Freeman-Sheldon syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

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), difficulty gaining weight and growing at the expected rate (faltering weight), 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.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

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.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

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.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

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

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormality of the dentition · Very frequent (99-80%)

Any abnormality of the teeth.

Camptodactyly of finger · Very frequent (99-80%)

The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers cannot be extended to 180 degrees by either active or passive extension.

Chin dimple · Very frequent (99-80%)

A persistent midline depression of the skin over the fat pad of the chin.

Depressed nasal ridge · Very frequent (99-80%)

Lack of prominence of the nose resulting from a posteriorly-placed nasal ridge.

Downslanted palpebral fissures · Very frequent (99-80%)

The palpebral fissure inclination is more than two standard deviations below the mean.

Failure to thrive · Very frequent (99-80%)

Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.

Feeding difficulties in infancy · Very frequent (99-80%)

Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.

Growth delay · Very frequent (99-80%)

A deficiency or slowing down of growth pre- and postnatally.

Other findings in the same source

From: Orphanet

Additional reported features include Hypertelorism (Very frequent (99-80%)); Joint stiffness (Very frequent (99-80%)); Narrow mouth (Very frequent (99-80%)); Scoliosis (Very frequent (99-80%)); Talipes equinovarus (Very frequent (99-80%)); Ulnar deviation of finger (Very frequent (99-80%)); Underdeveloped nasal alae (Very frequent (99-80%)); Wide nasal bridge (Very frequent (99-80%)); Abnormality of speech or vocalization (Frequent (79-30%)); Cryptorchidism (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Freeman-Sheldon syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Freeman-Sheldon syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.