delay in seeking medical advice which unfortunately resulted in severe deformities and significant loss of hands function. It is uncertain whether the presence of OI has accelerated the progression of our patient’s deformities, but this should consider, as it only took two years of joint inflammation to cause advanced deformities, whereas such changes typically take many years to develop in cases of RA [ 10 ]. This might be explained by the fact that some OI patients have systemic inflammation. In patients with OI-XI who carry an FKBP10 gene mutation, which encodes the immunophilin FKBP65, a chaperone that participates in type I procollagen folding, this mutation affects type I collagen folding and cross-linking [ 4 ]. Collagen-binding ligands, including cytokines, cell adhesion molecules, matrix metalloproteinases, proteoglycans, and other molecules, are autoimmunity targets in rheumatoid arthritis pathogenesis [ 8 ],[ 11 ]. Albeit this might explain why RA and OI might coexist, it doesn’t explain the scarcity of such an occurrence. The delayed diagnosis of rheumatoid arthritis (RA) in patients with osteogenesis imperfecta (OI) can have significant adverse sequalae, including permanent deformities. RA can lead to irreversible joint damage and deformities if not promptly recognized and managed [ 12 ]. The Management of RA in patients with OI requires a comprehensive approach, involving rheumatologists, endocrinologists, orthopedic surgeons, and other healthcare professionals. Treatment typically includes disease-modifying antirheumatic drugs (DMARDs) to suppress the autoimmune response, optimizing bone mineral health, bone targeted therapy, physical therapy to improve and preserve joint function, and possibly surgical intervention to correct deformities [ 13 ]. Differential Diagnosis In a patient with OI, symptoms such as joint pain and deformity might easily be attributed to chronic arthropathy, contractures, or secondary osteoarthritis. However, in this case, features like prolonged morning stiffness, joint swelling, high anti-CCP titers, and erosive joint changes were all characteristic of inflammatory arthritis—leading to the correct diagnosis of RA. Limitations This is a single case report, and while it provides a valuable teaching point, its findings cannot be generalized. Nonetheless, it raises awareness of a potential diagnostic oversight in rare disease populations. The rapid progression of deformities in this patient raises the question of whether OI-XI may have amplified the inflammatory process. Systemic inflammation and impaired collagen processing due to FKBP10 mutations might create an environment that facilitates autoimmunity. While speculative, this idea is consistent with emerging evidence of extracellular matrix involvement in RA pathogenesis. Early identification and treatment of RA in patients with OI are essential to avoid functional decline. These patients require a coordinated, multidisciplinary approach involving rheumatology, orthopedics, endocrinology, and physiotherapy. Methotrexate remains the first-line DMARD and has shown good tolerability in this case. Vitamin D and bone health optimization are also key. Conclusions This case represents the first known instance of seropositive RA in a patient with genetically confirmed OI-XI. It illustrates the challenges of diagnosing inflammatory arthritis in the context of pre-existing skeletal dysplasia and underscores the consequences of diagnostic delay. Clinicians should maintain a high index of suspicion for RA in any patient with new joint symptoms—even when another musculoskeletal diagnosis is already present. Early diagnosis and intervention are essential to preserving quality of life and preventing disability. Abbreviations • OI Osteogenesis imperfecta • OI-XI Osteogenesis imperfecta type XI • RA Rheumatoid arthritis • DMARDs Disease-modifying antirheumatic drugs • BMD Bone mineral density • DXA Dual-energy X-ray absorptiometry • CRP C-reactive protein • ESR Erythrocyte sedimentation rate • RF Rheumatoid factor • Anti-CCP Anti-cyclic citrullinated peptide Declarations Ethics approval and consent to participate: Not applicable. Consent for publication: Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal. Competing interests: The authors declare that they have no competing interests. Funding: This work received no specific funding from public, commercial, or not-for-profit agencies. Authors’ contributions: Anas Manhal: Concept and design, data collection, manuscript writing. Jamal Abdullah: Concept and design, data collection, corresponding author. Mahmoud M Qouqas: Genetic analysis and interpretation. Ahmad Waleed: Clinical management and manuscript editing. Layth Al-Karaja: Literature review and manuscript editing. Noor Sawalha: Clinical input and manuscript review. Laith Alamlih: Rheumatology expertise and manuscript review. All authors read and approved the final manuscript. Acknowledgements: The authors thank the patient and her family for their valuable contribution. Data availability: All data generated or analyzed during this study are included in this published article. References Bourgeois AB. Osteogenesis imperfecta: from diagnosis and multidisciplinary treatment to future perspectives. Swiss Med Wkly. 2016;146:w14322. Deguchi M, Tsuji S, Katsura D, et al. Current overview of osteogenesis imperfecta. Med (B Aires). 2021;57:464. Marom R, Rabenhorst BM, Morello R. Management of endocrine disease: Osteogenesis imperfecta: An update on clinical features and therapies. Eur J Endocrinol. 2020;183:R95–106. Alanay Y, Avaygan H, Camacho N, et al. Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet. 2010;86:551–9. Kelley BP, Malfait F, Bonafe L, et al. Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome. J Bone Min Res. 2011;26:666–72. Gibofsky A. Epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis: A Synopsis. Am J Manag Care. 2014;20:S128–35. Liu Z, Niu X, Wang J. Naringenin as a natural immunomodulator against T cell-mediated autoimmune diseases: literature review and network-based pharmacology study. Crit Rev Food Sci Nutr. 2023;63:11026–43. Damian LO, Miclea D, Vulturar R, et al. Osteogenesis imperfecta and rheumatoid arthritis: connective issues. Osteoporos Int. 2022;33:2237–9. McKiernan FE. Musculoskeletal manifestations of mild osteogenesis imperfecta in the adult. Osteoporos Int. 2005;16:1698–702. Toyama S, Tokunaga D, Tsuchida S, et al. Comprehensive assessment of alterations in hand deformities over 11 years in patients with rheumatoid arthritis using cluster analysis and analysis of covariance. Arthritis Res Ther. 2021;23:1–9. Boraschi-Diaz I, Wang J, Mort JS, et al. Collagen type I as a ligand for receptor-mediated signaling. Front Phys. 2017;5:12. Xu C, Wu Y, Zhao L, et al. Transdermal hormone delivery: Strategies, application and modality selection. J Drug Deliv Sci Technol. 2023;86:104730. Bullock J, Rizvi SAA, Saleh AM, et al. Rheumatoid arthritis: a brief overview of the treatment. Med Princ Pract. 2019;27:501–7. Tables Table 1. Laboratory results at presentation Test Item Patient Value (Unit) Reference Range Electrolytes & Minerals Total calcium 9.6 mg/dL 8.5 – 10.2 mg/dL Phosphorus 2.93 mg/dL 1.5 – 6.8 mg/dL Magnesium 1.7 mg/dL 1.7 – 2.2 mg/dL Sodium 138 mEq/L 135 – 145 mEq/L Potassium 4.6 mEq/L 3.5 – 5.0 mEq/L Chloride 106 mEq/L 98 – 107 mEq/L Albumin 3.97 g/dL 3.5 – 5.0 g/dL Uric acid 2.00 mg/dL 2.4 – 6.0 mg/dL Renal & Liver Function ALT (alanine aminotransferase) 26 U/L 7 – 35 U/L AST (aspartate aminotransferase) 25 U/L 10 – 34 U/L BUN (blood urea nitrogen) 14 mg/dL 7 – 20 mg/dL Creatinine 0.6 mg/dL 0.5 – 1.1 mg/dL Hematology WBC (white blood cells) 6.9 ×10⁹/L 4.0 – 10.5 ×10⁹/L HGB (hemoglobin) 11.9 g/dL 12.0 – 15.5 g/dL HCT (hematocrit) 33.9 % 36.0 – 46.0 % MCV (mean corpuscular volume) 72.7 fL 80 – 100 fL Ferritin 35 ng/mL 12 – 150 ng/mL Vitamin B12 426 pg/mL 200 – 900 pg/mL Inflammatory Markers CRP (C-reactive protein) 48 mg/L < 3.0 mg/L ESR (erythrocyte sedimentation rate) 33 mm/hr 0 – 20 mm/hr Endocrine Thyroid stimulating hormone 2.42 mIU/L 0.4 – 4.0 mIU/L Vitamin D 15.3 ng/mL 20 – 50 ng/mL Disease-Specific Anti-CCP (anti-cyclic citrullinated peptide) 596.7 U/mL < 20 U/mL Abnormal values are shown in bold. Abbreviations: HGB, hemoglobin; HCT, hematocrit; MCV, mean corpuscular volume; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; WBC, white blood cells; Anti-CCP, anti-cyclic citrullinated peptide antibody. Table 2. Clinical and Genetic Features of Reported Cases of Osteogenesis Imperfecta with Coexisting Inflammatory Arthritis Article / Year Age Sex Serology (RF/ACPA/ESR/CRP) Gene Mutation Delay to Diagnosis Major Deformities Treatment(s) Treatment Outcome Our case 27 F RF+, ACPA 596.7 U/mL, ESR 33, CRP 48 FKBP10 c.391+4A>T (homozygous) 2 years Bilateral hand deformities (ulnar deviation, swan-neck), severe kyphoscoliosis Methotrexate, glucocorticoids, NSAIDs, vitamin D Pain improved, deformity progression halted, inflammatory markers improved (10 months) Bica et al., 2013 [1] 53 F RF+, ESR 72 Clinical OI (no genetic test) 13 years (JIA at 15) Severe hand/foot deformities, TMJ limitation Alendronate, salicylates (irregular), steroids Bone mass stabilized, partial pain relief, persistent TMJ stiffness, incomplete arthritis control Damian et al., 2020 [2] 46 F RF 28 IU/dL, ACPA 224, ESR 43, CRP 24 COL1A1 c.3399del, p.Ala1134Profs*105 6 months Periarticular osteoporosis, tibiotarsal synovitis Sulfasalazine, methotrexate, leflunomide Pain and stiffness resolved, inflammation controlled, no NSAIDs/steroids used Damian et al., 2020 [2] 70 F RF 32, ACPA 218, ESR 34, CRP 12 COL1A1 c.3399del, p.Ala1134Profs*105 2 years Bone deformities, periarticular bone loss Methotrexate, leflunomide Pain and stiffness resolved, inflammation controlled, no NSAIDs/steroids used Mormile et al., 2022 [3] 43 F Seropositive RA (labs N/R) COL1A1 c.3399del, p.(Ala1134Profs*105) N/R N/R Adalimumab (anti-TNF) Complete remission Abbreviations: RF: rheumatoid factor; ACPA: anti-cyclic citrullinated peptide antibody; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; TMJ: temporomandibular joint; JIA: juvenile idiopathic arthritis; N/R: not reported. References : 1 Bica BERG, Ruiz DG, de Andrade Magalhães P, et al. Association between juvenile idiopathic arthritis and osteogenesis imperfecta-case report. Rev Bras Reumatol (English Ed 2013; 53 :535–7. 2 Damian LO, Zmarandache C-D, Vele P, et al. Osteogenesis imperfecta and rheumatoid arthritis: is there a link? Arch Osteoporos 2020; 15 :1–5. 3 Mormile I, Russo R, Andolfo I, et al. Rheumatoid arthritis and osteogenesis imperfecta: is there a genetic causal association? Osteoporos Int 2022; 33 :2233–5. Cite Share Download PDF Status: Published Journal Publication published 13 Jan, 2026 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Editorial decision: Minor revision 18 Jul, 2025 Reviewers agreed at journal 28 Jun, 2025 Reviewers invited by journal 24 Jun, 2025 Editor invited by journal 23 Jun, 2025 Editor assigned by journal 23 Jun, 2025 First submitted to journal 22 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6950688","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":475592133,"identity":"cffb88d6-38a5-4f7d-816f-3de77a5c825c","order_by":0,"name":"Anas Manhal","email":"","orcid":"","institution":"Hebron University","correspondingAuthor":false,"prefix":"","firstName":"Anas","middleName":"","lastName":"Manhal","suffix":""},{"id":475592134,"identity":"309498cd-3127-4341-be2d-0f6f84ae62e0","order_by":1,"name":"Jamal Abdallah","email":"data:image/png;base64,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","orcid":"https://orcid.org/0009-0009-4533-6919","institution":"Hebron University","correspondingAuthor":true,"prefix":"","firstName":"Jamal","middleName":"","lastName":"Abdallah","suffix":""},{"id":475592135,"identity":"c4b46b19-99bb-42b8-ab58-d49902c9f4cd","order_by":2,"name":"Mahmoud M Qouqas","email":"","orcid":"","institution":"Hebron