Case reportBecker’s muscular dystrophy aggravating facioscapulohumeral muscular dystrophy – double trouble as an explanation for an atypical phenotype
Introduction
With increasing knowledge of gene defects in neuromuscular disorders, the phenotypic spectrum has broadened considerably. If a patient has an atypical phenotype but displays a distinct gene defect, one is tempted to attribute the clinical picture to the variable phenotype caused by this genetic entity. This applies in particular to facioscapulohumeral muscular dystrophy (FSHD) which is well-known for its atypical presentations [1], [2].
We report a 12-year-old patient with proximal and facial weakness along with very high creatine kinase (CK) activity which prompted us to search for more than one disease mechanism. Finally, the diagnosis of FSHD and Becker’s muscular dystrophy (BMD) was established. Our patient is an illustrative example of a rare combination of two independently inherited myopathies and emphasizes the diagnostic challenges in atypical phenotypes.
Section snippets
Case report
The boy was the only son of healthy parents, his family history was negative regarding neuromuscular disorders. The patient was under pediatric supervision from age 3 because of muscular hypotonia and delayed language development. He sat at 8 months, walked alone at 17 months and started to speak single words at 3–4 years. The patient received regular physiotherapy until 10–12 years, when the therapist noted increasing muscle weakness and atrophy. Psychological testing (HAWIK III) revealed a
Discussion
Our patient illustrates the diagnostic challenges in the muscular dystrophies. Molecular genetic analysis has become the most important diagnostic tool for FSHD and DMD/BMD and replaces invasive methods in the majority of cases. The diagnostic algorithm for BMD started with multiplex deletion screening in the dystrophin gene, now increasingly replaced by MLPA for deletion and duplication detection, was completed by a muscle biopsy and finally by sequencing of the dystrophin gene. FSHD diagnosis
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Facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy: "double trouble" overlapping syndrome?
2015, Journal of the Neurological SciencesThe FSHD2 gene SMCHD1 Is a modifier of disease severity in families affected by FSHD1
2013, American Journal of Human GeneticsCitation Excerpt :In this context, the identification of three unrelated individuals with unusually severe clinical phenotypes associated with a borderline FSHD1 allele, and the presence of marked intrafamilial variability of disease severity in some familial carriers of the FSHD1 allele prompted us to consider the possibility that additional genetic defects may segregate in these families acting as disease modifiers. “Double trouble” in FSHD has been reported previously in isolated cases.46–48 In these cases, however, it was the result of concomitant mutations in other dystrophy genes and resulted in atypical FSHD phenotypes, suggesting synergistic effects of the two genetic lesions, rather than a genetic modifier acting on the D4Z4 locus itself.
Rippling muscle disease and facioscapulohumeral dystrophy-like phenotype in a patient carrying a heterozygous CAV3 T78M mutation and a D4Z4 partial deletion: Further evidence for "double trouble" overlapping syndromes
2012, Neuromuscular DisordersCitation Excerpt :This is particularly true for FSHD, in which various clinical features have been found in subjects carrying FSHD-sized D4Z4 alleles, including a facial-sparing form of FSHD (SHD) [42], limb-girdle muscular dystrophy [43], distal myopathy [44], asymmetric brachial weakness [43], chronic progressive external ophthalmoplegia [45], asymptomatic hyperCKemia [46], hypertrophic cardiomyopathy [47], adult-onset distal myopathies with rimmed vacuoles [48], isolated axial myopathy with camptocormia and bent spine syndrome [49,50]. In addition, overlapping FSHD phenotypes in which 4q35 deleted D4Z4 mutation is associated with other pathogenic mutations in other genes, have been reported in cases of patients with mitochondrial myopathy/FSHD [51], Becker dystrophy/FSHD [52], Duchenne dystrophy/FSHD [53,54], Leber’s hereditary optic neuropathy/FSHD [55], suggesting a synergistic effect of those simultaneous mutations in reaching disease threshold and determining overlapping phenotypes. In conclusion, our case may represent a further example of such atypical phenotypes in which D4Z4 deletion contributes to pathogenicity of heterozygous CAV3 T78M mutation for the observed myopathic phenotype, resulting in an overlapping syndrome.
Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy
2012, American Journal of Human GeneticsCitation Excerpt :In some rare cases, that could be by becoming homozygous20 and doubling the dose of a dominant factor such as DUX4. In others, it might be by the simultaneous heterozygosity for a different and recessive myopathy, as suggested by many reports in which the FSHD contractions are found in association with a second molecular defect.31–44 This possibility is also consistent with previous reports of expression changes of candidate proteins such as CRYM that were associated with FSHD in some families but that were unchanged when other families were examined.
Step-by-Step Double-Trouble OBAIRH and DMD Diagnosis in a One-Year-Old Boy
2023, International Journal of Molecular Sciences