Burn-McKeown Syndrome

Mendelian MONDO:0012064 Pathograph 26 Show in embeddings browser Craniofacial Malformation Syndrome Spliceosomopathy

Burn-McKeown syndrome (BMKS; choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome; OMIM 608572) is an extremely rare autosomal recessive craniofacial malformation syndrome caused by biallelic variants in TXNL4A (18q23), which encodes the U5 snRNP core protein TXNL4A/Dib1. Affected individuals have bilateral choanal atresia or stenosis together with a distinctive facial gestalt - short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin upper lip vermilion and prominent ears - plus frequent hearing loss, and less commonly cardiac septal defects, cleft lip and/or palate, preauricular tags, short stature and renal anomalies. Intelligence is usually normal, which is a key discriminator from EFTUD2-related mandibulofacial dysostosis with microcephaly. Almost all reported probands carry a 34-base-pair deletion in the TXNL4A promoter on at least one allele, in trans with a coding loss-of-function variant; the resulting reduction in TXNL4A expression disrupts U4/U6.U5 tri-snRNP function and impairs cranial neural crest cell formation and differentiation, which is why a lesion in a ubiquitously expressed spliceosome protein presents as a tissue-restricted craniofacial phenotype. TXNL4A variants also cause isolated choanal atresia and choanal atresia with minor anomalies, so BMKS is the severe end of a TXNL4A-related craniofacial spectrum.

Ask OpenScientist

Ask a research question about Burn-McKeown Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
5
Pathophys.
18
Phenotypes
1
Gaps
26
Pathograph
1
Genes
6
Medical Actions
6
Differentials
2
Models
1
References
1
Deep Research
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
BMKS is autosomal recessive. Most affected individuals are compound heterozygotes for a low-frequency 34-bp TXNL4A promoter deletion and a rare coding loss-of-function variant on the other allele; homozygosity for a promoter deletion also occurs. Sibs of a proband have a 25% recurrence risk, and prenatal and preimplantation testing are possible once the familial variants are known.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:27413799 SUPPORT Human Clinical
"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."
GeneReviews states the mode of inheritance and the recurrence risk.
PMID:32187816 SUPPORT Human Clinical
"Homozygosity or compound heterozygosity of promoter deletions and null variants in TXNL4A are known to cause most cases of BMKS."
Documents both the compound-heterozygous and homozygous promoter-deletion genotypes.
?

Discussions and Knowledge Gaps

1
Why does reduced dosage of TXNL4A, a ubiquitously expressed core spliceosome protein, produce a malformation restricted to craniofacial structures rather than a generalised phenotype?
KNOWLEDGE GAP OPEN bmks_spliceosome_tissue_specificity
Attached to
pathophysiology#Impaired U5 snRNP and Tri-snRNP Spliceosome Function
This is the central unsolved problem of the craniofacial spliceosomopathies as a class, and it is stated as open in the primary literature. Two partial answers exist and are curated as separate nodes here: transcript-intrinsic sensitivity (mis-spliced genes share length, branch-point-to-3'-splice-site distance and splice-site-strength properties) and a downstream pathway effect (dampened WNT responsiveness via TCF7L2 exon 4 mis-splicing). A third proposal in the field, not curated as a node here because it has not been demonstrated for TXNL4A specifically, is that neural crest cells have an elevated sensitivity to inefficient splicing that triggers a P53-associated stress response through mis-splicing of MDM2/MDM4. Distinguishing these matters because they imply different therapeutic entry points. A limitation applying to all three: the human cellular evidence comes from a single patient donor line.
Proposed experiments
Test the P53/MDM2-MDM4 stress axis in BMKS patient iNCCs
bmks_p53_axis_in_patient_incc
Assay MDM2 and MDM4 regulatory-exon skipping, P53 stabilisation and apoptosis in BMKS patient-derived induced neural crest cells versus the maternal control, and test whether P53 inhibition rescues the differentiation and EMT delay.
Decision criterion
Rescue by P53 inhibition would place BMKS in the same nucleolar/splicing stress-response mechanism proposed for the other craniofacial spliceosomopathies; absence of rescue would favour the transcript-selectivity and WNT explanations already curated.
TCF7L2 isoform rescue in BMKS neural crest
bmks_tcf7l2_rescue
Express the correctly spliced TCF7L2 isoform in BMKS patient iNCCs and test whether WNT responsiveness, EMT timing and differentiation are restored.
Decision criterion
Restoration would upgrade the TCF7L2 node from PROVISIONAL to an established mechanism; failure would indicate TCF7L2 mis-splicing is a marker rather than a cause.
Show evidence (2 references)
PMID:32735620 SUPPORT In Vitro
"However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development."
States the knowledge gap explicitly for TXNL4A/BMKS.
PMID:32315467 SUPPORT Other
"We speculate that mutations in a subset of core splicing factors lead to disrupted splicing in neural crest cells because these cells have increased sensitivity to inefficient splicing."
The P53/neural-crest-sensitivity proposal is explicitly framed by its authors as speculation, which is why it is curated in this discussion rather than as a pathophysiology node.
⚙

Pathophysiology

5
Reduced TXNL4A Expression from Biallelic Promoter and Loss-of-Function Variants
The characteristic BMKS genotype is a 34-bp deletion in the TXNL4A promoter (type 1 or type 2) in trans with a coding or splice loss-of-function variant, or homozygosity for a promoter deletion. The deleted 56-bp promoter region contains a 22-bp repeated motif that is essential for TXNL4A expression, and the splice-site variants at the final intron cause skipping of the final exon. The net effect is a quantitative reduction in TXNL4A protein rather than its complete absence, which is why BMKS behaves as a hypomorphic dosage disorder.
TXNL4A hgnc:30551 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TXNL4A (hgnc:30551). hgnc:30551 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired U5 snRNP and Tri-snRNP Spliceosome Function Reduced TXNL4A protein lowers the availability of a U5 snRNP core component needed for tri-snRNP assembly and catalytic spliceosome function.
Show evidence (5 references)
PMID:25434003 SUPPORT Human Clinical
"Our results indicate that BMKS is an autosomal-recessive condition, which is frequently caused by compound heterozygosity of low-frequency promoter deletions in combination with very rare loss-of-function mutations."
Establishes the defining compound-heterozygous promoter-deletion-plus-null genotype as the cause of BMKS.
PMID:25434003 SUPPORT In Vitro
"Reporter gene and in vivo assays showed that the promoter deletions led to reduced expression of TXNL4A."
Direct functional demonstration that the promoter deletions reduce TXNL4A expression, which is the dosage premise of this node.
PMID:34713892 SUPPORT In Vitro
"we identify putative transcription factor binding sites within the 56 bp of the TXNL4A promoter affected by the type 1 and type 2 Δ34 and use dual luciferase assays to identify a 22 bp repeated motif essential for TXNL4A expression within this promoter region"
Luciferase assays localise the essential expression element within the deleted promoter region, explaining why the deletions reduce TXNL4A expression.
+ 2 more references
Impaired U5 snRNP and Tri-snRNP Spliceosome Function
TXNL4A (Dib1) is a core protein of the U5 small nuclear ribonucleoprotein, which sits at the centre of the catalytic spliceosome and is a component of the U4/U6.U5 tri-snRNP. Reduced TXNL4A dosage therefore degrades general pre-mRNA splicing capacity. Crucially the consequence is not uniform: only a subset of transcripts is affected, and the mis-spliced genes share sequence properties (transcript length, branch-point-to-3'-splice-site distance, splice-site strength) that make them unusually sensitive to reduced TXNL4A. This selectivity is the current explanation for how a ubiquitously expressed housekeeping protein produces a tissue-restricted craniofacial phenotype.
migratory cranial neural crest cell CL:0000008 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves migratory cranial neural crest cell (CL:0000008). CL:0000008 is a cell type from the Cell Ontology.
mRNA splicing, via spliceosome GO:0000398 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mRNA splicing, via spliceosome (GO:0000398). GO:0000398 is a biological process from the Gene Ontology. ↓ DECREASED spliceosomal snRNP assembly GO:0000387 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased spliceosomal snRNP assembly (GO:0000387). GO:0000387 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
BMKS patient-derived iPSC induced neural crest cells IPSC DERIVED MODEL RNA-Seq of patient iPSCs and iNCCs shows altered gene expression and alternative splicing relative to the maternal control.
Downstream
Defective Cranial Neural Crest Formation and Differentiation Selective mis-splicing degrades transcripts required for neural crest specification, EMT and migration.
Dampened WNT Signalling via TCF7L2 Mis-Splicing Mis-splicing of TCF7L2 exon 4 is the identified candidate route from splicing failure to reduced WNT responsiveness.
Show evidence (4 references)
PMID:25434003 SUPPORT Model Organism
"Depletion of TXNL4A (Dib1) in yeast demonstrated reduced assembly of the tri-snRNP complex."
Direct functional evidence that TXNL4A depletion reduces tri-snRNP assembly, the specific molecular claim this node makes and the basis for the DECREASED spliceosomal snRNP assembly annotation.
PMID:40264708 SUPPORT Other
"At the centre of the catalytic spliceosome is the U5 small nuclear ribonucleoprotein (snRNP). Pathogenic variants in U5 snRNP core proteins are associated with various diseases commonly known as spliceosomopathies."
Establishes TXNL4A's U5 snRNP context and the spliceosomopathy disease class.
PMID:32735620 SUPPORT In Vitro
"mis-spliced genes shared common sequence properties such as length, branch point to 3' splice site (BPS-3'SS) distance and splice site strengths, suggesting that splicing of particular subsets of genes is particularly sensitive to changes in TXNL4A expression"
Provides the mechanistic basis for transcript selectivity, which is how a housekeeping-protein defect becomes tissue-restricted.
+ 1 more reference
Defective Cranial Neural Crest Formation and Differentiation
Cranial neural crest cells are the progenitors of the facial skeleton and are the cell type in which spliceosome dosage matters most. Txnl4a knockdown in Xenopus produces cranial neural crest formation defects, placing TXNL4A alongside Eftud2 and Snrpb in a common craniofacial spliceosomopathy aetiology. In patient-derived cells, BMKS iPSCs proliferate more slowly than control and show defective differentiation into induced neural crest cells, with a specific delay in undergoing the epithelial-to-mesenchymal transition that neural crest cells must complete in order to delaminate and migrate.
migratory cranial neural crest cell CL:0000008 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves migratory cranial neural crest cell (CL:0000008). CL:0000008 is a cell type from the Cell Ontology.
neural crest cell development GO:0014032 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neural crest cell development (GO:0014032). GO:0014032 is a biological process from the Gene Ontology. ↓ DECREASED epithelial to mesenchymal transition GO:0001837 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased epithelial to mesenchymal transition (GO:0001837). GO:0001837 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
BMKS patient-derived iPSC induced neural crest cells IPSC DERIVED MODEL Patient iPSCs differentiate defectively into induced neural crest cells with a delayed epithelial-to-mesenchymal transition.
Downstream
Craniofacial Neural-Crest-Derived Malformation Reduced or mis-differentiated cranial neural crest yields hypoplastic and malformed neural-crest-derived facial structures.
Show evidence (3 references)
PMID:35893124 SUPPORT Model Organism
"Our results point to defects in cranial neural crest cell formation as the likely culprit for MFD associated with EFTUD2, SNRPB and TXNL4A haploinsufficiency, and suggest a commonality in the etiology of these craniofacial spliceosomopathies."
Xenopus knockdown of Txnl4a produces cranial neural crest formation defects, establishing the neural crest as the affected cell population.
PMID:32735620 SUPPORT In Vitro
"Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT)."
Patient-derived cells show the neural crest differentiation and EMT defect directly in human cells, with an isogenic-adjacent maternal control.
PMID:32735620 SUPPORT In Vitro
"BMKS patient-derived iPSCs proliferated more slowly than both mother- and unrelated control-derived iPSCs"
Documents the proliferation deficit that accompanies the differentiation defect in patient cells.
Dampened WNT Signalling via TCF7L2 Mis-Splicing
RNA-Seq of BMKS patient-derived induced neural crest cells showed widespread mis-splicing in genes relevant to craniofacial and embryonic development, with the dominant signature being a dampened response to WNT signalling - the key pathway activated during induced neural crest differentiation. Mis-splicing of exon 4 of TCF7L2, which encodes a core WNT-pathway transcription factor, was identified as a candidate cause of that reduced WNT response. This node is curated at provisional confidence: the TCF7L2 link is proposed by the authors as a potential cause rather than demonstrated by rescue.
canonical Wnt signaling pathway GO:0060070 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
BMKS patient-derived iPSC induced neural crest cells IPSC DERIVED MODEL iNCC RNA-Seq shows a dampened WNT response, with TCF7L2 exon 4 mis-splicing proposed as the cause.
Downstream
Defective Cranial Neural Crest Formation and Differentiation Reduced WNT responsiveness impairs the neural crest differentiation program that WNT signalling drives.
Show evidence (2 references)
PMID:32735620 SUPPORT In Vitro
"RNA-Seq analysis of differentiated iNCCs revealed widespread gene expression changes and mis-splicing in genes relevant to craniofacial and embryonic development that highlight a dampened response to WNT signalling, the key pathway activated during iNCC differentiation."
Establishes reduced WNT responsiveness as the dominant transcriptomic signature in patient neural crest cells.
PMID:32735620 SUPPORT In Vitro
"we identified the mis-splicing of TCF7L2 exon 4, a key gene in the WNT pathway, as a potential cause of the downregulated WNT response in patient cells"
The TCF7L2 link is offered as a potential cause and is not established by rescue, which is why this node carries PROVISIONAL mechanism confidence and the evidence is curated as PARTIAL.
Craniofacial Neural-Crest-Derived Malformation
The tissue-level outcome is a distinctive, recognisable craniofacial malformation pattern: bilateral choanal atresia or stenosis, short palpebral fissures with coloboma of the outer third of the lower eyelids, a prominent nasal bridge with widely spaced eyes, a short philtrum, a thin upper lip vermilion, and prominent ears, with cleft lip and/or palate and preauricular tags in a minority. Middle- and inner-ear involvement produces conductive and sensorineural hearing loss. The malar and mandibular hypoplasia that defines mandibulofacial dysostosis is not part of this pattern, and the choanal atresia arises from failure of the bucconasal membrane rather than from an arch derivative.
face morphogenesis GO:0060325 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal face morphogenesis (GO:0060325). GO:0060325 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Choanal Atresia Failure of the bucconasal membrane to rupture produces bilateral choanal atresia or stenosis, the cardinal feature.
Lower Eyelid Coloboma Coloboma of the outer third of the lower eyelid.
Hearing Loss Middle- and inner-ear involvement produces conductive and sensorineural hearing loss.
Conductive Hearing Impairment Middle-ear (ossicular/tympanic) involvement of arch-derived structures produces the conductive component of the hearing loss.
Sensorineural Hearing Impairment Inner-ear involvement produces the sensorineural component of the hearing loss.
Prominent Ears Prominent/protruding ears are part of the facial gestalt.
Short Palpebral Fissures Short palpebral fissures are part of the periorbital component of the malformation pattern.
Hypertelorism Widely spaced eyes accompany the prominent nasal bridge in the midfacial component of the pattern.
Prominent Nasal Bridge A prominent nasal bridge is the midfacial element of the malformation pattern.
Short Philtrum A short philtrum arises from the same disturbance of frontonasal and maxillary prominence fusion.
Thin Upper Lip Vermilion A thin upper lip vermilion accompanies the short philtrum in the perioral component of the pattern.
Cleft Lip Failure of fusion of the medial nasal and maxillary prominences produces cleft lip in a minority.
Cleft Palate Failure of palatal shelf elevation and fusion produces cleft palate in a minority.
Preauricular Skin Tag Preauricular tags represent supernumerary first/second arch hillock derivatives.
Show evidence (2 references)
PMID:27413799 SUPPORT Human Clinical
"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)."
GeneReviews defines the composite craniofacial malformation pattern that this node represents.
PMID:14564154 SUPPORT Human Clinical
"bilateral choanal atresia, and a characteristic pattern of facial dysmorphic features consisting of hypertelorism, lower lid coloboma, narrow palpebral fissures, prominent nasal bridge, small mouth with thin lips, and protruding ears"
An independent family report documents the same recognisable facial pattern.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Burn-McKeown Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