University","correspondingAuthor":false,"prefix":"","firstName":"Mahmoud","middleName":"M","lastName":"Qouqas","suffix":""},{"id":475592136,"identity":"6c423278-4ffa-4938-a8ad-1b7a43a82e94","order_by":3,"name":"Ahmad Waleed","email":"","orcid":"","institution":"Hebron University","correspondingAuthor":false,"prefix":"","firstName":"Ahmad","middleName":"","lastName":"Waleed","suffix":""},{"id":475592137,"identity":"0e025600-3c74-4477-95a9-106530ae71db","order_by":4,"name":"Layth Al-Karaja","email":"","orcid":"","institution":"Al Quds University: Al-Quds University","correspondingAuthor":false,"prefix":"","firstName":"Layth","middleName":"","lastName":"Al-Karaja","suffix":""},{"id":475592138,"identity":"a287098e-0e95-461f-ad7b-8e95e1361da3","order_by":5,"name":"Noor Sawalha","email":"","orcid":"","institution":"Hebron University","correspondingAuthor":false,"prefix":"","firstName":"Noor","middleName":"","lastName":"Sawalha","suffix":""},{"id":475592139,"identity":"704233f1-e3c7-4219-bf56-1df63d6560e1","order_by":6,"name":"Laith Al-Amlih","email":"","orcid":"","institution":"Rheumatology Associates","correspondingAuthor":false,"prefix":"","firstName":"Laith","middleName":"","lastName":"Al-Amlih","suffix":""}],"badges":[],"createdAt":"2025-06-22 16:49:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6950688/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6950688/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13023-025-04071-x","type":"published","date":"2026-01-13T16:29:14+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85646388,"identity":"5683b888-e332-4d04-9fa4-92f4e82e0e91","added_by":"auto","created_at":"2025-06-30 08:38:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2656198,"visible":true,"origin":"","legend":"\u003cp\u003ePhotograph of the patient’s hands with deformities.\u003c/p\u003e","description":"","filename":"Figure12.png","url":"https://assets-eu.researchsquare.com/files/rs-6950688/v1/eb2d6ea06ad53cbe435e81d7.png"},{"id":85646389,"identity":"98fbbdfd-8400-4118-83f0-c9cb6b998783","added_by":"auto","created_at":"2025-06-30 08:38:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":372208,"visible":true,"origin":"","legend":"\u003cp\u003eMusculoskeletal ultrasound shows (A) Longitudinal scan of the second Metacarpophalangeal joint (MCP) shows Synovial effusion (asterisks) and bony erosion (arrow). (B) Longitudinal scan of the third Proximal interphalangeal joints (PIP) shows Synovial effusion (asterisks).\u003c/p\u003e","description":"","filename":"Figure22.png","url":"https://assets-eu.researchsquare.com/files/rs-6950688/v1/c971d2d9c22cac52915d638d.png"},{"id":100615928,"identity":"05b52022-e85f-47ff-908f-7a3306fb6b39","added_by":"auto","created_at":"2026-01-19 17:38:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4079824,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6950688/v1/4c26e4ac-dd23-4087-be5d-385cca1d1c4a.pdf"}],"financialInterests":"","formattedTitle":"Seropositive rheumatoid arthritis in osteogenesis imperfecta type XI (FKBP10 mutation): First case report and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOsteogenesis imperfecta (OI) is a rare skeletal dysplasia that occurs in approximately 1 in every 15,000 to 20,000 individuals [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. OI is a heterogeneous disorder primarily caused by mutations in genes involved in the production of type I collagen and is characterized by bone fragility resulting in fractures, bone deformities, and growth retardation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. OI can also lead to extra-skeletal manifestations such as blue sclera, dentinogenesis imperfecta (DI), joint hypermobility, hearing loss, cardiovascular and respiratory complications [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Osteogenesis imperfecta type XI (OI-XI) is a rare sub-type that is inherited as an autosomal recessive disorder and is caused by a bi-allelic mutation of FKBP10 gene that results in a defect of FKBP65 protein production that leads to a delayed type I procollagen secretion and accumulation in the endoplasmic reticulum [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. OI-XI is characterized by contractures affecting major joints and progressive kyphoscoliosis, interestingly, these patients rarely have blue sclera, DI or hearing loss [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e],[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRheumatoid arthritis (RA) is a common chronic inflammatory disorder marked by inflammation of the synovial membrane within the joints. This persistent inflammation ultimately if untreated leads to the destruction of joint components, including cartilage and bone, resulting in significant damage to the articular structures over time [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. RA affects approximately 1% of the global population, with an annual incidence rate of about 3 per 10,000 adults. The condition is two to three times more prevalent in women than men. About one-third of RA patients develop disabilities, depending on several factors including the disease's initial severity, time of diagnosis and commitment to treatment and follow up. Although the exact cause of RA remains unclear, genetic factors contribute up to 30% of disease susceptibility. Key genetic links include HLA-DR4 and DR1, which share specific regions that increase the risk of developing RA. Various infectious agents have also been proposed as potential triggers [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe coexistence of osteogenesis imperfecta and inflammatory arthritis is rare, but systemic inflammation has been found in osteogenesis imperfecta. Mutations in COL1A1 can affect collagen synthesis and interactions with the extracellular matrix, including ligands involved in rheumatoid arthritis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In this case report, we describe what we believe to be the first documented instance of RA in a patient with genetically confirmed OI-XI\u0026mdash;highlighting the diagnostic and clinical challenges involved.