Early onset facioscapulohumeral dystrophy – a systematic review using individual patient data

Highlights

• Comprehensive overview of all published individual patient data on early onset FSHD.

• At a mean age of 19 years, 40% is wheelchair dependent.

• Half of the patients have systemic complications, most frequently hearing loss (40%).

• Early onset FSHD has a more severe phenotype compared to classical FSHD.

• Early onset FSHD has a remarkable heterogeneity comparable to classical FSHD.

Abstract

Infantile or early onset is estimated to occur in around 10% of all facioscapulohumeral dystrophy (FSHD) patients. Although small series of early onset FSHD patients have been reported, comprehensive data on the clinical phenotype is missing. We performed a systematic literature search on the clinical features of early onset FSHD comprising a total of 43 articles with individual data on 227 patients. Additional data from four cohorts was provided by the authors. Mean age at reporting was 18.8 years, and 40% of patients were wheelchair-dependent at that age. Half of the patients had systemic features, including hearing loss (40%), retinal abnormalities (37%) and developmental delay (8%). We found an inverse correlation between repeat size and disease severity, similar to adult-onset FSHD. De novo FSHD1 mutations were more prevalent than in adult-onset FSHD. Compared to adult FSHD, our findings indicate that early onset FSHD is overall characterized by a more severe muscle phenotype and a higher prevalence of systemic features. However, similar as in adults, a significant clinical heterogeneity was observed. Based on this, we consider early onset FSHD to be on the severe end of the FSHD disease spectrum. We found natural history studies and treatment studies to be very scarce in early onset FSHD, therefore longitudinal studies are needed to improve prognostication, clinical management and trial-readiness.

Introduction

Facioscapulohumeral dystrophy (FSHD) is one of the most frequent hereditary muscular diseases with an estimated prevalence of 5–13 in 100,000 [1], [2]. In 3–21% of patients the symptoms start at an early age [3], [4]. Currently, two genetically distinct types of FSHD, called FSHD1 and FSHD2, are known. In both types, inefficient epigenetic repression of the retrogene DUX4 plays a key role in the pathogenesis [5], [6]. FSHD1 accounts for 95% of all patients and almost all early onset cases [7], it is associated with contraction of the D4Z4-repeat at chromosome 4q35 in combination with a disease-permissive 4qA allele [8], [9]. In the general population, the number of D4Z4 repeat units varies between 11 to more than 100, while patients with FSHD1 have only 1–10 repeat units. There is a roughly inverse correlation between repeat size and disease severity; most patients with short repeats have a severe disease phenotype [10], [11].

Historically, infantile FSHD was considered a distinct disease based on clinical onset before the age of two years (Brooke criteria, 1977 [12]). This concept evolved to early onset FSHD and was regarded a subgroup of FSHD, defined by signs or symptoms of facial weakness before the age of 5 and signs or symptoms of scapular weakness before the age of 10 (Brouwer criteria, 1994 [13]). Whereas the typical, classic form of FSHD is characterized by slowly progressive, often asymmetrical muscle weakness of facial- and shoulder muscles starting in the second decade of life [3], [14], the subgroup of early onset FSHD patients is characterized by severe muscle weakness, faster disease progression and systemic features. These systemic features include epilepsy, mental retardation, hearing loss, retinal vasculopathy, spinal deformities, respiratory problems and cardiac arrhythmias [3], [13], [15], [16], [17], [18], [19]. It should be noted that clinical variability in terms of age at onset and disease severity is typical of FSHD. Age at onset ranges from birth to 70 years of age and disease severity may vary from asymptomatic carriers to patients with severe muscle weakness causing functional dependence.

Our current understanding of disease severity, systemic features and prognosis in early onset FSHD is based on small case-series. Consequently, many questions about the clinical phenotype and natural history of early onset FSHD remain unanswered, thus limiting evidence based clinical management. Here, we systematically review the literature using individual patient data to gain insight into the clinical spectrum of early onset FSHD. The ultimate goals are to improve recognition and understanding of early onset FSHD and to advance clinical management.