18
Cardiovascular 1
Structural Cardiac Abnormality OCCASIONAL Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Structural cardiac abnormality, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27413799 SUPPORT Human Clinical
"Hearing loss is common and cardiac defects and short stature have been reported."
GeneReviews contrasts hearing loss ("common") with cardiac defects ("have been reported"), supporting a lower OCCASIONAL band for the cardiac defects.
PMID:28905882 SUPPORT Human Clinical
"structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip"
Lists structural cardiac abnormalities among the characterising features of BMKS.
Ear 3
Hearing Loss FREQUENT Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27413799 SUPPORT Human Clinical
"Hearing loss is common and cardiac defects and short stature have been reported."
GeneReviews describes hearing loss as common, which maps to the FREQUENT band.
PMID:28905882 SUPPORT Human Clinical
"conductive and sensorineural hearing loss"
Documents that both conductive and sensorineural components occur.
Conductive Hearing Impairment HP:0000405 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28905882 SUPPORT Human Clinical
"conductive and sensorineural hearing loss"
Explicitly lists conductive hearing loss among the characterising features.
Sensorineural Hearing Impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28905882 SUPPORT Human Clinical
"conductive and sensorineural hearing loss"
Explicitly lists sensorineural hearing loss among the characterising features.
Eye 1
Hypertelorism VERY_FREQUENT HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27413799 SUPPORT Human Clinical
"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)."
GeneReviews lists widely spaced eyes among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
PMID:14564154 SUPPORT Human Clinical
"a characteristic pattern of facial dysmorphic features consisting of hypertelorism, lower lid coloboma, narrow palpebral fissures"
An independent sibship documents hypertelorism as part of the characteristic facial pattern.
Head and Neck 2
Choanal Atresia VERY_FREQUENT HP:0000453 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Choanal atresia (HP:0000453). HP:0000453 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27413799 SUPPORT Human Clinical
"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)."
GeneReviews places bilateral choanal atresia/stenosis first among the typical craniofacial features of BMKS. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
PMID:27413799 SUPPORT Human Clinical
"Neonates with airway compromise at delivery may require intubation or surgical correction of choanal stenosis/atresia."
Documents the clinical consequence that makes choanal atresia the presenting and most urgent feature.
Cleft Palate OCCASIONAL HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:25434003 SUPPORT Human Clinical
"This rare condition is characterized by bilateral choanal atresia, hearing loss, cleft lip and/or palate, and other craniofacial dysmorphisms."
Cleft lip and/or palate is named in the core characterisation of BMKS but is not one of the constant features, supporting the OCCASIONAL band (the same band as the sibling Cleft Lip entry, which is drawn from the same sources).
PMID:27413799 SUPPORT Human Clinical
"Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team."
GeneReviews lists cleft palate among the craniofacial manifestations routinely managed in BMKS.
PMID:14564154 SUPPORT Human Clinical
"These brothers show some additional features that were not previously reported in patients with this syndrome including median cleft palate with oronasal fistula, preauricular tag, hypomimic face, and hypoplastic unilateral kidney, thus indicating that the clinical spectrum of this entity is broader."
Documents the specific median cleft palate with oronasal fistula variant as an expansion of the BMKS phenotypic spectrum.
Nervous System 1
Intellectual Disability VERY_RARE HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
A single case of severe intellectual disability in a patient with BMKS is reported in PMID:28225383 (Clin Dysmorphol letter). That record is abstract-only with no abstract body, so no quotable snippet exists and the claim is recorded here per the evidence SOP rather than as an evidence item.
Show evidence (2 references)
PMID:27413799 SUPPORT Human Clinical
"Hearing loss is common and cardiac defects and short stature have been reported. Intellectual disability is rare."
GeneReviews explicitly states intellectual disability is rare, which maps to the VERY_RARE band.
PMID:32187816 SUPPORT Human Clinical
"BMKS is characterized by craniofacial dysmorphism, choanal atresia, and normal intellect in affected individuals."
Independently states that intellect is normal in affected individuals, supporting the very low frequency band.
Growth 1
Short Stature OCCASIONAL HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27413799 SUPPORT Human Clinical
"cardiac defects and short stature have been reported"
GeneReviews reports short stature with the hedged phrase "have been reported". The band is set at OCCASIONAL rather than the stricter VERY_RARE that phrase would normally map to, because short stature is listed as a recurring feature of the syndrome rather than as a single-family spectrum expansion; the departure from the default mapping is recorded here deliberately.
Other 9
Lower Eyelid Coloboma VERY_FREQUENT HP:0000652 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower eyelid coloboma (HP:0000652). HP:0000652 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27413799 SUPPORT Human Clinical
"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)."
GeneReviews lists lower eyelid coloboma among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
PMID:27413799 SUPPORT Human Clinical
"Defects of the lower eyelids that can result in corneal exposure require care by an ophthalmologist to reduce the risk of corneal scarring."
Documents the corneal-exposure complication that makes the eyelid defect clinically actionable.
Short Palpebral Fissures VERY_FREQUENT HP:0012745 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short palpebral fissure (HP:0012745). HP:0012745 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27413799 SUPPORT Human Clinical
"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)."
GeneReviews lists short palpebral fissures among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
Prominent Nasal Bridge VERY_FREQUENT HP:0000426 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent nasal bridge (HP:0000426). HP:0000426 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27413799 SUPPORT Human Clinical
"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)."
GeneReviews lists the prominent nasal bridge among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
Short Philtrum VERY_FREQUENT HP:0000322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short philtrum (HP:0000322). HP:0000322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27413799 SUPPORT Human Clinical
"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)."
GeneReviews lists the short philtrum among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
Thin Upper Lip Vermilion VERY_FREQUENT HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27413799 SUPPORT Human Clinical
"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)."
GeneReviews lists a thin upper lip vermilion among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
Prominent Ears VERY_FREQUENT Protruding ear HP:0000411 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protruding ear (HP:0000411). HP:0000411 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27413799 SUPPORT Human Clinical
"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)."
GeneReviews lists prominent ears among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
PMID:28905882 SUPPORT Human Clinical
"Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelid, structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip."
Independently lists prominent ears as a characterising feature.
Cleft Lip OCCASIONAL Cleft upper lip HP:0000204 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft upper lip (HP:0000204). HP:0000204 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28905882 SUPPORT Human Clinical
"structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip"
Lists cleft lip among the characterising features.
PMID:27413799 SUPPORT Human Clinical
"Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team."
GeneReviews management section confirms cleft lip and/or palate occurs and requires multidisciplinary care.
Preauricular Skin Tag OCCASIONAL HP:0000384 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Preauricular skin tag (HP:0000384). HP:0000384 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27413799 SUPPORT Human Clinical
"cleft lip and/or palate, preauricular tags, prominent ears"
GeneReviews lists preauricular tags among the craniofacial manifestations requiring management.
Renal Hypoplasia VERY_RARE HP:0000089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal hypoplasia (HP:0000089). HP:0000089 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14564154 SUPPORT Human Clinical
"median cleft palate with oronasal fistula, preauricular tag, hypomimic face, and hypoplastic unilateral kidney"
Documents unilateral renal hypoplasia as an expansion of the BMKS spectrum. The snippet states these features "were not previously reported", i.e. isolated-report frequency, which is why the band is VERY_RARE.
🧬

Genetic Associations

1
TXNL4A (Causal - biallelic loss-of-function and promoter-deletion variants)
Gene: TXNL4A hgnc:30551 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TXNL4A (hgnc:30551). hgnc:30551 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (6 references)
PMID:27413799 SUPPORT Human Clinical
"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..."
GeneReviews states the biallelic requirement and the near-universal presence of a 34-bp promoter deletion allele.
PMID:25434003 SUPPORT Human Clinical
"a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele"
Enumerates the second-allele variant classes, including microdeletion, which is why copy-number analysis is required in addition to promoter sequencing.
PMID:25434003 SUPPORT Human Clinical
"Mutations were found in 9 of 11 affected families."
Quantifies the diagnostic yield of TXNL4A testing in a clinically ascertained BMKS cohort.
+ 3 more references
💊

Medical Actions

6
Neonatal Airway Management and Choanal Atresia Repair
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Bilateral choanal atresia causes airway compromise at delivery because neonates are obligate nasal breathers. Immediate management may require intubation, followed by surgical correction of the choanal stenosis/atresia.
Target Phenotypes: Choanal atresia HP:0000453 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Choanal atresia (HP:0000453). HP:0000453 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27413799 SUPPORT Human Clinical
"Neonates with airway compromise at delivery may require intubation or surgical correction of choanal stenosis/atresia."
GeneReviews states the acute airway management and definitive surgical treatment for the cardinal feature.
Ophthalmological Care for Lower Eyelid Defects
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Lower eyelid defects can cause corneal exposure. Ophthalmological care is required to reduce the risk of corneal scarring, and monitoring by an ophthalmologist is part of recommended surveillance.
Target Phenotypes: Lower eyelid coloboma HP:0000652 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Lower eyelid coloboma (HP:0000652). HP:0000652 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27413799 SUPPORT Human Clinical
"Defects of the lower eyelids that can result in corneal exposure require care by an ophthalmologist to reduce the risk of corneal scarring."
GeneReviews specifies ophthalmological care for the eyelid defect and its rationale.
Hearing Loss Management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Treatment of hearing loss is individualised and may involve hearing aids, with audiological monitoring as part of surveillance.
Target Phenotypes: Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27413799 SUPPORT Human Clinical
"Treatment of hearing loss is individualized and may involve hearing aids."
GeneReviews states the management approach for hearing loss.
Multidisciplinary Craniofacial Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Cleft lip and/or palate, preauricular tags and prominent ears are managed individually by a multidisciplinary craniofacial team, with craniofacial-team monitoring as part of recommended surveillance.
Show evidence (2 references)
PMID:27413799 SUPPORT Human Clinical
"Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team."
GeneReviews defines multidisciplinary craniofacial management.
PMID:27413799 SUPPORT Human Clinical
"Monitoring by an ophthalmologist, audiologist, and craniofacial team is recommended."
States the recommended surveillance regimen.
Cardiac Management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Cardiac defects are managed in a routine manner, without disorder-specific modification.
Target Phenotypes: Structural cardiac abnormality HP:0001627 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Structural cardiac abnormality, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27413799 SUPPORT Human Clinical
"Cardiac defects are managed in a routine manner."
GeneReviews states that cardiac management is standard rather than disorder-specific.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Counselling covers autosomal recessive inheritance, the 25% sib recurrence risk, the need to test the promoter region in relatives, and the availability of prenatal and preimplantation genetic testing once both familial variants are known.
Show evidence (1 reference)
PMID:27413799 SUPPORT Human Clinical
"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."
GeneReviews states the reproductive testing options that counselling addresses.
🔬

Diagnosis

1
Molecular Genetic Testing for TXNL4A Including the Promoter Region (Biallelic pathogenic variants in affected individuals)
The diagnosis is established by identifying biallelic pathogenic TXNL4A variants. Testing must explicitly interrogate the non-coding promoter region: because virtually every proband carries a 34-bp promoter deletion on at least one allele, standard exome or coding-only panel analysis will find only one variant and the diagnosis will be missed. When a single likely pathogenic coding TXNL4A variant is found in a clinically consistent individual, the promoter must be sequenced.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:27413799 SUPPORT Human Clinical
"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."
Establishes that promoter analysis is effectively mandatory for molecular diagnosis.
PMID:34713892 SUPPORT Human Clinical
"our data emphasises the need to analyse the non-coding sequence in individuals where a single likely pathogenic coding variant is identified"
States the specific diagnostic protocol point that follows from the promoter-allele architecture.
📊

