Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare autosomal dominant genetic disorder caused by mutations in the NR2F1 gene. It typically presents in early childhood with optic atrophy, intellectual disability, and developmental delay.
In 2014, Bosch et al. first reported six cases with cortical visual impairment or optic nerve abnormalities and mutations in the NR2F1 gene. Since then, case accumulation has progressed, and as of 2022, approximately 200 cases have been identified worldwide.
It is also classified as one of the hereditary disorders associated with cortical visual impairment1).
Because it follows an autosomal dominant inheritance pattern, theoretically there is a 50% chance of passing it to a child. However, most reported cases are due to de novo mutations, occurring without a family history.
Since BBSOAS manifests in early childhood, the affected child’s own complaints are limited. Symptoms noticed by caregivers are as follows:
It shows a wide range of phenotypes involving both ocular and systemic findings.
Ocular Findings
Optic atrophy: Pallor of the optic disc is the most classic finding.
Optic disc abnormalities: May be accompanied by cupping or hypoplasia.
Nystagmus: Observed in many cases.
Cortical visual impairment: This is a disorder of central processing of visual information.
Alacrima: May indicate decreased tear secretion.
Systemic Findings
Intellectual disability: Severity ranges from mild to severe.
Developmental delay: Affects both motor and language skills.
Epilepsy: Includes infantile spasms (West syndrome).
Hypotonia: Low muscle tone in the trunk and limbs.
Facial dysmorphism: Prominent ears, high nasal bridge, upturned nose, etc.
Other characteristic findings include autism spectrum disorder, hearing impairment, oral motor dysfunction, and abnormalities of the corpus callosum. Additionally, a tendency to enjoy music, good long-term memory, high pain threshold (resistance to pain), and sleep disturbances may also be observed.
It is highly variable. While optic atrophy is central, the degree of intellectual disability, presence of epilepsy, and severity of facial dysmorphism vary greatly among cases. The type and location of the mutation influence the severity of the phenotype.
BBSOAS is caused by heterozygous mutations in the NR2F1 gene (also known as COUP-TF1), located on chromosome 5 (5q15). NR2F1 encodes an orphan nuclear receptor protein.
The reported types of mutations are as follows:
Mutations in the DNA-binding domain are associated with high rates of epileptic seizures, tactile hypersensitivity, motor delay, inability to walk independently, and inability to communicate verbally.
Since it is an autosomal dominant disorder, having a parent with an NR2F1 mutation is a risk factor. However, most reported cases are due to de novo mutations, and most have no family history.
BBSOAS is suspected based on a combination of characteristic signs and symptoms and is confirmed by genetic testing. It is usually diagnosed in childhood, but some adults who were misdiagnosed before the disease concept was established in 2014 may later be identified.
The following tests are used for definitive diagnosis:
| Examination method | Evaluation target | Points to note |
|---|---|---|
| Fundus examination | Optic disc pallor and cupping | Most basic examination |
| OCT | Retinal nerve fiber layer thickness | Requires patient cooperation |
| Visual field test | Visual field defect extent | Limited by developmental disability or nystagmus |
The following findings have been reported on MRI.
Because optic atrophy is the main feature, the differential diagnosis is broad. Hereditary, compressive, toxic, infectious, and inflammatory optic atrophy are considered. There is a report of a case previously misdiagnosed as ALG6-CDG (a type of congenital disorder of glycosylation) that was later identified as BBSOAS.
It is usually discovered in childhood due to visual abnormalities or developmental delay. Before the disease concept was established in 2014, many cases were thought to be undiagnosed or misdiagnosed. The spread of genetic testing is expected to improve the diagnostic rate.
There is currently no curative treatment for BBSOAS. The goal of management is symptom relief and maximizing development.
The NR2F1 gene encodes an orphan nuclear receptor protein. Studies using mouse models have shown that NR2F1 is involved in the following processes.
NR2F1 is mainly expressed in the optic nerve, thalamus, and cerebral cortex. This reflects the specific roles of NR2F1 in the following developmental processes.
Mutations in NR2F1 cause loss of protein function and inhibit neurodevelopment. This forms the basis for optic atrophy, cortical visual impairment, and intellectual disability in BBSOAS.
The tendency for missense mutations to show more severe phenotypes than whole gene deletions suggests involvement of a dominant negative effect by the mutant protein.
Current knowledge indicates that progression of optic atrophy in BBSOAS has not been reported. Optic nerve abnormalities are considered congenital and static, with the condition established early in life and maintained. However, the disease concept is new and long-term data are limited.
