NORD gratefully acknowledges John B. Mulliken, MD, Director, Craniofacial Centre, Department of Plastic Oral Surgery, Boston Children’s Hospital, and Ingrid Ganske, MD, Craniofacial Fellow, Boston Children’s Hospital, for their assistance in the preparation of this report.
Moebius syndrome is a rare neurological disorder characterized by weakness or paralysis (palsy) of multiple cranial nerves, most often the 6th (abducens) and 7th (facial) nerves. Other cranial nerves are sometimes affected. The disorder is present at birth (congenital). If the 7th nerve is involved, the individual with Moebius syndrome is unable to smile, frown, pucker the lips, raise the eyebrows, or close the eyelids. If the 6th nerve is affected, the eye cannot turn outward past the midline. Other abnormalities include underdevelopment of the pectoral muscles and defects of the limbs. Moebius syndrome is not progressive. The exact cause is unknown. It appears to occur randomly (sporadically) in most cases; however, some cases occur in families suggesting that there may be a genetic component.Introduction
Congenital facial and abducens palsy was first described by Von Graefe (1880) and Moebius (1888), a German neurologist after whom the syndrome was later named.
The abnormalities and severity of Moebius syndrome vary greatly from one person-to-another. The classically accepted diagnostic criteria include: 1) facial paralysis or weakness affecting at least one but usually both sides of the face (7th cranial nerve), 2) paralysis of sideways (lateral) movement of the eyes (6th cranial nerve); and 3) preservation of vertical movements of the eyes. Less often, other cranial nerves, including the 5th, 8th, 9th, 10th, 11th, and 12th may be affected.
Infants with Moebius syndrome may drool excessively and exhibit crossed eyes (strabismus). Because the eyes do not move from side-to-side (laterally), the child is forced to turn the head to follow objects. Infants who lack facial expression often are described as having a “mask-like” face that is especially obvious when laughing or crying. Affected infants may also have difficulties feeding, including problems swallowing and poor sucking. Corneal ulceration may occur because the eyelids remain open during sleep.
There are a wide variety of additional abnormalities. Some children with Moebius syndrome have a short, malformed tongue and/or an abnormally small jaw (micrognathia). Cleft palate may also be present. These abnormalities contribute to feeding and breathing difficulties. Children with cleft palate are prone to ear infections (otitis media). There may be external ear anomalies including underdevelopment of the outer portion of the ear (microtia) or total absence of the outer portion of the ear (anotia). If the 8th cranial nerve is affected, there is likely hearing loss. Dental abnormalities are not uncommon. There is an increased risk for childhood cavities. Some affected children have difficulties with speech and delays in speech development.
Skeletal malformations of the limbs occur in over half of children with Moebius sydrome. Lower limb malformations include clubbed feet and underdevelopment of the lower legs; upper extremities may have webbing of the fingers (syndactyly), underdevelopment or absence of the fingers, and/or underdevelopment of the hand. In a few children there may be abnormal side-to-side curvature of the spine (scoliosis), and in approximately 15% of patients underdevelopment of the chest (pectoral) muscles and the breast on one side of the body also occur (see Poland-Moebius syndrome in the Related Disorder section below).
Some affected children exhibit delay in attaining certain milestones such as crawling or walking, most likely due to upper body weakness; however, most children eventually catch-up. Moebius syndrome rarely is associated with minor intellectual disability. Some children have been classified as being on the “autistic spectrum”. The exact relationship between Moebius syndrome and autism is unknown. Some studies have suggested that autism spectrum disorders occur with greater frequency in children with Moebius syndrome; other studies have not confirmed this and suggest that any such relationship is overstated. Moebius syndrome is often associated with a variety of social and psychological consequences. The lack of facial expressions and the inability to smile can cause observers to misinterpret what an affected individual is thinking or feeling or intends. Although clinical anxiety and depression are not more common in children and adolescents with Moebius syndrome, affected individuals may avoid social situations due to apprehension and frustration.
