Moebius Syndrome: An Ocular Overview

Sarah Coates

Introduction

Moebius syndrome is a rare congenital neurological disorder whereby there is an underdevelopment or absence of cranial nerve VI (abducens) and cranial nerve VII (facial), leading to weakness or paralysis of facial and extraocular muscles. Abnormalities can also occur in other cranial nerves including the 3rd, 5th, 8th, 9th, 11th and 12th (1, 2). This article will focus upon the ocular manifestations of Moebius syndrome.

Pathophysiology and Aetiology

A case of congenital facial diplegia was first described by Alfred von Graefe, a German Ophthalmologist in 1880. In 1888, a German Neurologist, Paul Julius Mobius, after whom the syndrome was named, drew the connection between congenital facial diplegia and other abnormalities. The aetiology of moebius syndrome has remained enigmatic since (3). Moebius syndrome has an incidence of approximately 2-20 cases per million and has no ethnic or gender bias (4).

The majority of cases are sporadic and are thought to be a result of environmental factors or a dominant ‘de novo’ mutation (5). It has also been found to be inherited in an autosomal dominant pattern (2).

Intrauterine environmental factors proposed include exposure to misoprostol, cocaine, thalidomide, alcohol and infection during pregnancy, leading to blood flow disruption during foetal development, causing hindbrain hypoxia and ultimately cranial nerve nuclei underdevelopment or absence (6, 7, 8). Blood flow disruption could also be secondary to genetic or mechanical factors. Neuroradiological and neuropathological investigations imply that a defect in the development of the entire rhombencephalon causes Moebius syndrome (9, 10).

The National Institute of Neurological Disorders and Stroke (2022) established four classes of Moebius Syndrome (1):

  • Group I: characterized by small or absent brain stem nuclei that control the cranial nerves.
  • Group II: characterized by loss and degeneration of neurons in the facial peripheral nerve.
  • Group III: characterized by loss and degeneration of neurons and other brain cells, microscopic areas of damage, and hardened tissue in the brainstem nuclei.
  • Group IV: characterized by muscular symptoms despite a lack of lesions in the cranial nerve.

Clinical Features

In Moebius syndrome, lagophthalmos, which is the incomplete closure of the eyelids, occurs secondary to a defective cranial nerve VII. A normal blink reflex and the ability to fully close the eye facilitate a healthy ocular surface and a stable tear film. Individuals with lagophthalmos are therefore at risk of dry eyes and subsequent exposure keratopathy leading to potential corneal ulceration (11).

Multiple studies on ocular manifestations of Moebius syndrome demonstrate the following features as the most prominent ophthalmic features; esotropia, abduction limitation, bilateral restriction of abduction and adduction, hyperopic astigmatism, orthotropia and a lack of binocular function (12, 13, 14).

Other Clinical Features: (1, 2)

  • Feeding, swallowing and choking issues
  • Lack of facial expression, inability to smile
  • Eye sensitivity
  • High or cleft palate
  • Hearing problems and speech difficulties
  • Deformities of the tongue, jaw or limbs (clubfoot, micrognathia, syndactyly)
  • Congenital heart disease
  • Global developmental delay
  • Autism

Clinical Diagnosis

Moebius syndrome is a clinical diagnosed. To aid in diagnostic consistency, a diagnostic criterion was formulated by an international group of experts at the Moebius Syndrome Foundation research conference in 2007 (15):

  1. Congenital facial uni- or diplegia, lower motor type in nature
  2. Paralysis of lateral movements of eyes and strabismus due to cranial nerve VI palsy

More recent research proposes for diagnostic criteria to now include “full vertical eye movements” with a diagnosis of Moebius syndrome made if a patient has “a congenital, uni- or bilateral, non-progressive facial weakness and limited abduction of the eye(s) and full vertical motility” (16). A more accurate clinical diagnosis can lead to a more accurate prognosis, enable genetic counselling and permit further research into the aetiology of Moebius Syndrome.

Although Moebius syndrome is a clinical diagnosis, electromyography can be utilised to investigate the timing of injury, but only if it has occurred within 2-6 weeks. Magnetic Resonance Imaging is utilised to investigate for cerebral malformation and other possible pathology (17).

Management

Treatment for Moebius syndrome is tailored to each individual’s presentation. Given the multiple potential cranial nerve, developmental and physical abnormalities, a multidisciplinary team will be utilised to meet the child’s needs.

A bilateral medial rectus muscle recession has yielded positive results for the surgical management of esotropia and has shown good long-term stability (18).

Lagophthalmos can be managed conservatively and medically, including using artificial tears, taping the eyelid closed at night and inserting punctal plugs for persistent dry eyes, with the aim of protecting and lubricating the cornea to prevent exposure keratopathy (19, 20). Surgical intervention, such as a tarsorrhaphy can be performed to provide short or long-term corneal protection (21).

