Bohring-Opitz Syndrome
Summary
Clinical characteristics.
Bohring-Opitz syndrome (BOS) is characterized by 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. 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.
Diagnosis/testing.
The diagnosis of Bohring-Opitz syndrome (BOS) is established in a proband with suggestive clinical features and/or the identification of a constitutional heterozygous pathogenic variant in ASXL1 by molecular genetic testing.
Management.
Treatment of manifestations. Cyclic vomiting may be managed by identification and avoidance of triggers, daily maintenance medication, and early abortive treatment; G-tubes or GJ-tubes may decrease aspiration and improve nutrition. Due to the prevalence of obstructive sleep apnea, polysomnography should be considered. Referral to a craniofacial team should be considered for those with palatal abnormalities, micrognathia, or obstructive sleep apnea. Tracheostomy may be considered for those with recurrent aspiration who develop secondary lung disease, or in those with severe sleep apnea that is not adequately treated with noninvasive pressure support (e.g., CPAP, BiPAP) or surgical intervention (e.g., mandibular distraction). Standard management is indicated for seizures, congenital heart defects, intellectual disability, myopia, urinary tract infections, urinary retention, and renal stones.
Prevention of primary manifestations. Adequate treatment of severe emesis can decrease hospitalizations, infectious exposures, and ascending aspiration.
Surveillance: Renal ultrasound every three months from birth to age eight to screen for the development of Wilms tumor; frequent monitoring of growth and development; close monitoring of feeding intolerance with a gastroenterology specialist; regular follow up for vision optimization.
Agents/circumstances to avoid. Triggers for vomiting should be avoided and managed with prophylactic antiemetics prior to the exposure.
Genetic counseling.
Bohring-Opitz syndrome (BOS) is typically the result of a de novo pathogenic variant in ASXL1. When BOS results from a de novo variant, the risk to the sibs of a proband is small. No individuals with BOS have been reported to reproduce. Although the vast majority of BOS occurs as the result of a de novo variant in ASXL1, molecular genetic testing can be used to evaluate a pregnancy at theoretically increased risk as a result of constitutional and/or germline mosaicism for an ASXL1 pathogenic variant in a clinically unaffected parent.
Diagnosis
Prior to the identification of the molecular cause of Bohring-Opitz syndrome (BOS), Hastings et al [2011] had proposed clinical diagnostic criteria for the condition. Ultimately, only five individuals used to develop these clinical diagnostic criteria were molecularly confirmed to have BOS. Therefore, the specificity of these diagnostic criteria is unclear.
Suggestive Findings
Bohring-Opitz syndrome should be suspected in individuals with the following clinical features [Bohring et al 1999, Bohring et al 2006, Hastings et al 2011, Magini et al 2012, Russell et al 2015].
Craniofacial appearance (Figure 1)
Figure 1.
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 presenting in infancy that may worsen over the first years of life
- Variable optic nerve and retinal anomalies
BOS posture (Figure 2)
Figure 2.
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
The diagnosis of Bohring-Opitz syndrome is established in a proband with suggestive clinical features (see Suggestive Findings) and/or by identification of a constitutional heterozygous pathogenic variant in ASXL1 on molecular genetic testing (see Table 1).
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 (see Differential Diagnosis) 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 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.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- 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).For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Bohring-Opitz Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| ASXL1 | Sequence analysis 3 | 20/24 (83%) 4, 5 |
| Gene-targeted deletion/duplication analysis 6 | None reported 7 | |
| Unknown 8 | NA |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
The denominator represents only those individuals in the literature who have undergone sequence analysis of ASXL1; some clinically diagnosed individuals whose information has been published have not undergone molecular genetic testing.
- 5.
Somatic mosaicism for ASXL1 variants, including BOS-associated variants, may be found in the elderly or in other non-BOS cohorts (i.e., cohorts of individuals with cancer); such variants may be reported in reference databases, leading to misclassification of potentially pathogenic variants [Carlston et al 2017]. See Molecular Genetics.
