Duchenne muscular dystrophy is characterized by progressive weakness and muscle atrophy. It is caused by mutations in the DMD gene on chromosome Xp21 and over 2000 mutations have been found.
Frontometaphyseal dysplasia1 (FMD1) is a genetic disorder caused by a mutation FLNA gene on chromosome Xq28 and characterized by various abnormalities in skeletal development. FMD1 has been reported in only a few dozen patients worldwide to date. Here, we describe a rare case who has two different X-linked genetic disorders (Duchenne muscular dystrophy and FMD1) coincidently.
Case)
A 7-year-old boy presented with progressive proximal muscle weakness and multiple joints contracture of upper and lower limbs joints. His family history was non-specific. On examination, he had facial dysmorphism with hypodontia, prominent supra-orbital ridge, broad and depressed nasal ridge, and micrognathia. He showed mild waddling gait and manual muscle test showed grade 4/5 and prominent proximal weakness. In whole spine x-ray, scoliosis (cobb’s angle 25º) was revealed. In laboratory study, CPK was increased to about 10,000 U/L. The MLPA study of DMD revealed two non-contiguous duplications of exon 2-36 and exon 77 which was a novel. The carrier test for his mother was negative. Based on the clinical characteristics and a novel de-novo variant of DMD, the proband was diagnosed with Duchenne muscular dystrophy.
Considering that the novel, two non-contiguous mutations of DMD can cause various features other than typical muscular dystrophy, the own distinctive features of the patient, such as multiple joint contractures or facial dysmorphism, was considered or ignored to be a kind of phenotypes of the specific gene mutation. However, by accident (or three years later), his cousin who resembled in appearance with the patient visited rehabilitation clinic with multiple contractures and back pain, and the cousin eventually diagnosed as FMD1 by FLNA mutation.
In the meantime, the joint contractures and scoliosis were deteriorated (Cobb’s angle 25º to 51º), and he had been wheelchair-bound condition due to progressive weakening of muscle strength. On examination, he showed facial dysmorphism and short stature (125 centimeters, <0.1 percentile).
He underwent targeted sequencing study, and a hemizygous missense variant (c.3775C>T) in FLNA, which is the same mutation as his cousin, was detected. Gene analysis of his mother revealed the same mutation (Figure 1). Finally, he was diagnosed with FMD1 caused by FLNA missense mutation (c.3775C>T) inherited from the asymptomatic maternal carrier, coincident with de novo two non-contiguous duplications of DMD which resulted in Duchenne muscular dystrophy.
Discussion)
Rarely, two or more unusual genetic disorders may occur simultaneously. Therefore, when a patient's symptoms are not completely explained by single genetic disorder, further efforts should be made to find out if there are any other accompanying disorders.
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