Recognizing multiple epiphyseal dysplasia in children presenting with joint pain: a commonly overlooked skeletal dysplasia.

Unlabelled: Multiple epiphyseal dysplasias are relatively common skeletal disorders, and diagnosing children can often be challenging due to various presenting complaints, including joint pain, short stature, waddling gait, joint deformities, and myopathy findings. Patients may experience early-onset osteoarthritis, and in some cases, joint replacement therapy may be required. Radiographs are characterized by flat, small, and irregularly shaped epiphyses, especially in the hips and knees. Multiple epiphyseal dysplasias are caused by variants in the genes encoding important cartilage extracellular matrix proteins, enzymes, and transporter proteins, including COMP, MATN3, COL9A1, COL9A2, COL9A3, CANT1, and SLC26A2. We aimed to investigate the clinical, radiographic, and molecular findings, along with the natural course of the disease, in a group of patients with multiple epiphyseal dysplasia. The children with a clinical diagnosis of multiple epiphyseal dysplasia and their affected parents registered at our center over a period of 20 years were evaluated. The clinical and radiographic findings were reviewed. The genetic test was performed whenever possible, with the aid of Sanger sequencing or exome sequencing as appropriate. A total of 27 patients (21 children and six affected parents) from 14 unrelated families were clinically diagnosed with multiple epiphyseal dysplasia. The genetic etiology could be revealed in 25 patients (n = 25/27, 92.5%) from 12 unrelated families. Of the 25 patients, 16 (64%) were male and nine (36%) were female. The age at genetic diagnosis ranged from 4 to 50 years, with a median age of 10 years. Nine patients (9/25, 36%) had short stature, 17 (17/25, 68%) experienced joint pain, and seven (7/25, 28%) required orthopedic surgery. The most frequent complaints leading to referral were joint pain and difficulty walking. Genetic tests revealed a total of 12 variants in 12 families, among which three were novel: COMP (13/25 patients, 52%; 7/12 families, 58.3%), MATN3 (5/25 patients, 20%; 2/12 families, 16.6%), SLC26A2 (5/25 patients, 20%; 2/12 families, 16.6%), and COL9A2 (2/25 patients, 8%; 1/12 families 8.3%). Of the patients who underwent orthopedic surgery (n = 7), five had COMP variants. Patients with COMP variants exhibited a more severe phenotype, consistent with the literature.

Conclusion: Multiple epiphyseal dysplasias represent a genetically heterogeneous group of disorders that may present clinical and diagnostic challenges. This condition should be considered when evaluating patients who experience joint pain and have radiographic findings suggestive of Perthes disease. A comprehensive skeletal survey and genetic tests are essential for the accurate diagnosis and management of this condition.

What Is Known: • MED represents one of the most prevalent categories of skeletal dysplasias, presenting clinically with progressive joint pain, skeletal deformities, gait disturbances, or features suggestive of an underlying myopathy.

What Is New: • In this study, we present 25 patients with MED, identify three novel variants, establish significant correlations between genotype and phenotype, and demonstrate how genetic analysis facilitates the differentiation of MED subtypes, thereby offering clearer insights into the genetic foundations and clinical implications of this condition.