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
- 8.
In four individuals with features suggestive of BOS molecular genetic testing of ASXL1 failed to identify a pathogenic variant [Brunner et al 2000, Hastings et al 2010, Hastings et al 2011, Hoischen et al 2011]. It is unclear if these individuals have a different genetic syndrome with clinical features overlapping those of BOS. Greenhalgh et al [2003] reported two sibs with clinical features of BOS in whom a different diagnosis was subsequently confirmed [Bruel et al 2017].
Clinical Characteristics
Clinical Description
Bohring-Opitz syndrome (BOS) is a rare condition characterized by distinctive facial features and posture, variable but usually severe intellectual disability, growth failure, and variable anomalies. Feeding difficulties have a significant impact on overall health in early childhood; feeding tends to improve with age. This section summarizes clinical data from numerous case reports and case series; see Russell et al [2015] and references therein, Dangiolo et al [2015], and Suggested Reading. Additional references are cited where appropriate.
Craniofacial. Individuals with BOS have a characteristic facial appearance (see Suggestive Findings), although significant variability is observed. The most striking and consistent features are a prominent glabellar nevus flammeus (simplex) that fades with age, synophrys that becomes more prominent with age, hypotonic facies with full cheeks, and prominent or proptotic eyes. The majority of affected individuals also have hypertrichosis with rapidly growing hair and nails.
Other features widely, but variably, reported include cleft lip with or without cleft palate, high arched palate, widely spaced eyes (hypertelorism), depressed and wide nasal bridge, anteverted nares, and low-set ears with increased posterior angulation.
Growth. Mild intrauterine growth restriction has been noted, but many infants are products of healthy pregnancies with average or low-average birth weights. Poor growth is typically noted in the first year of life and is often clinically attributed to chronic emesis and feeding intolerance. Adequate nutrition does play a role in early growth, but even those without feeding intolerance typically display poor long-term growth.
Feeding. Most children have had feeding issues beginning in infancy and generally improving or resolving in early childhood. Historically, feeding issues have been presumed to be secondary to severe gastroesophageal reflux, but initial case reports did not produce diagnostic evidence of gastroesophageal reflux or demonstrate improvement on traditional antireflux therapies. Recent publications have suggested a neurogenic etiology, including cyclic vomiting with possible poor gastric motility, as the underlying cause of the chronic emesis [Russell et al 2015]. Given the frequency of emesis, there is a high risk for aspiration and dehydration, typically resulting in multiple hospitalizations.
Development and behavior. All affected individuals reported in the literature have severe-to-profound intellectual disability. Few are able to speak, but many have been able to express basic needs using augmentative and alternative communication (AAC) devices as well as gestures with associated basic vocalizations. Individuals with BOS often have a happy and pleasant demeanor [Russell et al 2015]. Typically, they are able to recognize caregivers and have a social, interactive nature. Most are unable to walk independently, but some have had success using walkers and braces in late childhood. Given the recent increase in rate of diagnosis due to genomic testing, it is expected that affected individuals with a milder phenotype may be reported in the future.
Neurologic. Seizures are common in individuals with BOS and are typically responsive to standard antiepileptic medications. Affected individuals have also been described to have truncal hypotonia with hypertonia of the extremities. A wide range of primary brain anomalies have been reported. Corpus callosum defects are the most common and range from hypoplastic to absent. Dandy-Walker malformation, delayed myelination, and enlarged ventricles have also been described.
Cardiovascular. Idiopathic and transient bradycardia as well as apnea were widely reported in the initial literature that predated the identification of the genetic cause of BOS. Cardiovascular deaths associated with bradycardia and apnea account for four (33%) of the 12 deaths published in the literature (although none of those individuals had a molecular confirmation of BOS). Other minor cardiac anomalies including septal defects and cardiac hypertrophy have also been described in a small number of affected individuals.
