Suspected association of a novel MECOM variant with congenital radioulnar synostosis: a case report

Introduction

Congenital radioulnar synostosis (CRUS) is a rare forearm deformity caused by embryonic bone differentiation disorder (1), which was first described by Sandifort in 1793 (2). It commonly occurs in early childhood and is characterized by limited forearm rotation (3). Its pathogenesis has not been fully elucidated. CRUS may be associated with several other syndromes, such as Poland syndrome, Holt-Oram syndrome, Cornelia de Lange syndrome, tetrasomy X, and Cenani Lenz syndactyly (4). Furthermore, fetal alcohol exposure may also contribute to this condition (5). The diagnosis can be confirmed based on clinical manifestations combined with X-ray examination. In recent years, studies using whole-exome sequencing (WES) have gradually revealed the pathogenesis of CRUS. We reported a case of bilateral CRUS with a novel gene mutation site and summarized its embryonic genetic, diagnostic, and therapeutic characteristics. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-682/rc).

Case presentation

A 5-year-old boy was admitted to our hospital due to restricted rotation of both forearms, a symptom that had been noticed for 1 year. His bilateral elbow, wrist, and shoulder joints demonstrated normal mobility, while the motor function and sensation of his fingers remained intact. X-ray imaging revealed osseous fusion at the proximal segments of the bilateral ulnae and radii, accompanied by the absence of the radial heads. Additionally, the bilateral elbow joints exhibited abnormal morphology, with deformation of the ulnar olecranon. The joint spaces were widened, and the soft tissues within the joint cavities were thickened. These findings were consistent with a diagnosis of congenital bilateral radioulnar synostosis (Figure 1). The genetic mechanism underlying radioulnar synostosis is complex; therefore, genetic testing was performed on the patient and his family members. WES analysis identified a novel mutation in the MECOM gene (chr3:169098992 G>A, c.358C>T: p.P120S), which was inherited from his parents. His father had unilateral CRUS, while his mother was asymptomatic but carried the same gene mutation. The patient’s paternal grandmother did not carry the aforementioned gene mutation (Figures 2,3).

Figure 1 Anteroposterior and lateral radiographs of both forearms, demonstrating bilateral proximal congenital radioulnar synostoses.

Figure 2 First-generation sequencing.

Figure 3 Next-generation sequencing.

Complete preoperative hematological examinations were performed, and the complete blood count as well as platelet count were both within the normal reference range. Following a comprehensive assessment of the patient’s condition, the surgical plan was determined as follows: right ulnar-radial rotational osteotomy with internal fixation, and left radial rotational osteotomy with external plaster fixation. For the right side: under fluoroscopic guidance, the fusion site of the right ulna and radius was localized. A 3-cm incision was made, and the skin, subcutaneous tissue, and muscles were incised sequentially to fully expose the proximal ulna. A power drill was used to create transverse holes, and an osteotome was employed to completely osteotomize the fused ulna and radius. The forearm was rotated and fixed in the neutral position using three 2.0-mm Kirschner wires. The surgical site was irrigated to achieve hemostasis, and the incision was sutured. For the left side: A 2-cm incision was made at the middle-distal 1/3 of the left radius. The skin, subcutaneous tissue, and muscles were incised sequentially to fully expose the distal radius. A power drill was used to create transverse holes, and an osteotome was employed to completely osteotomize the radius. The forearm was supinated and fixed in the neutral position. The surgical site was irrigated to achieve hemostasis, and the incision was sutured. Both forearms were immobilized with plaster in the supinated position, and the operation was completed successfully. Nursing management is critical to surgical safety and patient prognosis, while targeted nursing measures and accurate counting of surgical supplies provide support for safe surgery. Regular postoperative follow-up was conducted, and the patient achieved favorable recovery 5 months after surgery (Figure 4).

