IllnessMuscular dystrophy, facio-scapulo-humeral 2; differential diagnosis FSHD

NGS +

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by muscle weakness and wasting, with symptoms usually occurring in adolescence and beginning with weakened facial muscles or shoulders. Muscle weakness slowly worsens over decades and can spread to other parts of the body (including foot dropping). In addition, affected individuals may develop lordosis, with ~20% eventually relying on a wheelchair. Other symptoms may include mild high-frequency hearing loss and increased (retinal-related) sensitivity to light. In rare cases, FSHD also affects the cardiac or respiratory muscles. Two types of FSHD show the same symptoms but differ in their genetic cause, which in both cases affects the D4Z4 region on chromosome 4q. This region normally consists of 11 - >100 repeating DNA segments, each 3.3 kb long. The entire D4Z4 region is normally hypermethylated, but hypomethylated in FSHD. In FSHD1, hypomethylation is due to contraction between 1-10 segment repeats. In FSHD2, hypomethylation usually results from mutations in the SMCHD1 gene, which normally causes hypermethylation of the D4Z4 region; rarely and alternatively, the DNMT3B gene is mutated. FSHD1 is inherited in an autosomal dominant manner. Mutations in the SMCHD1 gene that otherwise cause FSHD2 may also increase the severity of FSHD1. FSHD2 is inherited in a digenic pattern with mutations in the SMCHD1 or DNMT3B genes, in both cases additionally with an "FSHD-permissive DUX4 allele" (determined molecularly by restriction enzyme-digested DNA differentially hybridized with two specific probes). Since the DNA diagnostic yield for FSHD2 is only somewhat above 80%, a negative molecular genetic result may not exclude the clinical diagnosis in all cases.

Reference: https://www.ncbi.nlm.nih.gov/books/NBK1443

• Alias FSHD2
• Alias: Facioscapulohumeral dystrophy - FSHD
• Alias: Facioscapulohumeral muscular dystrophy 2
• Alias: Facioscapulohumeral myopathy
• Alias: Landouzy-Dejerine muscular dystrophy
• Alias: Landouzy-Dejerine myopathy
• Allelic: Bosma arhinia microphthalmia syndrome (SMCHD1)
• Allelic: Cardiomyopathy, dilated, 1G (TTN)
• Allelic: Cardiomyopathy, familial hypertrophic, 9 (TTN)
• Allelic: Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (DNMT3B)
• Allelic: Salih myopathy (TTN)
• Allelic: Tibial muscular dystrophy, tardive (TTN)
• Facioscapulohumeral muscular dystrophy 4, digenic (DNMT3B)
• Fascioscapulohumeral muscular dystrophy 2, digenic (SMCHD1)
• Glycogen storage disease II (GAA)
• Muscular dystrophy, limb-girdle, AR 10 (TTN)
• Myopathy, myofibrillar, 9, with early respiratory failure (TTN)
• Myotonic dystrophy 1 (DMPK)
• Myotonic dystrophy 2 (CNBP)
• Nonaka myopathy (GNE)
• Sialuria (GNE)