‘Double trouble’: Diagnostic challenges in Duchenne muscular dystrophy in patients with an additional hereditary skeletal dysplasia

Abstract

Duchenne muscular dystrophy (DMD) is caused by mutations in Dystrophin and affects 1 in 3600–6000 males. It is characterized by progressive weakness leading to loss of ambulation, respiratory insufficiency, cardiomyopathy, and scoliosis. We describe the unusual phenotype of 3 patients with skeletal dysplasias in whom an additional diagnosis of DMD was later established. Two unrelated boys presented with osteogenesis imperfecta due to point mutations in COL1A1 and were both subsequently found to have a 1 bp frameshift deletion in the Dystrophin gene at age 3 and age 15 years, respectively. The third patient had a diagnosis of pseudoachondroplasia caused by a mutation in the COMP gene and was found to have a deletion of exons 48–50 in Dystrophin at age 9. We discuss the atypical presentation caused by the concomitant presence of 2 conditions affecting the musculoskeletal system, emphasizing aspects that may confound the presentation of a well-characterized disease like DMD. Additional series of patients with DMD and a secondary inherited condition are necessary to establish the natural history in this “double trouble” population. The recognition and accurate diagnosis of patients with two independent genetic disease processes is essential for management, prognosis, genetic risk assessment, and discussion regarding potential therapeutic interventions.

Introduction

Duchenne muscular dystrophy (DMD) (OMIM#310200) is an X-linked disorder, caused by mutations in the Dystrophin gene, and affects 1 in 3600–6000 live male births [1], [2]. DMD was first described in the early 19th century, and the causative gene was only identified in 1987 [3], [4]. It is characterized by progressive muscle weakness leading to loss of ambulation, respiratory insufficiency, cardiomyopathy, and scoliosis. Boys typically present at age 3–5 years with evidence of proximal muscle weakness and calf hypertrophy. Diagnosis is made on the clinical presentation, elevated serum creatine kinase (CK) levels, and confirmatory genetic testing of the Dystrophin gene. In a small number of patients with intronic splice spite mutations interfering with normal splicing, confirmatory muscle biopsy staining or cDNA studies may be necessary. Immunohistochemistry on muscle biopsy tissue shows an absence of dystrophin, a large membrane-associated protein essential for muscle cell stabilization [5]. Frameshifting or terminating deletions and mutations are typically associated with the severe Duchenne phenotype, while frame-preserving deletions are typically associated with the milder Becker muscular dystrophy phenotype.

The clinical presentation of a well characterized disorder such as DMD may be masked and initially overlooked by the presence of another disorder of the musculoskeletal system. We present three patients with the rare combination of a hereditary skeletal dysplasia whose DMD diagnosis was delayed, illustrating the diagnostic challenges of their confounding phenotype.