Overview

Freeman-Sheldon Syndrome (FSS), also known by a range of other names such as Freeman-Burian syndrome, whistling face syndrome and distal arthrogryposis type 2A, is a rare genetic condition embodying some key facial features, joint contractures, and resultant skeletal deformities. These joint contractures, often affecting the hands and feet, can cause serious impairments to the quality of life of those affected, making it difficult to grasp objects and even walk. Orthopaedic intervention, especially earlier in life, can play a big role in determining the patient’s outlook, with levels of scarring, functional capacity, mobility and growth all affected by the use and correction of the affected musculoskeletal facets. The following article will now explore FSS, with a focus on orthopaedic interventions and their use in alleviating the detrimental effects of FSS  while improving their outlook through the use of different surgical approaches and holistic care.

The Cause Behind FSS 

FSS  is caused by a mutation in myosin-3 (MYH-3), a vital part of the musculoskeletal system during embryonic development.² This mutation can be inherited in an autosomal dominant or recessive manner with varying reports in literature, although most of these mutations are spontaneous with no previous family history.³ Unlike myosin-2 which normally acts to pull muscle inwards during muscle contraction, thus permitting movement, MYH-3 acts during embryonic muscle development and transiently during muscle regeneration in adult muscle fibres but is otherwise absent after birth.¹ This is why its mechanism of action is largely misunderstood, because although some studies have been carried out, further research is required to elucidate its mechanism of action. Research shows that approximately half of the neonates with this mutation die during pregnancy, with the resulting children having FSS or other contracture syndromes. Animal studies have also shown that MYH-3 mutations significantly increased the number of muscle fibres in all types of skeletal muscle, hinting that this may be true in FSS  patients too. A significant increase in all types of muscle may lead to an inability to shorten due to the sheer bulk of the muscle or may otherwise prevent the muscles from acting antagonistically to permit movement. In addition to this, MYH-3 mutations also reduced the size of slow-twitch muscles significantly, with a multitude of tiny muscle fibres replacing the average number of normal-sized muscle fibres normally found in slow-twitch muscles like the soleus in the legs.^1,4 This may be because MYH-3 causes muscle stem cells to differentiate faster, and they become mature muscle fibres before they are ready and are thus smaller in size. An additional impact of MYH-3 mutations in FSS during muscle formation is that the ratio of slow-twitch muscle fibres is greatly increased compared to fast-twitch muscle fibres, with the area of slow-twitch muscle fibre doubling.¹ After birth these effects were seen to continue, with the largest muscle fibres dying more quickly and an overall decrease in muscle mass. Some research suggests that myosin-2b is also affected by this, suggesting other downstream effects on the types of muscle proteins that may cause symptoms in FSS.^1,4

Due to the premature maturation of muscle stem cells, they are unable to differentiate completely along their normal route which ordinarily leads to the repletion of the muscle stem cell pool so that muscle fibres can continue to repair and regenerate muscle fibres throughout your life.¹ With fewer muscle stem cells generated with the production of new muscle fibres, there are a fewer muscle stem cells available throughout life which can affect muscle mass throughout the patient’s life.

A final characteristic of FSS  which plays an important role in symptoms is the fact that tendonous tissue becomes interspersed within muscles, with tendon tissue irregularly forming in areas of muscle where it wouldn’t in normal tissue.³ This can cause tight tendons which can cause difficulty in muscle contraction, to the extent that may even immobilise the muscles.³ This may be caused downstream of the MYH-3 mutation as other myogenic factor expressions are also altered by MYH-3 mutations. 

