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Burn-McKeown Syndrome

Synonym: BMKS

, PhD and , MD.

Author Information

Initial Posting: .

Estimated reading time: 12 minutes

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
Figure 1. . Craniofacial phenotype in individuals with Burn-McKeown 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:

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:

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 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
TXNL4APromoter deletion assays 311 of 11 4
Sequence analysis 54 of 11
Gene-targeted deletion/duplication analysis 62 of 11
CMA 74 of 11 8
UnknownSee footnote 9
1.
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/FeaturePercentage
Normal intellect14100%
Short palpebral fissures14100%
Bilateral choanal stenosis/atresia14100%
Prominent nasal bridge13~93%
Short philtrum12~86%
Defects of lower eyelids12~86%
Hypertelorism12~86%
Prominent ears10~71%
Hearing loss10~71%
Micrognathia9~64%
Preauricular tags8~57%
Cleft lip/palate8~57%
Thin lips8~57%
Cardiac defect4~29%
Short stature2~14%

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
  • 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Burn-McKeown syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one TXNL4A pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with Burn-McKeown syndrome are obligate heterozygotes (carriers) for a pathogenic variant in TXNL4A.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a TXNL4A pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the TXNL4A pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • BabyHearing.org
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Burn-McKeown Syndrome: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
TXNL4A18q23Thioredoxin-like protein 4ATXNL4ATXNL4A

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Burn-McKeown Syndrome (View All in OMIM)

608572BURN-MCKEOWN SYNDROME; BMKS
611595THIOREDOXIN-LIKE 4A; TXNL4A

Molecular Genetic Pathogenesis

TXNL4A encodes a highly conserved component of the U5 spliceosomal complex and essential for U4/U6·U5 tri-snRNP assembly and cell cycle progression. Although complete loss of TXNL4A is hypothesized to be lethal, reduced TXNL4A function results in BMKS.

Gene structure. TXNL4A spans approximately 17.8 kb of genomic DNA and comprises three exons. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. Two 34-bp deletions (type 1 and type 2) in the promoter region of TXNL4A have been described (see Table 3). The type 1 and type 2 promoter deletions partially overlap and occur at a fairly high frequency in the general population. Among 3,343 healthy individuals, 45 were heterozygous and one was homozygous for the type 1 promoter deletion; one individual was heterozygous for the type 2 promoter deletion [Wieczorek et al 2014].

Nearly all probands identified to date are compound heterozygous for the type 1 promoter deletion and a loss-of-function allele. In one highly consanguineous Alaskan family originally described by Hing et al [2006], homozygosity for the less common type 2 promoter deletion was observed [Wieczorek et al 2014].

Loss-of-function alleles are due to either nonsense or frameshift variants or whole-or partial-gene deletions. All inactivating pathogenic variants identified to date are private.

With only one exception, all individuals with molecularly proven Burn-McKeown syndrome (BMKS) are compound heterozygotes for a TXNL4A null allele and a type 1 promoter deletion [Wieczorek et al 2014].

The following correlations with genetic findings have been observed:

  • Compound heterozygosity for a loss-of-function variant and a promoter deletion leads to expression of the BMKS phenotype.
  • Homozygosity for the type 2 promoter deletion leads to expression of the BMKS phenotype.
  • Heterozygosity for any variant has no phenotypic effect.

The following correlations with genetic findings are hypothesized:

  • Homozygosity or compound heterozygosity for loss-of-function variants is lethal.
  • Homozygosity for the type 1 promoter deletion has no phenotypic effect.

Table 3.

TXNL4A Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.37C>Tp.(Gln13Ter)NM_006701​.2
GRCh37​/hg19
c.153+3A>GPotential splice variant, putatively truncating
c.131delTp.(Val44AlafsTer48)
c.349G>Tp.(Glu117Ter)
Chr18:g.77,736,960_77,738,660delComplete deletion of exon 2, putatively truncating
Exon 3 deletion 1Putatively truncating
Chr18:g.73,376,178_78,077,248delHeterozygous whole-gene deletion
Chr18:g.76,841,645_78,077,248delHeterozygous whole-gene deletion
Chr18:g.76,854,774_78,077,248delHeterozygous whole-gene deletion
Chr18:g.77,421,290_77,904,990delHeterozygous whole-gene deletion
Chr18:g.77,748,581_77,748,614delType 1 promoter deletion
Chr18:g.77,748,604_77,748,637delType 2 promoter deletion

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

The breakpoints of the exon 3 deletion have not been determined precisely.

Normal gene product. TXNL4A encodes a 142-aa protein (NP_006692). The protein (also known as DIM1 or U5-15kd) is a highly conserved component of the U5 spliceosomal complex and essential for U4/U6·U5 tri-snRNP assembly and cell cycle progression [Simeoni & Divita 2007].

Abnormal gene product. The type 1 and type 2 promoter deletions result in reduced promoter activity [Wieczorek et al 2014]. They must therefore be considered as hypomorphic alleles. Of note, the type 2 promoter deletion results in significantly lower transcription than the type 1 promoter deletion.

In yeast, homozygous null mutants of the orthologous gene, DIB1, are lethal [Liu et al 2006]. Thus, homozygous loss-of-function variants in humans may be lethal as well. This is compatible with findings in individuals with BMKS described to date.

References

Literature Cited

  • Hing AV, Leblond C, Sze RW, Starr JR, Monks S, Parisi MA. A novel oculo-oto-facial dysplasia in a Native Alaskan community with autosomal recessive inheritance. Am J Med Genet A. 2006;140:804–12. [PubMed: 16523509]
  • Liu S, Rauhut R, Vornlocher H-P, Lührmann R. The network of protein-protein interactions within the human U4/U6·U5 tri-snRNP. RNA. 2006;12:1418–30. [PMC free article: PMC1484429] [PubMed: 16723661]
  • Simeoni F, Divita G. The Dim protein family: from structure to splicing. Cell Mol Life Sci. 2007;64:2079–89. [PubMed: 17558560]
  • Wieczorek D, Newman WG, Wieland T, Berulava T, Kaffe M, Falkenstein D, Beetz C, Graf E, Schwarzmayr T, Douzgou S, Clayton-Smith J, Daly SB, Williams SG, Bhaskar SS, Urquhart JE, Anderson B, O'Sullivan J, Boute O, Gundlach J, Czeschik JC, van Essen AJ, Hazan F, Park S, Hing A, Kuechler A, Lohmann DR, Ludwig KU, Mangold E, Steenpaß L, Zeschnigk M, Lemke JR, Lourenco CM, Hehr U, Prott EC, Waldenberger M, Böhmer AC, Horsthemke B, O'Keefe RT, Meitinger T, Burn J, Lüdecke HJ, Strom TM. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome. Am J Hum Genet. 2014;95:698–707. [PMC free article: PMC4259969] [PubMed: 25434003]

Chapter Notes

Acknowledgments

The authors wish to gratefully acknowledge the contribution of the patients and their families.

Revision History

  • 14 July 2016 (bp) Review posted live
  • 19 January 2016 (dw) Original submission
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