‘Double trouble’: Diagnostic challenges in Duchenne muscular dystrophy in patients with an additional hereditary skeletal dysplasia.
Three unrelated young boys presented with skeletal dysplasia, in whom an additional diagnosis of Duchenne muscular dystrophy (DMD) was later established.
- Two of the boys had Osteogenesis Imperfecta (OI) caused by COL1A1 mutations and were later found to have mutations in the dystrophin gene (at 3 and 15 years respectively).
- The third boy had pseudoachondroplasia caused by a COMP mutation and also found to have a dystrophin mutation at age 9.
The authors conclude that:-
“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.”
But, what are chances of having two rare diseases like this?
DMD affects 1 in 4000-6000 live births; PSACH and OI both have a prevalence of ~1 in 15,000-20,000.
A back of an envelope calculation suggests a chance of 1 in 100 million for two de novo mutations !
Never-the-less, these ultra rare ‘digenic events’ do happen and will influence disease presentation and severity.
Note that in all three cases (not unsurprisingly) the skeletal manifestations preceded that of the myopathy.
Finally, the authors also comment that skeletal anomalies ‘mask’ the presentation of muscle weakness and thereby delaying a diagnosis. We would agree with this and also add that muscle weakness in pseudoachondroplasia and multiple epiphyseal dysplasia is often ‘passed off’ as of no consequence, whereas it has a pathological cause and represents a true co-morbidity.