Boring-Opitz syndrome (BOS) is a rare, multiple anomaly syndrome that has distinctive facial features and posture, growth failure, variable but usually severe intellectual disability, and variable anomalies. The facial features may include microcephaly or trigonocephaly / prominent (but not fused) metopic ridge, hypotonic facies with full cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex), prominent globes, widely set eyes, palate anomalies, and micrognathia 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 restrictions 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. Boring-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 Boring, et al. 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 trigonocephaly syndrome (C syndrome). Mutations in the ASXL1 gene were found in individuals with clinical features of BOS and reported in 2011.
Symptoms
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.
Facial features include glabellar and eyelid nevus flammeus (simplex) that fades with age, synophrys, facial hypotonia with full cheeks, prominent globes, widely spaced eyes (hypertelorism), depressed and wide nasal bridge, anteverted nares, palatal anomalies (cleft palate, high arched palate or prominent palatine ridges), cleft lip, micrognathia and/or retrognathia, low-set ears with increased posterior angulation, variable trigonocephaly, microcephaly, or normocephaly.
Infants with BOS may have feeding issues that 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 the structure of the heart or heart rhythm abnormalities. Frequent infections may be common and may be exacerbated by the 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 has been no documentation 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 can use various adaptive communication devices. Although few individuals with BOS walk independently, many also benefit from adaptive walkers, strollers, and leg braces 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.
The BOS posture, which is most striking in early childhood and often becomes less apparent with age, is characterized by flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints. Feeding difficulties in early childhood, including cyclic vomiting, have a significant impact on overall health; feeding tends to improve with age. Seizures are common and typically responsive to standard epileptic medications. Minor cardiac anomalies and transient bradycardia and apnea may be present. Affected individuals may experience recurrent infections, which also tend to improve with age. Isolated case reports suggest that individuals with BOS are at greater risk for Wilms tumor than the general population, but large-scale epidemiologic studies have not been conducted.
Causes
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 dominant disorders, individuals may have a 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.
Diagnosis
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.
Suggestive Findings
Boring-Opitz syndrome should be suspected in individuals with the following clinical features [rx, RX, RX, rx].
Craniofacial appearance
Facial features of individuals with BOS at varying ages A-B. 2 years
- Microcephaly or trigonocephaly / prominent (but not necessarily fused) metopic ridge
- Glabellar and eyelid nevus flammeus (simplex) that fades with age
- Prominent globes
- Cleft lip
- Palatal anomalies: cleft palate, high arched palate, or prominent palatine ridges
- Micrognathia and/or retrognathia
Growth and feeding
- Intrauterine growth restriction
- Severe feeding difficulties with chronic emesis that typically improves with age
- Poor postnatal weight gain and linear growth, often exacerbated by severe feeding intolerance
Neurologic
- Developmental delay or intellectual disability in the severe-to-profound range with minimal or complete lack of expressive language
- Seizures
Respiratory
- Recurrent infections (commonly respiratory) in early childhood that improve with age
Sleep
- Sleep disturbance
- Obstructive sleep apnea
Ophthalmologic
- High myopia presents in infancy that may worsen over the first years of life
- Variable optic nerve and retinal anomalies
BOS posture
Typical BOS posture with flexion at the elbows, ulnar deviation, flexion of the wrists and metacarpophalangeal joints, and hypertonic extremities with central hypotonia From Hastings et al [2011]. Republished with permission.
- Flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints; most noticeable in early childhood and usually less obvious with age
- Truncal hypotonia with hypertonia of the extremities
Establishing the Diagnosis
Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, or more comprehensive genomic testing:
- Single-gene testing. Sequence analysis of ASXL1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
- A multigene panel that includes ASXL1 and other genes of interest may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting the identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
- More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes ASXL1) fails to confirm a diagnosis in an individual with features of Bohring-Opitz syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
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.
Treatment
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.
Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.
Ages 5-21 years. In the US, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of the appropriate community, state, and educational agencies and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual’s needs is recommended. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
In the US:
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
- Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Motor Dysfunction
Gross motor dysfunction
- Physical therapy is recommended to maximize mobility.
- Consider the use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive functions such as feeding, grooming, dressing, and writing.
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy – typically from an occupational or speech therapist – is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
References