Respiratory. In addition to apnea and bradycardia, respiratory infections are common in infancy and account for about 42% of deaths (5/12). When chronic emesis is treated or improves with age, the rate of respiratory infections decreases [Russell et al 2015]. Tracheostomies have been necessary for some (see Management).
Sleep. Obstructive sleep apnea and sleep disturbances, including difficulty falling asleep and staying asleep, are frequently reported. Affected individuals with micrognathia may also exhibit tongue-based airway obstruction.
Ophthalmologic. Myopia, often severe, is common in individuals with BOS. Most affected individuals require corrective lenses in infancy. Retinal and optic nerve abnormalities including colobomas, retinal and optic nerve atrophy, and abnormal coloration of the retinas are also frequently reported.
Immunologic. Recurrent infections may be frequent in early life, although immunodeficiency has not been reported in the literature. The frequency of infections typically declines with age.
Urologic. Urinary retention and recurrent urinary tract infections have been reported in individuals with BOS [Russell et al 2015]. There also appears to be an increased risk for renal stones [Author, personal observation].
Skeletal. The typical BOS posture (see Suggestive Findings) is most notable in early childhood and usually becomes less obvious with age. Congenital contractures, dislocations, and pectus excavatum have also been reported.
Malignancy. Isolated case reports suggest that children with BOS are at greater risk for Wilms tumor than the general population; large-scale epidemiologic studies have not been conducted due to the limited number of individuals diagnosed with BOS. Of three individuals with a clinical diagnosis of BOS and renal neoplasia, two had documented pathogenic variants in ASXL1 and bilateral Wilms tumor; Wilms tumor was diagnosed in one at age two years and in the other at age six years [Russell et al 2015]. Another individual with BOS had nephroblastomatosis on autopsy at age five months. This infant later underwent molecular genetic testing of ASXL1; no pathogenic variant was identified [Brunner et al 2000, Hoischen et al 2011]. Overall, Wilms tumor appears to affect about 7% of individuals with BOS. This risk estimate is based on a very small number of reported cases and thus is likely to change over time as larger cohorts of children and adults with BOS are investigated.
The only other neoplastic process reported was medulloblastoma in a child age five years with clinical features of BOS in whom a pathogenic ASXL1 variant was not identified [Hastings et al 2010, Hoischen et al 2011].
Other
- Annular pancreas has been described in some affected individuals.
- Gallstones have been reported in several affected individuals [Author, personal observation].
- Historically, this condition had been associated with high infant mortality (27% based on data published before 2015), but the current survival rate is likely to be much better due to advances in pediatric care and more aggressive interventions [Russell et al 2015].
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been reported to date, but the total number of individuals in whom ASXL1 pathogenic variants have been identified is limited.
Nomenclature
BOS is occasionally known as Oberklaid-Danks syndrome after F Oberklaid and DM Danks, who described one of the early cases of BOS [Oberklaid & Danks 1975]. BOS is the more commonly used term.
Prevalence
The prevalence of BOS is unknown; out of 46 clinically diagnosed individuals reported in the literature, 20 had the diagnosis molecularly confirmed.
Note: Not all clinically diagnosed individuals reported in the literature have undergone molecular genetic testing of ASXL1.
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of Bohring-Opitz Syndrome (BOS)
| Disorder | Gene(s) | MOI | Clinical Features of the Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/BOS | Distinguishing from BOS | |||
| C syndrome (Opitz trigonocephaly syndrome) 1 (OMIM 211750) | CD96 | AD |
| Common in BOS, not in C syndrome:
|
| Shashi-Pena syndrome (ASXL2 syndrome) 2 (OMIM 617190) | ASXL2 | AD |
| Common in BOS:
|
| Bainbridge-Ropers syndrome (ASXL3-related disorder) 3 | ASXL3 | AD |
| Common in BOS; not typical in Bainbridge-Ropers syndrome:
|
| Cornelia de Lange syndrome (CdLS) | HDAC8 NIPBL RAD21 SMC1A SMC3 | AD XL 4 |
| Common in BOS:
|
| KLHL7-associated syndrome 6 | KLHL7 | AR |
| In KLHL7-associated syndrome:
|
AD = autosomal dominant; AR = autosomal recessive; DD/ID = developmental delay / intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; XL = X-linked
- 1.
