NORD gratefully acknowledges Samantha A. Vergano, MD, FAAP, Attending Physician, Division of Medical Genetics and Metabolism, Children’s Hospital of The King’s Daughters, Norfolk, VA, for the preparation of this report.
Bohring-Opitz syndrome (BOS) is a rare, multiple anomaly syndrome that most often is evident at birth (congenital) and affects an individual’s growth, development, and variable organ-systems. Individuals with BOS often have severe growth restriction and are therefore quite small; they may have feeding difficulties, characteristic facial features, and the presence of a red or pink birthmark (nevus flammeus) on the forehead or eyelids. Individuals may also have seizures, heart anomalies, and a characteristic ‘BOS posture’ where the elbows are bent and wrists angle outwards. Additional abnormalities may include a smaller than average head size (microcephaly), a visible ridge over the forehead (metopic ridge), a cleft lip and/or palate, eye abnormalities, recurrent infections, and pauses during breathing while asleep (sleep apnea), as well as sleep difficulties. Children with BOS may have varying degrees of learning differences, but these are generally severe, and most children do not attain typical speech or ambulation. Bohring-Opitz syndrome is caused by mutations in the ASXL1 gene. There are currently no known medications or disease-specific therapies, but supportive treatment involving physical/occupational/speech therapy and specific management of an individual’s symptoms are considered the standard of care. BOS can theoretically be transmitted in an autosomal dominant manner (where 50% of an individual’s children are at risk of inheriting the gene), but most individuals do not reproduce due to developmental and neurologic impairments. There are no reports of BOS mutations being passed down from parent to child. All reports of BOS indicate that neither parent carries the same mutation and the mutation was new in the child (de novo).
BOS was first described in 1999 by Bohring, et al. to describe four individuals with severe prenatal growth restriction, microcephaly, cleft lip, characteristic positioning of the elbows and wrists, and additional organ-system anomalies. Two prior reports described similar individuals with abnormalities to their skull shape who were felt to have Opitz trigonencephaly syndrome (C syndrome). Mutations in the ASXL1 gene were found in individuals with clinical features of BOS and reported in 2011.
BOS presents typically at birth, but not all signs may be evident immediately. Infants with BOS may display poor growth prenatally (intrauterine growth restriction), and may have brain abnormalities evident on prenatal ultrasound, including but not limited to agenesis of the corpus callosum, enlarged ventricles, or Dandy-Walker malformation.
Infants with BOS may have feeding issues which may necessitate the use of a feeding tube (G-tube or gastrostomy tube), as well as cyclic vomiting, gastroesophageal reflux, or oral aversion. Feeding issues may improve or resolve as children get older. Some children with BOS may have a cleft lip or palate which may further complicate feeding and swallowing. Individuals may have cardiac anomalies involving structure of the heart or heart rhythm abnormalities. Frequent infections may be common, and may be exacerbated by low tone and inability to clear secretions. Some children may need a breathing tube through the neck (tracheostomy) if they have significant airway issues or need help breathing. Although children with BOS are more susceptible to common respiratory infections, there have been no documentations of immunodeficiency in BOS. Some children may have sleep problems related to falling or staying asleep, and some may also have pauses in their breathing during sleep (sleep apnea). Children may also have eye abnormalities including difficulty seeing far away (myopia) or problems with eye muscles (strabismus).
All individuals with BOS have learning and developmental differences, which are often severe. Most children do not attain speech, although many are able to use various adaptive communication devices. Although few individuals with BOS walk independently, many also benefit from adaptive walkers, strollers, and leg bracing to assist with mobility. There are some individuals with BOS who have been reported to have a type of childhood kidney cancer called Wilms tumor; while there may be an increased risk for children with BOS to have Wilms tumor, and certain screening recommendations exist, not all children with BOS develop cancer.
BOS is thought to be caused by changes (mutations) in the ASXL1 gene. This gene is thought to play a role in chromatin remodeling, which is responsible in part for the packaging of genetic material in the body. The ASXL1 gene is also thought to be involved in activating and silencing other genes in the HOX family.
All individuals who have been reported to have a mutation in the ASXL1 gene appear to have developed it spontaneously, and not inherited it from a parent. If BOS were to be inherited, it is theorized that it would be in an autosomal dominant manner, meaning that the individual with BOS would have a 50% chance of passing down the affected gene change to any offspring.
In some disorders which are dominant, individuals may have varying expression of certain signs and symptoms. Therefore, not all individuals with BOS may be identical in regards to their medical issues, although many do share similar characteristics.
BOS is not thought to affect one population of individuals more than another, and does not show any higher prevalence in males or females. There are no areas of the world where BOS is thought to be more common due to founder mutations or inbreeding (consanguinity). The current prevalence is unknown; there have been approximately 50 individuals reported in the literature but there may be others who have either not had testing or who have not come to medical attention.
The definitive diagnosis of BOS is made after molecular testing for mutations in the ASXL1 gene. Clinical suspicion for BOS may be raised if an individual displays the characteristic BOS posturing of the hands and elbows, is having delayed growth and developmental milestones, and has the characteristic facial features seen in BOS, including the presence of characteristic birthmarks. While the aforementioned characteristics are considered classic, individuals may present more variably, so BOS should not be entirely excluded necessarily on clinical presentation alone, unless obvious signs of another condition are present.
Clinical Testing and Work-up
Children with BOS should receive regular abdominal ultrasounds every three months from birth (or at the time of diagnosis) until eight years to screen for Wilms tumor. They should also receive regular evaluations to focus on growth, feeding, nutrition, and management of other complications.
There are currently no definitive treatments, medications, or therapies that will reverse the symptoms of BOS as there are no proven treatments to change an individual’s mutation in the ASXL1 gene. While some work is being done in general with gene therapy and other advanced technologies (CRISPR/CAS9), there have been no studies on children with BOS.
Treatment is currently geared toward symptomatic treatment for an individual’s specific medical issues. Most children will benefit from a combination of various therapies, including physical, occupational, and speech. They may also benefit from an augmented communication device and other devices to assist with mobility, including standers, gait trainers, adaptive strollers, etc.
Children with feeding difficulties may benefit from G-tubes or GJ tubes; those who are at risk for recurrent aspiration and develop lung disease or who need supplemental oxygen may need a tracheostomy and/or ventilator support.
Individuals who obtain common respiratory infections should be aggressively treated with the assistance of clearance of secretions and managed appropriately to reduce complications. All individuals with BOS, unless there is evidence of cellular immunodeficiency, should receive the standard schedule of childhood immunizations, including prophylaxis for RSV, if appropriate, and influenza.
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