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Considerations on the etiology of congenital Brown syndrome

Coussens, Traceya,b; Ellis, Forrest J.a,b

Current Opinion in Ophthalmology: July 2015 - Volume 26 - Issue 5 - p 357–361
doi: 10.1097/ICU.0000000000000191
PEDIATRICS AND STRABISMUS: Edited by Bruce M. Schnall
Editor's Choice

Purpose of review Brown syndrome is an ocular motility disorder characterized by limited volitional and passive elevation of the eye in adduction. Although originally thought due to abnormalities in the trochlea or tendon sheath (limiting the free movement of the tendon through the trochlea), recent evidence suggests that some cases of congenital Brown syndrome may be related to neurodevelopmental abnormalities of the extraocular muscles (congenital cranial dysinnervation disorders, CCDD).

Recent findings CCDD is a term encompassing congenital abnormalities of eye movements caused by congenital innervational abnormalities. The abnormal development of cranial nerve nuclei or abnormalities in cranial nerve axonal transport affects the development of the extraocular muscle(s). Currently, congenital fibrosis of the extraocular muscles, Duane syndrome, Moebius syndrome, Horizontal gaze palsy and progressive scoliosis, and synergistic divergence are included as CCDDs. In addition, congenial ptosis, Jaw Wink ptosis, and congenital superior oblique palsy are also included. Recently, it has been suggested that some cases of congenital Brown syndrome and congenital superior oblique paresis are related, and these entities may be part of the CCDDs spectrum.

Summary Important findings regarding the cause of congenital Brown syndrome will be reviewed.

aNorthern Virginia Ophthalmology Associates

bInova FairFax Hospital for Children, Falls Church, Virginia, USA

Correspondence to Forrest J. Ellis, MD, Northern Virginia Ophthalmology Associates, 6231 Leesburg Pike, Suite 608, Falls Church VA, VA 22044, USA. Tel: +1 703 534 3900; e-mail: Jellis1217@aol.com

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INTRODUCTION

Brown syndrome is an ocular motility disorder characterized by limited active and passive elevation of the eye in adduction. It was originally thought due to abnormalities in the trochlea or tendon sheath (limiting the free movement of the tendon through the trochlea) [1]. Brodsky et al. [2] observed synkinetic eye movements in patients with congenital fibrosis of the extraocular muscles (CFEOM). He surmised that abnormal innervation of the extraocular muscles may underlie the pathologic features of the congenital fibrosis syndromes. Now referred to as congenital cranial dysinnervation disorders (CCDDs), these include congenital fibrosis syndrome and related disorders [3], all known to arise from abnormal development of individual or multiple cranial nerve nuclei or abnormalities in cranial nerve axonal transport [4]. Recent evidence suggests that some cases of congenital Brown syndrome may be related to these neurodevelopmental abnormalities of the extraocular muscles (CCDD) [5].

Box 1

Box 1

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CONGENITAL CRANIAL DYSINNERVATION DISORDERS

The umbrella term, congenital cranial dysinnervation disorders, include related conditions, which share common findings: absence or hypoplasia of one or more cranial nerves, limitation of extraocular movements, synkinetic eye movements, and/or hypoplasia of one or more extraocular muscles. Although many different CCDDs have been described, a few important and relevant types will be briefly described.

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Cause

The primary disorder in CCDDs is innervational. The abnormal development of the cranial nerve nuclei or abnormalities in cranial nerve axonal transport affects the development of the extraocular muscle [6].

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Types of congenital cranial dysinnervation disorders

Congenital fibrosis

CFEOM is a distinctive CCDD. This disorder is characterized by congenital nonprogressive ophthalmoplegia and ptosis. As a result of muscle stiffness and inelasticity, it was originally considered a restrictive process. We now know that the oculomotor nerve nucleus (or part thereof) does not develop properly, resulting in an absent or hypoplastic oculomotor nerve. Without proper innervation, the muscle(s) normally innervated by the nerve(s) is hypoplastic and underdeveloped. Consequently, the antagonist muscle develops unopposed and presents as contractured, inelastic, and taught (seemingly fibrotic). Several genes have been implicated in CFEOM, including KIF21A, PHOX2A, TUBB3, and TUKUS [6,7▪]