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Methods (Case Description)","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient Information\u003c/h2\u003e \u003cp\u003eThe patient is a 27-year-old woman born with multiple congenital contractures involving her knees, ankles, and\u0026mdash;less severely\u0026mdash;her elbows and hands. She achieved independent ambulation with a tiptoe gait by age one and underwent several tendon lengthening procedures early in life. At the age of four, she sustained her first low-trauma femoral fracture, which was managed with bilateral intramedullary rodding. At age seven, she sustained a tibial fracture that was treated with external fixation. She received a single infusion of pamidronate at age 12, but later suffered another femoral fracture, requiring further surgery.\u003c/p\u003e \u003cp\u003eFollowing her last major surgery, she remained fracture-free but reported intermittent hip pain. Despite developing progressive kyphoscoliosis, she did not experience hearing, dental, or speech issues. She maintained independence in her daily activities, even though she required a wheelchair. A strong family history of OI, combined with genetic testing, confirmed a homozygous FKBP10 mutation (c.391\u0026thinsp;+\u0026thinsp;4A\u0026thinsp;\u0026gt;\u0026thinsp;T), leading to a definitive diagnosis of OI-XI.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDiagnostic Assessment\u003c/h3\u003e\n\u003cp\u003eThe patient reported normal hand and arm function until the age of 25. Over the two years prior to presentation, she began to experience bilateral hand pain, prolonged morning stiffness lasting over an hour, and progressive deformities. Initially attributing these symptoms to her underlying OI, she delayed seeking medical advice. However, her hand function continued to decline, eventually affecting her independence.\u003c/p\u003e \u003cp\u003eOn examination, she measured 1.20 meters in height and weighed 23 kilograms. She had mild blue sclerae and severe kyphoscoliosis. Examination of her hands revealed classical signs of inflammatory arthritis, including ulnar deviation and swan-neck deformities (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), tenderness of the MCP and PIP joints, and a limited range of motion.\u003c/p\u003e \u003cp\u003eMusculoskeletal ultrasound demonstrated joint effusions and erosions, particularly in the second MCP joints bilaterally (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Laboratory studies showed high titers of anti-CCP antibodies (596.7 U/mL), a positive rheumatoid factor (RF), an elevated CRP of 48 mg/L, and an ESR of 33 mm/h. All other laboratory values\u0026mdash;including CBC, renal and liver function tests, and bone metabolism markers\u0026mdash;were within normal limits, except for a low vitamin D level. Laboratory findings are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eA DXA scan revealed severe osteoporosis with a lumbar spine BMD T-score of \u0026minus;\u0026thinsp;8.5 SD. Due to surgical implants, femoral measurements were not interpretable. The patient\u0026rsquo;s Disease Activity Score 28 for RA with ESR (DAS28-ESR) was 5, indicating moderate disease activity.\u003c/p\u003e\n\u003ch3\u003eInterventions\u003c/h3\u003e\n\u003cp\u003eThe patient was started on vitamin D3 (cholecalciferol) supplementation in preparation for bone-directed therapy. Based on her clinical presentation, laboratory findings, and imaging, she was diagnosed with seropositive RA. Methotrexate (20 mg/week orally) was initiated in line with international treatment recommendations. Folic acid was added, and NSAIDs were used briefly before being substituted with glucocorticoids.\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe patient responded well to treatment. Over a 10-month follow-up period, her symptoms improved significantly, and further joint deformities were halted. Repeat musculoskeletal ultrasound showed resolution of joint effusions. Her ESR decreased to 7 mm/h, and her DAS28-ESR improved from 5 to 2.3, indicating disease remission.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe clinical course, diagnostic evaluations, and treatment outcomes are outlined above. For comparison, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes previously published cases of RA in patients with other types of OI.\u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003eOsteogenesis imperfecta (OI) patients commonly experience joint pain, stiffness, and instability, particularly in the weight-bearing joints of the lower extremities, the occurrence of symptomatic inflammatory joint disease alongside OI is rare. A study by McKiernan et al. revealed that almost half of 111 type 1 OI patients reported a diagnosis of \"noninflammatory arthritis,\" typically osteoarthritis. In contrast, only 4% of patients had inflammatory arthritis, such as psoriatic or rheumatoid arthritis. To date, only four cases of rheumatoid arthritis associated with OI have been reported [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In these patients, the time between the onset of RA symptoms and diagnosis was delayed ranging from 6 months to 13 years. Our patient suffered for two years from inflammatory joint pain until she was seen at our clinic where her evaluation revealed the seropositive rheumatoid arthritis diagnosis.