Mobius syndrome is caused by abnormal development of the cranial nerves. This rare disorder has a number of causes. Most often affected are the cranial nerves VI and VII. Occasionally the cranial nerves V and VIII are affected.

If the cranial nerve VI is affected, the patient suffers from loss of lateral gaze. If cranial nerve VII is affected, the patient suffers from bilateral facial palsy — mask-like expressionless face with mouth constantly held open. If cranial VIII is affected the patient suffers from hearing loss.

Although its rarity often leads to late diagnosis, Infants with this disorder can be identified at birth: by a "mask-like" expression detectable during crying or laughing due to paralysis (palsy) of the sixth and seventh cranial nerves. Other characteristics include:

abnormalities in the limbs — their fingers may be webbed, shorter than usual or they may have more than 5 fingers on their hand
impaired sucking ability
inability to follow objects with the eye—instead the child turns his or her head to follow
crossed eyes
inability to smile
limitation of tongue movement

Later on, the child may develop speech difficulties, crossed eyes, abnormally small eyes, and fluid building up in the lungs, causing bronchopneumonia.

Treatment

There is no specific course of treatment for Mobius syndrome. Treatment is supportive and in accordance with symptoms. Infants may require feeding tubes or special bottles, such as the Haberman Feeder, to maintain sufficient nutrition. Surgery may correct crossed eyes and improve limb and jaw deformities. Physical and speech therapy often improves motor skills and coordination, and leads to better control of speaking and eating abilities. Plastic reconstructive surgery may be beneficial in some individuals. Nerve and muscle transfers to the corners of the mouth have been performed to provide limited ability to smile.

Pathological picture

The causes of Mobius syndrome are poorly understood. Many cases have no obvious cause. Others may be genetic.

Some cases are associated with reciprocal translocation between chromosomes or maternal illness. Some maternal trauma may result in impaired or interrupted blood flow (Ischemia) or lack of oxygen (Hypoxia) to a developing fetus. The use of drugs and a traumatic pregnancy may also be linked to the development of Mobius syndrome. The use of the drugs Misoprostol or Thalidomide by women during pregnancy has been linked to the development of Mobius syndrome in some cases.

Some researchers have suggested that the underlying problem of this disorder could be congenital hypoplasia or agenesis of the cranial nerve nuclei. Certain symptoms associated with Mobius syndrome may be caused by incomplete development of facial nerves, other cranial nerves, and other parts of the central nervous system.

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Pathologic quiz case: A child with facial and proximal limb weakness
From Archives of Pathology & Laboratory Medicine, 6/1/03 by Mitra, Sudeshna

The patient was a 6-year-old right-handed girl who presented with a slowly progressive drooping of the left side of her mouth of 9 months' duration. Review of photographs and prior medical records revealed that this facial asymmetry had in fact been present since 2 years of age. At age 5, she was treated with a course of oral steroids, based on a clinical diagnosis of Bell palsy. Magnetic resonance imaging of the brain performed at that time was normal. Retrospectively, the patient's mother mentioned having noticed bilateral incomplete eye closure in the patient when she slept since age 1 year. She later had difficulty unrolling "party favors" when she blew on them. There was no history of limb weakness, diplopia, fatigability, dysphagia, or excessive falling. She had never experienced any difficulty in ascending stairs or getting up from a squatting position. Early developmental milestones were normal, and she walked independently before her first birthday.

The patient was born at term by normal vaginal delivery with a birth weight of 3.24 kg. Antenatally, she was noted to have a fetal heart rate irregularity on one occasion, but an electrocardiogram shortly after birth was normal. Antenatal ultrasound was normal, and fetal movements were perceived to be normal. Postnatally, there were no breathing or feeding difficulties. The family history was unremarkable for any neurologic or neuromuscular disorders. The patient has 1 younger maternal half-brother who is healthy.

