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Facioscapulohumeral muscular dystrophy 2
This form of muscular dystrophy typically begins in adolescence or early adulthood and gradually worsens over time. The condition results from genetic changes that affect muscle tissue, leading to muscle wasting and functional limitations. FSHD2 shares clinical features with the more common FSHD1 but has a different genetic cause.
Overview
Facioscapulohumeral muscular dystrophy 2 (FSHD2) is a muscle-wasting disorder that primarily affects the muscles of the face (facio-), shoulder blades (scapulo-), and upper arms (humeral). The condition is rare and represents a subset of facioscapulohumeral muscular dystrophy cases. Affected individuals typically experience progressive muscle weakness that begins in specific muscle groups and may spread to other areas over time.
Prevalence data for FSHD2 specifically remain limited, though it accounts for a small proportion of all FSHD cases, with FSHD1 being considerably more common. The condition can vary substantially in its severity and age of onset, even within the same family. Some people experience only mild weakness that progresses slowly, whilst others may develop more significant disability affecting mobility and daily activities.
Symptoms & clinical features
The hallmark feature of FSHD2 is weakness that typically starts in the facial muscles and muscles around the shoulder blades. Early signs often include difficulty raising the arms above the head, prominent shoulder blades that stick out (sometimes called 'winging'), and facial weakness that may cause difficulty closing the eyes completely, whistling or drinking through a straw. Many people notice an asymmetrical pattern of weakness, with one side of the body more affected than the other.
As the condition progresses, weakness may extend to the muscles of the upper arms, lower legs (particularly the front of the lower leg), and occasionally the abdominal and hip muscles. Some individuals develop a characteristic forward tilt of the shoulders and difficulty lifting objects overhead. Facial weakness can result in a reduced ability to show facial expressions, though this varies considerably between affected individuals. Most people with FSHD2 retain the ability to walk throughout their lives, though some may require mobility aids in later years.
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Affected organs
FSHD2 predominantly affects skeletal muscle tissue, which is responsible for voluntary movement. The condition follows a distinctive pattern, typically beginning in the facial muscles and the muscles that stabilise the shoulder blades and move the upper arms. Unlike some other forms of muscular dystrophy, FSHD2 generally spares the heart and respiratory muscles in most cases, though careful monitoring is recommended.
Occasionally, individuals with FSHD2 may experience complications affecting other systems. These can include hearing loss (particularly high-frequency hearing loss), retinal changes in the eyes, and rarely, abnormalities in blood vessel development at the back of the eye. The degree of involvement beyond muscle tissue varies considerably between affected individuals.
Risks & severity
The severity of FSHD2 varies widely between individuals. Some people experience only mild symptoms that progress slowly over many years, whilst others develop more substantial weakness that affects daily functioning. Age of onset typically ranges from adolescence through to early adulthood, though onset in childhood or later adult life can occur. Research suggests that earlier age of onset often correlates with more severe progression, though this is not absolute.
Most individuals with FSHD2 maintain the ability to walk independently throughout their lives, and life expectancy is typically normal. However, progressive weakness can affect quality of life through reduced mobility, difficulty with overhead activities, and occasional chronic pain related to altered posture and muscle mechanics. A small proportion of affected individuals may eventually require wheelchair assistance for longer distances. Fatigue is commonly reported and can be a significant symptom even when muscle weakness is relatively mild.
Genetic causes
FSHD2 results from a distinctive genetic mechanism involving changes at two separate locations in the genome, which is described as digenic inheritance. The condition occurs when specific genetic variations combine to inappropriately activate a gene called DUX4. Normally, DUX4 is silenced in adult muscle tissue through chemical modifications called epigenetic changes. In FSHD2, alterations affecting these silencing mechanisms allow DUX4 to become active in skeletal muscle.
When DUX4 is inappropriately expressed in mature muscle cells, it triggers a cascade of cellular changes that are toxic to muscle fibres. This leads to inflammation, muscle cell death and progressive muscle wasting. The digenic nature of FSHD2 means that pathogenic variants at two distinct genomic locations must be present together for the condition to manifest. This genetic mechanism distinguishes FSHD2 from FSHD1, which results from a different type of genetic change but ultimately also leads to inappropriate DUX4 expression.
Inheritance pattern
FSHD2 follows a digenic inheritance pattern, meaning that changes at two different genetic locations are required for the condition to develop. This makes the inheritance pattern more complex than typical single-gene disorders. One of the genetic changes is usually inherited from a parent, whilst the other may be inherited separately or arise as a new change.
Because two separate genetic alterations must occur together, the risk to relatives is difficult to predict without detailed genetic testing of family members. Each child of an affected individual may inherit one or both of the necessary genetic changes, but siblings and other relatives may carry different combinations. Genetic counselling is particularly valuable for families affected by FSHD2 to understand the specific risks in their situation. Some family members may carry one genetic change without symptoms because they have not inherited or developed the second required change.
Diagnosis & testing
Diagnosis of FSHD2 typically begins with clinical evaluation by a neurologist or specialist in neuromuscular disorders, who will assess the pattern and distribution of muscle weakness. The characteristic pattern of facial and shoulder girdle weakness, particularly when asymmetrical, raises suspicion for FSHD. Initial investigations often include blood tests to measure creatine kinase (an enzyme released from damaged muscle) and electromyography studies to assess electrical activity in muscles.