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Duane syndrome

Clinical features of Duane syndrome are deficits of abduction, adduction, or both. With attempted adduction, the globe retracts and the lid fissure narrows due to relative enophthalmos from the simultaneous contraction of both the medial and lateral rectus muscles. In patients with Duane syndrome, the abducens nerve has been found either hypoplastic or absent on magnetic resonance imaging (MRI) [8]. The motility defects are caused by aberrant innervation of the lateral rectus from a branch of the oculomotor nerve. It is usually unilateral, occasionally familial, and often associated with other development disorders. Several genes have been found to have the Duane syndrome phenotype, including CHN1 and HOXA1 [7▪]. MRI of the muscles suggests that the superior oblique is affected in some patients with Duane syndrome (DRS). In a series of 11 patients with DRS type 1 and DRS type 2, 10 had superior oblique hypoplasia [9]. Another study of the DURS2 genotype found four of eight patients studied had superior oblique hypoplasia [10]. Superior oblique volume was decreased in three of five patients with Duane syndrome and a CHN1 mutation [11].

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Congenital superior oblique paresis

Patients with congenital superior oblique palsy exhibit a hypertropia of the affected eye, which is worse on contralateral gaze and with ipsilateral tilt of the head. There is often superior oblique underaction and inferior oblique overaction on versions and extorsion is observed on fundus exam. Abnormalities in the superior oblique tendon are often present. Helveston observed abnormalities in 87% of surgical subjects with congenital superior oblique paresis (SOP) [12]. Findings included superior oblique tendon redundancy, misdirection, and abnormal insertion of the tendon on the globe. Tendon laxity on traction test was observed in 14 congenital cases of SOP, but no cases of acquired SOP [13]. Congenital superior oblique palsy has recently been recognized as a CCDD. Evidence of this has been observed in MRI studies, which found an absence of the trochlear nerve/nucleus in 88/128 eyes with superior oblique palsy in one series [14] and 10/10 eyes in another [15]. In addition, hypoplasia of the superior oblique muscle has been found [14,15]. Similar to the other CCDDs, a genetic locus, ARIX, has been linked to the SOP phenotype [16].

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BROWN SYNDROME AS A POSSIBLE CONGENITAL CRANIAL DYSINNERVATION DISORDERS

Congenital superior oblique palsy and Brown syndrome are both disorders of the superior oblique muscle and/or superior oblique tendon. Consideration of this concept requires an understanding of the development of the superior oblique muscle tendon trochlea complex, reports of Brown syndrome in association with other CCDDs, and inheritance patterns of Brown syndrome and other CCDDS.

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Development of the superior oblique muscle tendon trochlea complex

Sevel [17] performed extensive studies of the development of the extraocular muscles and their tendons of origin and insertion. His studies suggest that the trochlea, superior oblique tendon, and the superior oblique muscle develop together from common mesenchymal tissue origins and are indistinguishable early in development. The connective tissue elements of the trochlea and the tendon become separately identifiable only later during development of the superior oblique muscle–tendon–trochlea complex. With further differentiation, the fibers of the developing superior oblique tendon become increasingly mobile through the developing trochlea. Sevel [18] proposed that a gradual separation of these tendon/trochlea attachments may explain the occasional improvement seen in Brown syndrome. Likewise, the gradual increase in the vertical deviation with superior oblique paresis is explained by the same theory.

Abnormal development of the fourth cranial nerve or its axon is expected to result in abnormal development of the superior oblique muscle–trochlea–tendon complex. A thin atrophic tendon may develop with abnormal fibers with or without an abnormal insertion on the on the globe [12]. This may produce the clinical findings of SOP. However, a tight and short tendon may develop because of poor differentiation of the tendon–trochlea complex and this may result in the clinical findings of Brown syndrome. Helveston et al. [12] demonstrated abnormalities in the superior oblique tendon in 87% of cases of congenital superior oblique paresis. Abnormalities in tendon development, a bifid insertion of the superior oblique tendon in a patient with Brown syndrome, have been reported [19]. Magnetic resonance imaging on patients with Brown syndrome have demonstrated several abnormalities, including an absent trochlear nerve [20], an absent superior oblique muscle, and atrophy of the superior oblique muscle [21]. Superior oblique muscle hypoplasia has been found on CT and MRI [5] (Fig. 1a and b).