Prevalence

2
Published families worldwide
Cases In Literature Ultra Rare
Only 15 families had been described as of 2020; the MONDO/Orphanet definition characterises the syndrome as extremely rare. No population prevalence estimate exists.
Show evidence (1 reference)
PMID:32187816 SUPPORT Human Clinical
"Till date, 15 families have been described with BMKS."
Quantifies the total published caseload as of 2020, supporting an ultra-rare classification.
Control alleles surveyed in the TXNL4A discovery study
Carrier Frequency 760.0 per 100,000 >1 in 1,000
Allele frequency of the recurrent 34 bp TXNL4A core-promoter deletion is 0.76%. This is the frequency of the common hypomorphic allele, not of the disease: BMKS requires this allele in trans with a very rare loss-of-function coding variant, which is why the syndrome remains ultra-rare despite the relatively common promoter deletion.
Show evidence (1 reference)
PMID:25434003 SUPPORT Human Clinical
"a low-frequency 34 bp deletion (allele frequency 0.76%) in the core promoter region on the other allele"
Reports the population allele frequency of the recurrent TXNL4A promoter deletion.
🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Burn-McKeown Syndrome:

CHARGE Syndrome (CHD7)
Overlapping Features The principal clinical differential. CHARGE also features choanal atresia, coloboma, cardiac defects, ear anomalies and hearing loss, and the MONDO definition of BMKS notes that the features overlap considerably. CHD7 testing distinguishes them.
Treacher Collins Syndrome (TCOF1, POLR1C/POLR1D)
Overlapping Features Shares lower eyelid coloboma and ear anomalies and is the closest mechanistic analogue - a ribosome-biogenesis rather than spliceosome defect depleting cranial neural crest. Distinguished by the malar and mandibular hypoplasia that BMKS lacks.
Mandibulofacial Dysostosis with Microcephaly (EFTUD2)
Overlapping Features The other U5 snRNP spliceosomopathy. Shares the core splicing-factor mechanism but differs clinically in having microcephaly, mandibulofacial dysostosis and intellectual disability, whereas BMKS intellect is usually normal. Curated separately in dismech as `Mandibulofacial_Dysostosis_with_Microcephaly`.
Nager Syndrome (SF3B4)
Overlapping Features An acrofacial dysostosis caused by a different core splicing factor; shares the craniofacial spliceosomopathy mechanism but adds preaxial limb defects.
Cerebrocostomandibular Syndrome (SNRPB)
Overlapping Features A further craniofacial spliceosomopathy, characterised by Robin sequence and rib defects.
Isolated Choanal Atresia
Overlapping Features Allelic - homozygosity for a TXNL4A promoter deletion has been found in individuals with isolated choanal atresia, so isolated choanal atresia is both a differential and a milder point on the same TXNL4A spectrum.
🧫

Experimental Models

1
BMKS patient-derived iPSC induced neural crest cells IPSC_DERIVED_MODEL
The principal experimental system for BMKS mechanism. The unaffected mother's line provides a closely matched (though not isogenic) control. Limitation: the single patient donor is an atypical case, so findings should be replicated in additional lines before being generalised across the BMKS phenotypic spectrum.
migratory cranial neural crest cell CL:0000008 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses migratory cranial neural crest cell (CL:0000008). CL:0000008 is a cell type from the Cell Ontology.
Cell source
Peripheral blood mononuclear cells from a BMKS patient (TXNL4A compound heterozygote) and from her unaffected mother
Culture
iPSC reprogramming followed by directed differentiation to induced neural crest cells (iNCCs)
Publication
PMID:32735620
Pathograph links
Impaired U5 snRNP and Tri-snRNP Spliceosome Function RNA-Seq of patient iPSCs and iNCCs shows altered gene expression and alternative splicing relative to the maternal control.
Defective Cranial Neural Crest Formation and Differentiation Patient iPSCs differentiate defectively into induced neural crest cells with a delayed epithelial-to-mesenchymal transition.
Dampened WNT Signalling via TCF7L2 Mis-Splicing iNCC RNA-Seq shows a dampened WNT response, with TCF7L2 exon 4 mis-splicing proposed as the cause.
Findings
BMKS patient iPSCs proliferate more slowly than maternal and unrelated control lines and show significant differences in gene expression and alternative splicing.
"BMKS patient-derived iPSCs proliferated more slowly than both mother- and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing."
Differentiation to induced neural crest cells is defective, with a delay in undergoing the epithelial-to-mesenchymal transition.
"Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT)."
Show evidence (1 reference)
PMID:32735620 SUPPORT In Vitro
"Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development."
Describes the patient-derived cellular model and its maternal control, the principal experimental system for BMKS mechanism.
🐁

Animal Models

1
Txnl4a morpholino knockdown Xenopus laevis
Knockdown of Txnl4a in Xenopus embryos, assayed across successive stages of neural crest and craniofacial development alongside Eftud2 and Snrpb knockdown, produces cranial neural crest formation defects. The parallel design establishes that the three core splicing factors converge on the same neural crest aetiology.
Defective cranial neural crest formation
Species
Xenopus laevis
Genotype
Txnl4a morpholino knockdown
Genes
TXNL4A hgnc:30551 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns TXNL4A (hgnc:30551). hgnc:30551 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:35893124 SUPPORT Model Organism
"Here we characterize the knockdown phenotype of Eftud2, Snrpb and Txnl4a in Xenopus embryos at different stages of neural crest and craniofacial development."
Describes the Xenopus knockdown model used to establish the neural crest phenotype of Txnl4a loss.
{ }