\u003c/p\u003e \u003cp\u003eThe presence of her OI-XI disease has resulted in significant delay in seeking medical advice which unfortunately resulted in severe deformities and significant loss of hands function. It is uncertain whether the presence of OI has accelerated the progression of our patient\u0026rsquo;s deformities, but this should consider, as it only took two years of joint inflammation to cause advanced deformities, whereas such changes typically take many years to develop in cases of RA [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This might be explained by the fact that some OI patients have systemic inflammation. In patients with OI-XI who carry an FKBP10 gene mutation, which encodes the immunophilin FKBP65, a chaperone that participates in type I procollagen folding, this mutation affects type I collagen folding and cross-linking [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Collagen-binding ligands, including cytokines, cell adhesion molecules, matrix metalloproteinases, proteoglycans, and other molecules, are autoimmunity targets in rheumatoid arthritis pathogenesis [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e],[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Albeit this might explain why RA and OI might coexist, it doesn\u0026rsquo;t explain the scarcity of such an occurrence.\u003c/p\u003e \u003cp\u003eThe delayed diagnosis of rheumatoid arthritis (RA) in patients with osteogenesis imperfecta (OI) can have significant adverse sequalae, including permanent deformities. RA can lead to irreversible joint damage and deformities if not promptly recognized and managed [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The Management of RA in patients with OI requires a comprehensive approach, involving rheumatologists, endocrinologists, orthopedic surgeons, and other healthcare professionals.\u003c/p\u003e \u003cp\u003eTreatment typically includes disease-modifying antirheumatic drugs (DMARDs) to suppress the autoimmune response, optimizing bone mineral health, bone targeted therapy, physical therapy to improve and preserve joint function, and possibly surgical intervention to correct deformities [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eDifferential Diagnosis\u003c/h3\u003e\n\u003cp\u003eIn a patient with OI, symptoms such as joint pain and deformity might easily be attributed to chronic arthropathy, contractures, or secondary osteoarthritis. However, in this case, features like prolonged morning stiffness, joint swelling, high anti-CCP titers, and erosive joint changes were all characteristic of inflammatory arthritis\u0026mdash;leading to the correct diagnosis of RA.\u003c/p\u003e\n\u003ch3\u003eLimitations\u003c/h3\u003e\n\u003cp\u003eThis is a single case report, and while it provides a valuable teaching point, its findings cannot be generalized. Nonetheless, it raises awareness of a potential diagnostic oversight in rare disease populations.\u003c/p\u003e \u003cp\u003eThe rapid progression of deformities in this patient raises the question of whether OI-XI may have amplified the inflammatory process. Systemic inflammation and impaired collagen processing due to FKBP10 mutations might create an environment that facilitates autoimmunity. While speculative, this idea is consistent with emerging evidence of extracellular matrix involvement in RA pathogenesis.\u003c/p\u003e \u003cp\u003eEarly identification and treatment of RA in patients with OI are essential to avoid functional decline. These patients require a coordinated, multidisciplinary approach involving rheumatology, orthopedics, endocrinology, and physiotherapy. Methotrexate remains the first-line DMARD and has shown good tolerability in this case. Vitamin D and bone health optimization are also key.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis case represents the first known instance of seropositive RA in a patient with genetically confirmed OI-XI. It illustrates the challenges of diagnosing inflammatory arthritis in the context of pre-existing skeletal dysplasia and underscores the consequences of diagnostic delay. Clinicians should maintain a high index of suspicion for RA in any patient with new joint symptoms\u0026mdash;even when another musculoskeletal diagnosis is already present. Early diagnosis and intervention are essential to preserving quality of life and preventing disability.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; OI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOsteogenesis imperfecta\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; OI-XI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOsteogenesis imperfecta type XI\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; RA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRheumatoid arthritis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; DMARDs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDisease-modifying antirheumatic drugs\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; BMD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBone mineral density\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; DXA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDual-energy X-ray absorptiometry\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; CRP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eC-reactive protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; ESR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eErythrocyte sedimentation rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; RF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRheumatoid factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; Anti-CCP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAnti-cyclic citrullinated peptide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate:\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eConsent for publication:\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the consent is available for review by the Editor-in-Chief of this journal.\u003c/p\u003e\n\u003cp\u003eCompeting interests:\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding:\u003c/p\u003e\n\u003cp\u003eThis work received no specific funding from public, commercial, or not-for-profit agencies.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contributions:\u003c/p\u003e\n\u003cp\u003eAnas Manhal: Concept and design, data collection, manuscript writing.\u003c/p\u003e\n\u003cp\u003eJamal Abdullah: Concept and design, data collection, corresponding author.