Genetic testing provides definitive diagnosis and helps distinguish FSHD2 from FSHD1 and other forms of muscular dystrophy. Within the NHS Genomic Medicine Service, testing for FSHD is typically accessed through referral to clinical genetics services. The genetic analysis for FSHD2 is complex, requiring assessment of multiple genetic and epigenetic factors. Confirmation of the diagnosis helps guide management and provides important information for family planning and genetic counselling. Muscle biopsy is now rarely required given advances in genetic testing methods.
Management & lifestyle
Management of FSHD2 focuses on maintaining function, managing symptoms and preventing complications. A multidisciplinary approach typically involves neurologists, physiotherapists, occupational therapists and genetic counsellors. Regular physiotherapy can help maintain muscle strength and flexibility, though exercise programmes must be carefully tailored - whilst moderate activity is generally beneficial, excessive muscle exertion may potentially worsen weakness in some individuals.
Occupational therapy assessment can identify practical aids and home modifications to support independence with daily activities. Orthotic devices such as ankle-foot orthoses may assist with foot drop if lower leg weakness develops. Regular monitoring for potential complications such as hearing loss and retinal changes is recommended. Pain management strategies, including physiotherapy and appropriate analgesia when needed, can address discomfort related to altered posture and muscle mechanics. Whilst no specific treatment currently exists to halt or reverse the muscle weakness in FSHD2, management decisions should be made in discussion with the specialist multidisciplinary team familiar with neuromuscular conditions.
UK care pathway
Within the NHS, individuals with suspected FSHD2 are typically referred to neurology services or specialist neuromuscular clinics for initial assessment. Following clinical evaluation, referral to regional genetics services enables access to genetic testing through the NHS Genomic Medicine Service. Genetic counselling is an important component of care, helping affected individuals and their families understand the genetic mechanism, inheritance pattern and implications for relatives.
Ongoing care usually involves regular review in specialist neuromuscular clinics, with access to physiotherapy, occupational therapy and other allied health services as needed. The highly variable nature of FSHD2 means that care plans are individualised based on each person's symptoms, rate of progression and functional needs. Patient organisations can provide valuable peer support and information about living with the condition.
Frequently asked questions
How quickly does FSHD2 progress?
The rate of progression varies considerably between individuals. Some people experience very slow progression over many decades, whilst others may notice more rapid changes in muscle strength. Generally, most people with FSHD2 maintain the ability to walk throughout their lives.
Will my children inherit FSHD2?
Because FSHD2 requires changes at two genetic locations, inheritance is complex. Your children may inherit one, both or neither of the genetic changes. Genetic counselling and family testing can clarify the specific risks in your situation.
Should I avoid exercise if I have FSHD2?
Moderate exercise is generally beneficial and helps maintain muscle function and overall fitness. However, exercise programmes should be tailored to your abilities and developed with guidance from a physiotherapist experienced in neuromuscular conditions, as excessive exertion may be unhelpful.
Is there a cure for FSHD2?
Currently, no treatment can cure or reverse FSHD2. Management focuses on maintaining function, preventing complications and supporting quality of life.
Does FSHD2 affect life expectancy?
Life expectancy for individuals with FSHD2 is typically normal. The condition primarily affects skeletal muscle and usually spares the heart and breathing muscles, though regular monitoring is recommended.
References
- Giacomucci G, Monforte M, Diaz-Manera J. Deep phenotyping of facioscapulohumeral muscular dystrophy type 2 by magnetic resonance imaging. European journal of neurology. 2020. PMID: 32697863
- Hamanaka K, Goto K, Arai M. Clinical, muscle pathological, and genetic features of Japanese facioscapulohumeral muscular dystrophy 2 (FSHD2) patients with SMCHD1 mutations. Neuromuscular disorders : NMD. 2016. PMID: 27061275
- de Greef JC, Lemmers RJ, Camaño P. Clinical features of facioscapulohumeral muscular dystrophy 2. Neurology. 2010. PMID: 20975055
- Mair D, Biskup S, Kress W. Differential diagnosis of vacuolar myopathies in the NGS era. Brain pathology (Zurich, Switzerland). 2020. PMID: 32419263
- Lee JH, Park HJ, Seong MW. Two Cases of Facioscapulohumeral Muscular Dystrophy 2 in Korea. Yonsei medical journal. 2021. PMID: 33381940
- Hamanaka K, Goto K, Arai M. Corrigendum to "Clinical, muscle pathological, and genetic features of Japanese facioscapulohumeral muscular dystrophy 2 (FSHD2) patients with SMCHD1 mutations": [Neuromuscular Disorders 26/4-5 (2016) 300-308]. Neuromuscular disorders : NMD. 2016. PMID: 27312129
- Mitsuhashi S, Boyden SE, Estrella EA. Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral muscular dystrophy 2. Neuromuscular disorders : NMD. 2013. PMID: 24128691
- Ohta Y, Tadokoro K, Sasaki R. Different clinicopathological features between Japanese siblings with facioscapulohumeral muscular dystrophy 2 with a novel nonsense SMCHD1 mutation (Arg552(∗)). Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2018. PMID: 30327220