Overview

Freeman-Sheldon Syndrome (FSS), also known as distal arthrogryposis type 2A (DA2A) or formerly known as ‘Whistling Face Syndrome’ is an extremely rare genetic condition that affects the musculoskeletal system, i.e., the muscles and the bones.^1,2 The exact number of people who have been diagnosed with this condition is unknown, but its prevalence is estimated at about 100 people from the first description of the condition to date.³ 

Freeman-Sheldon syndrome is a congenital disease, meaning it occurs before birth whilst the foetus is still developing. As it is a genetic disorder, it can be inherited from the parents or sometimes arise sporadically with no family members being affected previously. Genetic counsellors play an important role for the family in diagnosis, care plan formulation and in supporting the patient and their families with medical interventions and emotional wellbeing throughout their lifetimes.⁴ 

This article will outline the symptoms, cause and prognosis for people diagnosed with FSS, and the role genetic counsellors play in their lifelong care.

Symptoms of freeman-sheldon syndrome

FSS has a wide umbrella of symptoms. However, there is a strict criterion for diagnosis where a patient must show specific features. This diagnostic list is known as the Stevensons’ diagnostic criteria.⁵

A patient must show all these symptoms:

• Microstomia, an undersized mouth
• Pursed lips in a distinctive ‘whistling’ shape, hence the former name ‘whistling man syndrome’
• Nasolabial crease- this is a crease that forms a distinctive ‘V’ or ‘W’ shape on the chin
• Pronounced nasolabial fold, a deep crease going from the side of the nose to the corners of the mouth

 The patient must show at least two of these symptoms:

• Ulnar deviation of wrists and fingers, where the fingers and wrist bend towards the little finger from swelling of the knuckle joints
• Camptodactyly, where the little finger is bent outward at the middle knuckle joint
• Hypoplastic/ absent flexion creases, This is where the lines in the fingers and hand where the knuckles of the fingers lie, called the flexion creases, are underdeveloped or not present at all
• Overriding fingers, where the hand is clenched with fingers overlapping
• Talipes equinovarus, clubbed feet which point inwards and down
• Vertical talus, where a deformity of the Talus bone in the ankle causes a deformity of the foot/ feet
• Metatarsus varus, where the metatarsal bones in the feet are deformed so the foot bends in a crescent shape inward

Other rare symptoms may include malignant hyperthermia, which causes severe allergic reactions to anaesthetic medication.2 Another symptom can be a narrow airway, which causes breathing difficulties.²  Other general symptoms include a flattened face, a wide space between the eyes, and prominent squinting or narrowing of the eyes. There may be developmental delays caused by the physical impairments, and there may be mild to severe learning difficulties, but this is not always the case.² 

Cause of freeman-sheldon syndrome

One identified gene that often causes FSS is embryonic myosin heavy chain gene 3 (MYH3).¹ However, genetics are quite complicated and not always as simple as one gene being an on/ off switch for if someone is affected with a condition. Someone may still have all the symptoms of FSS but no identifiable mutation in their copy of the MYH3 gene. Sometimes, the causative gene is never identified.²

The role of a genetic counsellor

Genetic counsellors are highly specialised healthcare professionals who play a crucial part in delivering care for patients with genetic conditions and their families. Genomic counselling is not the same as counselling you would get from a psychologist. Their responsibilities can include diagnosing genetic conditions, investigating the cause and inheritance of a diagnosed condition, and empowering the family to make the right choice for them by educating them on the condition and all possible options in an empathetic manner.³ 

The main roles and responsibilities of a genetic counsellor are listed below:
diagnosis

 The genetic counsellor conducts a clinical evaluation to see if the symptoms align with the diagnostic criteria detailed above. If the patient’s symptoms match the criteria, then a diagnosis of FSS can be made.. The family may opt for a genetic test, typically a MYH3 single gene test, which uses Next-generation sequencing technology. The DNA sample can be taken from blood, either from the patient or umbilical cord, or a saliva sample from a simple cheek swab.⁶

Empowerment and education through genetic testing

A genetic counsellor will help educate the patient's family on the genetics of the disease, genetic testing options and what the inheritance patterns are in their case so that the family feels empowered and able to make fully informed decisions.