\u003c/p\u003e\n\u003cp\u003eMahmoud M Qouqas: Genetic analysis and interpretation.\u003c/p\u003e\n\u003cp\u003eAhmad Waleed: Clinical management and manuscript editing.\u003c/p\u003e\n\u003cp\u003eLayth Al-Karaja: Literature review and manuscript editing.\u003c/p\u003e\n\u003cp\u003eNoor Sawalha: Clinical input and manuscript review.\u003c/p\u003e\n\u003cp\u003eLaith Alamlih: Rheumatology expertise and manuscript review.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements:\u003c/p\u003e\n\u003cp\u003eThe authors thank the patient and her family for their valuable contribution.\u003c/p\u003e\n\u003cp\u003eData availability:\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBourgeois AB. Osteogenesis imperfecta: from diagnosis and multidisciplinary treatment to future perspectives. Swiss Med Wkly. 2016;146:w14322.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeguchi M, Tsuji S, Katsura D, et al. Current overview of osteogenesis imperfecta. Med (B Aires). 2021;57:464.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarom R, Rabenhorst BM, Morello R. Management of endocrine disease: Osteogenesis imperfecta: An update on clinical features and therapies. Eur J Endocrinol. 2020;183:R95\u0026ndash;106.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlanay Y, Avaygan H, Camacho N, et al. Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet. 2010;86:551\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKelley BP, Malfait F, Bonafe L, et al. Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome. J Bone Min Res. 2011;26:666\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGibofsky A. Epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis: A Synopsis. Am J Manag Care. 2014;20:S128\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Z, Niu X, Wang J. Naringenin as a natural immunomodulator against T cell-mediated autoimmune diseases: literature review and network-based pharmacology study. Crit Rev Food Sci Nutr. 2023;63:11026\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDamian LO, Miclea D, Vulturar R, et al. Osteogenesis imperfecta and rheumatoid arthritis: connective issues. Osteoporos Int. 2022;33:2237\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcKiernan FE. Musculoskeletal manifestations of mild osteogenesis imperfecta in the adult. Osteoporos Int. 2005;16:1698\u0026ndash;702.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eToyama S, Tokunaga D, Tsuchida S, et al. Comprehensive assessment of alterations in hand deformities over 11 years in patients with rheumatoid arthritis using cluster analysis and analysis of covariance. Arthritis Res Ther. 2021;23:1\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoraschi-Diaz I, Wang J, Mort JS, et al. Collagen type I as a ligand for receptor-mediated signaling. Front Phys. 2017;5:12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu C, Wu Y, Zhao L, et al. Transdermal hormone delivery: Strategies, application and modality selection. J Drug Deliv Sci Technol. 2023;86:104730.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBullock J, Rizvi SAA, Saleh AM, et al. Rheumatoid arthritis: a brief overview of the treatment. Med Princ Pract. 2019;27:501\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Laboratory results at presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003eTest Item\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003ePatient Value (Unit)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003eReference Range\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eElectrolytes \u0026amp; Minerals\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eTotal calcium\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e9.6 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e8.5 \u0026ndash; 10.2 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003ePhosphorus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e2.93 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e1.5 \u0026ndash; 6.8 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eMagnesium\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e1.7 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e1.7 \u0026ndash; 2.2 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSodium\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e138 mEq/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e135 \u0026ndash; 145 mEq/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003ePotassium\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e4.6 mEq/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e3.5 \u0026ndash; 5.0 mEq/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eChloride\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e106 mEq/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e98 \u0026ndash; 107 mEq/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eAlbumin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e3.97 g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e3.5 \u0026ndash; 5.0 g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eUric acid\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e2.00 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e2.4 \u0026ndash; 6.0 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eRenal \u0026amp; Liver Function\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eALT (alanine aminotransferase)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e26 U/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e7 \u0026ndash; 35 U/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eAST (aspartate aminotransferase)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e25 U/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e10 \u0026ndash; 34 U/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eBUN (blood urea nitrogen)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e14 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e7 \u0026ndash; 20 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eCreatinine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e0.6 