Freeman-Sheldon Syndrome: Congenital Skeletomuscular Abnormalities

Introduction

Joseph Harold Sheldon and Ernest Arthur Freeman 1938 first described Freeman-Sheldon syndrome. Freeman-Sheldon syndrome (FSS) is an inherited condition that is present before birth and primarily involves the muscles of the skull and face and also affects the joints of the feet and hands. It affects males and females equally, and nearly 100 cases were reported in 2007. The affected individuals typically exhibit various craniofacial abnormalities and malformations of the feet and hands. The most distinctive feature of Freeman-Sheldon syndrome is that the affected individuals have a small puckered mouth, causing a whistling face appearance.

What Is a Freeman-Sheldon Syndrome?

Freeman-Sheldon syndrome (Freeman-Burian syndrome) is a genetic condition that causes alterations in the craniofacial muscles and may also affect the hand and feet joints. Freeman-Sheldon syndrome is characterized by permanent tightening of the skin, tendons, muscles, and surrounding tissues, causing restrictive movements of the affected part (contractures). The affected individuals show a characteristic whistling appearance due to contractures in the face and smallmouth with pursed lips. Because of this characteristic appearance in the affected individuals, Freeman -Sheldon syndrome is also known as whistling face syndrome. Freeman-Sheldon syndrome can be divided into three subtypes based on the characteristic features.

They are:

• Freeman-Sheldon Syndrome Type 1 - It is also known as classic Freeman-Sheldon syndrome. In this type, there will be facial deformities along with two or more areas of limited movement of joints.

• Freeman-Sheldon Syndrome Type 2 - Also known as craniofacial Freeman-Sheldon syndrome. In this type, the patients show only facial deformities.

• Freeman-Sheldon Syndrome Type 3 - There will be facial deformities along with limited movements involving other body parts in this type.

What Are the Causes of Freeman-Sheldon Syndrome?

Freeman-Sheldon syndrome occurs due to mutations in the MYH3 gene. The MYH3 gene provides instructions for the production of the protein myosin-3. Proteins such as actin and myosin are the major components of muscle fibers and function as a major factor in the growth and development of muscles.

The exact mechanism behind the mutations or variations involving the MYH3 gene is not yet identified. The genetic mutations alter the functions of myosin-3 protein and impair relaxation and muscle contraction, causing difficulties in muscle movement. Limitations in muscle movement before birth disrupt the normal development of the body parts and account for other abnormal features of Freeman-Sheldon syndrome.

How Is Freeman-Sheldon Syndrome Inherited?

Freeman-Sheldon syndrome is inherited in an autosomal dominant pattern. In autosomal dominant disorders, the offspring of affected individuals have a 50 percent chance of developing the genetic condition. Thus one copy of an altered gene present in each cell may cause the disorder. For some people, Freeman-Sheldon syndrome may occur from new gene variations with no family history of the disorder.

What Are the Symptoms Associated With Freeman-Sheldon Syndrome?

The most prominent and significant features associated with Freeman-Sheldon syndrome are craniofacial abnormalities and other malformations.

They are:

Craniofacial Abnormalities

• Small puckered mouth.

• Small jaw.

• Flat or sunken appearance of the midface.

• Malocclusion.

• Full cheeks.

• Small jaw.

• Prominent forehead.

• Small tongue.

• Deep skin folds between the lips and nose.

• Short nose.

• Wide philtrum.

• Prominent brow ridges.

• Deep-set-eyes.

• Strabismus.

• High-arched palate.

• Underdeveloped nose cartilage.

• Raised H or V-shaped mark on the chin.

• Droopy upper eyelids.

• Narrowed eye-opening.

• Ocular hypertelorism.

• Downslanting eyelid folds.

Other Malformations

• Club foot.

• Hand malformations.

• Contracture of the joints.

• Flexed thumbs and fingers.

• Contractures of the shoulders, hips, and knees.

• Curved spine.

• Camptodactyly.

• Ulnar deviation.

• Abnormalities of ribs and spine.

• Delayed development milestones.

• Abnormal curvature.

• Walking difficulties.

How Can We Diagnose Freeman-Sheldon Syndrome?

Diagnosis of Freeman-Sheldon syndrome can be made through medical history and physical examination. Features such as a whistling face, a small mouth, V or H-shaped chin dimple, and Down-slanting nasolabial creases associated with Freeman-Sheldon syndrome can be used as diagnostic criteria. Breathing tests, medical imaging, and nerve and muscle function tests can also be used.

What Are the Treatment Options for Freeman-Sheldon Syndrome?

Treatment for Freeman-Sheldon syndrome involves a coordinated effort involving healthcare professionals and specialists. The treatment options include therapies and surgical interventions for specific symptoms to improve the outcome. The affected individuals must take craniofacial and orthopedic surgeon's consultation as early as possible to manage clubfoot, craniofacial abnormalities, and hand correction to improve esthetics and function. The operative measure must be undertaken to minimize developmental delays and improve functions.

General health maintenance is an important aspect of managing Freeman-Sheldon syndrome. Preventive measures must be implemented to reduce exposure to infectious diseases. Bronchitis and pneumonitis are often seen in affected individuals.

Other treatment strategies are the following.

• Orthopedic surgeries to improve feet and hand malformations.

• Craniofacial surgery to improve the craniofacial abnormalities associated with Freeman-Sheldon syndrome.

• Surgeries to reshape the frontal bone.

• Dental treatments to improve oral health.

• Orthodontic treatments in affected individuals to straighten teeth.

• Surgeries to improve eyelid opening.

• Plastic surgery to increase mouth size.

• Physical therapies to improve movements and function.

Conclusion

Freeman-Sheldon syndrome (FSS) is a rare genetic disorder that affects craniofacial structures, feet, and hands. This condition occurs due to genetic mutations involving the MYH3 gene that regulates the secretion of certain proteins responsible for normal muscle contractions causing reduced bone and muscle functions and developmental abnormalities in the fetus. The affected individuals show characteristic features like a whistling face, small mouth, prominent forehead, reduced eye-opening, and sunken midface appearance. Treatment options include coordinated therapeutic management for skeletal defects and other associated abnormalities.