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Show Journal of Neiiro- Ophlluilmology 18( 4): 281- 283, 1998. © 1998 Lippincoll Williams & Wilkins, Philadelphia Mobius Syndrome With Oculomotor Nerve Paralysis Without Abducens Paralysis Dan B. Tran, M. D., Martin C. Wilson, M. D., Catherine A. Fox, M. S., OTR/ L, Robert Clancy, M. D., James W. Teener, M. D., Jeffrey A. Golden, M. D., and Grant T. Liu, M. D. Mobius syndrome is typified by bilateral facial nerve palsies, usually with abducens palsies. We examined an infant with Mobius syndrome who had bifacial weakness and third nerve palsies, but intact abduction of both eyes. Lower cranial nerve involvement, leading to respiratory, swallowing, and cardiac difficulties, was also present. Pathologic examination of the brainstem showed absent or hypoplastic third, seventh, tenth, and twelfth nerve nuclei. The fourth, fifth, sixth, and eighth nerve nuclei were intact. In Mobius syndrome with ocular motor palsies, rarely the sixth nerve may be spared. Mobius syndrome was classified by Mobius in 1888 ( I). The main feature is congenital bilateral facial nerve palsies, often with abducens palsies. The clinical features were later expanded to include multiple cranial nerve defects ( 2), craniofacial malformations with limb anomalies ( 3), and somatoskeletal dysmorphic features ( 4). We report a case of congenital bilateral facial nerve and pupil- sparing oculomotor nerve palsies without abducens palsies. CASE REPORT The patient was delivered via Caesarean section at 42 weeks of gestational age. The mother was a G4P2 with negative syphilis, hepatitis, and HIV serologies. The baby girl was noted to have poor respiratory effort and was intubated shortly after birth. Her Apgar scores were 2 at 1 minute, 3 at 5 minutes, and 6 at 10 minutes. Her subsequent hospital course was significant for hypotensive episodes. The patient was noted to have poor eye opening, and Manuscript received October 20, 1997; accepted April 29, 1998. From the Scheie Eye Institute ( D. B. T., M. C. W., G. T. L.); the Pediatric Ophthalmology ( M. C. W.), Neurology ( R. C.), Pathology ( J. A. G.), and Neuro- ophthalmology ( G. T. L.) services of The Children's Hospital of Philadelphia; the Department of Neurology ( J. W. T., G. T. L.), Hospital of the University of Pennsylvania; and The Pediatric Center for Dysphagia and Feeding Management ( C. A. F.), Children's Seashore House, Philadelphia, Pennsylvania. Address correspondence to Dr. Liu, Division of Neuro-ophthalmology, Department of Neurology, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104. neuro- ophthalmic evaluation showed bilateral ptosis with no facial movements on either side. She had a large angle exotropia with adduction, elevation, and depression deficits ( Fig. 1). Her pupils were reactive to light without an afferent pupillary defect. Her anterior segment and fundus exams were normal without coloboma. Electromyographic studies ( EMG) were performed showing markedly reduced or absent innervation of facial muscles. A few motor units were detected in lower facial muscles, but no voluntary EMG activity was identified in upper facial muscles. The results of a Edrophonium ( Tensilon) test were negative, and her electroencephalogram results were normal. Magnetic resonance imaging prior to discharge showed a right frontal subdural hematoma, thin corpus callosum, and normal optic chiasm, pons, and midbrain. Chromosomal analysis was unremarkable. In the neonatal intensive care unit, the patient had poor respiratory effort associated with a large floppy epiglottis and normal cord mobility with multiple failed attempts at extubation; she subsequently underwent successful tracheostomy. A swallowing study showed no pharyngeal mobility, with subglottic aspiration, and a G- tube was placed without complication. On subsequent exam at the age of 6 months, the patient continued to have complete bilateral ptosis and no facial strength bilaterally. She preferred her right eye and the left eye was markedly exotropic. She continued to have bilateral adduction, supraduction, and infraduction deficits. Her pupils were 3 mm and reactive. She had no intorsion of either eye on attempted downgaze, but this part of the examination was difficult. Alternate patching of her eyes was recommended. She had been noted to have several episodes of bradycardia throughout the day with episodes of apnea at night. At age 2 years, the patient died unexpectedly in her sleep, and an autopsy was performed. The brain, and the brainstem in particular, showed no gross abnormalities. Histologic section from the cerebral hemispheres, basal ganglia, thalamus, and cerebellum were unremarkable. Sections of the brainstem showed cranial nerve nuclei four, five, six ( Fig. 2A), and eight to be unremarkable. In contrast, there was a relative paucity of cells in the third nerve nucleus, particularly in the dorsal lateral regions. A 281 282 D. B. TRAN ET AL. FIG. 1. Photograph depicting infant with bifacial paresis and ptosis. The eyes are exotropic, and the pupils are small and reactive to light. few reactive astrocytes were seen in the third nerve nucleus, a finding confirmed with immunohistochemis-try using an antibody to glial fibrillary acid protein ( data not shown). The seventh nerve nucleus was remarkable for a nearly complete absence of neurons with no evidence of a glial reaction ( Fig. 2B). These changes are indicative of a primary failure of the nucleus to form or possibly of very early embryonic injury. The twelfth nerve nucleus showed similar findings to those seen in the seventh nerve nucleus. The dorsal motor nucleus of the tenth nerve showed neuronal loss and reactive gliosis similar to that seen in the third nerve nucleus. No other pathologic changes