Source YAML

click to show 
name: Burn-McKeown Syndrome
creation_date: "2026-07-31T00:00:00Z"
description: >-
  Burn-McKeown syndrome (BMKS; choanal atresia-hearing loss-cardiac
  defects-craniofacial dysmorphism syndrome; OMIM 608572) is an extremely rare
  autosomal recessive craniofacial malformation syndrome caused by biallelic
  variants in TXNL4A (18q23), which encodes the U5 snRNP core protein
  TXNL4A/Dib1. Affected individuals have bilateral choanal atresia or stenosis
  together with a distinctive facial gestalt - short palpebral fissures,
  coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes,
  short philtrum, thin upper lip vermilion and prominent ears - plus frequent
  hearing loss, and less commonly cardiac septal defects, cleft lip and/or
  palate, preauricular tags, short stature and renal anomalies. Intelligence is
  usually normal, which is a key discriminator from EFTUD2-related
  mandibulofacial dysostosis with microcephaly. Almost all reported probands carry a
  34-base-pair deletion in the TXNL4A promoter on at least one allele, in trans
  with a coding loss-of-function variant; the resulting reduction in TXNL4A
  expression disrupts U4/U6.U5 tri-snRNP function and impairs cranial neural
  crest cell formation and differentiation, which is why a lesion in a
  ubiquitously expressed spliceosome protein presents as a tissue-restricted
  craniofacial phenotype. TXNL4A variants also cause isolated choanal atresia
  and choanal atresia with minor anomalies, so BMKS is the severe end of a
  TXNL4A-related craniofacial spectrum.
category: Mendelian
parents:
- Craniofacial Malformation Syndrome
- Spliceosomopathy
notes: >-
  Scope and disambiguation. TXNL4A is frequently mentioned in the literature on
  the OTHER craniofacial spliceosomopathies - Nager syndrome (SF3B4),
  mandibulofacial dysostosis with microcephaly (EFTUD2), cerebrocostomandibular
  syndrome (SNRPB), Richieri-Costa-Pereira syndrome (EIF4A3) - as a member of the
  same mechanistic family. This entry is the TXNL4A disorder specifically. In
  particular, dismech's existing `Mandibulofacial_Dysostosis_with_Microcephaly`
  entry mentions TXNL4A but is the EFTUD2 disorder and is a distinct entity;
  the two are cross-referenced under `differential_diagnoses` without
  duplication. TXNL4A is separately reported as a hepatocellular-carcinoma
  biomarker; that oncology literature is unrelated to BMKS and was excluded.
  Module conformance. This entry declares `conforms_to` against the first two
  nodes of `pharyngeal_arch_patterning_serial_homology` - the cranial neural
  crest / arch-program perturbation node and the disrupted arch-patterning and
  neural-crest-skeletogenesis node - because BMKS is mechanistically parallel to
  Treacher Collins: a core biogenesis defect (spliceosome rather than ribosome)
  that depletes or mis-differentiates cranial neural crest, demonstrated directly
  for TXNL4A in Xenopus knockdown and in patient iPSC-derived neural crest.
  Conformance is deliberately NOT declared against the module's third node,
  `Serially Homologous Craniofacial Malformation Across Arch Derivatives`. That
  node asserts a symmetric multi-element bundle of zygomatic, maxillary and
  mandibular hypoplasia with ear anomalies and palatal clefting. BMKS does have
  the ear and clefting components, but it lacks the malar/mandibular hypoplasia
  bundle that defines mandibulofacial dysostosis, and its cardinal feature -
  bilateral choanal atresia, a failure of the bucconasal membrane to rupture - is
  not a pharyngeal-arch derivative at all. Declaring conformance at that node
  would assert a phenotype bundle BMKS does not have. Two caveats are recorded
  against that decision rather than suppressed: the literature does note that
  BMKS "has overlapping clinical features with Treacher Collins syndrome", and
  small mouth/small chin have been described in individual reports. Neither
  amounts to the symmetric zygoma-maxilla-mandible hypoplasia bundle the module
  node asserts, so the decline stands, but it is a judgement rather than a
  clear-cut exclusion and should be revisited if a systematic craniofacial
  morphometric series is published.
disease_term:
  preferred_term: Burn-McKeown syndrome
  term:
    id: MONDO:0012064
    label: choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome
synonyms:
- BMKS
- Burn-McKeown syndrome
- choanal atresia-deafness-cardiac defects-dysmorphism syndrome
- TXNL4A-related craniofacial disorder
- oculootofacial dysplasia
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
references:
- reference: PMID:27413799
  title: "TXNL4A-Related Craniofacial Disorders."
  tags:
  - GeneReviews
prevalence:
- population: Published families worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Only 15 families had been described as of 2020; the MONDO/Orphanet definition
    characterises the syndrome as extremely rare. No population prevalence
    estimate exists.
  evidence:
  - reference: PMID:32187816
    reference_title: "Burn-McKeown syndrome with biallelic promoter type 2 deletion in TXNL4A in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Till date, 15 families have been described with BMKS."
    explanation: Quantifies the total published caseload as of 2020, supporting an ultra-rare classification.
- population: Control alleles surveyed in the TXNL4A discovery study
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 760.0
  notes: >-
    Allele frequency of the recurrent 34 bp TXNL4A core-promoter deletion is
    0.76%. This is the frequency of the common hypomorphic allele, not of the
    disease: BMKS requires this allele in trans with a very rare
    loss-of-function coding variant, which is why the syndrome remains
    ultra-rare despite the relatively common promoter deletion.
  evidence:
  - reference: PMID:25434003
    reference_title: "Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a low-frequency 34 bp deletion (allele frequency 0.76%) in the core promoter region on the other allele"
    explanation: Reports the population allele frequency of the recurrent TXNL4A promoter deletion.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    BMKS is autosomal recessive. Most affected individuals are compound
    heterozygotes for a low-frequency 34-bp TXNL4A promoter deletion and a rare
    coding loss-of-function variant on the other allele; homozygosity for a
    promoter deletion also occurs. Sibs of a proband have a 25% recurrence risk,
    and prenatal and preimplantation testing are possible once the familial
    variants are known.
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: GeneReviews states the mode of inheritance and the recurrence risk.
  - reference: PMID:32187816
    reference_title: "Burn-McKeown syndrome with biallelic promoter type 2 deletion in TXNL4A in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygosity or compound heterozygosity of promoter deletions and null variants in TXNL4A are known to cause most cases of BMKS."
    explanation: Documents both the compound-heterozygous and homozygous promoter-deletion genotypes.
pathophysiology:
- name: Reduced TXNL4A Expression from Biallelic Promoter and Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    The characteristic BMKS genotype is a 34-bp deletion in the TXNL4A promoter
    (type 1 or type 2) in trans with a coding or splice loss-of-function variant,
    or homozygosity for a promoter deletion. The deleted 56-bp promoter region
    contains a 22-bp repeated motif that is essential for TXNL4A expression, and
    the splice-site variants at the final intron cause skipping of the final
    exon. The net effect is a quantitative reduction in TXNL4A protein rather
    than its complete absence, which is why BMKS behaves as a hypomorphic dosage
    disorder.
  genes:
  - preferred_term: TXNL4A
    term:
      id: hgnc:30551
      label: TXNL4A
  downstream:
  - target: Impaired U5 snRNP and Tri-snRNP Spliceosome Function
    causal_link_type: DIRECT
    description: >-
      Reduced TXNL4A protein lowers the availability of a U5 snRNP core component
      needed for tri-snRNP assembly and catalytic spliceosome function.
  evidence:
  - reference: PMID:25434003
    reference_title: "Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results indicate that BMKS is an autosomal-recessive condition, which is frequently caused by compound heterozygosity of low-frequency promoter deletions in combination with very rare loss-of-function mutations."
    explanation: Establishes the defining compound-heterozygous promoter-deletion-plus-null genotype as the cause of BMKS.
  - reference: PMID:25434003
    reference_title: "Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Reporter gene and in vivo assays showed that the promoter deletions led to reduced expression of TXNL4A."
    explanation: Direct functional demonstration that the promoter deletions reduce TXNL4A expression, which is the dosage premise of this node.
  - reference: PMID:34713892
    reference_title: "Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we identify putative transcription factor binding sites within the 56 bp of the TXNL4A promoter affected by the type 1 and type 2 Δ34 and use dual luciferase assays to identify a 22 bp repeated motif essential for TXNL4A expression within this promoter region"
    explanation: Luciferase assays localise the essential expression element within the deleted promoter region, explaining why the deletions reduce TXNL4A expression.
  - reference: PMID:34713892
    reference_title: "Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show the c.258-3C>G variant and a previously reported c.258-2A>G variant, cause skipping of the final exon of TXNL4A in a minigene splicing assay."
    explanation: Minigene assays demonstrate the loss-of-function mechanism of the intronic splice-site alleles.
  - reference: PMID:32735620
    reference_title: "Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The majority of affected individuals with BMKS have a 34 base pair deletion in the promoter region of one allele of TXNL4A combined with a loss-of-function variant on the other allele, resulting in reduced TXNL4A expression."
    explanation: Background restatement of the human genetics in the introduction of an in vitro study; tagged OTHER because it is not that paper's own finding. It is retained because it states the dosage premise of this node in one sentence.
- name: Impaired U5 snRNP and Tri-snRNP Spliceosome Function
  biological_scale: MOLECULAR
  conforms_to: "pharyngeal_arch_patterning_serial_homology#Cranial Neural Crest and Pharyngeal Arch Program Perturbation"
  description: >-
    TXNL4A (Dib1) is a core protein of the U5 small nuclear ribonucleoprotein,
    which sits at the centre of the catalytic spliceosome and is a component of
    the U4/U6.U5 tri-snRNP. Reduced TXNL4A dosage therefore degrades general
    pre-mRNA splicing capacity. Crucially the consequence is not uniform: only a
    subset of transcripts is affected, and the mis-spliced genes share sequence
    properties (transcript length, branch-point-to-3'-splice-site distance,
    splice-site strength) that make them unusually sensitive to reduced TXNL4A.
    This selectivity is the current explanation for how a ubiquitously expressed
    housekeeping protein produces a tissue-restricted craniofacial phenotype.
  cell_types:
  - preferred_term: migratory cranial neural crest cell
    term:
      id: CL:0000008
      label: migratory cranial neural crest cell
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: DECREASED
  - preferred_term: spliceosomal snRNP assembly
    term:
      id: GO:0000387
      label: spliceosomal snRNP assembly
    modifier: DECREASED
  downstream:
  - target: Defective Cranial Neural Crest Formation and Differentiation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Selective mis-splicing degrades transcripts required for neural crest
      specification, EMT and migration.
  - target: Dampened WNT Signalling via TCF7L2 Mis-Splicing
    causal_link_type: DIRECT
    description: >-
      Mis-splicing of TCF7L2 exon 4 is the identified candidate route from
      splicing failure to reduced WNT responsiveness.
  evidence:
  - reference: PMID:25434003
    reference_title: "Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Depletion of TXNL4A (Dib1) in yeast demonstrated reduced assembly of the tri-snRNP complex."
    explanation: Direct functional evidence that TXNL4A depletion reduces tri-snRNP assembly, the specific molecular claim this node makes and the basis for the DECREASED spliceosomal snRNP assembly annotation.
  - reference: PMID:40264708
    reference_title: "Addressing the tissue specificity of U5 snRNP spliceosomopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "At the centre of the catalytic spliceosome is the U5 small nuclear ribonucleoprotein (snRNP). Pathogenic variants in U5 snRNP core proteins are associated with various diseases commonly known as spliceosomopathies."
    explanation: Establishes TXNL4A's U5 snRNP context and the spliceosomopathy disease class.
  - reference: PMID:32735620
    reference_title: "Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "mis-spliced genes shared common sequence properties such as length, branch point to 3' splice site (BPS-3'SS) distance and splice site strengths, suggesting that splicing of particular subsets of genes is particularly sensitive to changes in TXNL4A expression"
    explanation: Provides the mechanistic basis for transcript selectivity, which is how a housekeeping-protein defect becomes tissue-restricted.
  - reference: PMID:32735620
    reference_title: "Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RNA-Seq analysis revealed significant differences in gene expression and alternative splicing"
    explanation: Patient-derived iPSCs show measurable gene-expression and alternative-splicing changes, confirming the splicing lesion in patient cells.
- name: Defective Cranial Neural Crest Formation and Differentiation
  biological_scale: CELLULAR
  conforms_to: "pharyngeal_arch_patterning_serial_homology#Disrupted Pharyngeal-Arch Patterning and Neural-Crest Skeletogenesis"
  description: >-
    Cranial neural crest cells are the progenitors of the facial skeleton and are
    the cell type in which spliceosome dosage matters most. Txnl4a knockdown in
    Xenopus produces cranial neural crest formation defects, placing TXNL4A
    alongside Eftud2 and Snrpb in a common craniofacial spliceosomopathy
    aetiology. In patient-derived cells, BMKS iPSCs proliferate more slowly than
    control and show defective differentiation into induced neural crest cells,
    with a specific delay in undergoing the epithelial-to-mesenchymal transition
    that neural crest cells must complete in order to delaminate and migrate.
  cell_types:
  - preferred_term: migratory cranial neural crest cell
    term:
      id: CL:0000008
      label: migratory cranial neural crest cell
  biological_processes:
  - preferred_term: neural crest cell development
    term:
      id: GO:0014032
      label: neural crest cell development
    modifier: DECREASED
  - preferred_term: epithelial to mesenchymal transition
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
    modifier: DECREASED
  downstream:
  - target: Craniofacial Neural-Crest-Derived Malformation
    causal_link_type: DIRECT
    description: >-
      Reduced or mis-differentiated cranial neural crest yields hypoplastic and
      malformed neural-crest-derived facial structures.
  evidence:
  - reference: PMID:35893124
    reference_title: "The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our results point to defects in cranial neural crest cell formation as the likely culprit for MFD associated with EFTUD2, SNRPB and TXNL4A haploinsufficiency, and suggest a commonality in the etiology of these craniofacial spliceosomopathies."
    explanation: Xenopus knockdown of Txnl4a produces cranial neural crest formation defects, establishing the neural crest as the affected cell population.
  - reference: PMID:32735620
    reference_title: "Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT)."
    explanation: Patient-derived cells show the neural crest differentiation and EMT defect directly in human cells, with an isogenic-adjacent maternal control.
  - reference: PMID:32735620
    reference_title: "Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "BMKS patient-derived iPSCs proliferated more slowly than both mother- and unrelated control-derived iPSCs"
    explanation: Documents the proliferation deficit that accompanies the differentiation defect in patient cells.
- name: Dampened WNT Signalling via TCF7L2 Mis-Splicing
  biological_scale: MOLECULAR
  description: >-
    RNA-Seq of BMKS patient-derived induced neural crest cells showed widespread
    mis-splicing in genes relevant to craniofacial and embryonic development, with
    the dominant signature being a dampened response to WNT signalling - the key
    pathway activated during induced neural crest differentiation. Mis-splicing of
    exon 4 of TCF7L2, which encodes a core WNT-pathway transcription factor, was
    identified as a candidate cause of that reduced WNT response. This node is
    curated at provisional confidence: the TCF7L2 link is proposed by the authors
    as a potential cause rather than demonstrated by rescue.
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  downstream:
  - target: Defective Cranial Neural Crest Formation and Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced WNT responsiveness impairs the neural crest differentiation program
      that WNT signalling drives.
  evidence:
  - reference: PMID:32735620
    reference_title: "Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RNA-Seq analysis of differentiated iNCCs revealed widespread gene expression changes and mis-splicing in genes relevant to craniofacial and embryonic development that highlight a dampened response to WNT signalling, the key pathway activated during iNCC differentiation."
    explanation: Establishes reduced WNT responsiveness as the dominant transcriptomic signature in patient neural crest cells.
  - reference: PMID:32735620
    reference_title: "Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we identified the mis-splicing of TCF7L2 exon 4, a key gene in the WNT pathway, as a potential cause of the downregulated WNT response in patient cells"
    explanation: The TCF7L2 link is offered as a potential cause and is not established by rescue, which is why this node carries PROVISIONAL mechanism confidence and the evidence is curated as PARTIAL.
- name: Craniofacial Neural-Crest-Derived Malformation
  biological_scale: TISSUE
  description: >-
    The tissue-level outcome is a distinctive, recognisable craniofacial
    malformation pattern: bilateral choanal atresia or stenosis, short palpebral
    fissures with coloboma of the outer third of the lower eyelids, a prominent
    nasal bridge with widely spaced eyes, a short philtrum, a thin upper lip
    vermilion, and prominent ears, with cleft lip and/or palate and preauricular
    tags in a minority. Middle- and inner-ear involvement produces conductive and
    sensorineural hearing loss. The malar and mandibular hypoplasia that defines
    mandibulofacial dysostosis is not part of this pattern, and the choanal
    atresia arises from failure of the bucconasal membrane rather than from an
    arch derivative.
  biological_processes:
  - preferred_term: face morphogenesis
    term:
      id: GO:0060325
      label: face morphogenesis
    modifier: ABNORMAL
  downstream:
  - target: Choanal Atresia
    causal_link_type: DIRECT
    description: >-
      Failure of the bucconasal membrane to rupture produces bilateral choanal
      atresia or stenosis, the cardinal feature.
  - target: Lower Eyelid Coloboma
    causal_link_type: DIRECT
    description: Coloboma of the outer third of the lower eyelid.
  - target: Hearing Loss
    causal_link_type: DIRECT
    description: >-
      Middle- and inner-ear involvement produces conductive and sensorineural
      hearing loss.
  - target: Conductive Hearing Impairment
    causal_link_type: DIRECT
    description: >-
      Middle-ear (ossicular/tympanic) involvement of arch-derived structures
      produces the conductive component of the hearing loss.
  - target: Sensorineural Hearing Impairment
    causal_link_type: DIRECT
    description: >-
      Inner-ear involvement produces the sensorineural component of the hearing
      loss.
  - target: Prominent Ears
    causal_link_type: DIRECT
    description: Prominent/protruding ears are part of the facial gestalt.
  - target: Short Palpebral Fissures
    causal_link_type: DIRECT
    description: Short palpebral fissures are part of the periorbital component of the malformation pattern.
  - target: Hypertelorism
    causal_link_type: DIRECT
    description: Widely spaced eyes accompany the prominent nasal bridge in the midfacial component of the pattern.
  - target: Prominent Nasal Bridge
    causal_link_type: DIRECT
    description: A prominent nasal bridge is the midfacial element of the malformation pattern.
  - target: Short Philtrum
    causal_link_type: DIRECT
    description: A short philtrum arises from the same disturbance of frontonasal and maxillary prominence fusion.
  - target: Thin Upper Lip Vermilion
    causal_link_type: DIRECT
    description: A thin upper lip vermilion accompanies the short philtrum in the perioral component of the pattern.
  - target: Cleft Lip
    causal_link_type: DIRECT
    description: >-
      Failure of fusion of the medial nasal and maxillary prominences produces
      cleft lip in a minority.
  - target: Cleft Palate
    causal_link_type: DIRECT
    description: >-
      Failure of palatal shelf elevation and fusion produces cleft palate in a
      minority.
  - target: Preauricular Skin Tag
    causal_link_type: DIRECT
    description: >-
      Preauricular tags represent supernumerary first/second arch hillock
      derivatives.
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: GeneReviews defines the composite craniofacial malformation pattern that this node represents.
  - reference: PMID:14564154
    reference_title: "Two brothers with Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bilateral choanal atresia, and a characteristic pattern of facial dysmorphic features consisting of hypertelorism, lower lid coloboma, narrow palpebral fissures, prominent nasal bridge, small mouth with thin lips, and protruding ears"
    explanation: An independent family report documents the same recognisable facial pattern.
phenotypes:
- category: Craniofacial
  name: Choanal Atresia
  description: >-
    Bilateral choanal atresia or stenosis is the cardinal feature and the usual
    presenting problem, since bilateral atresia causes neonatal airway compromise
    in an obligate nasal breather.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: GeneReviews places bilateral choanal atresia/stenosis first among the typical craniofacial features of BMKS. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonates with airway compromise at delivery may require intubation or surgical correction of choanal stenosis/atresia."
    explanation: Documents the clinical consequence that makes choanal atresia the presenting and most urgent feature.
- category: Ophthalmological
  name: Lower Eyelid Coloboma
  description: >-
    Coloboma of the outer third of the lower eyelid, characteristically with
    eyelashes present medial to the defect, is a highly distinctive feature and
    can cause corneal exposure.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Lower eyelid coloboma
    term:
      id: HP:0000652
      label: Lower eyelid coloboma
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: GeneReviews lists lower eyelid coloboma among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defects of the lower eyelids that can result in corneal exposure require care by an ophthalmologist to reduce the risk of corneal scarring."
    explanation: Documents the corneal-exposure complication that makes the eyelid defect clinically actionable.
- category: Craniofacial
  name: Short Palpebral Fissures
  description: >-
    Short (narrow) palpebral fissures are part of the recognisable facial gestalt.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Short palpebral fissure
    term:
      id: HP:0012745
      label: Short palpebral fissure
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: GeneReviews lists short palpebral fissures among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
- category: Craniofacial
  name: Hypertelorism
  description: >-
    Widely spaced eyes accompany the prominent nasal bridge.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: GeneReviews lists widely spaced eyes among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
  - reference: PMID:14564154
    reference_title: "Two brothers with Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a characteristic pattern of facial dysmorphic features consisting of hypertelorism, lower lid coloboma, narrow palpebral fissures"
    explanation: An independent sibship documents hypertelorism as part of the characteristic facial pattern.
- category: Craniofacial
  name: Prominent Nasal Bridge
  description: >-
    A prominent nasal bridge with widely spaced eyes is a consistent component of
    the facial gestalt.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Prominent nasal bridge
    term:
      id: HP:0000426
      label: Prominent nasal bridge
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: GeneReviews lists the prominent nasal bridge among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
- category: Craniofacial
  name: Short Philtrum
  description: >-
