Bohring-Opitz syndrome (BOS) is a rare autosomal genetic disorder. It is a serious condition characterized by physical and intellectual disabilities. It presents with a wide range of clinical symptoms. BOS was first reported in 1999 by Bohring and fellow researchers. De novo truncating mutations in the ASXL1 gene have been linked to nearly half of Bohring-Opitz syndrome cases. A total of 31 cases have been documented worldwide.
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Cause – The ASXL1 gene
BOS is caused by alterations in the ASXL1 gene (human extra sex combs similar to 1). The gene, which is on chromosome 20q11, has 13 exons and 12 introns. It codes for a nucleoprotein of 1,541 amino acids widely expressed in many tissues. Children with ASXL1 variations have been primarily documented in Western countries, with only seven examples recorded in Asian countries. Three of these incidents occurred in China, with a single documented case in Japan, Korea, Turkey and India.
The ASXN domain (also known as the HARE-HTH domain) is found at the N-terminus of the protein. It is expected to promote DNA interactions. The ASX (ASXH) peering domain (otherwise known as the DEUBAD domain) follows the ASXN domain. It is encoded by exons 9-11 and interacts with epigenetic regulatory proteins like BRCA1-related protein 1 (BAP1). Exon 13 codes for the plant homology domain (also known as the PHD domain), which can bind methylated lysine, and is located at the C-terminus.
In general, the ASXL1 gene encodes a protein that has a role in epigenetic and transcriptional control. In particular, animal studies have revealed that the BOS phenotype exists in ASXL1 knockout mice, and truncating variations of the ASXL1 gene have been found in cases meeting the clinical diagnostic criteria for BOS, implying a mechanism of haploinsufficiency.
ASXL1 is a chromatin modulator. It performs a dual function in transcriptional regulation depending on the cell type. Recent research using ASXL1 knockout mice has shown that it plays an essential role in the proliferation and differentiation of hematopoietic progenitor cells. It is also vital for organ development.
The facial features and posture of people with Bohring-Opitz syndrome (BOS) are different. Growth retardation, variable but usually severe intellectual disability, and various abnormalities are also present. Microcephaly or trigonocephaly/prominent (but not fused) metopic ridge, synophrys, glabellar and hypotonic facies with broad cheeks, are some of the facial anomalies.
Other noticeable facial changes include nevus Flammeus of the eyelids (simplex), widely set eyes, palate abnormalities, prominent globes, and micrognathia. The BOS posture is defined by the flexion of the elbows with ulnar deviation. It is also defined by the flexion of the wrists and metacarpophalangeal joints. It is most visible in early childhood and frequently fades with age.
One of the most common cardinal signs is intrauterine growth retardation. Early childhood eating problems, such as cyclic vomiting, have a significant impact on overall health. However, diet improves with age. Seizures are common and they are usually treated with normal epileptic drugs. There may be minor heart abnormalities, as well as temporary bradycardia and apnea. Recurrent infections are common in those affected, but they tend to get better with age.
The majority of those affected die in childhood from unexplained bradycardia, lung infections, or obstructive sleep apnea. Those who survive are often unable to walk on their own and are non-verbal. By late childhood, some people have had success using walkers and braces. While few can communicate verbally, several have been able to express basic demands through the use of communication devices and gestures accompanied by basic vocalizations.
In this situation, infant mortality remains high (40%) due to infections, which are the leading cause of death. Common problems, such as eating difficulties and repeated infections, become less difficult if the period of infancy is successfully managed. Although there is significant variation in terms of the level of communication and mobility achieved.
Severe to profound developmental delay is universal. Although he had made only minor improvements before, one of the patients achieved considerable developmental growth later in childhood. Adolescents have been found to have central obesity, sleep apnea and type 1 diabetes, but the numbers are too small to say whether these are more common in BOS.
Diagnosis and treatment
A proband with suggestive clinical signs and/or detection of a constitutional heterozygous pathogenic mutation in ASXL1 by molecular genetic testing forms the basis for the diagnosis of Bohring-Opitz syndrome (BOS). Molecular genetic testing can be applied to assess a pregnancy at theoretically increased risk due to constitutional and/or germline mosaicism for a pathogenic ASXL1 variant in a clinically unaffected parent.
Treatment usually begins with managing the manifestations. Identifying and avoiding triggers can help reduce cyclic vomiting. Regular maintenance medications and early abortion treatment can also help reduce vomiting. G or GJ tubes can help with feeding and suctioning. Polysomnography should be reviewed because of the high prevalence of obstructive sleep apnea. Patients with micrognathia, palate abnormalities, or obstructive sleep apnea should be referred to a craniofacial team. Those with repeated aspirations who develop secondary lung disease may benefit from a tracheotomy.
- Zhao, W., Hu, X., Liu, Y., Wang, X., Chen, Y., Wang, Y., & Zhou, H. (2021). A de novo variant of ASXL1 is associated with an atypical Bohring-Opitz syndrome phenotype: case report and review of the literature. Frontiers in Pediatrics, 9, 678615. https://doi.org/10.3389/fped.2021.678615
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