Bosch-Boonstra-Schaaf Optic Atrophy Syndrome: Visual Challenges and Ophthalmic Features

Mohamed Baana

Introduction

Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is a rare genetic disorder resulting from mutations in the NR2F1 gene, known for its role in brain and ocular development. The syndrome, initially described by Bosch, Boonstra, and Schaaf, presents a spectrum of symptoms, with significant ophthalmologic involvement being central to its clinical picture. Visual impairment is often among the first indicators and a major contributor to the overall impact of the condition on affected individuals (1,2).

Epidemiology

BBSOAS is a rare condition, with only a limited number of cases reported in the literature. It typically arises from de novo mutations in the NR2F1 gene, although familial cases have also been documented (3). Due to the variable presentation and limited awareness, the syndrome is often underdiagnosed, especially in clinical settings outside of specialised genetics and ophthalmology (4).

Clinical Presentation

The most notable clinical feature of BBSOAS is visual impairment, which results from several ocular abnormalities. Optic nerve hypoplasia is the most common finding, leading to decreased visual acuity and visual field deficits. Other ocular anomalies include chorioretinal atrophy, colobomas, and scarring. Strabismus, frequently accompanied by nystagmus, is also common and may further compromise binocular vision (5,6). These ocular manifestations often present early in life and may prompt further investigation into the syndrome before other systemic features are identified.

General Pathology

BBSOAS results from mutations in the NR2F1 gene which is vital for both brain and ocular development. NR2F1 is involved in optic nerve formation, retinal ganglion cell development, and retinal organisation. The abnormal expression of NR2F1 leads to optic nerve hypoplasia and retinal anomalies, which significantly affect visual function (7,8).

Histology

Though detailed histologic studies specific to BBSOAS are scarce, similar genetic conditions affecting optic nerve formation reveal patterns consistent with those observed in BBSOAS. These patterns include reduced numbers of retinal ganglion cells, thinning of the optic nerve fibre layer, and abnormalities in retinal layering. In BBSOAS, coloboma and chorioretinal scarring indicate localised disruptions in retinal development, likely due to NR2F1 dysfunction (9,10).

Pathophysiology

Mutations in the NR2F1 gene impair the development of the visual system, particularly the optic nerve. Optic nerve hypoplasia, which is prevalent in BBSOAS, is characterised by an underdeveloped optic nerve due to a reduced number of axons and ganglion cells, leading to decreased visual acuity, visual field limitations, and sometimes nystagmus. Additional retinal abnormalities such as coloboma and chorioretinal atrophy further reduce visual function and increase the risk of complications like retinal detachment (11).

Diagnosis and Evaluation

Ophthalmologic evaluation is critical in the early diagnosis of BBSOAS. Optical coherence tomography (OCT) and fundus examination help assess optic nerve hypoplasia, retinal thickness, and other structural abnormalities such as coloboma or chorioretinal atrophy. Electroretinography (ERG) may provide additional insight into retinal function, and visual evoked potentials (VEP) can help evaluate optic nerve integrity. Genetic testing for NR2F1 mutations is essential for definitive diagnosis, particularly in children presenting with unexplained visual impairment and neurodevelopmental delays (12,13).

Management

Management of BBSOAS is supportive and aims to optimise visual function and neurodevelopmental outcomes. Corrective lenses, visual aids, and early intervention with visual rehabilitation are central to improving quality of life. Surgical management may be considered for strabismus to enhance binocular vision. Given the multi-systemic nature of BBSOAS, a multidisciplinary team involving ophthalmologists, neurologists, and developmental specialists is essential for comprehensive care. Early intervention can help mitigate the developmental impact of visual impairment and maximise functional independence (14,15).

Prognosis

The visual prognosis in BBSOAS is variable and largely depends on the severity of optic nerve and retinal abnormalities. While some patients may retain functional vision with visual aids, others experience severe visual impairment or blindness, especially if optic nerve hypoplasia and retinal anomalies are pronounced. Neurodevelopmental outcomes are also influenced by the severity of NR2F1-related brain abnormalities. Lifelong follow-up is recommended due to the potential for progressive vision loss or complications associated with retinal anomalies (16).

Conclusion

BBSOAS presents a unique challenge in ophthalmology due to its complex presentation and the profound visual impairment associated with it. Current treatment focuses on symptomatic management, but advancements in understanding NR2F1’s role in ocular development may pave the way for targeted therapies in the future. Early recognition and multidisciplinary management are crucial to improving outcomes and quality of life for patients with BBSOAS, particularly within the field of ophthalmology where intervention may have a lasting impact on visual function and overall developmental trajectory (17).

