Facioscapulohumeral Muscular Dystrophy

Excerpt

Clinical characteristics: Facioscapulohumeral muscular dystrophy (FSHD) typically presents with weakness of the facial muscles, the stabilizers of the scapula, and/or the dorsiflexors of the foot. Severity is highly variable. Weakness can be slowly progressive and approximately 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened.

Diagnosis/testing: The diagnosis of FSHD1 is established in a proband with characteristic clinical features and a heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype. The diagnosis of FSHD2 is established in a proband with characteristic clinical features and hypomethylation of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype. Hypomethylation of the D4Z4 repeat array can be the result of a heterozygous pathogenic variant in SMCHD1 or DNMT3B, or biallelic pathogenic variants in LRIF1.

Management: Treatment of manifestations: Consultation with a physical therapist to establish appropriate exercise regimen; ankle-foot orthoses to improve mobility and prevent falls; occupational and speech therapy in individuals with infantile onset; surgical fixation of the scapula to the chest wall may improve range of motion of the arms; management of chronic pain by physical therapy and medication; ventilatory support as needed; ocular lubricants or taping the eyes shut during sleep to treat exposure keratitis; treatment for retinal vasculopathy per ophthalmologist; standard treatment of sensorineural hearing loss.

Surveillance: Physical therapy assessment annually or more frequently as needed; pain should be assessed at regular visits to the primary care physician or physical therapist; occupational and speech therapy assessment as needed throughout childhood in those with infantile onset; screening for hypoventilation in individuals with abnormal pulmonary function tests, severe proximal weakness, kyphoscoliosis, wheelchair dependence, or comorbid disease affecting ventilation; pulmonary consultation for forced vital capacity <60%, excessive daytime somnolence, or nonrestorative sleep, and prior to surgical procedures requiring anesthesia; annual dilated ophthalmoscopy in individuals with early childhood-onset FSHD with large pathogenic contraction of D4Z4 and adults with visual symptoms; audiometry in infants at each visit and annually in children.

Genetic counseling: FSHD1: FSHD1 is inherited in an autosomal dominant manner. Approximately 70%-90% of individuals diagnosed with FSHD1 have a parent with clinical findings of FSHD and one D4Z4 repeat array with a pathogenic contraction; ~10%-30% of probands have the disorder as the result of a de novo constitutional or mosaic pathogenic contraction of the D4Z4 repeat array. Each offspring of a proband with FSHD1 has a 50% chance of inheriting the pathogenic D4Z4 repeat array contraction. Once a diagnosis of FSHD1 has been established in an affected family member, predictive testing for at-risk relatives and prenatal testing are possible. Preimplantation genetic testing (PGT) may be possible but verification of PGT results using prenatal testing is typically recommended.

FSHD2: FSHD2 is associated with complex inheritance. If the proband has a heterozygous pathogenic variant in SMCHD1 or DNMT3B and a permissive chromosome 4 haplotype and the proband's reproductive partner does not have FSHD2-related genetic alteration(s), each child of the proband has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations. If the proband has homozygous nonsense variants in LRIF1 and a permissive chromosome 4 haplotype and the proband's reproductive partner does not have FSHD2-related genetic alteration(s), each child of the proband will be an obligate heterozygote for an LRIF1 pathogenic variant; each child has an additional 50% chance of inheriting a permissive chromosome 4 haplotype. Offspring who inherit a heterozygous LRIF1 pathogenic variant and a permissive chromosome 4 haplotype are not expected to be affected with FSHD2. If the proband has hypomethylation of the D4Z4 repeat array of unknown cause, offspring are presumed to be at risk of inheriting FSHD2-related genetic alterations and being affected with FSHD2. Once a diagnosis of FSHD2 has been established in an affected family member, predictive testing for at-risk relatives is possible. Prenatal testing and PGT for FSHD2 are not available to date.