Overview

Freeman-sheldon syndrome (FSS) has many names, some include: ‘whistling-face syndrome’, freeman-burian syndrome, distal arthrogryposis type 2B, and cranio-carpo tarsal dystrophy.It was first found in 1938 and studied in 1962 by Dr John Howard Sheldon who understood that it manifested in utero affecting muscles in the face and skull. It was classed as a rare congenital disorder since there have only been 100 reported cases since its discovery. 

In this article, the symptoms, causes, and manifestations of FSS will be detailed, specifically, the neurological manifestations and the future implications on a patient with FSS.

Introduction to FSS

Brief description of FSS

As previously explained, FSS is an extremely rare congenital syndrome; this means that symptoms can be seen in utero. In 1962, technology for ultrasounds, sonographies, and genetic tests were not invented, therefore there was no way of knowing if a baby had FSS since first signs were seen congenitally, however currently, these strategies can be used to conduct examinations in utero to diagnose FSS.¹

Genetic basis

Cells in humans contain a structure that provides instructions to make proteins, this structure is called DNA (deoxyribonucleic acid). Sections of DNA are called genes and they code for particular proteins. A particular gene: MYH3 is mutated and the protein that is made is changed; this mutated protein is what causes FSS. The genetic mutation causes a protein called: myosin-3, which normally assists muscles around the body to contract and then relax, to cause the muscles to contract for a longer period of time.

This affects muscular and skeletal development because the muscle is no longer moving and triggers stiffening around bones and in the tissues nearby. This mutation occurs in utero during foetal development, therefore, the earliest stages of skeletal development are disrupted and hence result in severe abnormalities as listed in ‘physiological manifestations.⁵

Types of FSS manifestations and their symptoms

Physiological manifestations

Physiological manifestations of FSS include all elements of the body other than the central nervous system (CNS) or peripheral nervous system (PNS.) These manifestations are seen through hallmark symptoms that can assist in its diagnosis in utero or post-birth:

• Camptodactyly (contractures where there is restricted movement in peripheral limbs)²
• Microstomia³
• Microglossia (small tongue)
• High arch in the roof of the mouth 
• Dysphagia (harder to swallow)
• Clubfoot
• Difficulty growing and gaining weight
• Pursed lips 
• H or V-shaped chin 
• Abnormally large nasolabial creases
• Tendons replacing muscles (mainly in the face)
• Muscles in the craniofacial region are mostly affected

Physiological symptoms seen in the body can sometimes be as a result of neurological manifestations. Neurological symptoms affect the development and formation of the brain and spinal cord (CNS) in utero. Furthermore, PNS nerves are also affected, they run around the body and could be a cause for some of the physiological symptoms since they are directly in contact with peripheral limbs.

Neurological manifestations

Neurological symptoms manifest in utero where FSS is primarily seen to develop, this means that FSS can affect the formation and growth of the CNS and PNS (which are major neurological structures).⁶

Cognitive impairments in the CNS

The brain and the spinal cord manifest impairments in utero, some examples include:

• Hearing and listening difficulties
• Cerebellar atrophy 
• Motor response delay
• Hypoplasia of the brainstem
• Spina bifida
• Curving the spine (scoliosis, kyphosis, lordosis)

Seizures and epilepsy

It is common for patients with FSS to have seizures similar to that of an epileptic patient. Normally, neurons in the body and brain rely on electrical activity to function, however, in epileptic patients, there is a continuous surge of electrical activity that is abnormal and triggers epileptic fits or seizures. 

FSS is known for its musculoskeletal abnormalities and a known side effect is these abnormalities also hinder proper brain development in utero, thus predisposing FSS patients to epileptic seizures and fits. The direct reasoning and pathway for FSS to cause these fits are unknown but they are observed in many patients earlier in development.⁷

Behavioural and psychological issues

In FSS patients, physical deformities affect their mental health too. There are not just visual issues, but also unseen psychological and behavioural implications of FSS. 

