Clinical characteristics.

TXNL4A-related craniofacial disorders comprise a range of phenotypes that includes: isolated choanal atresia; choanal atresia with minor anomalies; and Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears). Hearing loss is common and cardiac defects and short stature have been reported. Intellectual disability is rare.

Diagnosis/testing.

The diagnosis of a TXNL4A-related craniofacial disorder is established in a proband with suggestive findings and biallelic pathogenic variants in TXNL4A identified by molecular genetic testing. 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 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 by an ophthalmologist, audiologist, and craniofacial team is recommended.

Genetic counseling.

TXNL4A-related craniofacial disorders are 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 inheriting neither of the familial TXNL4A pathogenic variants. Once the TXNL4A pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

A TXNL4A-related craniofacial disorder should be suspected in individuals with the following clinical findings and family history.

Clinical findings. Bilateral choanal atresia/stenosis WITH OR WITHOUT:

• 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, leading 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 a TXNL4A-related craniofacial disorder. 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. (more...)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of a TXNL4A-related craniofacial disorder is established in a proband with suggestive findings and biallelic pathogenic variants in TXNL4A identified by molecular genetic testing (see Table 1).

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.

Note: Identification of biallelic TXNL4A variants of uncertain significance (or identification of one known TXNL4A pathogenic variant and one TXNL4A variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.

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.

Clinical Description

TXNL4A-related craniofacial disorders range from isolated choanal atresia to choanal atresia with minor anomalies to Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears). Hearing loss is common and cardiac defects and short stature have been reported. Intellectual disability is rare [Wieczorek et al 2014].

To date, 20 individuals with biallelic pathogenic variants in TXNL4A have been identified [Wieczorek et al 2014, Goos et al 2017, Narayanan et al 2020, Wood et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Bilateral choanal stenosis/atresia is potentially life threatening.

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 and patent foramen ovale.

Short stature is proportionate and mild.

Intellectual disability. One female had mild learning disabilities and another had severe intellectual disability [Strang-Karlsson et al 2017].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

Initially described as a distinct entity in a highly consanguineous Alaskan family by Hing et al [2006], oculootofacial dysplasia (OOFD) was reclassified as Burn-McKeown syndrome (BMKS) when Wieczorek et al [2014] identified homozygous type 2 TXNL4A promoter deletions in affected members of this family.

Prevalence

The prevalence of TXNL4A-related craniofacial disorders has not been established. To date 20 individuals with a TXNL4A-related craniofacial disorder have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a TXNL4A-related craniofacial disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

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 EU Clinical Trials Register 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.

Mode of Inheritance

TXNL4A-related craniofacial disorders are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a TXNL4A pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a TXNL4A pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a TXNL4A pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial TXNL4A pathogenic variants.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with a TXNL4A-related craniofacial disorder 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 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 and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the TXNL4A pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

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

Two 34-bp deletions (type 1 and type 2) in the promoter region of TXNL4A have been described. 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].

Probands identified to date are compound heterozygous for the type 1 promoter deletion and a loss-of-function allele, or homozygous for the type 2 promoter deletion, or more rarely, homozygous for the type 1 promoter deletion [Goos et al 2017].

Mechanism of disease causation. The type 1 and type 2 promoter deletions result in reduced promoter activity and reduced TXNL4A expression [Wieczorek et al 2014]. They must therefore be considered hypomorphic alleles. Of note, the type 2 promoter deletion results in significantly lower transcription than the type 1 promoter deletion.

In yeast, homozygous null variants of the orthologous gene DIB1 are lethal [Liu et al 2006]. Thus, homozygous loss-of-function TXNL4A variants in humans may be lethal as well. This is compatible with findings in individuals with a TXNL4A-related craniofacial disorder described to date.

TXNL4A-specific laboratory technical considerations. The ability of a clinical molecular genetic laboratory to detect one or two deletions in the promoter region of TXNL4A is important for diagnosis of TXNL4A-related craniofacial disorders. Confirmation of clinical diagnosis is possible in every molecular laboratory that offers Sanger sequencing, multiplex ligation-dependent probe amplification, and chromosomal microarray analysis. Genome sequencing also allows detection of the promoter deletions, larger deletions, and loss-of-function pathogenic variants.

Author Notes

Dagmar Wieczorek has longstanding expertise in syndromic entities, especially those with intellectual disability (ID) and craniofacial malformations. She was principal investigator in the German Mental Retardation Network, funded by NGFNplus, and in the CRANIRARE, FACE, and Chromatin-Net consortia, all funded by the BMBF. She has published many papers on gene identification in individuals with ID and with craniofacial anomalies (e.g., Treacher Collins syndrome, Burn-McKeown syndrome, and acrofacial dysostosis, Cincinnati type), as well as papers on the clinical spectrum of new entities with special emphasis on the facial phenotype.

Dagmar Wieczorek
Institut für Humangenetik
Universitätsklinikum Düsseldorf
Universitätsstr. 1
40225 Düsseldorf, Germany
Email: dagmar.wieczorek@hhu.de

Acknowledgments

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

Revision History

• 12 May 2022 (ha) Comprehensive update posted live
• 14 July 2016 (bp) Review posted live
• 19 January 2016 (dw) Original submission

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