The family will also be educated on their rights to consent to testing. Being told that your family member may have an inherited genetic condition can be very distressing, and they may not wish to conduct a genetic test due to numerous personal factors. The role of the genetic counsellor is to inform, support and understand the family members so that after the genetic counsel, the family is able to make the best choice.

The genetic counsellor guides the family through the ethics of genetic testing and helps the family decide what is best for them, their lifestyles and their beliefs. The genetic counsellor delivers holistic care, which takes into consideration everyone’s personal life circumstances. 

Investigating the inheritance patterns

If the family chooses to undergo genetic investigation, and the single-gene MYH3 test  is positive for a mutation causative of FSS, the genetic counsellor can order more tests to see if the parents carry the same mutation. The genetic counsellor may also conduct interviews with the family and ask questions about the family's medical history to see if they can identify other family members who may have been affected, and may invite more distant family members for testing. This is all done so the genetic counsellor can determine an inheritance pattern, which is a map of how the condition may have been passed through the family tree.

The genetic counsellor may find an autosomal dominant inheritance pattern, where only one copy of the mutated gene must be present to cause symptoms, and one parent may be affected with Freeman-Sheldon syndrome.¹ 

In the case of an autosomal recessive inheritance pattern, this indicates that both parents carry a copy of the mutated gene that is non-active in themselves, but the affected child would have inherited both mutated copies, one from each parent. The parents would be the carriers.¹ 

There is another case in which both parents may be entirely unaffected, but one or both parents may have gonadal mosaicism.¹ This means the cells in the rest of the body do not have a copy of the mutated gene, but some of their sperm or ovary cells carry copies. This may lead to a child inheriting the condition, but neither of the parent's somatic cells – the cells that are not gametes (egg or sperm) – have any copy of the faulty mutation.¹  

If an inheritance pattern is found, the genetic counsellor will address the likelihood that another child of the family would also inherit Freeman-Sheldon syndrome:

• If the inheritance pattern follows an autosomal recessive manner, the likelihood of condition inheritance is 25%¹ 
• If the pattern follows an autosomal dominant manner, then the likelihood of a sibling to inherit the condition is 50%¹ 
• In cases of gonadal mosaicism, the recurrence of having another child with FSS is very low¹ 

Family planning

If the parents of a child with FSS plan to have more children, they may consult the genetic counsellor for family planning: 

• In future pregnancies, diagnostic testing can be done during pregnancy. They may take a sample of the amniotic fluid via amniocentesis and conduct a genetic test¹ 
• Features of FSS may also be identifiable at 20 weeks’ gestation via ultrasonography, such as clubbed feet, pursing lips, and clenched fists with overlapping fingers² 
• The genetic counsellor can also support the person with FSS through their own family planning if they choose to have children in the future

Emotional well-being support

The genetic counsellor could signpost the family and FSS patients to charities and support services. 

The group Changing Faces provides counselling, education, and support for people with visible differences in appearance.

Treatment and prognosis

Each case of FSS is different from another, and each affected person requires individualised and holistic care. This care plan will be made through the collaboration of different medical specialists. The genetic counsellor will help formulate a plan along with the family and patient.

Treatment could include surgery to widen the mouth opening if there are breathing difficulties, which will be done under specialised anaesthesia if the patient also has malignant hyperthermia. 

Speech therapists may help with any eating issues, orthopaedic surgery may be used to correct clubbed feet or allow the hands to be more easily used if they are clenched or deformed. Dental treatment, physiotherapy and other interventions can also be undertaken if required. 

The prognosis for people with FSS is generally positive after any breathing issues are resolved. They should have no limitations to their lifespan or quality of life.²

Summary

Freeman-Sheldon syndrome is a complex condition which requires individual care and highly personalised care plans. Diagnosis is also complex, and patients need to meet a strict set of criteria, and although there is a gene identified which can cause the condition, sometimes the gene that causes the condition is never identified.

Genetic counselling helps empower through education and support to help the family feel in control of their decision and care plan. The genetic counsellors help the family and patient throughout their lifetime to adapt to challenges that may arise because of their condition. The genetic counsellor can also support the family and patient through difficult decisions regarding family planning and genetic testing.

People with Freeman-Sheldon can thrive and live healthy, full lives with the support of a multidisciplinary healthcare team.