On examination, she was nondysmorphic. Her height, weight, and head circumference were appropriate for a girl her age. She had facial diplegia, with the left side being more affected than the right. Her smile was horizontal and, on eye closure, there was a weak burying of her eyelashes (Figure 1). Motor examination showed proximal weakness of upper and lower extremities, with a Medical Research Council grade 4/5 power of neck flexion, shoulder abduction, shoulder external rotation, hip flexion, and hip abduction. All other muscle groups were of normal strength. There was no scapular winging. Muscle tone was normal. Calves were mildly prominent bilaterally, and she had a positive Gowers sign. Sensory, cerebellar, and gait examinations were normal. Deep tendon reflexes were difficult to elicit in the upper extremities, absent at the knees, and normal at the ankles. An ophthalmologic evaluation was normal. Investigations showed a normal electrocardiogram and echocardiogram. Serum lactate dehydrogenase was 330 U/L (normal, 35-250 U/L), and creatine kinase was 663 U/L (normal, 7-220 U/L).

The muscle biopsy showed chronic myopathic features including focal increased endomysial fibrofatty tissue (Figures 2 and 3). There were numerous atrophic muscle fibers interspersed with hypertrophic fibers. Rare degenerating and scattered regenerating fibers were seen. Scattered foci of endomysial and perivascular chronic inflammation consisting of lymphocytes and macrophages were noted. Immunoperoxidase studies showed normal membranous patterns of staining with antibodies to dystrophin, P-dystroglycan, merosin, and alpha-, beta-, gamma, and delta-sarcoglycans. Specific genetic testing (Southern immunoblot) showed a deletion on chromosome 4q35. The mother's genetic test and creative kinase levels were normal. The father was not available for testing.

What is your diagnosis?

Pathologic Diagnosis: Facioscapulohumeral Dystrophy

The muscular dystrophies are a heterogeneous group of inherited disorders characterized by progressive muscle weakness. Historically, they have been classified on the basis of clinical presentation and mode of inheritance. The best known of these, Duchenne/Becker muscular dystrophy, is X-linked, as is the common form of Emery-Dreifuss muscular dystrophy. There are a number of autosomal-- dominant muscular dystrophies including limb-girdle muscular dystrophy type I, myotonic dystrophy, autosomal-dominant Emery-Dreifuss muscular dystrophy, and facioscapulohumeral dystrophy (FSHD). The common recessive muscular dystrophies include limb-girdle muscular dystrophy type 2 and congenital muscular dystrophy. In many of these disorders, the gene has been cloned and the gene product identified. An alternate classification has been proposed based on the deficient protein.1

After Duchenne and myotonic dystrophy, FSHD is the most common form of muscular dystrophy. The age of onset, the severity, and, to some extent, the distribution of muscle weakness show both intra- and interfamilial variability. The typical manifestation is early involvement of facial and scapular muscles, with subsequent proximal muscular involvement including biceps, triceps, and eventually pelvic girdle muscles. The exception to this is the early involvement of the tibialis anterior muscle. An asymmetric pattern of muscle involvement is frequent and often striking. Bulbar, extraocular, masseter, temporalis, and respiratory muscles are usually spared. Besides a rare association with Coats disease, with or without sensorineural hearing loss, extramuscular manifestations do not occur. Cardiac muscle is not involved in most cases, although arrhythmias have been reported. The disease progresses very slowly and is often interrupted by periods of arrests in progression.2,3 Up to one third of the individuals carrying the genetic mutation are asymptomatic, but 95% show evidence of weakness on clinical examination by 20 years of age.4 The insidious onset, slow progression, and characteristic pattern of asymmetric weakness are typical of FSHD and were all observed in the patient described. However, she did not have any significant weakness of scapular fixators.

Routine laboratory tests are generally unrevealing in FSHD. Serum creative kinase levels are elevated in 50% and serum lactate dehydrogenase in 20% of patients.5 In our patient, the creative kinase level was elevated to 3 times the upper limit of normal, and there was a mild elevation of serum lactate dehydrogenase. Muscular dystrophies, as a group, demonstrate chronic myopathic features including variation in muscle fiber size, fiber necrosis or degeneration, regeneration of muscle fibers, and partial replacement of muscle by fibrofatty tissue. In FSHD and limb-girdle 2B muscular dystrophy, inflammatory cells are a more prominent feature. The muscle biopsy findings are not pathognomonic in FSHD, but they confirm the presence of a dystrophic process and help exclude certain congenital myopathies that may present with an FSHD-like clinical phenotype. The presence of inflammatory cells in the endomysium and around the blood vessels raises the possibility of an inflammatory myopathy such as polymyositis. Perifascicular atrophy, typical of dermatomyositis, was not observed in our patient, and rimmed vacuoles and tubulofilaments suggestive of inclusion body myositis were not seen. Although 75% of FSHD biopsies will have some inflammatory cell infiltration,6 there are no non-necrotic muscles invaded by lymphocytes as seen in polymyositis. The duration of illness and facial weakness also make polymyositis clinically unlikely. Muscles that are known to be spared in FSHD, such as the deltoid, or those that are already at end stage should not be biopsied.