The reasons as to why FSS patients end up developing depression and/or anxiety include:⁸

• Feelings of frustration, helplessness, and a strong loss of independence contributes to the development of mental health issues 
• Patients can be socially isolated, especially during early developmental years as children, they feel isolated, ostracised, and develop low self-esteem which contributes to developing social anxiety and depression
• FSS patients need to be monitored and tested regularly to ensure FSS is not worsening or posing any dangerous risks. The repetitive and frequent medical appointments and testing can be stressful and tiring often making a patient feel anxious and depressed

The effect of neurological manifestations on the patient's quality of life

Neurological manifestations are essential because, they influence the quality and health of a patient. Examples of neurological manifestations include:

• Cognitive impairments such as cerebellar atrophy or motor response delay play a role in a patient's functional independence. Abnormalities can result in the strong reliance on a healthcare professional or caregiver⁴
• Psychological impairments such as anxiety, depression, and general mental health will be affected by FSS and these can result in behavioural issues and require psychological care along with assistance for physical limitations⁴

Peripheral nervous system (PNS) involvement

The central nervous system is not the only system that is affected by FSS. Many issues explored thus far explain the brain and spinal cord involvement, as well as their effect on the rest of the body, the PNS delves into physiological manifestations in more detail and how they are developed from FSS. 

The PNS is more directly associated with physiological manifestations in FSS than the CNS because, it is more close and directly in contact with organs, tissues, muscles, tendons, and bones. Despite the CNS showing downstream effects of physiological musculoskeletal manifestations, the PNS is likely to be the culprit which causes these physiological manifestations in the first place. There are a few PNS manifestations listed and explained below:

Neuromuscular issues 

• The PNS innervates muscles from the spinal cord, and FSS can damage motor neurons (which travel directly into muscles) 
• The motor neurons damage can result in muscle weakness, hypotonia, or hypertonia.
• There are also more downstream results of muscular weakness in the skeletal structure of the patient namely the development of contractures (as mentioned earlier)

Peripheral neuropathy⁹

• Starting from nerves outside the brain, spinal cord, and in the PNS, nerves are compressed and damaged, usually due to skeletal and muscle abnormalities
• Nerve compression causes peripheral neuropathy to develop in FSS patients and symptoms include: numbness, pins and needles, and tingling in hands and feet (or other peripheral limbs)

Autonomic nervous system (ANS) dysfunctions

The autonomic nervous system (ANS) is responsible for involuntary physiological processes that are needed to keep the body functioning and keep humans alive. In FSS, there can be parts of the ANS which are dysfunctional, this is characterised as dysautonomia.^11,12

• Incidence of autonomic dysfunctions such as orthostatic hypotension are found amongst many patients with FSS. It is a condition where blood pressure drops when changing postural positions
• Another way in which FSS affects the ANS is in an individual's cardiovascular health and overall stability¹⁰

Pathophysiology of freeman-sheldon syndrome

In order to properly understand neurological manifestations in FSS properly, it is helpful to understand the genetic basis of FSS and how it triggers these neurological issues.

Neurological and musculoskeletal interactions

Muscular and tendon contractures can trigger nerve compression which creates muscular spasms or weaknesses and severe nerve damage or neuropathies. These muscular impairments can exacerbate neurological conditions such as difficulties in swallowing, speech, and coordination; these difficulties listed all rely on muscles and tendons to contract and relax correctly.

Similarly, neurological abnormalities can also worsen musculoskeletal issues and this creates a vicious cycle where one abnormality affects the other.

Summary

FSS is a rare congenital syndrome that is triggered by a genetic mutation in the MYH3 gene, this causes muscular, skeletal, and neurological abnormalities in a foetus during pregnancy, furthermore, this syndrome manifests these abnormalities through physiological and neurological symptoms. 

Symptoms can range from physical issues such as craniofacial muscle issues or contractures in peripheral limbs to neurological manifestations which include cognitive deficits, motor neuron function delays, and epileptic-like seizures. 

Neurological symptoms also include the psychological effects of living with FSS. Mental health issues such as depression, anxiety, social isolation, and chronic stress are common amongst patients. Muscular, skeletal, and neurological symptoms observed and recorded are all interlinked with one another, additionally, there is a strong interplay between physiological and neurological manifestations in FSS, often worsening as the patient ages thus affecting their psychological health too.