Freeman-Sheldon syndrome (also known as Freeman-Burian syndrome) is a condition that primarily affects muscles in the face and skull (craniofacial muscles) and can often affect joints in the hands and feet. The condition is characterized by abnormalities known as contractures, which result from permanent tightening of muscles, skin, tendons, and surrounding tissues, and restrict movement of the affected body part. In Freeman-Sheldon syndrome, contractures in the face lead to a distinctive facial appearance including a small mouth (microstomia) with pursed lips, giving the appearance of whistling. For this reason, Freeman-Sheldon syndrome is sometimes called "whistling face syndrome." Other facial features common in this condition include a chin dimple shaped like an "H" or "V" and unusually deep folds in the skin between the nose and the corners of the mouth (nasolabial folds).

People with Freeman-Sheldon syndrome may also have a variety of other facial features, such as a prominent forehead and brow ridges, a sunken appearance of the middle of the face (midface hypoplasia), a short nose, a long area between the nose and mouth (philtrum), and full cheeks. Affected individuals may have a number of abnormalities that affect the eyes. These features can include widely spaced eyes (hypertelorism), deep-set eyes, outside corners of the eyes that point downward (down-slanting palpebral fissures), a narrowing of the eye opening (blepharophimosis), droopy eyelids (ptosis), and eyes that do not look in the same direction (strabismus).

Other features that can occur in Freeman-Sheldon syndrome include an unusually small tongue (microglossia) and jaw (micrognathia) and a high arch in the roof of the mouth (high-arched palate). People with Freeman-Sheldon syndrome may have difficulty swallowing (dysphagia), a failure to gain weight and grow at the expected rate (failure to thrive), and breathing complications that may be life-threatening. Speech problems or hearing impairment can also occur in people with this disorder.

In people with Freeman-Sheldon syndrome, contractures in the hands and feet can lead to permanently bent fingers and toes (camptodactyly), a hand deformity in which all of the fingers are angled outward toward the fifth finger (ulnar deviation, also called "windmill vane hand"), and inward- and downward-turning feet (clubfoot). Less commonly, contractures affect the hips, knees, shoulders, or elbows.

People with Freeman-Sheldon syndrome may also have abnormalities of the spine, ribs, or chest. Many affected individuals have abnormal side-to-side or front-to-back curvature of the spine (scoliosis or kyphosis) or an abnormally curved lower back (lordosis). In many affected individuals, the muscles between the ribs do not function properly, which can impair breathing or coughing. The ribs or breastbone (sternum) may be abnormally shaped in people with this condition.

Intelligence is unaffected in most people with Freeman-Sheldon syndrome, but development of normal milestones may be delayed due to physical abnormalities.

Freeman-Sheldon syndrome is caused by variants (also known as mutations) in the MYH3 gene. The MYH3 gene provides instructions for making a protein called myosin-3. Myosin and another protein called actin are the primary components of muscle fibers and are important for the tensing of muscles (muscle contraction). Myosin-3 is a part of muscle fibers in the fetus before birth, and the protein is important for normal development of the muscles.

It is not completely understood how MYH3 gene variants lead to the signs and symptoms of Freeman-Sheldon syndrome. The genetic changes are thought to disrupt the function of the myosin-3 protein. Studies suggest that the genetic changes prolong muscle contraction and impair relaxation, which prevents movement of the muscles. Limited muscle and limb movement during development likely result in stiffening of the muscles and surrounding tissues, causing the contractures that lead to the characteristic “whistling face” appearance and hand, foot, and spine deformities. Researchers suggest that limited muscle movement before birth impairs normal development of other parts of the body, which may account for other features of Freeman-Sheldon syndrome.

A small number of people with Freeman-Sheldon syndrome do not have mutations in the MYH3 gene. In these individuals, the cause of the disorder is unknown.