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e0.5 \u0026ndash; 1.1 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eHematology\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eWBC (white blood cells)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e6.9 \u0026times;10⁹/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e4.0 \u0026ndash; 10.5 \u0026times;10⁹/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eHGB (hemoglobin)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e11.9 g/dL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e12.0 \u0026ndash; 15.5 g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eHCT (hematocrit)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e33.9 %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e36.0 \u0026ndash; 46.0 %\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eMCV (mean corpuscular volume)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e72.7 fL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e80 \u0026ndash; 100 fL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eFerritin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e35 ng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e12 \u0026ndash; 150 ng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eVitamin B12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e426 pg/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e200 \u0026ndash; 900 pg/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eInflammatory Markers\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eCRP (C-reactive protein)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e48 mg/L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026lt; 3.0 mg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eESR (erythrocyte sedimentation rate)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e33 mm/hr\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e0 \u0026ndash; 20 mm/hr\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eEndocrine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eThyroid stimulating hormone\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e2.42 mIU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e0.4 \u0026ndash; 4.0 mIU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eVitamin D\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e15.3 ng/mL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e20 \u0026ndash; 50 ng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eDisease-Specific\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eAnti-CCP (anti-cyclic citrullinated peptide)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e596.7 U/mL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026lt; 20 U/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp dir=\"LTR\"\u003e\u003cstrong\u003eAbnormal values are shown in bold.\u003c/strong\u003e\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003e\u003cem\u003eAbbreviations: HGB, hemoglobin; HCT, hematocrit; MCV, mean corpuscular volume; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; WBC, white blood cells; Anti-CCP, anti-cyclic citrullinated peptide antibody.\u003c/em\u003e\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003e\u003cstrong\u003eTable 2. Clinical and Genetic Features of Reported Cases of Osteogenesis Imperfecta with Coexisting Inflammatory Arthritis\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eArticle / Year\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSerology (RF/ACPA/ESR/CRP)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eGene Mutation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eDelay to Diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eMajor Deformities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eTreatment(s)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eTreatment Outcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eOur case\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e27\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eRF+, ACPA 596.7 U/mL, ESR 33, CRP 48\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eFKBP10 c.391+4A\u0026gt;T (homozygous)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e2 years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eBilateral hand deformities (ulnar deviation, swan-neck), severe kyphoscoliosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eMethotrexate, glucocorticoids, NSAIDs, vitamin D\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003ePain improved, deformity progression halted, inflammatory markers improved (10 months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eBica et al., 2013\u0026nbsp;\u003c/strong\u003e[1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e53\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eRF+, ESR 72\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eClinical OI (no genetic test)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e13 years (JIA at 15)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSevere hand/foot deformities, TMJ limitation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eAlendronate, salicylates (irregular), steroids\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eBone mass stabilized, partial pain relief, persistent TMJ stiffness, incomplete arthritis control\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eDamian et al., 2020\u0026nbsp;\u003c/strong\u003e[2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e46\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eRF 28 IU/dL, ACPA 224, ESR 43, CRP 24\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eCOL1A1 c.3399del, p.Ala1134Profs*105\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e6 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003ePeriarticular osteoporosis, tibiotarsal synovitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSulfasalazine, methotrexate, leflunomide\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003ePain and stiffness