Figure 4 Anteroposterior and lateral radiographs of both forearms at 5 months postoperatively.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient’s parent for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Embryology and genetics

CRUS is a rare congenital disorder caused by the failure of normal separation at the site of bone fusion. During the 6th week of embryogenesis, the differentiation of cartilage around the elbow joint enables the separation of the humerus, ulna, and radius. However, the failure of separation of the fused cartilaginous precursors of the radius and ulna can lead to permanent proximal radioulnar tissue bridging at the 7th week of embryogenesis, which eventually results in an osseous or cartilaginous union (6). CRUS may be associated with several other syndromes, such as Poland syndrome, Holt-Oram syndrome, Cornelia de Lange syndrome, tetrasomy X, and Cenani Lenz syndactyly (4). It is often sporadic and isolated without associated lesions (7). However, it also has a familial, autosomal dominant pattern of inheritance (8). As early as 1985, Cleary and Omer (9) reported an autosomal dominant inheritance pattern for this disease, showing a variable penetrance of 20%. Subsequently, a study focused on non-syndromic CRUS, which demonstrated no definite inheritance pattern (10). However, with the continuous advancements and discoveries enabled by WES technology, it is believed that we will gain a more comprehensive understanding of the genetic characteristics and pathogenesis of CRUS. Yang et al. (10) described frequent mutations in the SMAD Family Member 6 (SMAD6) protein and associated non-syndromic CRUS with chromosome 15q22.31. SMAD6 can inhibit the bone morphogenetic protein (BMP) signaling pathway. Loss-of-function mutations in the SMAD6 gene suggest that the unrestrained BMP signaling pathway may contribute to the development of CRUS. Suzuki et al. (11) performed WES on one CRUS patient and confirmed the presence of a de novo missense mutation in the zinc finger matrin-type protein 2 (ZMAT2) gene. The ZMAT2 gene can affect the normal forelimb development of animal embryos by influencing the BMP signaling pathway. Al-Abboh et al. (12) reported a c.2282A>G mutation in the MECOM gene in the case of a single patient, with CRUS complicated with congenital amegakaryocytic thrombocytopenia. Our patient harbors a previously unreported variant in the MECOM gene. This c.C358T missense variant results in the proline to serine substitution at codon 120 (p.P120S). This mutant allele was inherited from his parents, while his paternal grandmother was unaffected. His father had unilateral CRUS, while his mother was asymptomatic but carried the same gene mutation. Whether the patient’s bilateral onset of the disease is associated with both of his parents carrying the mutant gene requires further investigation.

Diagnosis and classification

Patients with CRUS, who typically present with functional impairment in early childhood due to restricted forearm rotation and fixed forearm position (9,13), usually receive their first diagnosis between the ages of 2 and 5 years (14). They are often accompanied by compensatory movements and excessive activity in the wrists and shoulders, which may render these joints more susceptible to overuse injuries (15). In some cases, compensatory activities of adjacent joints in patients with unilateral non-syndromic CRUS—where the forearm is fixed in a neutral or slightly pronated position—may mask the symptoms, potentially leading to misdiagnosis or missed diagnosis. Diagnosis and classification primarily rely on plain radiography. Some patients may also exhibit associated features such as increased curvature of the radial shaft, hypoplastic radial head, dislocated radial head, mushroom-shaped radial head, and dorsal subluxation of the ulna at the wrist (13,14,16-18). Based on the presence or absence of osseous fusion at the synostosis site and the position of the radial head, the currently used Cleary-Omer classification system (9) categorizes CRUS into the following types: (I) Type I: no osseous union at the fusion site; cartilaginous union may be present, with a normal radial head; (II) Type II: osseous union present at the fusion site, with a normal radial head; (III) Type III: osseous union present at the fusion site, with a hypoplastic radial head and posterior dislocation; (IV) Type IV: osseous union present at the fusion site, with a “mushroom-shaped” radial head and anterior dislocation. However, the most commonly used classification system at present offers no assistance in treatment decision-making (14).