The underlying defect of FSHD has been identified as a partial deletion of multiple copies of a tandem repeat built up from 3.3-kilobase (kb) units (D4Z4) in the subtelomeric region of chromosome 4q.(7) Neither the specific gene nor the protein product has been identified. The deletion can be demonstrated in leukocyte DNA and is present in 85% to 95% of affected individuals in both sporadic and familial cases.4 Recently, other disorders marked by muscular weakness have been reported in patients with this deletion.8 In our patient, DNA testing using Southern blot analysis was performed. DNA was double digested with EcoRI and EcoRI/BInI restriction enzymes (University of Iowa). Cleavage with these 2 enzymes allows distinction of the 4q35 locus from a homologous repeat on chromosome 10q26. A standard probe pl3E-11 was used to hybridize these digests. Restriction fragment lengths of 14 and 11 kb were detected. It has been suggested that in FSHD-associated deletions, probe pl3E-11 detects EcoRI fragments in the length of 10 to 27 kb, while in normal individuals, the restriction fragments are 30 to 300 kb.9 The double-digestion method approaches a sensitivity of 95% and a specificity of 100%.(10) The deleted repeat region appears to be in a part of the chromosome where DNA is compacted and transcriptionally inactive. If the deletion does not disrupt a functioning gene, then how does it result in disease phenotype? It has been postulated that a change in chromosomal structure interferes with the expression of a gene in a proximal location, thereby impairing function.

References

1. Emery AEH. The muscular dystrophies. Lancet. 2002;359:687-695.

2. Munsat TL. Facioscapulohumeral dystrophy. In: Engel AG, Franzini-Armstrong C, eds. Myology. 2nd ed. New York, NY: McGraw Hill; 1994:1220-1232.

3. Kissel JT. Facioscapulohumeral dystrophy. Semin Neurol. 1999;49:35-43.

4. Tawil R, Figlewicz DA, Griggs RC, et al. Facioscapulohumeral dystrophy: a distinct regional myopathy with a novel molecular pathogenesis. Ann Neurol. 1998;43:279-282.

S. Munsat TL, Baloh R, Pearson CM, et al. Serum enzyme alterations in neuromuscular disorders. JAMA. 1973;226:1536-1543.

6. Arahata K, Ishihara T, Fukunaga H, et al. Inflammatory response in facioscapulohumeral muscular dystrophy (FSHD): immunocytochemical and genetic analyses. Muscle Nerve. 1995;2:556-566.

7. Orrell RW, Tawil R, Forrester BS, et al. Definitive molecular diagnosis of facioscapulohumeral dystrophy. Neurology. 1999;52:1822-1826.

8. Felice KJ, Moore SA. Unusual clinical presentations in patients harboring the facioscapulohumeral dystrophy 4q35 deletion. Muscle Nerve. 2001;24:352356.

9. Wijmenga C, Hewitt JE, Sandkuijl LA, et al. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet. 1992;2:26-30.

10. Upadhyaya M, Maynard J, Rogers MT, et al, Improved molecular diagnosis of facioscapulohumeral muscular dystrophy (FSHD): validation of the differential double digestion for FSHD. J Med Genet. 1997;34:476-479.

Sudeshna Mitra, MD; Richard A. Prayson, MD; Neil R. Friedman, MD

Accepted for publication September 6, 2002.

From the Departments of Pediatric Neurology (Drs Mitra and Friedman) and Anatomic Pathology (Dr Prayson), Cleveland Clinic Foundation, Cleveland, Ohio.

Corresponding author: Richard A. Prayson, MD, Department of Anatomic Pathology (L25), Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195 (e-mail: praysor@cesmtp.ccf.org).

Reprints not available from the author.

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