Brown Syndrome

Description

Brown syndrome, originally described by Brown (1950), is characterized by the inability to elevate the adducted eye actively or passively. There is less elevation deficit with the eye in midposition, and minimal or no deficit in abduction. There can also be divergence on upgaze, downshoot, or widening of the palpebral fissure on adduction, primary hypotropia, and anomalous head posture. Brown syndrome accounts for approximately 2% of strabismus cases. Ten percent of cases are bilateral, and left- and right-sided unilateral cases are equal in frequency. There is no gender predilection (summary by Heidary et al., 2012).

Clinical Features

Hamed (1991) reported 3 sibs with bilateral Brown syndrome. The proband was a 19-year-old woman who presented with a 1-month history of diplopia on lateral and upward gaze. Examination revealed 20/20 visual acuity and slight chin elevation. She had been diagnosed with Brown syndrome at 5 years of age, and chin elevation was also seen in multiple photographs dating back to childhood. Her eyes were orthotropic in the chin-up position but showed the typical motility features of Brown syndrome bilaterally: version testing up and to either side revealed underaction of both inferior oblique muscles that was more pronounced on the left side, and forced duction testing confirmed restriction of both eyes to elevation in the adducted and, to a lesser degree, in the primary positions. Forced duction testing while displacing the globe posteriorly exacerbated the restriction, indicating restriction in the superior oblique tendon/trochlear complex area. CT scan of the orbits, with coronal views of the trochlear area, were unremarkable. Her brothers, who were 23 and 16 years of age, had also been diagnosed in childhood and exhibited similar motility findings. There was no history of squint in the family, and examination of their mother revealed no ocular motility abnormalities. Hamed (1991) noted that patients with certain congenital ocular motility disorders may become 'suddenly' aware of diplopia when gazing in the fields of ocular misalignment and, once noted, may report the disorder to have rapidly worsened, possibly due to increased visual introspection as the patient pays increasing attention to the annoying symptom.

Iannaccone et al. (2002) studied 3 Italian sibs with late-onset unilateral Brown syndrome that developed at 12 to 13 years of age. The male proband presented at age 13 years with a 3-week history of diplopia, more marked in the morning immediately after awakening. Examination revealed a moderate chin-up head posture and limited elevation of the left eye in the adducted position, associated with slight widening of the palpebral fissure and downshoot of the affected eye. Palpation of the left trochlear region produced mild pain, and the forced duction test was positive. Ultrasonography of the trochlear region and CT scan of the orbit were within normal limits. Periodic reexamination over the following decade showed no change in the ocular motility findings. A sister of the proband presented at 12 years of age with similar symptoms and ocular motility findings; periodic reexamination over the next 9 years showed no change. Because of the family history, another sister underwent a screening examination at 8 years of age, which showed normal ocular motility; however, at age 12, she developed limitation of monocular vertical gaze in the left eye. Iannaccone et al. (2002) noted that symptoms were more persistent and stable in the proband than his sisters, who had a milder and possibly intermittent form of the disorder that showed improvement with repeated forced upward movements in adduction. Family history was negative for ocular problems, and examination of the parents and a 9-year-old sister showed normal ocular motility. There was no documented consanguinity, and the parents originated from geographically distinct areas.

Kenawy et al. (2008) reported a mother and 2 daughters with childhood-onset unilateral Brown syndrome. The mother had undergone a left superior oblique partial tenotomy procedure at 1 year of age; although she was asymptomatic at age 45 years, examination revealed persistent limited elevation on adduction of the left eye. Her affected daughters, aged 6.5 years and 4.5 years, exhibited limited dextro-elevation of the left eye, with downshoot on adduction. A 12-year-old daughter and a 1-year-old son did not show any extraocular motility abnormality; the father was unavailable for examination but was not known to have any such abnormalities, and there was no relevant family history.

Kim et al. (2008) reported 6-year-old monozygotic twin girls with congenital bilateral Brown syndrome. One sister exhibited A-pattern esotropia and profound inability to elevate either eye in the adducted position, but she had no other eye problems and her health was otherwise unremarkable. Forced duction under anesthesia confirmed the severe restriction of both eyes, with almost complete inability to force the eyes into a supraducted nasal position. No audible or palpable click was associated with the manipulation. Bilateral superior oblique tenotomy resulted in restoration of full motility of supraduction in the adducted position. Her twin sister also exhibited bilateral Brown syndrome, but because her eyes were relatively well aligned in the primary position with only a small chin-up head position, it was elected that she be observed without intervention. Apart from the affected twins, there was no other family history of strabismus.

Volk et al. (2010) studied 13 unrelated patients diagnosed with Brown syndrome, including 10 unilateral and 3 bilateral cases. Ten of the probands were reported to have affected relatives.

Pathogenesis

Brown syndrome was orginally thought to result from anomalies of the superior oblique tendon sheath and was referred to as the 'superior oblique tendon sheath syndrome (SOTSS).' It was later thought to result from restriction of free movement of the tendon through the trochlea pulley mechanism, due to anomalies of the tendon or the trochlear apparatus (summary by Heidary et al., 2012).

Inheritance

Paul and Hardage (1994) reviewed the heritability of strabismus, noting that although most cases of Brown syndrome are sporadic, there are some reports of an autosomal dominant transmission pattern.

Molecular Genetics

Exclusion Studies

In 3 sibs with unilateral Brown syndrome, Iannaccone et al. (2002) sequenced the candidate gene ARIX (602753) but did not detect any mutations or polymorphisms.

In 29 unrelated patients with a congenital ocular motility disorder, including 13 patients diagnosed with Brown syndrome, Volk et al. (2010) screened the CHN1 gene (118423) but did not detect any mutations.