Symptoms of FSS

FSS is characterised by a range of classic facial features that may lead to feeding, breathing and speech difficulties. Primarily this is because FSS  is part of a family of distal arthrogryposis: a family of different joint contracture conditions that can cause difficulty in moving the joints. Mental ability isn’t affected in FSS, although key milestones may be achieved later in life because of physical limitations. Although there is a vast array of different phenotypes, typically, physical characteristics of FSS include.^3,4

• Small puckered mouth
• Flat midface (including a flatter nose)
• A big forehead
• Scoliosis (lateral spine curvature)
• Lordosis (inwards curved lower-spine)
• Kyphosis (humpback)
• Clubfoot
• Curved fingers
• Nasolabial creases (from nose to mouth)
• H or V-shaped dimples on the chin
• Very high roof palate in the mouth
• Misaligned teeth
• Drooping eyelids
• Strabismus (cross-eyes)
• Small tongue (macroglossia)
• Epicanthal folds (skin across the tear ducts in the corner of the eye)
• Hypoplastic alae nasi (underdeveloped nostrils in the nose)
• Small skull (microcephaly)
• Short neck

There is a vast array of symptoms associated with FSS. This is because of the type of mutation of the MYO-3, with mutations that prevent it from causing severe symptoms than the mutations which simply mutate part of the protein, thus preventing it from working properly all the time.^3,4 The vast array of symptoms could also be attributed to interactive gene expression, as well as the point during pregnancy when the mutation occurs if it is not an inherited mutation (de novo).³

Orthopaedic Approaches to Treating Joint Contractures in Freeman-Sheldon Syndrome

FSS presents significant challenges, with joint contractures hindering mobility and affecting daily life. Current orthopaedic approaches can offer a better quality of life by improving mobility through tendon release and musculoskeletal rearrangements. Both conservative and operative approaches are available depending on the individual patient’s circumstances. 

Conservative Management

Physical therapy and bracing are the primary forms of treatments soon after birth to alleviate symptoms of FSS and provide support during skeletal growth. Both range-of-motion exercises and passive movements can help encourage proper alignment, with bracing providing the support needed to prevent worsening of issues like scoliosis and clubfoot. An interesting type of bracing for clubfoot is Ponseti casting, with sequential casting followed by bracing to prevent recurrence of the deformity after correction.^4,5 However, many issues often result in surgical intervention later in life. 

Surgical Interventions

Laparoscopic and open surgical interventions are both possible for FSS, although certain severe phenotypes may necessitate surgical intervention in order to correctly align all the associated anatomy in the affected area. Although laparoscopic surgeries may cause less tissue damage and offer shorter recovery times, the complexity of the surgeries and the skill of the surgeons will both dictate the types of surgery performed. Some examples of surgical interventions are: 

• Clubfoot Correction: If casting and bracing do not correct clubfoot in  FSS patients, tight tendons and ligaments can be released through surgical intervention. Arthroscopic or open techniques are both available depending on the severity of the clubfoot. Surgeons will enter the foot from behind the centre of the ankle (posteromedial),  to carry out the surgery to correct issues.
• Spinal Surgery: Many children with FSS develop scoliosis, kyphosis or lordosis. If the curvature of the spine is severe then 2 or more vertebrae may be fused together in order to align the spine, improving the posture and possibly relieving pressure on the internal organs, depending on the extent of the curvature. As this is quite a risky surgery, ordinarily this is performed in an open fashion, although some endoscopic options have been explored. 
• Hand Surgery: Many hand deformities can occur in FSS, including permanently contracted fingers and/ or clenched fists.⁶ Due to many different tendons and muscles involved in the hand, often open surgery is required, with tendon release and tendon transfers aiding functional improvement. 

In some cases in the past, FSS patients have experienced irregular adverse effects during the surgery in the form of muscle rigidity following anaesthetic administration.^7,8 Ultimately, each individual FFS patient will be treated in accordance with their own health needs, and often a multidisciplinary approach may be required to treat the patient as a whole, including speech therapists, surgeons, anaesthetists and ophthalmologists.²

Summary

FSS is a rare genetic disorder caused by the mutations in the MYH3 gene, which affects muscle contraction and leads to joint contractures and skeletal deformities. Characteristic features such as a small, puckered mouth, joint stiffness and distal limb deformities are all typical of the condition. Mental cognition is not affected by FSS, but conservative and operative surgical options may be advised to alleviate symptoms of the condition. Earlier interventions can improve quality of life, preventing long-lasting disabilities and enabling better manual dexterity.