    A short philtrum is part of the facial gestalt.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Short philtrum
    term:
      id: HP:0000322
      label: Short philtrum
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: GeneReviews lists the short philtrum among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
- category: Craniofacial
  name: Thin Upper Lip Vermilion
  description: >-
    A thin upper lip vermilion, often with a small mouth, is part of the facial
    gestalt.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: GeneReviews lists a thin upper lip vermilion among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
- category: Craniofacial
  name: Prominent Ears
  description: >-
    Prominent or protruding ears are a consistent external feature.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Protruding ear
    term:
      id: HP:0000411
      label: Protruding ear
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: GeneReviews lists prominent ears among the typical craniofacial features. The band comes from GeneReviews describing these as the "typical craniofacial features" of BMKS; per the project frequency-mapping guidance that maps to the VERY_FREQUENT band.
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelid, structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip."
    explanation: Independently lists prominent ears as a characterising feature.
- category: Auditory
  name: Hearing Loss
  description: >-
    Hearing loss is common and may be conductive, sensorineural or mixed,
    reflecting both external/middle-ear and inner-ear involvement.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss is common and cardiac defects and short stature have been reported."
    explanation: GeneReviews describes hearing loss as common, which maps to the FREQUENT band.
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "conductive and sensorineural hearing loss"
    explanation: Documents that both conductive and sensorineural components occur.
- category: Auditory
  name: Conductive Hearing Impairment
  description: >-
    A conductive component to the hearing loss is described alongside the
    sensorineural component, consistent with middle-ear involvement of
    arch-derived structures. No source quantifies the conductive component
    separately from hearing loss overall, so no frequency band is asserted
    for it.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "conductive and sensorineural hearing loss"
    explanation: Explicitly lists conductive hearing loss among the characterising features.
- category: Auditory
  name: Sensorineural Hearing Impairment
  description: >-
    A sensorineural component to the hearing loss is described alongside the
    conductive component, so audiological assessment must distinguish the two.
    No source quantifies the sensorineural component separately from hearing loss
    overall, so no frequency band is asserted for it.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "conductive and sensorineural hearing loss"
    explanation: Explicitly lists sensorineural hearing loss among the characterising features.
- category: Cardiovascular
  name: Structural Cardiac Abnormality
  description: >-
    Structural cardiac abnormalities occur in a minority and are managed in a
    routine manner. The published sources report only "cardiac defects" or
    "structural cardiac abnormalities" without specifying the lesion, so no more
    specific cardiac malformation is asserted here.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Structural cardiac abnormality
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss is common and cardiac defects and short stature have been reported."
    explanation: GeneReviews contrasts hearing loss ("common") with cardiac defects ("have been reported"), supporting a lower OCCASIONAL band for the cardiac defects.
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip"
    explanation: Lists structural cardiac abnormalities among the characterising features of BMKS.
- category: Craniofacial
  name: Cleft Lip
  description: >-
    Unilateral cleft lip, with or without cleft palate, occurs in a minority.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cleft upper lip
    term:
      id: HP:0000204
      label: Cleft upper lip
  evidence:
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip"
    explanation: Lists cleft lip among the characterising features.
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team."
    explanation: GeneReviews management section confirms cleft lip and/or palate occurs and requires multidisciplinary care.
- category: Craniofacial
  name: Cleft Palate
  description: >-
    Cleft palate occurs in a minority. Cleft lip and/or palate is part of the
    core characterisation of BMKS and is listed by GeneReviews among the
    craniofacial manifestations requiring multidisciplinary management; the
    specific variant of median cleft palate with oronasal fistula was reported
    in a single sibship as an expansion of the phenotypic spectrum.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:25434003
    reference_title: "Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This rare condition is characterized by bilateral choanal atresia, hearing loss, cleft lip and/or palate, and other craniofacial dysmorphisms."
    explanation: Cleft lip and/or palate is named in the core characterisation of BMKS but is not one of the constant features, supporting the OCCASIONAL band (the same band as the sibling Cleft Lip entry, which is drawn from the same sources).
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team."
    explanation: GeneReviews lists cleft palate among the craniofacial manifestations routinely managed in BMKS.
  - reference: PMID:14564154
    reference_title: "Two brothers with Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These brothers show some additional features that were not previously reported in patients with this syndrome including median cleft palate with oronasal fistula, preauricular tag, hypomimic face, and hypoplastic unilateral kidney, thus indicating that the clinical spectrum of this entity is broader."
    explanation: Documents the specific median cleft palate with oronasal fistula variant as an expansion of the BMKS phenotypic spectrum.
- category: Craniofacial
  name: Preauricular Skin Tag
  description: >-
    Preauricular tags occur in a minority and are managed as part of the
    craniofacial care plan.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Preauricular skin tag
    term:
      id: HP:0000384
      label: Preauricular skin tag
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cleft lip and/or palate, preauricular tags, prominent ears"
    explanation: GeneReviews lists preauricular tags among the craniofacial manifestations requiring management.
- category: Growth
  name: Short Stature
  description: >-
    Short stature has been reported in a minority of affected individuals.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac defects and short stature have been reported"
    explanation: GeneReviews reports short stature with the hedged phrase "have been reported". The band is set at OCCASIONAL rather than the stricter VERY_RARE that phrase would normally map to, because short stature is listed as a recurring feature of the syndrome rather than as a single-family spectrum expansion; the departure from the default mapping is recorded here deliberately.
- category: Renal
  name: Renal Hypoplasia
  description: >-
    Unilateral renal hypoplasia was reported in a single sibship as an expansion
    of the BMKS phenotypic spectrum, having not been reported in earlier patients.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Renal hypoplasia
    term:
      id: HP:0000089
      label: Renal hypoplasia
  evidence:
  - reference: PMID:14564154
    reference_title: "Two brothers with Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "median cleft palate with oronasal fistula, preauricular tag, hypomimic face, and hypoplastic unilateral kidney"
    explanation: Documents unilateral renal hypoplasia as an expansion of the BMKS spectrum. The snippet states these features "were not previously reported", i.e. isolated-report frequency, which is why the band is VERY_RARE.
- category: Cognitive
  name: Intellectual Disability
  description: >-
    Intelligence is usually normal, which is a key discriminator from
    EFTUD2-related mandibulofacial dysostosis with microcephaly, in which
    intellectual disability is typical.
    Intellectual disability in BMKS is rare, though a severely affected
    individual has been reported.
  notes: >-
    A single case of severe intellectual disability in a patient with BMKS is
    reported in PMID:28225383 (Clin Dysmorphol letter). That record is
    abstract-only with no abstract body, so no quotable snippet exists and the
    claim is recorded here per the evidence SOP rather than as an evidence item.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss is common and cardiac defects and short stature have been reported. Intellectual disability is rare."
    explanation: GeneReviews explicitly states intellectual disability is rare, which maps to the VERY_RARE band.
  - reference: PMID:32187816
    reference_title: "Burn-McKeown syndrome with biallelic promoter type 2 deletion in TXNL4A in two siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BMKS is characterized by craniofacial dysmorphism, choanal atresia, and normal intellect in affected individuals."
    explanation: Independently states that intellect is normal in affected individuals, supporting the very low frequency band.
genetic:
- name: TXNL4A
  gene_term:
    preferred_term: TXNL4A
    term:
      id: hgnc:30551
      label: TXNL4A
  association: Causal - biallelic loss-of-function and promoter-deletion variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: Positive
  notes: >-
    TXNL4A is at 18q23 and encodes the U5 snRNP core protein TXNL4A/Dib1. The
    BMKS genotype is biallelic and hypomorphic rather than null. Almost every
    reported proband carries at least one copy of one of two partially
    overlapping 34-bp deletions in the TXNL4A promoter (type 1 or type 2), which
    remove part of a 22-bp repeated motif essential for TXNL4A expression. The
    second allele is usually a coding or splice loss-of-function variant
    (nonsense, frameshift, microdeletion, or an intronic variant at the final
    intron causing skipping of the final exon); homozygosity for a promoter
    deletion also occurs. Because copy-number loss is one of the second-allele
    classes, deletion/duplication analysis must be part of the testing strategy
    alongside promoter sequencing. The same
    gene causes a milder allelic spectrum - isolated choanal atresia and choanal
    atresia with minor anomalies - so BMKS is the severe end of a TXNL4A-related
    craniofacial spectrum rather than an isolated entity.
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: GeneReviews states the biallelic requirement and the near-universal presence of a 34-bp promoter deletion allele.
  - reference: PMID:25434003
    reference_title: "Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele"
    explanation: Enumerates the second-allele variant classes, including microdeletion, which is why copy-number analysis is required in addition to promoter sequencing.
  - reference: PMID:25434003
    reference_title: "Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations were found in 9 of 11 affected families."
    explanation: Quantifies the diagnostic yield of TXNL4A testing in a clinically ascertained BMKS cohort.
  - reference: PMID:28905882
    reference_title: "Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hence, we identified causative recessive variants in TXNL4A in two individuals with BMKS as well as in three individuals (from two families) with isolated choanal atresia."
    explanation: Establishes the allelic spectrum in which the same gene causes both BMKS and isolated choanal atresia.
  - reference: PMID:34713892
    reference_title: "Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients have a loss-of-function variant in trans with a 34-base pair (bp) deletion (type 1 Δ34) in the promoter region."
    explanation: Confirms the canonical compound-heterozygous architecture.
  - reference: PMID:34713892
    reference_title: "Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, our data emphasises the need to analyse the non-coding sequence in individuals where a single likely pathogenic coding variant is identified in an autosomal recessive disorder consistent with the clinical presentation."
    explanation: States the diagnostic implication that the promoter (non-coding) allele will be missed unless specifically sought.
diagnosis:
- name: Molecular Genetic Testing for TXNL4A Including the Promoter Region
  description: >-
    The diagnosis is established by identifying biallelic pathogenic TXNL4A
    variants. Testing must explicitly interrogate the non-coding promoter region:
    because virtually every proband carries a 34-bp promoter deletion on at least
    one allele, standard exome or coding-only panel analysis will find only one
    variant and the diagnosis will be missed. When a single likely pathogenic
    coding TXNL4A variant is found in a clinically consistent individual, the
    promoter must be sequenced.
  presence: Biallelic pathogenic variants in affected individuals
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Establishes that promoter analysis is effectively mandatory for molecular diagnosis.
  - reference: PMID:34713892
    reference_title: "Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our data emphasises the need to analyse the non-coding sequence in individuals where a single likely pathogenic coding variant is identified"
    explanation: States the specific diagnostic protocol point that follows from the promoter-allele architecture.
differential_diagnoses:
- name: CHARGE Syndrome (CHD7)
  description: >-
    The principal clinical differential. CHARGE also features choanal atresia,
    coloboma, cardiac defects, ear anomalies and hearing loss, and the MONDO
    definition of BMKS notes that the features overlap considerably. CHD7
    testing distinguishes them.
- name: Treacher Collins Syndrome (TCOF1, POLR1C/POLR1D)
  description: >-
    Shares lower eyelid coloboma and ear anomalies and is the closest
    mechanistic analogue - a ribosome-biogenesis rather than spliceosome defect
    depleting cranial neural crest. Distinguished by the malar and mandibular
    hypoplasia that BMKS lacks.
- name: Mandibulofacial Dysostosis with Microcephaly (EFTUD2)
  description: >-
    The other U5 snRNP spliceosomopathy. Shares the core splicing-factor
    mechanism but differs clinically in having microcephaly, mandibulofacial
    dysostosis and intellectual disability, whereas BMKS intellect is usually
    normal. Curated separately in dismech as
    `Mandibulofacial_Dysostosis_with_Microcephaly`.
- name: Nager Syndrome (SF3B4)
  description: >-
    An acrofacial dysostosis caused by a different core splicing factor; shares
    the craniofacial spliceosomopathy mechanism but adds preaxial limb defects.
- name: Cerebrocostomandibular Syndrome (SNRPB)
  description: >-
    A further craniofacial spliceosomopathy, characterised by Robin sequence and
    rib defects.
- name: Isolated Choanal Atresia
  description: >-
    Allelic - homozygosity for a TXNL4A promoter deletion has been found in
    individuals with isolated choanal atresia, so isolated choanal atresia is both
    a differential and a milder point on the same TXNL4A spectrum.
treatments:
- name: Neonatal Airway Management and Choanal Atresia Repair
  description: >-
    Bilateral choanal atresia causes airway compromise at delivery because
    neonates are obligate nasal breathers. Immediate management may require
    intubation, followed by surgical correction of the choanal
    stenosis/atresia.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonates with airway compromise at delivery may require intubation or surgical correction of choanal stenosis/atresia."
    explanation: GeneReviews states the acute airway management and definitive surgical treatment for the cardinal feature.
- name: Ophthalmological Care for Lower Eyelid Defects
  description: >-
    Lower eyelid defects can cause corneal exposure. Ophthalmological care is
    required to reduce the risk of corneal scarring, and monitoring by an
    ophthalmologist is part of recommended surveillance.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Lower eyelid coloboma
    term:
      id: HP:0000652
      label: Lower eyelid coloboma
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defects of the lower eyelids that can result in corneal exposure require care by an ophthalmologist to reduce the risk of corneal scarring."
    explanation: GeneReviews specifies ophthalmological care for the eyelid defect and its rationale.
- name: Hearing Loss Management
  description: >-
    Treatment of hearing loss is individualised and may involve hearing aids,
    with audiological monitoring as part of surveillance.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: DEVICE
  target_phenotypes:
  - preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of hearing loss is individualized and may involve hearing aids."
    explanation: GeneReviews states the management approach for hearing loss.
- name: Multidisciplinary Craniofacial Care
  description: >-
    Cleft lip and/or palate, preauricular tags and prominent ears are managed
    individually by a multidisciplinary craniofacial team, with craniofacial-team
    monitoring as part of recommended surveillance.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team."
    explanation: GeneReviews defines multidisciplinary craniofacial management.
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Monitoring by an ophthalmologist, audiologist, and craniofacial team is recommended."
    explanation: States the recommended surveillance regimen.
- name: Cardiac Management
  description: >-
    Cardiac defects are managed in a routine manner, without disorder-specific
    modification.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Structural cardiac abnormality
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac defects are managed in a routine manner."
    explanation: GeneReviews states that cardiac management is standard rather than disorder-specific.
- name: Genetic Counseling
  description: >-
    Counselling covers autosomal recessive inheritance, the 25% sib recurrence
    risk, the need to test the promoter region in relatives, and the availability
    of prenatal and preimplantation genetic testing once both familial variants
    are known.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:27413799
    reference_title: "TXNL4A-Related Craniofacial Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: GeneReviews states the reproductive testing options that counselling addresses.
animal_models:
- species: Xenopus laevis
  genotype: Txnl4a morpholino knockdown
  genes:
  - preferred_term: TXNL4A
    term:
      id: hgnc:30551
      label: TXNL4A
  associated_phenotypes:
  - Defective cranial neural crest formation
  description: >-
    Knockdown of Txnl4a in Xenopus embryos, assayed across successive stages of
    neural crest and craniofacial development alongside Eftud2 and Snrpb
    knockdown, produces cranial neural crest formation defects. The parallel
    design establishes that the three core splicing factors converge on the same
    neural crest aetiology.
  evidence:
  - reference: PMID:35893124
    reference_title: "The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we characterize the knockdown phenotype of Eftud2, Snrpb and Txnl4a in Xenopus embryos at different stages of neural crest and craniofacial development."
    explanation: Describes the Xenopus knockdown model used to establish the neural crest phenotype of Txnl4a loss.
experimental_models:
- name: BMKS patient-derived iPSC induced neural crest cells
  experimental_model_type: IPSC_DERIVED_MODEL
  cell_source: Peripheral blood mononuclear cells from a BMKS patient (TXNL4A compound heterozygote) and from her unaffected mother
  culture_system: iPSC reprogramming followed by directed differentiation to induced neural crest cells (iNCCs)
  publication: PMID:32735620
  cell_types:
  - preferred_term: migratory cranial neural crest cell
    term:
      id: CL:0000008
      label: migratory cranial neural crest cell
  description: >-
    The principal experimental system for BMKS mechanism. The unaffected mother's
    line provides a closely matched (though not isogenic) control. Limitation: the
    single patient donor is an atypical case, so findings should be replicated in
    additional lines before being generalised across the BMKS phenotypic spectrum.
  modeled_mechanisms:
  - target: Impaired U5 snRNP and Tri-snRNP Spliceosome Function
    description: >-
      RNA-Seq of patient iPSCs and iNCCs shows altered gene expression and
      alternative splicing relative to the maternal control.
  - target: Defective Cranial Neural Crest Formation and Differentiation
    description: >-
      Patient iPSCs differentiate defectively into induced neural crest cells with
      a delayed epithelial-to-mesenchymal transition.
  - target: Dampened WNT Signalling via TCF7L2 Mis-Splicing
    description: >-
      iNCC RNA-Seq shows a dampened WNT response, with TCF7L2 exon 4 mis-splicing
      proposed as the cause.
  findings:
  - statement: >-
      BMKS patient iPSCs proliferate more slowly than maternal and unrelated
      control lines and show significant differences in gene expression and
      alternative splicing.
    supporting_text: "BMKS patient-derived iPSCs proliferated more slowly than both mother- and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing."
  - statement: >-
      Differentiation to induced neural crest cells is defective, with a delay in
      undergoing the epithelial-to-mesenchymal transition.
    supporting_text: "Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT)."
  evidence:
  - reference: PMID:32735620
    reference_title: "Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development."
    explanation: Describes the patient-derived cellular model and its maternal control, the principal experimental system for BMKS mechanism.
discussions:
- discussion_id: bmks_spliceosome_tissue_specificity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does reduced dosage of TXNL4A, a ubiquitously expressed core spliceosome
    protein, produce a malformation restricted to craniofacial structures rather
    than a generalised phenotype?
  attaches_to:
  - pathophysiology#Impaired U5 snRNP and Tri-snRNP Spliceosome Function
  rationale: >-
    This is the central unsolved problem of the craniofacial spliceosomopathies as
    a class, and it is stated as open in the primary literature. Two partial
    answers exist and are curated as separate nodes here: transcript-intrinsic
    sensitivity (mis-spliced genes share length, branch-point-to-3'-splice-site
    distance and splice-site-strength properties) and a downstream pathway effect
    (dampened WNT responsiveness via TCF7L2 exon 4 mis-splicing). A third
    proposal in the field, not curated as a node here because it has not been
    demonstrated for TXNL4A specifically, is that neural crest cells have an
    elevated sensitivity to inefficient splicing that triggers a P53-associated
    stress response through mis-splicing of MDM2/MDM4. Distinguishing these
    matters because they imply different therapeutic entry points. A limitation
    applying to all three: the human cellular evidence comes from a single patient
    donor line.
  proposed_experiments:
  - experiment_id: bmks_p53_axis_in_patient_incc
    name: Test the P53/MDM2-MDM4 stress axis in BMKS patient iNCCs
    description: >-
      Assay MDM2 and MDM4 regulatory-exon skipping, P53 stabilisation and
      apoptosis in BMKS patient-derived induced neural crest cells versus the
      maternal control, and test whether P53 inhibition rescues the
      differentiation and EMT delay.
    decision_criterion: >-
      Rescue by P53 inhibition would place BMKS in the same nucleolar/splicing
      stress-response mechanism proposed for the other craniofacial
      spliceosomopathies; absence of rescue would favour the transcript-selectivity
      and WNT explanations already curated.
  - experiment_id: bmks_tcf7l2_rescue
    name: TCF7L2 isoform rescue in BMKS neural crest
    description: >-
      Express the correctly spliced TCF7L2 isoform in BMKS patient iNCCs and test
      whether WNT responsiveness, EMT timing and differentiation are restored.
    decision_criterion: >-
      Restoration would upgrade the TCF7L2 node from PROVISIONAL to an established
      mechanism; failure would indicate TCF7L2 mis-splicing is a marker rather
      than a cause.
  evidence:
  - reference: PMID:32735620
    reference_title: "Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development."
    explanation: States the knowledge gap explicitly for TXNL4A/BMKS.
  - reference: PMID:32315467
    reference_title: "Spliceosomopathies and neurocristopathies: Two sides of the same coin?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We speculate that mutations in a subset of core splicing factors lead to disrupted splicing in neural crest cells because these cells have increased sensitivity to inefficient splicing."
    explanation: The P53/neural-crest-sensitivity proposal is explicitly framed by its authors as speculation, which is why it is curated in this discussion rather than as a pathophysiology node.
📚