Most cases of Moebius syndrome occur randomly for unknown reasons (sporadically) in the absence of a family history of the disorder. The syndrome is listed as Online Mendelian Inheritance in Man (OMIM) Number 15700, with a gene map locus of 13q12.2-q13. Sporadic mutations in PLXND1 and REV3L genes have also been identified in a number of patients and confirmed to cause a constellation of findings consistent with Moebius syndrome when introduced in animal models.
In rare cases, familial patterns have been reported. Most likely, Moebius syndrome is multifactorial, which means that both genetic and environmental factors play some causative role. It is possible that in different cases there are different underlying causes (heterogeneity).
In familial cases, there is evidence that Moebius syndrome is inherited as an autosomal dominant trait. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
The spectrum of findings in Moebius syndrome suggests a developmental defect of the hindbrain. Several different theories have been proposed to explain the cause of Moebius syndrome. One hypothesis is the disorder is the result of diminished or interrupted blood flow (ischemia) to the developing fetus during pregnancy (in utero). Recent research suggests that the lack of blood affects certain areas of the lower brainstem that contain the cranial nerve nuclei. This lack of blood flow could result from an environmental, mechanical or genetic cause. Nevertheless, cause of the syndrome remains inconclusive and more basic and clinical research is necessary.
Moebius syndrome affects males and females in equal numbers. The disorder is present at birth (congenital). The exact incidence and prevalence rates of Moebius syndrome are unknown. One estimate places the incidence at 1 case per 50,000 live births in the United States.
A diagnosis of Moebius syndrome is based upon the characteristic signs/symptoms, a detailed patient history, and a thorough clinical evaluation. There are no diagnostic tests that confirm a diagnosis of Moebius syndrome. Some specialized tests may be performed to rule out other causes of facial palsy.
The treatment of Moebius syndrome is directed toward the specific abnormalities in each individual. Usually these children are managed by a multidisciplinary team, often in a craniofacial center. Involved specialists include: pediatricians; neurologists; plastic surgeons; ear, nose, and throat specialists (otolaryngologists); orthopedists; dental specialists; speech pathologists; specialists who assess and treat hearing problems (audiologists), specialists who treat eye abnormalities (ophthalmologists) and other healthcare professionals.
Corrective procedures for facial paralysis involve transfer of muscle and/or graft nerves from another area of the face or the body. An old procedure, known as temporalis tendon transfer, involves taking the temporalis muscle, one of the muscles normally used for chewing (mastication), and transferring it to the corners of the mouth. This same type of operation can be also used to improve closure of the eyelids. If the paralysis is on only one side (unilateral), a “cross-facial nerve graft” is an option. The procedure involves taking a sensory nerve from the calf, attaching it to a branch of the functioning facial nerve on the normal side of the face and then waiting until the regenerating nerve fibers cross over the face to reach the paralyzed side where it is joined to a motor nerve of a thin muscle transferred to the face by microvascular anastomosis.
The most recent procedure, called “the smile operation”, involves microvascular transfer of a muscle from the thigh (gracillis) to the face and connecting the nerves that normally supply the masseter muscle (one of the muscles used for chewing). This operation has shown remarkable results in terms of speech, facial mobility and self-esteem. Frequent lubrication for dry eyes is often necessary.
Physical therapy may be needed for individuals with various orthopedic abnormalities. Occupational therapy may also be beneficial, especially in patients with abnormalities of the hands, fingers and toes. Speech therapy may be necessary for some affected children. Strabismus is usually surgically correctable, although some physicians recommend delaying these procedures as the condition sometimes improves with age. Operations may also be necessary for the various skeletal malformations affecting the limbs and jaws. Specialized procedures to correct abnormalities and/or underdevelopment of the chest wall and breast are available.
Splints, braces and prostheses may be necessary for individuals with congenital limb abnormalities. Genetic counseling may be of benefit for affected individuals and their families.
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