Bosch-Boonstra-Schaaf Optic Atrophy Syndrome
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Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare autosomal dominant disorder presenting in early childhood. It was first described by Bosch et al in 2014 when they identified six individuals with cortical visual impairment or optic nerve abnormalities who had a mutation in the nuclear receptor subfamily 2, group F, member 1 (NR2F1) gene, also known as COUP-TF1. The underlying cause of BBSOAS is an autosomal dominant mutation in NR2F1. This is thought to cause loss of function of this protein and dysregulation of neurodevelopment. The most common features of this syndrome include intellectual disability, developmental delay, and visual impairment. Optic nerve pathology is the most classic finding on ophthalmologic exam. As of 2022, there are roughly 200 known cases worldwide. Currently there are no treatments for BBSOAS. Management focuses on regular comprehensive eye exams, comprehensive therapies, behavioral education, and symptom management.
This syndrome has autosomal dominant inheritance, so having parents with NR2F1 mutations is a risk factor. However, most reported cases are from de novo mutations. No other risk factors have been identified at this time.
BBSOAS originates from mutations in the NR2F1 gene that encodes an orphan nuclear receptor protein. Studies have reported missense mutations, nonsense mutations, frameshifting insertions/deletions, non-frameshifting insertions/deletions, translation initiation variants, and whole-gene deletions. There is evidence that missense mutations have a more severe phenotype than deletions. Other reports have shown that mutations in the DNA-binding domain are associated with a higher prevalence of seizures, touch sensitivity, motor delay, inability to walk unassisted, and inability to communicate verbally. Mouse models have shown NR2F1 is involved in cell-fate determination, differentiation, migration, and survival as well as playing a role in organogenesis. They have also shown it is mainly expressed in the optic nerve, thalamus, and cortex. This explains its specific role in cortical patterning, guidance of thalamocortical axons, and eye and optic nerve development. Therefore, the current hypothesis is that mutations in NR2F1 cause loss of function of the protein, which disrupts neurodevelopment.
BBSOAS is typically identified by a characteristic set of signs and symptoms and then confirmed through genetic testing. Characteristic findings include intellectual disability, developmental delay, and visual impairment. It is typically identified in childhood but can also be diagnosed in older individuals who may have been initially misdiagnosed prior to the description of BBSOAS in 2014.
The phenotype of BBSOAS is highly variable. The most common characteristics include intellectual disability, developmental delay, and visual impairment. Other common findings include autism spectrum disorder, epilepsy, infantile spasms, hypotonia, hearing impairment, oromotor dysfunction, dysmorphic facial features, and abnormalities of the corpus callosum. Parents of these patients have also reported that they commonly have a love of music, good long-term memory, high pain tolerance, and difficulty sleeping.
On ophthalmic examination there is typically evidence of optic atrophy with pale optic discs. There can also be excavation or hypoplasia of the optic discs. Patients also commonly present with nystagmus, cortical visual impairment, and alacrima.
Definitive diagnosis is made through full exome sequencing or NR2F1 specific sequencing. There is one case of amniocentesis with fetal karyotyping and CNV-seq confirming an NR2F1 gene deletion in a fetus with enlarged ventricles. Optical coherence tomography is typically performed to evaluate the optic nerve if the patient is able to cooperate. As children get older, they may have visual field testing performed, though this may be limited by the presence of developmental disability or nystagmus. Neuroimaging can show abnormalities of the corpus callosum including thickening or thinning, bilateral optic nerve volume loss, hypoplastic lacrimal glands, and dysgyria of the temporal lobes and perisylvian cortex.
One of the most common findings of BBSOAS is optic atrophy so a broad differential including genetic, compressive, toxic, infectious, inflammatory, and other causes should be considered. There is one report of a patient previously diagnosed with the glycosylation disorder ALG6-CDG that was later found to have BBSOAS.
There is no treatment for BBSOAS, but therapies can help with symptom management. Low vision specialists can be helpful for individuals with significant visual impairment. Physical, occupational, speech, and behavioral therapy can also be helpful for the developmental aspects of BBSOAS. Additionally, medical management can be beneficial if individuals develop infantile spasms or seizures. For family members of patients with BBSOAS, connecting with support groups can be helpful.
There is no known regression or progression of this syndrome over time. There are no reported cases of progression of optic atrophy, so the optic nerve anomalies in these patients are considered congenital and static. Most individuals will continue to require assistance and therapies throughout their life. There is no known difference in average life expectancy. BBSOAS is a newly identified syndrome and as more patients are identified, there will likely be more information on the prognosis of this condition.
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