resolved, inflammation controlled, no NSAIDs/steroids used\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eDamian et al., 2020\u0026nbsp;\u003c/strong\u003e[2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e70\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eRF 32, ACPA 218, ESR 34, CRP 12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eCOL1A1 c.3399del, p.Ala1134Profs*105\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e2 years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eBone deformities, periarticular bone loss\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eMethotrexate, leflunomide\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003ePain and stiffness resolved, inflammation controlled, no NSAIDs/steroids used\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eMormile et al., 2022\u0026nbsp;\u003c/strong\u003e[3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e43\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSeropositive RA (labs N/R)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eCOL1A1 c.3399del, p.(Ala1134Profs*105)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eN/R\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eN/R\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eAdalimumab (anti-TNF)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eComplete remission\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp dir=\"LTR\"\u003e\u003cstrong\u003eAbbreviations: RF: rheumatoid factor; ACPA: anti-cyclic citrullinated peptide antibody; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; TMJ: temporomandibular joint; JIA: juvenile idiopathic arthritis; N/R: not reported.\u003c/strong\u003e\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003eReferences :\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003e1 \u0026nbsp; \u0026nbsp;\u0026nbsp;Bica BERG, Ruiz DG, de Andrade Magalh\u0026atilde;es P, \u003cem\u003eet al.\u003c/em\u003e Association between juvenile idiopathic arthritis and osteogenesis imperfecta-case report. \u003cem\u003eRev Bras Reumatol (English Ed\u003c/em\u003e 2013;\u003cstrong\u003e53\u003c/strong\u003e:535\u0026ndash;7.\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003e2 \u0026nbsp; \u0026nbsp; Damian LO, Zmarandache C-D, Vele P, \u003cem\u003eet al.\u003c/em\u003e Osteogenesis imperfecta and rheumatoid arthritis: is there a link? \u003cem\u003eArch Osteoporos\u003c/em\u003e 2020;\u003cstrong\u003e15\u003c/strong\u003e:1\u0026ndash;5.\u003c/p\u003e\n\u003cp dir=\"LTR\"\u003e3 \u0026nbsp; \u0026nbsp; Mormile I, Russo R, Andolfo I, \u003cem\u003eet al.\u003c/em\u003e Rheumatoid arthritis and osteogenesis imperfecta: is there a genetic causal association? \u003cem\u003eOsteoporos Int\u003c/em\u003e 2022;\u003cstrong\u003e33\u003c/strong\u003e:2233\u0026ndash;5.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Osteogenesis imperfecta, rheumatoid arthritis, FKBP10, rare disease, case report, bone fragility, autoimmune disease","lastPublishedDoi":"10.21203/rs.3.rs-6950688/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6950688/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOsteogenesis imperfecta (OI) is a rare genetic disorder primarily caused by mutations in genes involved in type I collagen production. We report a 27-year-old female with genetically confirmed OI type XI (OI-XI) who experienced a delayed diagnosis of seropositive rheumatoid arthritis (RA), resulting in irreversible deformities.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCase Presentation:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe patient had multiple congenital contractures and became wheelchair-dependent in early childhood. She received only one course of bone protection therapy in her lifetime. Two years prior to presentation, she developed bilateral hand pain, stiffness, and progressive deformities. The diagnosis of RA was confirmed based on clinical features, imaging, and high titers of anti-cyclic citrullinated peptide (anti-CCP) antibodies. Genetic analysis revealed a homozygous FKBP10 mutation (c.391\u0026thinsp;+\u0026thinsp;4A\u0026thinsp;\u0026gt;\u0026thinsp;T), confirming OI-XI. Treatment with methotrexate, folic acid, and vitamin D led to symptom improvement and stabilization of deformities.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis is the first reported case of RA in a patient with genetically confirmed OI-XI. The case underscores the importance of early detection and treatment of RA in individuals with OI to prevent irreversible joint damage.\u003c/p\u003e","manuscriptTitle":"Seropositive rheumatoid arthritis in osteogenesis imperfecta type XI (FKBP10 mutation): First case report and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-30 08:38:10","doi":"10.21203/rs.3.rs-6950688/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2025-07-18T16:40:47+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-06-28T21:56:03+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-24T07:39:07+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Orphanet Journal of Rare Diseases","date":"2025-06-23T15:01:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-23T13:25:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2025-06-22T12:48:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c2a39b3f-42b8-41cb-8af3-e8c3397b90b7","owner":[],"postedDate":"June 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T17:03:39+00:00","versionOfRecord":{"articleIdentity":"rs-6950688","link":"https://doi.org/10.1186/s13023-025-04071-x","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2026-01-13 16:29:14","publishedOnDateReadable":"January 13th, 2026"},"versionCreatedAt":"2025-06-30 08:38:10","video":"","vorDoi":"10.1186/s13023-025-04071-x","vorDoiUrl":"https://doi.org/10.1186/s13023-025-04071-x","workflowStages":[]},"version":"v1","identity":"rs-6950688","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6950688","identity":"rs-6950688","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}