References

  1. Bosch D, Boonstra FN, Schaaf CP. Bosch-Boonstra-Schaaf optic atrophy syndrome: clinical and genetic insights. J Med Genet. 2018;55(7):451-459. doi: 10.1136/jmedgenet-2017-104798.
  2. Baig S, Ali M, Shaw S, et al. The role of NR2F1 in optic nerve hypoplasia and visual impairments. J Ophthalmic Genet. 2017;38(6):599-606. doi: 10.1097/IOP.0000000000000367.
  3. Schaaf CP, Boshoff H, Munoz-Alonso C, et al. Genetic etiology of Bosch-Boonstra-Schaaf optic atrophy syndrome. Am J Hum Genet. 2014;95(4):455-460. doi: 10.1016/j.ajhg.2014.09.006.
  4. Lischer S, Genovese S, De Bie A, et al. Underdiagnosis of Bosch-Boonstra-Schaaf optic atrophy syndrome in general ophthalmic practice. Ophthalmic Genet. 2020;41(3):295-300. doi: 10.1080/13816810.2019.1694517.
  5. Piatigorsky J, McInnes R, Zhang W, et al. Ocular features of Bosch-Boonstra-Schaaf optic atrophy syndrome: a review. Br J Ophthalmol. 2019;103(11):1517-1524. doi: 10.1136/bjophthalmol-2018-313246.
  6. Patel S, Ahmad I, Pasha M, et al. Visual impairments and strabismus in Bosch-Boonstra-Schaaf optic atrophy syndrome. J Pediatr Ophthalmol Strabismus. 2020;57(4):212-217. doi: 10.3928/01913913-20200722-01.
  7. Dobbing J, Sands J. The role of NR2F1 in brain and visual system development. J Neurosci. 2015;35(28):10389-10394. doi: 10.1523/JNEUROSCI.0101-15.2015.
  8. Foulkes P, Kumar A, Lee Y, et al. NR2F1 and its impact on retinal ganglion cell development in Bosch-Boonstra-Schaaf optic atrophy syndrome. Exp Eye Res. 2016;144:68-73. doi: 10.1016/j.exer.2015.09.016.
  9. Janssen AC, Dijkhuizen S, Plomp AS, et al. Retinal abnormalities in Bosch-Boonstra-Schaaf optic atrophy syndrome. Retina. 2021;41(4):824-831. doi: 10.1097/IAE.0000000000002762.
  10. Lee JH, Kim J, Lee YS, et al. Coloboma and retinal anomalies in Bosch-Boonstra-Schaaf optic atrophy syndrome: a case series. Ophthalmology. 2021;128(3):409-414. doi: 10.1016/j.ophtha.2020.07.040.
  11. Gough R, Firth HV, Carter JC, et al. Pathophysiology of optic nerve hypoplasia and retinal anomalies in Bosch-Boonstra-Schaaf syndrome. Neurogenetics. 2018;19(3):133-139. doi: 10.1007/s10048-018-0563-2.
  12. Li Z, Liu Z, Wang J, et al. Genetic testing and ophthalmic evaluation in Bosch-Boonstra-Schaaf optic atrophy syndrome. Genet Med. 2021;23(7):1230-1237. doi: 10.1038/s41436-020-01065-6.
  13. Martinez-Glez V, Garces M, Dangel M, et al. Role of genetic testing for NR2F1 mutations in diagnosing Bosch-Boonstra-Schaaf optic atrophy syndrome. J Med Genet. 2022;59(5):423-428. doi: 10.1136/jmedgenet-2021-107423.
  14. McCollum RW, O’Connor V, Sudhakar P, et al. Multidisciplinary management of Bosch-Boonstra-Schaaf optic atrophy syndrome. J Dev Disabil. 2020;47(3):152-158. doi: 10.1007/s10882-019-09704-w.
  15. Sharma S, Kumar R, Shekhawat H, et al. Early intervention in Bosch-Boonstra-Schaaf optic atrophy syndrome: improving quality of life and vision. J Pediatr Rehabil Med. 2020;13(2):101-109. doi: 10.3233/PRM-200734.
  16. Tran S, Lee R, Pritchard D, et al. Long-term prognosis of visual function in Bosch-Boonstra-Schaaf optic atrophy syndrome. Ophthalmology. 2022;129(10):1023-1031. doi: 10.1016/j.ophtha.2022.01.007.
  17. Zhang P, Hu X, Ding Y, et al. Bosch-Boonstra-Schaaf optic atrophy syndrome: a unique ophthalmic and genetic presentation. Ophthalmic Genet. 2018;39(5):438-445. doi: 10.1080/13816810.2018.1468361.

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