The phenotypic spectrum of C syndrome is not well defined, apart from the reportedly more common features. The mode of inheritance is also unclear since the molecular etiology remains elusive. A Japanese individual with a clinical diagnosis of C syndrome had a chromosomal translocation that disrupted CD96 (also known as TACTILE), and another Japanese individual with a clinical diagnosis of C syndrome had a heterozygous missense variant in CD96 [Kaname et al 2007]. However, these findings have not been replicated since 2007, so it remains unclear whether pathogenic variants in CD96 could result in C syndrome. More recently, compound heterozygous pathogenic variants in IFT140 were found in an individual with a clinical diagnosis of C syndrome – along with clinical features suggestive of a ciliopathy, which had not been previously reported in C syndrome [Peña-Padilla et al 2017]. Thus, it is unclear whether this is distinct from "classic" C syndrome.
- 2.
Shashi et al [2016]
- 3.
Balasubramanian et al [2017], Kuechler et al [2017]
- 4.
NIPBL-, RAD21-, and SMC3-related CdLS are inherited in an autosomal dominant manner; HDAC8- and SMC1A-related CdLS are inherited in an X-linked manner.
- 5.
Pathogenic variants in HDAC8 result in an X-linked subtype of CdLS that is more severe in males and bears facial resemblance to BOS, with features not typically seen in "classic" CdLS: nevus flammeus (simplex) over the glabella and widely spaced eyes [Kaiser et al 2014, Parenti et al 2016].
- 6.
Angius et al [2016], Bruel et al [2017]
Management
Evaluations Following Initial Diagnosis
To establish the spectrum of manifestations and medical needs in an individual diagnosed with Bohring-Opitz syndrome (BOS), the following evaluations are recommended if they have not already been completed.
Table 3.
Recommended Evaluations Following Initial Diagnosis of Bohring-Opitz Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Growth | Weight, length/height, & head circumference measurements plotted on standard growth chart |
|
| ENT/Mouth | Craniofacial evaluation if cleft lip/palate, micrognathia, or obstructive sleep apnea is present | If mainly due to tongue-based airway obstruction, severe obstructive sleep apnea may be treatable by adenoidectomy or mandibular distraction. |
| Gastrointestinal |
| |
| Neurologic | Assessment for signs/symptoms of seizures | If present, consider neurology evaluation & head MRI. |
| Evaluation by developmental specialists incl speech, occupational, & physical therapists | ||
| Cardiovascular | Echocardiogram for cardiac anatomy | |
| Respiratory | Assessment for apnea/bradycardia (more common in younger individuals) | Consider sleep study if sleep apnea is a concern. |
| Eyes | Ophthalmology evaluation | For high myopia & retinal/optic nerve defects |
| Genitourinary | Baseline renal ultrasound | To assess renal structure & screen for Wilms tumor |
| Musculoskeletal | Orthopedic evaluation if bony anomalies noted | |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with BOS
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Poor growth & feeding due to chronic severe emesis 1 |
| Fundoplication & traditional antireflux management w/acid blockers are typically not beneficial if gastroesophageal reflux is not the underlying etiology. |
| Cleft lip &/or palate |
|
|
| Frequent infections &/or aspiration pneumonia 4 | Aggressive management of chronic emesis | |
| Fever or increase in emesis |
| |
| Seizures | Standard antiepileptic medications | Most individuals respond to monotherapy. |
| Congenital heart defects | Standard management | |
| Respiratory symptoms | Tracheostomy may be effective in:
|