Classification, clinical care, outcome measures and biomarkers in childhood onset FSHD: towards standardising clinical care and ensuring clinical trial readiness.

279^st ENMC International Workshop:

Location: Hoofddorp, The Netherlands

Title: Classification, clinical care, outcome measures and biomarkers in childhood onset FSHD: towards standardizing clinical care and ensuring clinical trial readiness.

Date: November 1-3, 2024

Organisers: Dr C. E. Erasmus (The Netherlands), Prof. K. Mathews (USA), Dr K. de Valle (Australia), Prof. T. Willis (UK).

Translations of this report by:
German by  Wolfgang Müller-Felber
Swedish by  Thomas Sejersen
French by  Pierre Laurian
Dutch by Jildou Dijkstra
Spanish by  Andrés Nacimiento
Portuguese by Cristiane Moreno
Italian by Valeria Sansone

Participants:

Tracey Willis, Katy de Valle, Katherine Mathews, Corrie Erasmus, Nicol Voermans, Wolfgang Muller-Felber, Thomas Sejersen, Tayla Dor, Valeria Sansone, Meredith James, Andrea Klein, Derek Willis, Sam Geuens, Andres Nacimiento, Ria de Haas, Ian Woodcock, Jeff Statland, Linda Lowes, Hugh McMillan, Christiane Moreno, Bettina Henzi, Jildou Dijkstra, Michelle Mellion, Anke Lanser, Ally Roets, Pierre Laurian, Renatta Knox, Violeta Stoyanova, Georgio Tasca, Amy Halseth, Ash Dugar.

Summary of the workshop:

The 279^st ENMC international workshop was held from the 1^st-3^th of November 2024 in Hoofddorp, the Netherlands. Twenty-seven participants, including clinicians, research experts, patient advocates and industry representatives, from 14 different countries engaged in the workshop.

Background and aims:

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disease that typically weakens facial and shoulder muscles first, then progresses to involve the legs, torso and other muscles. While FSHD is often considered an adult disease, many affected individuals develop symptoms in childhood. Those who present in early childhood often experience more physical limitations and disability. Recent efforts by international research networks have highlighted the unique needs of children with FSHD, but standard care globally and consistent methods of tracking symptoms in this young group have not been established. Differences in the way data is collected and symptoms measured makes it challenging to compare results across research studies. Clinical trials of potential treatments for adults and older teens with FSHD are underway.  It is essential to describe (or classify) the spectrum of disease in childhood, establish standard guidelines for care, and find accurate ways to measure disease progression to ensure that children can benefit from new treatments as they emerge.

Workshop aims included describing recognized clinical groups (or phenotypes) and establishing an agreement on classification/terminology and severity markers for children with FSHD, reviewing and refining current care guidelines, and identifying any gaps in knowledge. Additionally, the workshop aimed to pinpoint challenges and facilitators for clinical trials involving children, foster collaboration among healthcare professionals worldwide, and engage with pharmaceutical companies to help shape the design of clinical trials to best serve all children, including those at the more severe end of the spectrum.  A survey completed by participants prior to the meeting helped to shape the discussion.

Session 1: natural history and classification of clinical phenotypes in paediatric FSHD

The workshop began with an overview on FSHD in children. It was agreed that FSHD represents a continuum of disease with onset at different ages. There was consensus to discontinue use of the term “infantile FSHD”. Early-onset FSHD with facial weakness under the age of 5 years was a suggested alternative.

Approximately half of the patients with FSHD have symptoms before age 18 years with a wide range of clinical presentations. The diverse manifestations of FSHD have been highlighted in several longitudinal studies that monitor patients over time.  At one end of this spectrum are children with clear weakness that is progressing more rapidly and a higher rate of other system involvement, including hearing loss, vision problems and in some cases learning difficulties or epilepsy.

When considering the disease spectrum, options for group classification could relate to genetics, clinical presentation or rates of progression based on genetic or MRI findings. Division into clinical subgroups must consider the context and purpose of the subgroup development, e.g. clinical trials, underlying biology or clinical care.  Researchers of all types should be careful to describe the population they are studying. Further research is required to identify the best predictors of- and timeframes for- symptom progression.