FIGURE 1

FIGURE 1

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Brown syndrome in association with other congenital cranial dysinnervation disorders

There are several cases of Brown syndrome in association with known CCDDs. Bagheri [22] described a boy with both Duane and Brown syndrome. Ellis [5] presented a series of patients with concurrent Brown syndrome and other CCDDs: three with unilateral Brown syndrome and a contralateral SOP, two cases of unilateral Brown and contralateral Duane syndrome (Fig. 2a–c), one case of Brown syndrome and ipsilateral ptosis. However, no reports have yet identified a known genetic mutation associated with Brown syndrome.

FIGURE 2

FIGURE 2

Kaeser and Brodsky [23] posited that congenital Brown syndrome could be analogous to Duane syndrome. They propose a dysinnervated or hypo-innervated superior oblique muscle is mis-innervated by the oculomotor nerve, specifically a branch that normally innervates the medial rectus or inferior oblique. In their theory, the limited elevation observed in Brown syndrome is because of the co-contraction of the superior oblique and medial rectus or inferior oblique with attempted elevation of the eye in adduction. Kaeser [20] used MRI to view the trochlear nerve and superior oblique muscle in patients with Brown syndrome. He found the fourth cranial nerve was unable to be identified in two of four patients. In addition, the volume of the superior oblique muscle in different positions of gaze was measured and he found that the ipsilateral superior oblique remains the same size in both upgaze and downgaze. They concluded that the ipsilateral superior oblique is contracting in both positions rather than relaxing in upgaze as seen with the unaffected muscles. Their theory fails to fully explain the marked restriction of the superior oblique tendon on forced ductions. Although some restriction on forced ductions is found in patients with Duane syndrome, it is rarely as significant as that found in most cases of congenital Brown syndrome.

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Inheritance patterns of brown syndrome

Although Brown syndrome often occurs sporadically, several cases of familial Brown syndrome have been reported [24–27], including in identical twins [28–30]. Although typically unilateral, 10% of Brown syndrome cases are bilateral [1]. Congenital SOP and congenital Brown syndrome could be related entities. Imaging studies have found the superior oblique muscle underdeveloped and trochlear nerve absent in both disorders [14,15,20,21]. However, the trochlear nerve and the superior oblique muscle may be normal on MRI in patients with congenital Brown syndrome [31]. Tendon abnormalities are commonly found in congenital superior oblique palsy and by definition the tendon is abnormal in Brown syndrome. Similar rates of bilaterality exist with both SOP and Brown syndrome. Both are primarily sporadic, but have cases of familial presentation. Both disorders have been seen concurrently with other disorders of innervation such as CFEOM, Duane, and ptosis. We proposed that some cases of congenital Brown and SOP share a common origin. There is a lack of sufficient innervation, either because of an absent or hypoplastic trochlear nerve. With abnormal development of the fourth cranial nerve or its axon, the superior oblique muscle–tendon–trochlea complex may develop abnormally. If a hypoplastic muscle develops with a long and lax tendon, the characteristic features of congenital SOP are typically observed. However, if the tendon develops as short and taut, or is immobile through the trochlea, then Brown syndrome is observed (Fig. 3). Subsequent to this proposed relationship, we observed a child with congenital Brown syndrome whose father had congenital superior oblique paresis (Fig. 4).

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

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CONCLUSION

Some cases of congenital Brown syndrome may be because of an abnormal development of the fourth cranial nerve and or its axon. This may result in abnormal development of the superior oblique muscle–tendon–trochlea complex. Although congenital SOP is typically seen, Brown syndrome may occur if the tendon develops abnormally short, taut, or is restricted in its free movement through the trochlea. Genetic studies have revealed the underlying basis for CCDDs, a group of inherited eye movement disorders known to arise from abnormal neurogenic development. Although a Brown syndrome gene has not been described, the many similarities of some cases of congenital Brown syndrome to other CCDDs suggest that congenital Brown syndrome may fall within the umbrella category of CCDDs.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

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Excellent review article

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Keywords:

congenital Brown syndrome

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