References & Deep Research

References

1
PMID:27413799
TXNL4A-Related Craniofacial Disorders.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Burn–McKeown Syndrome: Disease-Characteristics Research Report
Edison Scientific Literature 23 citations 2026-07-31T17:56:14.025744

Burn–McKeown Syndrome: Disease-Characteristics Research Report

Executive summary

Burn–McKeown syndrome (BMKS) is an exceptionally rare, congenital, autosomal-recessive craniofacial spliceosomopathy caused by biallelic variants that reduce TXNL4A function. Bilateral choanal atresia or stenosis is the defining manifestation; hearing loss, cleft lip/palate, lower-eyelid coloboma, short palpebral fissures, a prominent high-bridged nose, short philtrum, large ears, and occasional cardiac or other visceral anomalies form the broader phenotype. Fewer than 20 affected families had been reported by 2020, precluding reliable prevalence, survival, penetrance, or quality-of-life estimates. (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 1-2)

The usual molecular architecture is a hypomorphic 34-bp TXNL4A promoter deletion in trans with a rare loss-of-function allele. Reduced TXNL4A disrupts U4/U6.U5 tri-snRNP assembly and selectively changes pre-mRNA splicing. Patient-derived neural-crest models implicate diminished WNT signaling, abnormal TCF7L2 splicing, delayed epithelial-to-mesenchymal transition (EMT), and reduced proliferation; Xenopus knockdown additionally supports apoptosis-mediated depletion of cranial neural-crest progenitors. (wieczorek2014compoundheterozygosityof pages 7-8, wood2020modellingthedevelopmental pages 37-41, park2022thecoresplicing pages 7-10)

No disease-modifying treatment, validated biomarker, formal clinical guideline, or BMKS-specific interventional trial was identified. Current care is multidisciplinary and directed at airway obstruction, hearing impairment, clefting, cardiac defects, and other individual anomalies.

domain established finding quantitative evidence suggested ontology terms evidence type/source
Disease identity Burn-McKeown syndrome is a rare congenital craniofacial spliceosomopathy; OMIM 608572 Fewer than 20 affected families reported worldwide by 2020 (wood2020modellingthedevelopmental pages 1-5) OMIM: 608572; congenital disorder; craniofacial developmental disorder Human disease synthesis and patient-derived model background (wood2020modellingthedevelopmental pages 1-5)
Inheritance Autosomal recessive disease caused by biallelic TXNL4A variants 9 of 11 families in the discovery study had biallelic TXNL4A mutations (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 7-8) autosomal recessive inheritance; TXNL4A Human clinical genetics, AJHG 2014 (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 7-8)
Causal gene/mechanism class TXNL4A encodes a U5 snRNP/spliceosome component; disease reflects reduced TXNL4A dosage rather than simple heterozygous haploinsufficiency Unaffected heterozygous relatives carried single variants; disease required biallelic hypomorphic/LoF combinations (wieczorek2014compoundheterozygosityof pages 4-6) TXNL4A; U5 snRNP; pre-mRNA splicing Human genetics with functional interpretation (wieczorek2014compoundheterozygosityof pages 4-6)
Pathogenic variant architecture Typical genotype is compound heterozygosity for a 34-bp promoter deletion on one allele plus a loss-of-function allele on the other; homozygous promoter deletion also reported Promoter D1: chr18:g.77,748,581_77,748,614del; promoter D2: chr18:g.77,748,604_77,748,637del; LoF examples: c.349G>T p.(Glu117), c.37C>T p.(Gln13), c.131delT p.(Val44Alafs*48); terminal 18q deletions also observed (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 4-6) TXNL4A; promoter deletion; nonsense variant; frameshift variant; copy-number loss Human clinical genetics and molecular characterization (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 4-6)
Population genetics The commonest disease-associated promoter allele is low frequency in the general population, consistent with a rare recessive disorder Type 1 promoter deletion allele frequency 0.76%; predicted homozygous frequency ~1 in 17,300 (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 7-8) low-frequency regulatory allele Human case-control/segregation data (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 7-8)
Core phenotype Choanal atresia/stenosis is the defining feature; reported synthesis states it was observed in all patients, with associated craniofacial, hearing, and occasional visceral anomalies Choanal atresia observed in all patients in the 2020 synthesis; common additional features include hearing loss, cleft lip/palate, short palpebral fissures, lower eyelid coloboma, short philtrum, prominent nose/high bridge, large ears; congenital heart defects can occur (wood2020modellingthedevelopmental pages 1-5) choanal atresia; cleft palate; hearing impairment; eyelid coloboma; short philtrum; prominent nose; congenital heart defect Human disease synthesis and original family series (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 1-2)
Additional variable features Reported variable findings extend beyond the canonical craniofacial pattern Patent foramen ovale, persistent ductus arteriosus, imperforate anus, fifth-finger clinodactyly, hallux valgus, preauricular tags, renal agenesis, inguinal hernia reported across families (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 2-3) imperforate anus; clinodactyly; renal agenesis; preauricular tag Human family series (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 2-3)
Neurodevelopment Intellectual development is usually normal, but severe intellectual disability has been reported rarely One exceptional severe intellectual disability case noted in the literature/model background (wood2020modellingthedevelopmental pages 1-5, wood2020modellingthedevelopmental pages 37-41) intellectual disability Human case-based synthesis and iPSC-study background (wood2020modellingthedevelopmental pages 1-5, wood2020modellingthedevelopmental pages 37-41)
Molecular pathophysiology upstream Promoter deletions reduce TXNL4A expression; reduced TXNL4A impairs U4/U6.U5 tri-snRNP assembly Type 1 and type 2 promoter deletions reduced promoter activity by 59% and 72%, respectively; yeast DIB1 depletion impaired tri-snRNP assembly (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 7-8) TXNL4A; U4/U6.U5 tri-snRNP assembly; mRNA splicing Human regulatory assay plus yeast functional model (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 7-8)
Molecular pathophysiology downstream Reduced TXNL4A causes selective mis-splicing and altered gene expression, especially in neural crest-relevant programs In patient iPSCs: 1,511 alternative splicing events in 1,096 genes and 1,181 DEGs; in iNCCs: 2,991 splicing events in 2,029 genes and 5,746 DEGs, with 88% of differential splicing unique to iNCCs (wood2020modellingthedevelopmental pages 24-27, wood2020modellingthedevelopmental pages 27-31, wood2020modellingthedevelopmental pages 69-74) alternative splicing; gene expression regulation; neural crest development Human patient-derived iPSC/iNCC transcriptomics (preprint) (wood2020modellingthedevelopmental pages 24-27, wood2020modellingthedevelopmental pages 27-31, wood2020modellingthedevelopmental pages 69-74)
WNT/neural crest mechanism A leading mechanistic model links TXNL4A deficiency to dampened WNT signaling via TCF7L2 mis-splicing, delaying neural crest epithelial-to-mesenchymal transition Patient iNCC EMT score -5 vs +5 (mother) and +8 (controls); AXIN2 downregulated (p=0.0004); TCF7L2 exon 4 mis-splicing validated; patient iPSCs proliferated 52%-65% more slowly than controls/mother (wood2020modellingthedevelopmental pages 34-37, wood2020modellingthedevelopmental pages 27-31, wood2020modellingthedevelopmental pages 21-24) WNT signaling; TCF7L2; epithelial to mesenchymal transition; neural crest cell Human patient-derived iPSC/iNCC functional model (preprint) (wood2020modellingthedevelopmental pages 34-37, wood2020modellingthedevelopmental pages 27-31, wood2020modellingthedevelopmental pages 21-24)
Developmental cell biology Neural crest depletion/dysfunction is supported across models as a proximate cause of craniofacial malformation Xenopus Txnl4a knockdown increased apoptosis in dorsal ectoderm at stage 15 (n=41, p<0.0005) and produced craniofacial cartilage defects in 38% of tadpoles; sox10 reduction was partially rescued by morpholino-resistant txnl4a (park2022thecoresplicing pages 7-10, park2022thecoresplicing pages 4-7, park2022thecoresplicing pages 1-2) neural crest cell; apoptosis; craniofacial cartilage development; sox10 Xenopus morpholino/rescue model (park2022thecoresplicing pages 7-10, park2022thecoresplicing pages 4-7, park2022thecoresplicing pages 1-2)
Onset/course Disease onset is congenital/developmental and non-remitting; manifestations arise from embryonic craniofacial development defects Choanal atresia and craniofacial anomalies are present from birth; no evidence for episodic course or spontaneous remission (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 1-2) congenital onset; craniofacial malformation Human clinical description/synthesis (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 1-2)
Diagnostic strategy Diagnosis is clinical plus molecular: recognize the choanal-atresia/facial dysostosis pattern, then confirm biallelic TXNL4A variants including regulatory deletion and CNV detection Discovery study used exome/genome sequencing, microarray, and MLPA; CNVs ranged from 0.484 Mb to 4.7 Mb; promoter deletions would be missed by coding-only analysis if regulatory regions are not interrogated (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 4-6) facial dysostosis; TXNL4A molecular testing; copy-number analysis; promoter variant analysis Human genetics workflow evidence (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 4-6)
Management No disease-modifying BMKS therapy is established; care is supportive and anomaly-directed No BMKS-specific interventional trials identified; reported care needs include airway management for choanal atresia, hearing support including possible cochlear implantation, and management of cleft/cardiac/other anomalies as indicated (wieczorek2014compoundheterozygosityof pages 2-3) supportive care; surgical repair; hearing rehabilitation Human case series plus evidence gap on trials (wieczorek2014compoundheterozygosityof pages 2-3)
Prognosis/evidence gaps Prognosis is poorly quantified because of the rarity of the condition; survival, QoL, and natural-history metrics are not well defined in the literature retrieved No robust prevalence, incidence, survival, or treatment-response statistics identified beyond family counts and phenotype summaries (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 1-2) rare disease epidemiology Evidence-gap synthesis from available literature (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 1-2)
Model systems BMKS has mechanistic models in yeast, patient-derived iPSC/iNCC systems, and Xenopus embryos Yeast DIB1 depletion showed tri-snRNP assembly defects; iPSC/iNCC model demonstrated proliferation, splicing, and EMT/WNT abnormalities; Xenopus knockdown caused neural crest/apoptosis/cartilage phenotypes with partial rescue (wieczorek2014compoundheterozygosityof pages 7-8, wood2020modellingthedevelopmental pages 37-41, park2022thecoresplicing pages 7-10) Saccharomyces cerevisiae model; induced pluripotent stem cell; induced neural crest cell; Xenopus laevis Yeast, in vitro human, and amphibian model evidence (wieczorek2014compoundheterozygosityof pages 7-8, wood2020modellingthedevelopmental pages 37-41, park2022thecoresplicing pages 7-10)

