Burn-Mckeown Syndrome
Summary
Clinical characteristics.
Burn-McKeown syndrome (BMKS) is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge and widely spaced eyes, and large and protruding ears), congenital heart defects, and short stature. Intellect is usually normal. To date, the diagnosis of BMKS has been molecularly confirmed in 14 individuals from 11 families.
Diagnosis/testing.
The diagnosis of BMKS is difficult to establish solely on clinical findings and thus is established in a proband with biallelic pathogenic variants in TXNL4A. All probands described to date have had at least one copy of one of the two partially overlapping 34-bp deletions in the TXNL4A promoter.
Management.
Treatment of manifestations: Neonates with airway compromise at delivery may require intubation or surgical correction of choanal stenosis/atresia. Defects of the lower eyelids that can result in corneal exposure require care by an ophthalmologist to reduce the risk of corneal scarring. Treatment of hearing loss is individualized and may involve conventional hearing aids. Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team. Cardiac defects are managed in a routine manner.
Surveillance: Monitoring of development by a physician with expertise in craniofacial disorders; routine measurements of height and weight, hearing assessment, and ophthalmologic examination.
Genetic counseling.
BMKS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the TXNL4A pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options.
Diagnosis
Suggestive Findings
Burn-McKeown syndrome should be suspected in individuals with the following features:
Commonly seen features (>80% of individuals)
- Bilateral choanal atresia/stenosis
- Distinctive facies (Figure 1):
- Short palpebral fissures (i.e., distance between inner canthus and outer canthus)
- Lower eyelid defects including coloboma and thick eyelashes
- Prominent nasal bridge and widely spaced eyes, which lead to a typical facial profile
- Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth
- Normal intellect
syndrome.">Figure 1.
Craniofacial phenotype in individuals with Burn-McKeown syndrome. Note short palpebral fissures (i.e., the distance between inner and outer canthi), prominent nasal bridge, large and (to some extent) protruding ears, and short philtrum. From Wieczorek (more...)
Less common features (<80% of individuals)
- Ears
- Prominent and often protruding ears; microtia (1 individual)
- Congenital mixed hearing loss (i.e., conductive and sensorineural)
- Preauricular tags
- Oral structures
- Micrognathia
- Cleft lip or palate
- Bifid uvula
- Cardiac defects
- Multicystic dysplastic kidney
- Imperforate anus
- Short stature
Establishing the Diagnosis
The diagnosis of Burn-McKeown syndrome is difficult to establish solely on clinical findings; it is established in a proband with biallelic pathogenic variants in TXNL4A. All probands described to date have had at least one copy of a 34-bp deletion in the promoter of TXNL4A. Two partially overlapping 34-bp deletions have been described:
- Type 1: chr18:g. 77,748,581_77,748,614del [GRCh37/hg19]
- Type 2: chr18:g.77,748,604_77,748,637del [GRCh37/hg19]
The majority of reported probands have a type 1 promoter deletion on one allele and a loss-of-function pathogenic variant on the other. One proband was homozygous for a type 2 promoter deletion [Hing et al 2006, Wieczorek et al 2014].
It is hypothesized that complete loss of TXNL4A is lethal. Both type 1 and type 2 promoter deletions result in reduced TXNL4A expression (see Molecular Genetics).
Molecular genetic testing approaches can include targeted assay to detect promoter deletions, single-gene testing, chromosomal microarray analysis (CMA), use of a multigene panel, and more comprehensive genomic testing.
Recommended Testing
Tier 1 testing. Targeted assay to detect the type 1 and type 2 promoter deletions (e.g., PCR and sequence analysis of the TXNL4A promoter, allele-specific PCR, or other targeted assay) is performed first.
Note: If a deletion that includes TXNL4A was previously detected by CMA, detection of one copy of the type 1 or type 2 promoter deletion establishes the diagnosis of BMKS.
Tier 2 testing. If Tier 1 testing detects one copy of a type 1 or type 2 promoter deletion, additional studies to detect a second variant can include:
- Sequence analysis of TXNL4A to test for loss-of-function variants;
- Chromosomal microarray analysis (CMA) to identify larger deletions in 18q23, which cannot be detected by either sequence analysis or gene-targeted deletion/duplication analysis;
- Gene-targeted deletion/duplication analysis of TXNL4A to test for whole-exon deletions or duplications.
Other Testing to Consider
A multigene panel that includes promoter deletion assays of TXNL4A and testing of 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 serial single-gene testing (and/or use of a multigene panel that includes TXNL4A) fails to confirm a diagnosis in an individual with features of Burn-McKeown 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 Burn-McKeown Syndrome
| Gene 1 | Test Method | Proportion of Probands with Pathogenic Variants 2 Detectable by This Method |
|---|---|---|
| TXNL4A | Promoter deletion assays 3 | 11 of 11 4 |
| Sequence analysis 5 | 4 of 11 | |
| Gene-targeted deletion/duplication analysis 6 | 2 of 11 | |
| CMA 7 | 4 of 11 8 | |
| Unknown | See footnote 9 | |
- 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.
The two reported 34-bp promoter deletions can be detected and distinguished by targeted assays (e.g., PCR and subsequent sequence analysis of PCR products).
- 4.
