Clinical features of facioscapulohumeral muscular dystrophy 1 in childhood

Abstract

Aim To explore the clinical course of patients presenting with facioscapulohumeral dystrophy type 1 (FSHD1) in childhood, with a view to identifying areas where they differed from older patients and where extra support or monitoring might be required. Method A retrospective case‐notes review of children with FSHD1 seen at a tertiary paediatric neuromuscular centre between 2002 and 2016 was performed. Data collected included age at and nature of presentation, path to diagnosis, genetic testing results, motor function, and occurrence of extramuscular features and complications. Results Eighteen children (11 females, seven males; mean [SD] age at latest review 13y 10mo [3y 9mo], range 8–19y) from 16 families were identified. Age at onset of FSHD1 correlated with the size of deletion (r=0.81) and most presentations were in children either younger than 5 years or older than 10 years. Children with onset before 5 years were more likely to present with non‐muscular symptoms and to develop extramuscular pathology, including developmental and psychiatric issues, hearing or visual impairments, and problems involving respiratory function and nutrition. No cases of epilepsy or cardiac arrhythmia were identified but two children died. Interpretation The complexity and severity of FSHD1 presenting in early childhood underlines the importance of a multidisciplinary approach to the disorder. What this paper adds Young children often present with non‐muscular pathology in facioscapulohumeral dystrophy type 1 (FSHD1), especially hearing loss. Age at onset in paediatric FSHD1 appears bimodal: under 5 years or in adolescence. Prolonged delays to diagnosis are common. Children with very early‐onset FSHD1 may require nutritional and/or respiratory support. Developmental and psychiatric comorbidities are common.

Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice

“…In addition to temporal and histological relevance, the longterm iDUX4pA-HSA model shows impaired contractile function, using both in vitro and in vivo assays. As a consequence of this muscle weakness, the iDUX4pA-HSA mice develop kyphosis, a common feature of the most severe cases of FSHD, particularly in cases with respiratory issues (32,33). Furthermore, the decline in function is mechanistically distinct from that seen in muscle disease due to mutation in dystrophin-associated glycoprotein complex proteins, as observed by eccentric contraction-coupled force loss.…”

Early-Onset Infantile Facioscapulohumeral Muscular Dystrophy: A Timely Review

“…In general, there are two significant risk factors associated with disease severity of FSHD: (1) D4Z4 repeat size, as smaller D4Z4 repeat size is probably associated with a more rapid progression of disease course, and (2) age at onset, as the younger age at onset appears to be associated with a premature loss of ambulation [ 4 , 10 , 19 ]. Clinically, FSHD1 has been divided into classic FSHD, with a typical onset in the second decade (usually 15–30 years of age), and a severe early-onset (less than 10 years of age) called infantile FSHD.…”

“…The link between the substantial deletion of D4Z4 repeat and infantile FSHD has been suggested. Very short Eco RI fragments (≤14 kb) are found in most infantile FSHD patients, but not all [ 19 , 20 , 30 , 31 ]. Furthermore, an association between a short Eco Rl fragment and systemic involvements, such as auditory and ophthalmological impairments, has been reported [ 16 , 20 ].…”

“…A higher prevalence (8–11%) of chronic respiratory failure requiring assisted ventilation has been documented in the infantile FSHD patients [ 15 , 16 , 19 , 20 , 39 ], compared to the general FSHD populations (0–7%) [ 40 , 41 , 42 ]. A common finding of the restrictive ventilatory defect in patients with infantile FSHD implies an associated with extensive involvement of respiratory muscles, long-term wheelchair dependence, and spinal deformities (kyphoscoliosis) [ 15 , 16 , 20 , 39 ].…”

“…Of these, about two-thirds of infantile FSHD patients had a single extramuscular feature, and the other third had multiple systemic features [ 20 ]. A genotype–phenotype correlation between the contraction of D4Z4 and the frequency of systemic involvement has been proposed, especially in neurosensory hearing loss and brain dysfunction (intellectual disability and epilepsy) [ 16 , 19 , 20 , 43 ]. These two features are also the most reported first extramuscular features in children with infantile FSHD [ 16 , 19 ].…”