Conclusion

Moebius syndrome is rare and although at present has no cure, if it is recognised early and appropriate care and treatment is given, many individuals can live a normal life expectancy (1). Moebius syndrome is a clinical diagnosis of a congenital non-progressive uni- or bilateral facial weakness, paralysis of abduction of the eye(s) with full vertical motility alongside other clinical findings. Management includes conservative, medical and surgical measures to treat individuals’ abnormalities.

References

  1. National Institute of Neurological Disorders and Stroke. (2022). Moebius Syndrome. Available at: https://www.ninds.nih.gov/health-information/disorders/moebius-syndrome
  2. National Organisation for Rare Diseases (2016). Moebius Syndrome. Available at: https://rarediseases.org/rare-diseases/moebius-syndrome/?filter=ovr-ds-resources
  3. Pitner,S.E. Edwards,J.E. Mccormick,W.F. (1965). Observations on the pathology of the Moebius syndrome. J Neurol Neurosurg Psychiatry. 28:362–74.
  4. Serge,O. Gaurav,S. Sherri,B. (2005). Mobius syndrome. Am J Neuroradiol. 26:430–2.
  5. Veltman,J.A. Brunner,H.G. (2012). De novo mutations in human genetic disease. Nat. Rev. Genet. 13, 565–575.
  6. Puvabanditsin,S. Garrow,E. Augustin,G. Titapiwatanakul,R. Kuniyoshi,K.M. (2005). Poland-Möbius syndrome and cocaine abuse: a relook at vascular etiology. Pediatr. Neurol. 32, 285–287.
  7. Ventura,B.V. et al. (2012). Profile of ocular and systemic characteristics in Möbius sequence patients from Brazil and Italy. Arq. Bras. Oftalmol. 75, 202–206.
  8. Weaver,D.D. (1986). Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and Möbius anomalies. Am. J. Med. Genet. 23, 903–918.
  9. Pedraza,S. et al. (2000). MRI findings in Möbius syndrome: correlation with clinical features. Neurology 55, 1058–1060.
  10. Verzijl,H.T. van der Zwaag,B. Cruysberg,J.R. Padberg,G.W. (2003). Möbius syndrome redefined: a syndrome of rhombencephalic maldevelopment. Neurology 61, 327–333.
  11. Fu,L. Patel,B.C. (2022). Lagophthalmos. Treasure Island (FL): StatPearls Publishing; Available at: https://www.ncbi.nlm.nih.gov/books/NBK560661/
  12. Carta,A. Mora,P. Neri,A. Favilla,S. Sadun,A.A. (2011). Ophthalmologic and systemic features in Möbius syndrome. An Italian case series. Ophthalmology. 20. Pp.1-6
  13. Cronemberger,M.F. de Castro Moreira,J.B. Brunoni,D. Mendonça,T.S. Alvarenga,E.H. Rizzo,A.M. Diogo,S.M. (2001). Ocular and clinical manifestations of Möbius’ syndrome. J Pediatr Ophthalmol Strabismus. 38(3):156-62. doi: 10.3928/0191-3913-20010501-09. PMID: 11386648.
  14. Wright,K.W. (Unkown). Complex strabismus: restriction paresis dissociated strabismus torticollis. Handbook of pediatric eye and systemic disease, pp. 146-227
  15. Miller,G. (2007). Neurological disorders. The mystery of the missing smile. Science. 316:826-7
  16. MacKinnon,S. Oystreck,D.T. Andrews,C. Chan,W.M. Hunter,D.G. Engle,E.C. (2014). Diagnostic distinctions and genetic analysis of patients diagnosed with moebius syndrome. Ophthalmology. 121(7):1461-8. doi: 10.1016/j.ophtha.2014.01.006. PMID: 24612975; PMCID: PMC4082742.
  17. Piña-Garza,J.E. (2013). Fenichel’s Clinical Pediatric Neurology (Seventh Edition).
  18. Lueder,G.T. Galli,M. (2019). Long-term outcomes of strabismus surgery in Mobius sequence. Strabismus. Jun;27(2):43-46. doi: 10.1080/09273972.2019.1599402. PMID: 30958093.
  19. Sadiq,S. (2007). Ophthalmic Management of Facial Nerve Palsy: A Review. Survey of a Ophthalmology. 52(2):121-144.
  20. Sohrab,M. Abugo,U. Grant,M. Merbs,S. (2015). Management of the Eye in Facial Paralysis. Facial Plastic Surgery. 31:140–144.
  21. Lee,V. Currie,Z. Collin,J.R.O. (2004). Ophthalmic Management of Facial Nerve Palsy. Eye. 18: 1225-1234.

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