Table: This table condenses the main disease-level, genetic, mechanistic, diagnostic, and model-system findings for Burn-McKeown syndrome. It highlights established evidence and key quantitative details while preserving citations to the retrieved source contexts.

Evidence scope and currency

The principal human genetic evidence remains the 2014 American Journal of Human Genetics study of 11 families. The most detailed disease-specific mechanistic investigation is a May 2020 bioRxiv patient-iPSC study and should be treated as preprint evidence. The principal organismal BMKS model is a peer-reviewed 2022 Xenopus study. Searches prioritizing 2023–2024 identified no new BMKS-specific clinical cohort, natural-history study, therapeutic trial, or definitive molecular update; recent spliceosomopathy work remains largely contextual rather than BMKS-specific.

1. Disease information

Definition and classification

BMKS is a Mendelian congenital craniofacial developmental disorder, more specifically a U5-snRNP-related craniofacial spliceosomopathy or mandibulofacial dysostosis spectrum disorder. It was clinically recognized before its genetic cause was established; biallelic TXNL4A variants were demonstrated in 2014. (wieczorek2014compoundheterozygosityof pages 1-2)

Identifiers and synonyms

  • OMIM: 608572.
  • MONDO: A dedicated MONDO identifier was not verified in the retrieved primary literature; it should be resolved directly against the current MONDO release rather than inferred.
  • Orphanet: Not verified from the retrieved evidence.
  • ICD-10/ICD-11: No disease-specific code was identified. Coding generally requires congenital-malformation codes for choanal atresia and associated defects.
  • MeSH: No dedicated BMKS descriptor was verified.
  • Synonyms: Burn–McKeown syndrome; Burn-McKeown syndrome; BMKS; occasionally discussed in relation to oculo-oto-facial dysplasia, which may lie within the same phenotypic spectrum. (wieczorek2014compoundheterozygosityof pages 1-2)

The evidence is predominantly aggregated disease-level literature assembled from individually phenotyped families, not population EHR data. The 2014 study evaluated 11 families and found the relevant biallelic TXNL4A genotype in 9. (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 3-4)

Key abstract statement: the discovery report described BMKS as a rare autosomal-recessive condition “characterized by bilateral choanal atresia” with characteristic craniofacial anomalies and identified biallelic TXNL4A mutations. (wieczorek2014compoundheterozygosityof pages 1-2)

2. Etiology

Causal factor

The cause is genetic: insufficient TXNL4A dosage from biallelic germline variants. The common configuration combines a low-frequency promoter deletion with a severe coding or copy-number loss on the other chromosome. Heterozygous relatives can be unaffected, arguing against ordinary monoallelic haploinsufficiency. (wieczorek2014compoundheterozygosityof pages 4-6)

Genetic risk factors

  • TXNL4A 34-bp promoter deletion D1/type 1: chr18:g.77,748,581_77,748,614del in the reference used by the 2014 report.
  • D2/type 2: chr18:g.77,748,604_77,748,637del.
  • Reported loss-of-function examples include c.349G>T, p.(Glu117Ter); c.37C>T, p.(Gln13Ter); and c.131delT, p.(Val44AlafsTer48).
  • Larger terminal 18q deletions encompassing TXNL4A, ranging from approximately 0.484 to 4.7 Mb in the discovery series, can constitute one allele. (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 4-6)

The type-1 promoter deletion had an estimated allele frequency of 0.76% in the original study. Its predicted homozygous frequency was approximately 1 in 17,300, but homozygosity for that allele was not established as equivalent to classic BMKS; pathogenicity depends on allelic context and residual expression. (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 7-8)

Environmental, infectious, and lifestyle risk factors

No toxin, infection, diet, smoking, occupation, parental age, or lifestyle exposure has been demonstrated to cause or modify BMKS. It is not infectious or multifactorial on present evidence.

Protective factors and gene–environment interaction

No protective allele, environmental protective factor, modifier gene, or reproducible gene–environment interaction has been reported. Avoidance of ordinary environmental exposures cannot prevent the inherited developmental defect.

3. Phenotypes

All manifestations are congenital or developmentally determined. Exact percentages are unavailable for most findings because published cohorts are extremely small and ascertainment is non-uniform.

Phenotype Type, onset, frequency/course Functional impact Suggested HPO term
Bilateral choanal atresia/stenosis Structural sign; neonatal; reported as universal in the 2020 synthesis Potential neonatal airway emergency; feeding and breathing impairment; surgical burden Choanal atresia; Bilateral choanal atresia
Hearing loss Sensorineural and/or conductive impairment; congenital/childhood; recurrent but not quantified Speech-language, educational, and social effects; severe cases may need implantation Hearing impairment; Sensorineural hearing impairment; Conductive hearing impairment
Cleft lip/palate, bifid uvula Congenital structural signs; variable Feeding, speech, dental, and middle-ear morbidity Cleft palate; Cleft lip; Bifid uvula
Short palpebral fissures Congenital dysmorphism; characteristic Primarily morphological Short palpebral fissure
Lower-eyelid coloboma Congenital ocular/adnexal sign; variable Exposure and ocular-surface risk depending on severity Coloboma of eyelid
Prominent nose/high nasal bridge Congenital facial morphology; characteristic Primarily morphological Prominent nose; High nasal bridge
Short philtrum, thin lips, small mouth/chin or micrognathia Congenital; variable Feeding, dental, airway, and speech consequences can occur Short philtrum; Thin upper lip vermilion; Microstomia; Micrognathia
Large/protruding ears, preauricular tags Congenital; variable Cosmetic and audiological relevance Large ears; Protruding ear; Preauricular skin tag
Congenital heart defects Variable: patent foramen ovale, persistent ductus arteriosus and other defects reported Depends on anatomy and hemodynamic significance Congenital heart defect; Patent ductus arteriosus
Renal agenesis Rare reported associated anomaly Reduced renal reserve when unilateral; severe if bilateral Renal agenesis
Imperforate anus Rare congenital anomaly Neonatal obstruction requiring surgery Anal atresia
Clinodactyly/hallux valgus Variable skeletal signs Usually mild functional effect Clinodactyly of the fifth finger; Hallux valgus
Short stature Variable Growth and psychosocial effects Short stature
Intellectual disability Usually absent; one severe case highlighted Potential major lifelong support need in the exceptional case Intellectual disability

The clinical series also reported hypertelorism and inguinal hernia. Intellectual development is generally normal, so severe intellectual disability should prompt assessment for a larger deletion, blended diagnosis, complications, or expanded phenotype. (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 2-3)

No BMKS-specific EQ-5D, SF-36, PROMIS, caregiver-burden, or disease-specific quality-of-life data were found. Quality-of-life effects above are clinically plausible consequences of the lesions, not measured BMKS outcomes.

4. Genetic and molecular information

Causal gene

TXNL4A at 18q23, also called DIB1, encodes an essential U5 small nuclear ribonucleoprotein component. A current HGNC identifier and transcript accession should be imported directly from HGNC/NCBI for production annotation because reference-transcript differences affect variant nomenclature.

Variant classes and interpretation

Established disease alleles include promoter deletions, nonsense and frameshift variants, splice-disrupting variants, intragenic/terminal copy-number deletions, and possibly other severe loss-of-function alleles. They are constitutional germline variants, not somatic mutations. The original severe coding variants were absent from 1000 Genomes, dbSNP, and approximately 3,000 control exomes available at the time. (wieczorek2014compoundheterozygosityof pages 4-6)

D1 and D2 reduced promoter activity by 59% and 72%, respectively. Classic BMKS therefore appears to require residual expression: a hypomorphic regulatory allele paired with a null allele, or an appropriate biallelic hypomorphic configuration. Complete biallelic null loss is considered likely incompatible with life because DIB1 is essential in experimental organisms. (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 7-8)

Variant classifications should nevertheless be checked in current ClinVar and assessed using ACMG/AMP rules, including noncoding-variant guidance. A common promoter allele should not be called pathogenic in isolation; phase, second-allele severity, phenotype, segregation, and functional evidence are essential.

Modifiers, epigenetics, and chromosomal abnormalities

No validated modifier gene or BMKS-specific DNA-methylation/chromatin signature is known. Large 18q deletions may broaden the phenotype through contiguous-gene effects. No recurrent aneuploidy, balanced translocation, or inversion defines BMKS. (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 4-6)

5. Environmental information

No environmental toxin, radiation exposure, pollutant, occupational factor, diet, alcohol, smoking behavior, or infectious agent is causally associated with BMKS. Environmental influences may affect general pregnancy or postoperative outcomes but are not established components of disease etiology. CTD-style chemical–disease assertions should therefore not be populated as causal without separate evidence.

6. Mechanism and pathophysiology

Causal chain

  1. Upstream genetic defect: biallelic TXNL4A alleles lower functional protein dosage.
  2. Spliceosomal defect: insufficient TXNL4A/DIB1 compromises U5-snRNP and U4/U6.U5 tri-snRNP assembly and control of spliceosome activation.
  3. Selective RNA-processing vulnerability: transcripts with particular exon/intron architecture and weaker splice sites are disproportionately mis-spliced rather than all transcripts failing uniformly.
  4. Developmental signaling disturbance: neural-crest-relevant expression programs, cell adhesion, WNT/β-catenin signaling, and EMT become abnormal.
  5. Cellular phenotype: reduced proliferation, delayed/failed neural-crest differentiation and EMT, and—in Xenopus—excess dorsal-ectoderm/neural-crest apoptosis deplete or impair cranial neural-crest progenitors.
  6. Tissue phenotype: deficient formation of neural-crest-derived craniofacial cartilage, bone, and nasal/choanal structures produces choanal atresia and facial dysostosis. (wieczorek2014compoundheterozygosityof pages 7-8, wood2020modellingthedevelopmental pages 37-41, park2022thecoresplicing pages 1-2)

Human iPSC/iNCC evidence

Patient iPSCs proliferated 52% more slowly than maternal cells and 65% more slowly than unrelated controls, without increased apoptosis. RNA sequencing identified 1,181 differentially expressed genes and 1,511 alternative-splicing events in 1,096 genes; 1,154 were exon-skipping events. (wood2020modellingthedevelopmental pages 24-27, wood2020modellingthedevelopmental pages 21-24)

After neural-crest differentiation, there were 5,746 differentially expressed genes and 2,991 differential-splicing events in 2,029 genes; 88% of affected splicing events were iNCC-specific. Patient cells retained epithelial markers and had reduced mesenchymal/neural-crest markers, with an EMT score of −5 versus +5 in maternal and +8 in unrelated-control cells. Extending differentiation to 168 hours did not rescue the defect. (wood2020modellingthedevelopmental pages 34-37, wood2020modellingthedevelopmental pages 27-31, wood2020modellingthedevelopmental pages 69-74)

AXIN2 was downregulated (p=0.0004), supporting reduced WNT activation. Abnormal inclusion of TCF7L2 exon 4, which is associated with a dampened WNT response, was proposed as one mechanistic link. This is a leading model, not yet proof that TCF7L2 alone causes the human phenotype. (wood2020modellingthedevelopmental pages 34-37, wood2020modellingthedevelopmental pages 27-31)

Exact abstract excerpt from the 2020 preprint: “Patient iPSCs displayed defective differentiation into iNCCs … in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT).” The abstract further reports “a dampened response to WNT signalling” and identifies TCF7L2 exon-4 mis-splicing as a potential cause. (wood2020modellingthedevelopmental pages 1-5, wood2020modellingthedevelopmental pages 37-41)

Model-organism evidence

In Xenopus, 30-ng Txnl4a morpholino knockdown reduced sox10 in 85.7% and tfap2e in 32.4% of embryos; morpholino-resistant txnl4a increased normal sox10 expression from 14% to 62%, supporting specificity. TUNEL-positive apoptosis increased in dorsal ectoderm at stage 15 (n=41, p<0.0005), and 38% of stage-45 morphants showed craniofacial cartilage defects (p<0.0001). (park2022thecoresplicing pages 7-10, park2022thecoresplicing pages 4-7)

Ontology suggestions

  • GO biological process: mRNA splicing via spliceosome; spliceosomal complex assembly; neural crest cell development; epithelial-to-mesenchymal transition; canonical WNT signaling; regulation of apoptotic process; craniofacial morphogenesis; cartilage development.
  • GO cellular component: spliceosomal complex; U5 snRNP; U4/U6.U5 tri-snRNP; nucleus/nucleoplasm.
  • Cell Ontology: neural crest cell; cranial neural crest cell; craniofacial chondrocyte; osteoblast progenitor; craniofacial mesenchymal cell. Exact CL identifiers should be ontology-validated before ingestion.