Treatment

With the increasing number of publications on case reports and pedigree case studies related to this disease, the diagnostic and therapeutic experience has gradually accumulated. For patients who have either unilateral involvement, more neutral to slight pronated positioning, or minimal functional limitation, the most common treatment is observation (9). Simmons et al. proposed that patients whose forearms are fixed at more than 60° of pronation require surgical treatment (19). Multiple surgical protocols have been documented in the literature, primarily categorized into two types: separated fusion area reconstruction and derotational osteotomy. In the early stages, the reconstruction of rotational function via the separated fusion area was not widely accepted, as it failed to prevent recurrent fusion postoperatively (20). Later, Kanaya et al. (21) incorporated additional procedures, including proximal radial osteotomy for radial head reduction, reconstruction of the soft tissues around the proximal radioulnar joint, and free transplantation of composite soft tissues from the upper arm to fill the separated fusion area. This approach—known as the Kanaya procedure—significantly improved forearm rotational function in patients with CRUS, except for those with Cleary-Omer Type III. Sakamoto et al. (22) modified the Kanaya procedure by changing the radial osteotomy site to the middle segment of the radius. For patients with Cleary-Omer Type III CRUS, this modified technique achieved significant improvement in postoperative forearm rotation, with the rotation range reaching 80° in all cases. Long-term follow-up results further demonstrated favorable outcomes. Tsumura et al. (23) customized radial osteotomy guides via three-dimensional (3D) reconstruction using computed tomography (CT) for patients with Cleary-Omer Type III CRUS. For patients with persistent forearm supination limitation after osteotomy, additional ulnar rotational osteotomy and biceps tendon transposition were performed, and the separated fusion area was filled with the posterior interosseous artery perforator fascial flap. Postoperatively, the patients achieved a forearm supination of up to 60°, but this approach was prone to causing habitual radial head dislocation.

Rotational osteotomy is the most commonly used surgical method (24). Such surgeries correct rotational deformities through forearm osteotomy and fix the forearm in a functional position using various methods—including plaster casts, Kirschner wires, intramedullary nails, and plates—to improve forearm function. Shingade et al. (25) performed ulnar osteotomy 1 cm away from the fusion area and radial osteotomy at the metaphyseal-diaphyseal junction of the distal radius in 36 CRUS patients with an average pronation of 56.3°. The forearms were immobilized with long-arm plaster splints in a 20–30° supination range for 5–9 weeks, and the desired functional position was basically achieved during postoperative follow-up. Satake et al. (26) only performed radial osteotomy at the insertion of the pronator teres muscle to correct forearm pronation deformity. The palm was then supinated to 90° through wrist joint compensation, followed by immobilization with a plaster cast. Long-term follow-up results showed that the average fixed angle of the forearm improved from 51.3° preoperatively to 4° postoperatively, with no neurovascular complications. Currently, the optimal fixation angle of the forearm after rotational osteotomy for CRUS patients remains a subject of debate. Early scholars (27) suggested that after rotational osteotomy for bilateral CRUS, the forearm of the dominant hand should be fixed in a 30–45° pronation position, while that of the non-dominant hand should be fixed in a 20–35° supination position. Later, Pei et al. (28) proposed that for bilateral CRUS, both forearms should be fixed in a 0–20° supination position, which should meet the needs of daily activities. For CRUS patients with severe forearm rotational deformity, the application of the Ilizarov technique for gradual correction enables progressive realignment while effectively avoiding acute neurovascular injury caused by excessive traction (29), allowing patients to select the position that best meets their daily activity needs (14). In patients with Cleary-Omer Type IV CRUS, the radial head may lose the constraint of the capitellum of the humerus due to long-term anterior dislocation, leading to abnormal growth. This ultimately results in late-onset radiocapitellar joint locking and limited elbow flexion; thus, radial head resection or replacement is unavoidable to improve the above-mentioned functions (30,31).

Conclusions

This study reports a novel variant site of the MECOM gene in a child with bilateral CRUS, which was inherited from his parents. This variant is putatively associated with bilateral CRUS, yet the definitive correlation awaits further verification via functional experiments and expanded cohort studies. This study contributes a novel variant to the known mutational spectrum of the MECOM gene. It provides a potential candidate variant for the genetic profile of the disease and offers new insights for the etiological analysis of bilateral CRUS. Meanwhile, by integrating recent literature, this study reviews the genetic mechanisms and diagnostic/therapeutic guidelines of CRUS, clarifying the core role of WES technology in revealing the genetic etiology of CRUS. It also confirms that the genetic mechanism of this disease involves multi-locus gene variations, and that its diagnosis and treatment should be based on the Cleary-Omer classification, with individualized treatment plans selected according to the degree of deformity and functional needs.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-682/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-682/prf

Funding: This study was supported by the Youth Science Foundation of Shandong First Medical University (No. 202201-066), the China Postdoctoral Science Foundation (No. 2023M741507), the Shandong Provincial Natural Science Foundation (Nos. ZR2020QH263, ZR2020QH078, ZR2022MH095, and ZR2024QH004), and Shandong Province Natural Science Foundation (No. ZR2020QH078).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-682/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient’s parent for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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