were seen in the midbrain or brainstem. DISCUSSION In addition to congenital facial diplegia, abducens nerve palsy is the feature most commonly associated with Mobius syndrome, occurring in 82% of the cases in the series reported by Henderson ( 2). In addition, total external ophthalmoplegia occurred in 25% of the cases, oculomotor palsy in 21%, and bilateral ptosis in 10%. Our patient had bilateral pupil- sparing oculomotor and facial nerve palsies. Clinically, abducens nerve function was normal. The facial nerve paralysis was confirmed by EMG studies. Pathologic examination confirmed absence or hypoplasia of the third, seventh, tenth, and twelfth nerves, but preservation of the fourth, fifth, sixth, and eighth nerves. We have found only one other case report in the En- ./ Neiiro- Ophllwlmol, Vol. 18, No. 4, 1998 glish language literature of Mobius syndrome with oculomotor and facial nerves palsies without abducens palsies. This patient also had bilateral disc colobomas ( 5). According to this report ( 5), the EMG studies were refused. They also mentioned that there was only one other case of oculomotor paralysis and facial nerve palsy without abducens palsies diagnosed as Mobius syndrome in the German literature ( 6). The etiology of Mobius syndrome remains unclear but is probably multifactorial. The major theories regarding pathogenesis include primary brainstem nuclear hypoplasia, secondary brainstem nuclear degeneration, brainstem atrophy secondary to peripheral neuromuscular defect, and vascular insufficiency prior to the sixth week of gestation affecting certain brainstem structures ( 7,8). A cluster of familial cases challenge these theories and continue to suggest genetic predisposition ( 9). Neuropatho-logic studies ( 10,11) have shown that brain- stem atrophy and multiple brain- stem mineralized necrotic foci can be associated with Mobius syndrome. These studies support the hypothesis that Mobius syndrome in some patients could be the result of intrauterine asphyxia ( 11). Radiologic abnormalities of the brain- stem in Mobius syndrome have been reported including brain- stem hypoplasia and calcification ( 7). Towfighi et al. ( 10) classified the neuropathologic findings in 15 autopsy cases cited in the literature into four groups. The first three groups support the anterograde theory of dysmorphogenesis in Mobius syndrome with primary developmental lesions in the cranial nerve nuclei causing secondary damage to the peripheral musculature. Sudarshan and Goldie ( 12) proposed that the fourth group, consisting of patients with myopathy, should be classified in a separate category because these cases have clinical features similar to congenital muscu- FIG. 2. Photomicrographs of the sixth and seventh nerve nuclei. ( A) The sixth nerve nucleus shows a normal population of large neurons. ( B) The seventh nerve nucleus shows a subtotal depletion of neurons without secondary reactive changes. The arrows point to remaining large neurons. Several smaller neurons are also seen in the background. The pathologic findings were the same on both sides of the brainstem. ( A and B; Kluver stain, 200x) MOBIUS SYNDROME 283 lar dystrophy or congenital myopathies. No lesions were found in the brainstem or cranial nerves of this group. The pathologic findings in our patient are consistent with two possible mechanisms, although both are highly conjectural. The absence of neurons without gliosis in some locations might have resulted from an abnormality in the genetic programming for development of those cranial nerve nuclei. However, nuclei that showed a reduced number of neurons with gliosis suggest these nuclei were the target of some secondary destructive process. With either mechanism, it is unclear why some nuclei were selectively spared. In conclusion, this patient with pathologic confirmation expands the boundaries on the pattern of cranial nerve involvement in Mobius syndrome. This syndrome is probably a part of the spectrum of congenital neuromuscular disorders, often with unknown etiology. REFERENCES 1. Mobius PJ. Uber angeborenen doppelseitige abducens- facialis- Lahnumg. Munchen Med Wochenschr 1888; 35: 91- 4, 108- 11. 2. Henderson JL. The congenital facial diplegia syndrome: clinical features, pathology and etiology. Brain 1939; 62: 381^- 03. 3. Jones KL. Smith's recognizable patterns of hitman malformations. 4th ed. Philadelphia: W. B. Saunders, 168- 9. 4. Miller MX, Ray V, Owens P, Chen F. Mobius and Mobius- like syndromes ( TTV- OFM, OMLH). J Pediat Ophthalmol Strabismus 1989; 26: 176- 88. 5. Ten Tusscher MPM, Houlman AC, Van Oostcnbrugge R. I, Wilm-ink JT. Oculofacial paralysis with simultaneous bilateral abduction in Bell's phenomenon and bilateral disc colobomas. Neuro-ophthalmology 1993; 13: 297- 302. 6. Papst W, Esslen E. Elcktromyographischcr Beilrag zum Mobius Syndrome. Klin Mbl Augenheilk 1960; 137: 401- 410. 7. D'Cruz OF, Swisher CN, Jaradeh S, Tang T, Konkol RJ. Mobius syndrome: evidence for a vascular etiology. ,/ Child Neurol 1993; 8: 260- 4. 8. Charles S, DiMario Jr FJ, Grunnct ML. Mobius sequence: further in vivo support for the subclavian artery supply disruption sequence. Am .] Med Genetics 1993; 47: 289- 93. 9. MacDermot KD, Winter RM, Taylor D, Baraitser M. Oculofacial-bulbar palsy in mother and son: review of 26 reports of familial transmission within the ' Mobius spectrum of defects'. ./ Med Genetics 1990,27: 18- 26. 10. Towfighi J, Marks K, Palmer E, Vannucci R. Mobius syndrome: neuropathologic observations. Acta Neuropathol I979; 48: l 1- 7. 11. Wilson ER, Mirra SS, Schwartz JF. Congenital diencephalic and brain stem damage: neuropathologic study of three cases. Acta Neuropathol 1982; 57: 7( M. 12. Sudarshan A, Goldie WD. 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