Session 2: guidelines on clinical management of paediatric FSHD

The second session focused on the clinical management of paediatric FSHD. So far, there are no paediatric-specific clinical management guidelines for FSHD. It was agreed that guidelines should cover general as well as features seen primarily in paediatric FSHD, like vision problems and hearing loss. Furthermore, the importance of psychological aspects, rehabilitation/sporting activities, and the transition of young people into adult care should be taken into consideration. Patient representatives highlighted the importance of addressing issues relating to communication and social participation and how these relate to mental health and psychological functioning.

Session 3: clinical outcome measures

The session on clinical outcome measures highlighted the complexity of accurately assessing motor function and quality of life (QoL) using performance-based, patient-reported (PROs), and more complex technology-assisted measures in paediatric FSHD. The influence of childhood growth and developmental progress in motor function was noted. Key tools like FSHD-COM Peds and reachable workspace provide reliable ways to measure movement, although they may not be suitable in all situations. The need for age matched normative data and a standardized set of measures to describe function for use across registries and research trials was emphasized. PROs showed that children with FSHD experience higher pain, fatigue, and lower quality QoL compared to healthy peers. Wearable devices and video assessments capture real-world movement data in children with FSHD, although consistent parental support and standardization in home settings remain challenging.

Several considerations for planning paediatric FSHD clinical trials were addressed. Besides the need for clinically meaningful outcome measures, the need for carefully considered inclusion/exclusion criteria was emphasized. Ongoing challenges include defining key outcome measures, understanding the rate of disease progression, and accounting for the impact of normal growth on muscle and development, which could be mistaken for a treatment effect. Practical considerations, such as completing muscle MRI and biopsies in younger children, were also discussed. Ethical considerations relating to paediatric trials underscored the importance of consent and emphasizing the difference between a trial and a treatment using common language. Regulatory and pharmaceutical perspectives explored the drug approval processes and unique considerations for paediatric drug development, from biomarker validation to engaging with regulators. The session concluded with the need for trial infrastructure and patient involvement to ensure fair access to future treatments.

Session 4: clinical trial readiness and patient participation

The final session covered several challenges in planning FSHD clinical trials in children, pointing out the need for accurate biomarkers to measure change or progression of disease and assess the effect of treatment. It was acknowledged that variability in disease severity and rate of change among children with FSHD makes trial design more complex. Biomarkers or clinical information related to health can be used for diagnosis, to monitor disease changes, or to track a response to treatment. Blood-based markers are being explored but have limitations. Muscle imaging using MRI and ultrasound are useful for tracking muscle changes over time and have distinct advantages and disadvantages. Future and ongoing muscle MRI and ultrasound projects will clarify rate and nature of change in children. A patient representative highlighted the importance of including diverse populations in trials to improve safety data and provide treatment options for all. Also highlighted in this session was how patient groups like the FSHD Society can support research, partnerships, and advocacy for families affected by childhood onset FSHD. Discussions also focused on the need for global, standardized protocols and core outcome measures for paediatric FSHD trials to better compare data and ensure consistency.

Conclusions and consensus:

There was consensus that the term infantile FSHD should no longer be used, that FSHD is a disease spectrum, and it was agreed that when discussing FSHD in children, the population included should be described (eg. age of onset, genetic test results, other). It is clear that that more research is warranted to establish a paediatric sub-category based on observed and verified metrics.

Consensus was also reach on the need for clinical management considerations for paediatric FSHD including (but not limited to) aspects of disease specific clinical care, psychological care, and management of transition.

Defining key outcome measures for clinical care, understanding the rate of disease progression, and accounting for the impact of normal growth on outcome measure assessment, and MRI and ultrasound biomarkers requires additional research.

Global, standardized protocols and core outcome measures across paediatric FSHD trials are required to allow meaningful comparison of data and ensure consistency across studies.

Next steps:

• Establish an outcome measures task force to develop a suggested minimal dataset for both clinical care and clinical research, including therapeutic trials.
• Establish a care standards task force to develop consensus-based care recommendations for children with FSHD. This document will serve as a supplement to the forthcoming FSHD care guidelines expected to be published in 2024/2025.

 

Both task forces will collaborate closely with the International Clinical Research Network (ICRN), a global collaboration of researchers and clinicians dedicated to advancing the understanding and treatment of FSHD.

 

• Patient representatives are updating the FSHD Society's "Guide for Schools" to make it applicable worldwide. They are also developing FAQs to serve as information resources for children and young people with FSHD and their parents.
• Dissemination of the outcomes from task force groups and workshop at the FSHD International Research Congress (IRC) in Netherlands 2025.
• A full report will be published in Neuromuscular Disorders journal.