P4HA1 mutations cause a unique congenital disorder of connective tissue involving tendon, bone, muscle and the eye.

Collagen prolyl 4-hydroxylases (C-P4Hs) play a central role in the formation and stabilization of the triple helical domain of collagens. P4HA1 encodes the catalytic α(I) subunit of the main C-P4H isoenzyme (C-P4H-I). We now report human bi-allelic P4HA1 mutations in a family with a congenital-onset disorder of connective tissue, manifesting as early-onset joint hypermobility, joint contractures, muscle weakness and bone dysplasia as well as high myopia, with evidence of clinical improvement of motor function over time in the surviving patient. Similar to P4ha1 null mice, which die prenatally, the muscle tissue from P1 and P2 was found to have reduced collagen IV immunoreactivity at the muscle basement membrane. Patients were compound heterozygous for frameshift and splice site mutations leading to reduced, but not absent, P4HA1 protein level and C-P4H activity in dermal fibroblasts compared to age-matched control samples. Differential scanning calorimetry revealed reduced thermal stability of collagen in patient-derived dermal fibroblasts versus age-matched control samples. Mutations affecting the family of C-P4Hs, and in particular C-P4H-I, should be considered in patients presenting with congenital connective tissue/myopathy overlap disorders with joint hypermobility, contractures, mild skeletal dysplasia and high myopia.

'Double trouble': diagnostic challenges in Duchenne muscular dystrophy in patients with an additional hereditary skeletal dysplasia.

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.