Genetic Diseases Mimicking Rheumatic Disorders: Insights From Southeastern Turkey.

Abstract

A subset of genetic conditions, particularly skeletal dysplasias, comprises a heterogeneous group of inherited disorders characterized by abnormal bone development, joint stiffness, and short stature. Their musculoskeletal manifestations frequently mimic those of rheumatic diseases, especially Juvenile Idiopathic Arthritis (JIA), complicating accurate diagnosis. We conducted a comprehensive clinical, radiological, and molecular evaluation of 47 individuals (23 males, 24 females) from 22 distinct families who presented primarily with non-inflammatory musculoskeletal complaints. Genomic investigations included targeted next-generation sequencing panels, chromosomal microarray analysis, and multiplex ligation-dependent probe amplification. Pathogenic or likely pathogenic variants were identified in all cases, establishing the following diagnoses: Hereditary Multiple Exostoses (n = 9), Camptodactyly-Arthropathy-Coxa Vara-Pericarditis syndrome (n = 12), Progressive Pseudorheumatoid Dysplasia (n = 7), Trichorhinophalangeal Syndrome types I/II (n = 5), Spondyloenchondrodysplasia with Immune Dysregulation (n = 6), Pseudoachondroplasia (n = 3), Primary Hypertrophic Osteoarthropathy type 1 (n = 1), Ehlers-Danlos Syndrome (n = 2), Multicentric Osteolysis-Nodulosis-Arthropathy (n = 1), and Mucopolysaccharidosis type VI (n = 1). Certain genetic disorders may present with musculoskeletal manifestations that closely resemble those of rheumatic diseases. Therefore, a comprehensive evaluation for underlying genetic causes is essential in patients with non-inflammatory skeletal findings, as it improves diagnostic precision and guides appropriate management strategies. This study aims to investigate the clinical and molecular features of patients with non-inflammatory musculoskeletal involvement, with a particular focus on the phenotypic overlap between genetic disorders and rheumatic diseases. Furthermore, seven novel variants were identified, expanding the mutational spectrum associated with these rare conditions and contributing new insights to the existing literature.