Normal Function

The MYH3 gene provides instructions for making a protein called myosin-3. This protein belongs to a group of proteins called myosins, which are involved in movement and the transport of materials within and between cells. In addition, muscle fibers are primarily composed of thick filaments made of myosin and thin filaments of another protein called actin. Thick and thin filaments are involved in muscle tensing (contraction). Muscle fibers containing myosin-3 are found primarily in the fetus before birth, and they are important for early development of the muscles.

Myosins function when they are part of a group (complex). Each myosin complex consists of two pairs of myosin light chains (produced from other genes), which regulate the complex, and one pair of myosin heavy chains such as that produced from the MYH3 gene. The heavy chains each have two parts: a head region and a tail region. The head region interacts with actin, which allows the thick and thin filaments to move relative to one another so that muscles can contract. The head region also includes a segment that attaches (binds) to ATP, which is a molecule that supplies energy for cells' activities, including muscle contraction. The long tail region of the myosin heavy chain interacts with other proteins, including the tail regions of other myosins, to form thick filaments.

Health Conditions Related to Genetic Changes

Freeman-Sheldon syndrome

Variants (also known as mutations) in the MYH3 gene cause Freeman-Sheldon syndrome. This disorder affects muscle and skeletal development before birth and is characterized by abnormalities known as contractures that cause a distinctive facial appearance and deformities of the hands and feet. Contractures result from permanent tightening of muscles, skin, and surrounding tissues, and they restrict movement of the affected body part.

Studies suggest that MYH3 gene variants that cause Freeman-Sheldon syndrome prolong the attachment of myosin to actin, possibly because the variants affect the way myosin uses ATP. Prolonged attachment of myosin to actin keeps the muscle tensed and does not allow it to relax, which prevents movement. It is thought that abnormal muscle contraction and limited muscle and limb movement during development leads to stiffening of the muscles and surrounding tissues, causing contractures characteristic of Freeman-Sheldon syndrome. Researchers suggest that limited muscle movement before birth impairs normal development of other parts of the body, which may account for other features of Freeman-Sheldon syndrome.

Sheldon-Hall syndrome

MYH3 gene variants can cause Sheldon-Hall syndrome, a muscle and skeletal disorder that impairs joint movement in the hands and feet, similar to but milder than Freeman-Sheldon syndrome (described above). The MYH3 gene variants that cause Sheldon-Hall syndrome are believed to interfere with the ability of the myosin-3 protein to attach to actin and other muscle proteins, and may also impair the formation of thick filaments. The variants likely prevent muscle contractions from being controlled and interfere with muscle development before birth, resulting in the contractures and other muscle and skeletal abnormalities associated with Sheldon-Hall syndrome.

Spondylocarpotarsal synostosis syndrome

MedlinePlus Genetics provides information about Spondylocarpotarsal synostosis syndrome

Other Names for This Gene

• HEMHC
• muscle embryonic myosin heavy chain
• MYH3_HUMAN
• MYHC-EMB
• MYHSE1
• myosin heavy chain, fast skeletal muscle, embryonic
• myosin, heavy chain 3, skeletal muscle, embryonic
• myosin, heavy polypeptide 3, skeletal muscle, embryonic
• myosin, skeletal, heavy chain, embryonic 1
• myosin-3
• SMHCE

Genomic Location

Freeman-Sheldon syndrome follows an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases result from new variants in the gene and occur with no history of the disorder in the family. Some affected people inherit the variant from one affected parent. Very rarely, the parent has the gene variant only in some or all of their sperm or egg cells, which is known as germline mosaicism. In these cases, the parent has no signs or symptoms of the condition.

• Small mouth with pursed lips ("whistling face")
• Deep nasolabial folds (the skin between the nose and the lips)
• V-shaped chin dimple
• Abnormally flexed joints (joint contractures)
• Narrow opening for the eye (blepharophimosis)
• Club feet (talipes equinovarus)
• Curvature of the spine

• Craniofacial surgeon
• Orthopedist
• Ophthalmologist
• Otolaryngologist
• Speech language pathologist
• Physical therapist
• Psychologist

Freeman-Sheldon syndrome is a rare disorder. It is estimated to affect 200 to 300 individuals worldwide.