Bohring-Opitz Syndrome (BOS) is a rare and severe genetic disorder that affects the development of multiple body systems. The condition is characterized by multiple congenital anomalies, profound developmental delays, and significant medical complexity from birth. BOS requires intensive medical care and a highly specialized multidisciplinary approach to management. While the syndrome was first described in the late 1990s, the underlying molecular cause was identified relatively recently.
Genetic Basis of Bohring-Opitz Syndrome
Bohring-Opitz Syndrome is caused by mutations affecting the ASXL1 gene, located on chromosome 20. The ASXL1 gene provides instructions for a protein involved in chromatin remodeling, a process that activates or deactivates other genes in the cell nucleus. This places BOS within a group of epigenetic disorders, where gene expression is altered without changing the underlying DNA sequence.
The ASXL1 protein plays a role in epigenetic and transcriptional control, fundamental to early embryonic development. The genetic changes causing BOS are typically de novo, meaning the mutation occurs spontaneously and is not inherited. BOS is usually caused by a truncating loss-of-function variant, resulting in a shorter, nonfunctional protein. This premature stop disrupts the regulation of numerous other genes, leading to the wide spectrum of anomalies seen across organ systems.
Distinctive Clinical Manifestations
The physical characteristics and health problems in Bohring-Opitz Syndrome are distinctive. Individuals typically experience growth failure, starting with intrauterine growth restriction (IUGR) and continuing with severe postnatal failure to thrive. This poor growth is often compounded by severe feeding difficulties, including chronic gastroesophageal reflux and cyclic vomiting.
A set of distinctive craniofacial anomalies often alerts clinicians to the diagnosis. These features include:
- A prominent, heart-shaped birthmark on the forehead, known as a glabellar nevus flammeus.
- Synophrys, where the eyebrows grow together.
- Head shape abnormalities like microcephaly (small head size) or trigonocephaly (a triangular-shaped forehead).
- Prominent eyes (proptosis) and widely spaced eyes (hypertelorism).
- Other facial differences, including micrognathia (small lower jaw), a depressed nasal bridge, and sometimes a cleft lip or palate.
The syndrome is also defined by a characteristic limb positioning known as the “BOS posture.” This posture involves flexion at the elbows, ulnar deviation of the wrists, and flexion of the wrists and fingers. This is often associated with truncal hypotonia (low core muscle tone) combined with hypertonia (increased muscle tension) in the extremities. Individuals with BOS universally present with severe to profound intellectual disability and developmental delay, and many experience seizures requiring ongoing management.
Confirming the Diagnosis
A definitive diagnosis for Bohring-Opitz Syndrome involves a clinical evaluation based on the distinctive phenotype, followed by molecular confirmation. The presence of recognizable features, such as the characteristic posture, severe feeding issues, and specific craniofacial markers, raises clinical suspicion.
Today, the diagnosis is established by identifying a pathogenic variant in the ASXL1 gene through molecular genetic testing. Sequence analysis of the ASXL1 gene is the standard procedure to detect the loss-of-function variants responsible for the condition. If single-gene testing is inconclusive but the presentation is suggestive, comprehensive genomic testing, such as a multigene panel or whole exome sequencing, may be used.
Prenatal diagnosis is possible if a pathogenic ASXL1 variant has been identified in a family member. Testing is performed on cells obtained from amniotic fluid or chorionic villi, confirming the de novo mutation before birth. Differentiation from other syndromes, such as Cornelia de Lange Syndrome, often relies on the presence of the specific BOS posture and trigonocephaly.
Long-Term Supportive Care Strategies
Long-term care for Bohring-Opitz Syndrome focuses on managing complex symptoms through a multidisciplinary supportive strategy. Nutritional support is a primary concern due to severe feeding difficulties, cyclic vomiting, and failure to thrive. Many affected individuals require a gastrostomy tube (G-tube) to ensure adequate calorie intake and hydration, especially early in life.
Respiratory management is also a frequent focus, as individuals with BOS may experience transient apnea, bradycardia, and a high risk of pulmonary infections. Physical, occupational, and speech therapy are integral components of care to address developmental delays, low muscle tone, and communication challenges. Physical therapy helps manage the skeletal issues and joint contractures associated with the BOS posture.
Children with BOS have an increased, though small, risk of developing certain pediatric cancers, such as Wilms tumor. Regular screenings, such as abdominal ultrasounds, are recommended to monitor for tumor development. Palliative and comfort care considerations are often a part of the long-term management plan, aimed at maximizing the individual’s comfort and quality of life.