All 11 individuals with a molecularly confirmed diagnosis of BMKS had at least one copy of a type 1 or type 2 promoter deletion (10 heterozygotes, 1 homozygote) [Wieczorek et al 2014; Wieczorek, unpublished observations].
- 5.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.
- 6.
Gene-targeted deletion analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions. To date, no partial or complete TXNL4A gene duplications have been identified.
- 7.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 18q23 region.
- 8.
Large deletions may not be fully characterized by gene-targeted methods.
- 9.
In eight individuals with a tentative diagnosis of BMKS, sequence analysis did not identify a TXNL4A variant and whole-genome dosage analysis (to screen for deletions and duplications based on coverage data) did not suggest other candidate loci.
Clinical Characteristics
Clinical Description
Burn-McKeown syndrome (BMKS) is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, narrow palpebral fissures, coloboma of the lower eyelids, and large and protruding ears), congenital heart defects, and short stature. Intellect is normal [Wieczorek et al 2014].
To date the diagnosis of BMKS has been confirmed in 14 individuals from 11 families [Wieczorek et al, personal communication], including the family originally described with oculootofacial dysplasia (OOFD) [Hing et al 2006] and later molecularly confirmed to have BMKS [Wieczorek et al 2014]. Their clinical features are summarized in Table 2.
Table 2.
Clinical Features in 14 Persons with Molecularly Confirmed Burn-McKeown Syndrome
| Feature | # of Persons Reported w/Feature | Percentage |
|---|---|---|
| Normal intellect | 14 | 100% |
| Short palpebral fissures | 14 | 100% |
| Bilateral choanal stenosis/atresia | 14 | 100% |
| Prominent nasal bridge | 13 | ~93% |
| Short philtrum | 12 | ~86% |
| Defects of lower eyelids | 12 | ~86% |
| Hypertelorism | 12 | ~86% |
| Prominent ears | 10 | ~71% |
| Hearing loss | 10 | ~71% |
| Micrognathia | 9 | ~64% |
| Preauricular tags | 8 | ~57% |
| Cleft lip/palate | 8 | ~57% |
| Thin lips | 8 | ~57% |
| Cardiac defect | 4 | ~29% |
| Short stature | 2 | ~14% |
Bilateral choanal stenosis/atresia is potentially life threatening (see Management).
Defects of lower eyelids can result in corneal exposure and, hence, drying.
Hearing loss. Detailed clinical information regarding the severity and course of hearing loss has not been reported.
Cleft lip/palate. Submucous cleft palate and uni-/bilateral cleft lip/palate have been described.
Cardiac defects include persistent ductus arteriosus (PDA) and patent foramen ovale.
Short stature is proportionate and mild.
Intellectual disability. One female had mild learning disabilities.
Genotype-Phenotype Correlations
Because only 14 individuals (from 11 families) with molecularly confirmed Burn-McKeown syndrome have been published to date, no genotype-phenotype correlations are possible [Wieczorek et al 2014; Wieczorek, unpublished observations].
Nomenclature
Initially described as a distinct entity in a highly consanguineous Alaskan family by Hing et al [2006], oculootofacial dysplasia (OOFD) was reclassified as BMKS when Wieczorek et al [2014] identified homozygous type 2 TXNL4A promoter deletions in affected members of this family.
Prevalence
The prevalence of BMKS has not been established. To date only eleven unrelated individuals with molecularly confirmed BMKS have been reported.
Differential Diagnosis
Treacher Collins syndrome (TCS) is a mandibulofacial dysostosis with variable expressivity. Anomalies are usually restricted to the craniofacial region and comprise downslanted palpebral fissures, hypoplasia of the zygomatic bones, lower-eyelid coloboma, microtia, and micrognathia.
Although there is some overlap between TCS and BMKS, downslanted palpebral fissures, hypoplasia of the zygomatic bones, and microtia have not been reported in BMKS. Cardiac defects and short stature are uncommon in TCS.
A heterozygous pathogenic variant in TCOF1 or POLR1D causes autosomal dominant TCS and biallelic pathogenic variants in POLR1C cause autosomal recessive TCS.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Burn-McKeown syndrome, the following evaluations are recommended:
- In newborns, airway assessment for evidence of upper-airway obstruction with choanal stenosis/atresia
- Ophthalmology assessment for lower-eyelid coloboma for possible corneal involvement
- Audiology assessment (see Deafness and Hereditary Hearing Loss Overview)
- Examination for midline cleft palate or unilateral cleft lip/palate; referral to multidisciplinary cleft palate team as required
- Cardiology and/or echocardiographic assessment for structural heart defects
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Neonates with airway compromise at delivery may require intubation or surgical correction of choanal stenosis/atresia.
Defects of the lower eyelids that can result in corneal exposure require care by an ophthalmologist to reduce the risk of corneal scarring.
Treatment of hearing loss is individualized and may involve conventional hearing aids.
Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team, which may include: oromaxillofacial surgery, plastic surgery, otolaryngology, dentistry/orthodontics, and speech/language therapy.
Cardiac defects are managed in a routine manner.
Surveillance
Surveillance includes monitoring of development by a physician with expertise in craniofacial disorders. Clinical follow up should include body measurements, hearing assessment, and ophthalmologic examination.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.