No BMKS-specific proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, epigenomic, organoid, or in-vivo CRISPR-screen dataset was identified. The iPSC experiment is bulk transcriptomic evidence from one family, a major limitation. (wood2020modellingthedevelopmental pages 37-41, wood2020modellingthedevelopmental pages 45-49)

7. Anatomical structures affected

Primary structures

  • Posterior nasal apertures/choanae and nasal airway.
  • Craniofacial skeleton and neural-crest-derived cartilage.
  • Palate and lip.
  • Eyelids and periocular region.
  • External/middle/inner auditory system, depending on the basis of hearing loss.

Secondary or variable structures

Heart and great-vessel derivatives, kidney, anus/rectum, digits, feet, and inguinal region can be involved. (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 2-3)

Suggested anatomy terms: choana; nasal cavity; nasopharynx; palate; mandible; eyelid; external ear; middle ear; inner ear; craniofacial skeleton; heart; kidney; anus. Exact UBERON identifiers should be resolved against the active release. Bilateral involvement is characteristic for choanal atresia; other anomalies may be unilateral, bilateral, or asymmetric.

At the subcellular level, the primary compartment is the nuclear spliceosome, especially the U5 and U4/U6.U5 snRNP assemblies.

8. Temporal development

BMKS begins during embryogenesis and is clinically evident at birth. Bilateral choanal atresia can present acutely with neonatal respiratory compromise, whereas hearing, speech, dental, growth, and educational consequences become clearer through childhood.

The underlying malformations are stable congenital lesions rather than relapsing or degenerative disease. Functional morbidity may evolve with growth or after reconstructive procedures. There are no validated disease stages, progression rate, remission pattern, or longitudinal natural-history model. Critical developmental vulnerability probably coincides with cranial neural-crest specification, EMT, migration, and craniofacial morphogenesis; clinically, birth is the critical airway-intervention window. (wood2020modellingthedevelopmental pages 1-5, park2022thecoresplicing pages 7-10)

9. Inheritance and population

  • Inheritance: autosomal recessive.
  • Recurrence risk: when both parents carry relevant alleles, each pregnancy conventionally has a 25% probability of an affected child, 50% of a carrier, and 25% of inheriting neither familial allele, subject to confirmation of phase and variant pathogenicity.
  • Penetrance: apparently high for appropriately damaging biallelic genotypes, but not numerically estimable.
  • Expressivity: variable for clefting, hearing loss, heart/renal/anal defects, growth, and neurodevelopment.
  • Anticipation: not expected and not reported.
  • Germline mosaicism: not established.
  • Consanguinity: can facilitate homozygosity; one consanguineous family was homozygous for the D2 promoter deletion. (wieczorek2014compoundheterozygosityof pages 1-2)
  • Founder effect: no confirmed founder population was identified.
  • Carrier frequency: cannot be equated with the 0.76% D1 allele frequency because multiple alleles and genotype-dependent pathogenicity are involved.

Fewer than 20 families were reported worldwide by 2020. No defensible cases-per-100,000 prevalence, annual incidence, geographic concentration, ethnic enrichment, age distribution, or sex ratio is available. (wood2020modellingthedevelopmental pages 1-5)

10. Diagnostics

Clinical recognition and immediate evaluation

Suspect BMKS in a neonate or child with bilateral choanal atresia/stenosis plus the characteristic oculo-oto-facial pattern, clefting, hearing loss, or congenital heart disease. Immediate priorities are airway patency, feeding, and cardiorespiratory stability.

A reasonable phenotype-directed work-up includes nasal endoscopy and thin-section CT for choanal anatomy; formal audiology; ophthalmologic assessment; cleft/craniofacial examination; echocardiography; renal ultrasonography; assessment for anal patency, feeding, growth, development, and speech. These are anomaly-directed clinical practices; no BMKS-specific consensus protocol was found.

Molecular testing

  1. Preferred: a craniofacial/choanal-atresia panel or genome analysis that includes TXNL4A coding exons, splice regions, the recurrent promoter interval, and copy-number analysis.
  2. WES: can identify coding loss-of-function alleles but may miss the 34-bp promoter deletion and some CNVs.
  3. WGS: potentially best single assay because it can interrogate coding, promoter, and structural alleles, provided the pipeline calls and interprets the repetitive promoter region reliably.
  4. Targeted testing: PCR/fragment analysis or Sanger sequencing for D1/D2 plus sequencing of coding/splice regions in a strongly suggestive case.
  5. CMA/MLPA: useful when a deletion encompassing TXNL4A is suspected; the discovery study used microarray and MLPA.
  6. Karyotype, FISH, mtDNA, and repeat-expansion testing have no routine disease-specific role unless another diagnosis is suspected. (wieczorek2014compoundheterozygosityof pages 3-4, wieczorek2014compoundheterozygosityof pages 4-6)

Confirm trans configuration through parental testing. RNA analysis or promoter functional studies may help resolve unusual splice/regulatory VUS but are not validated routine biomarkers.

Differential diagnosis

Important alternatives include CHARGE syndrome/CHD7 disorder; Treacher Collins syndrome (TCOF1, POLR1D, POLR1C); mandibulofacial dysostosis with microcephaly (EFTUD2); Nager syndrome (SF3B4); cerebro-costo-mandibular syndrome (SNRPB); Miller syndrome (DHODH); craniofacial microsomia; isolated choanal atresia; and 18q deletion syndromes. BMKS is favored by bilateral choanal atresia together with short palpebral fissures, lower-eyelid coloboma, prominent high-bridged nose, short philtrum, large ears, hearing loss, clefting, usually normal intellect, and biallelic TXNL4A variants. Oculo-oto-facial dysplasia may overlap the same spectrum. (wieczorek2014compoundheterozygosityof pages 2-3, wieczorek2014compoundheterozygosityof pages 1-2)

No biochemical, histopathologic, electrophysiologic, circulating, proteomic, metabolomic, or liquid-biopsy marker is established. There are no standardized diagnostic criteria beyond phenotype plus molecular confirmation.

11. Outcome and prognosis

No 5- or 10-year survival estimate, life expectancy, disease-specific mortality rate, disability score, or validated prognostic biomarker exists. The main immediate risk is neonatal airway obstruction from bilateral choanal atresia. Longer-term morbidity is expected to reflect restenosis or repeated airway procedures, hearing and speech impairment, cleft-related feeding/dental problems, and the severity of cardiac, renal, or anorectal anomalies.

Normal intellectual development is typical, but rare severe disability has been reported. Recovery means correction or adaptation to individual malformations; the constitutional molecular defect is lifelong. Prognosis is therefore anatomy-dependent rather than governed by a validated TXNL4A genotype score. (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 2-3)

12. Treatment

There is no approved TXNL4A-directed therapy, pharmacotherapy, gene therapy, RNA therapy, cell therapy, or splice-correcting treatment.

Current clinical management

  • Bilateral choanal atresia: emergency airway stabilization followed by definitive otolaryngologic repair, generally using an endoscopic transnasal approach according to anatomy and local expertise; monitor for restenosis.
  • Hearing loss: serial audiology, hearing aids or bone-conduction devices as appropriate, and cochlear-implant assessment for severe sensorineural loss. Cochlear implantation was contemplated in reported BMKS care. (wieczorek2014compoundheterozygosityof pages 2-3)
  • Cleft lip/palate: multidisciplinary craniofacial repair, feeding support, dental/orthodontic care, and speech-language therapy.
  • Eyelid coloboma: ocular-surface protection and ophthalmic reconstruction when indicated.
  • Cardiac, renal, anorectal, and hernia anomalies: standard specialty-specific surveillance and surgery.
  • Development: early-intervention, educational, occupational, and speech support based on individual assessment.

Suggested NCIT intervention concepts include surgical procedure, reconstructive surgery, airway management, hearing aid, cochlear implantation, speech therapy, genetic counseling, and supportive care; exact NCIT codes should be terminology-validated.

No treatment-response rate, comparative surgical outcome, pharmacogenomic recommendation, or BMKS-specific adverse-event profile was found. The ClinicalTrials.gov search identified no relevant BMKS interventional study or NCT identifier.

The WNT/TCF7L2 and apoptosis findings are mechanistic research leads, not justification for prenatal or postnatal WNT- or apoptosis-targeted therapy. (wood2020modellingthedevelopmental pages 34-37, park2022thecoresplicing pages 7-10)

13. Prevention

Primary lifestyle or vaccine prevention is not applicable. Evidence-based prevention is reproductive and complication-focused:

  • Offer genetic counseling and parental testing after molecular confirmation.
  • Provide cascade testing to at-risk adult relatives for the known familial alleles.
  • For a known familial genotype, discuss prenatal diagnosis by chorionic-villus sampling or amniocentesis and preimplantation genetic testing for monogenic disease.
  • Ensure assays test both the promoter deletion and the family’s second allele.
  • Targeted fetal imaging may detect clefting or major associated anomalies but cannot exclude BMKS or reliably establish choanal patency.
  • Tertiary prevention consists of early airway treatment, newborn/serial hearing assessment, feeding support, cardiac and renal evaluation, and timely craniofacial intervention.

BMKS is not part of standard biochemical newborn screening, and population carrier screening is not established.

14. Other species and natural disease

No naturally occurring veterinary syndrome definitively homologous to human BMKS was identified, and there is no zoonotic or cross-species transmission. TXNL4A/DIB1 function is evolutionarily conserved. Experimental ortholog evidence exists in:

  • Saccharomyces cerevisiae DIB1: depletion reduces U4/U6.U5 tri-snRNP assembly.
  • Caenorhabditis elegans: null ortholog loss is reported as lethal in the disease-model literature.
  • Xenopus laevis: experimentally reduced txnl4a produces neural-crest and craniofacial defects. (wood2020modellingthedevelopmental pages 1-5, wieczorek2014compoundheterozygosityof pages 7-8, park2022thecoresplicing pages 2-4)

These are induced models, not natural animal disease. Exact NCBI Taxonomy and ortholog Gene IDs should be imported from NCBI/Alliance rather than inferred here.

15. Model organisms and experimental systems

Yeast

Conditional DIB1 depletion models the upstream spliceosome defect and demonstrated impaired tri-snRNP assembly. It is powerful for molecular spliceosome biology but cannot model vertebrate neural crest or facial anatomy. (wieczorek2014compoundheterozygosityof pages 7-8)

Patient-derived iPSCs and induced neural-crest cells

Peripheral blood cells from one affected individual and her unaffected carrier mother were reprogrammed and compared with unrelated controls. This system recapitulated reduced proliferation, extensive mis-splicing, diminished WNT response, and delayed EMT during neural-crest differentiation. Its strengths are human genetic context and disease-relevant cell lineage; limitations include one family, a patient with atypical severe intellectual disability, non-isogenic controls, bulk RNA sequencing, and preprint publication status. (wood2020modellingthedevelopmental pages 37-41, wood2020modellingthedevelopmental pages 1-5, wood2020modellingthedevelopmental pages 45-49)

Xenopus

Morpholino knockdown at the two-cell stage reduced neural-crest markers, increased apoptosis, and produced craniofacial-cartilage defects; partial rescue with morpholino-resistant txnl4a supports on-target action. Limitations include transient knockdown, incomplete phenotype penetrance, dosage sensitivity, and absence of the precise human promoter/compound-heterozygous architecture. (park2022thecoresplicing pages 7-10, park2022thecoresplicing pages 2-4)

No published BMKS-specific knock-in mouse, zebrafish germline mutant, patient organoid, or isogenic CRISPR-corrected iPSC model was identified in the retrieved literature. The highest-value next steps are isogenic correction/introduction of D1 and D2 alleles, multiple-patient iPSC cohorts, single-cell time courses of cranial neural-crest differentiation, direct spliceosome-complex proteomics, and animal knock-in models reproducing human residual TXNL4A dosage.

Key publications

  1. Wieczorek et al. “Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.” American Journal of Human Genetics 95:698–707. Published December 2014. DOI/URL: https://doi.org/10.1016/j.ajhg.2014.10.014. This is the landmark human genetic and functional study. (wieczorek2014compoundheterozygosityof pages 1-2, wieczorek2014compoundheterozygosityof pages 4-6)
  2. Wood et al. “Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells.” bioRxiv preprint, posted May 14, 2020. DOI/URL: https://doi.org/10.1101/2020.05.13.094029. This is the principal patient-derived transcriptomic/mechanistic study but was retrieved as a preprint. (wood2020modellingthedevelopmental pages 1-5, wood2020modellingthedevelopmental pages 37-41)
  3. Park et al. “The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development.” Journal of Developmental Biology 10:29. Published July 2022. DOI/URL: https://doi.org/10.3390/jdb10030029. This provides the principal TXNL4A Xenopus knockdown/rescue evidence. (park2022thecoresplicing pages 7-10, park2022thecoresplicing pages 1-2)

PMIDs were not consistently exposed by the retrieved full-text records and have therefore not been guessed. For database ingestion, they should be resolved through PubMed using the exact titles/DOIs above.

Overall evidence assessment

The causal association between biallelic TXNL4A insufficiency and BMKS is strong, based on segregation across multiple human families plus promoter assays and conserved functional evidence. The detailed WNT/TCF7L2–EMT mechanism is biologically coherent but rests principally on one-family, preprint iPSC data and should be represented as supported/provisional, not definitive. Xenopus data independently support neural-crest progenitor loss and craniofacial consequences. Clinical epidemiology, longitudinal outcome, quality of life, genotype–phenotype prediction, standardized management, and disease-modifying treatment remain major evidence gaps.

References

  1. (wood2020modellingthedevelopmental pages 1-5): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.

  2. (wieczorek2014compoundheterozygosityof pages 1-2): Dagmar Wieczorek, William G. Newman, Thomas Wieland, Tea Berulava, Maria Kaffe, Daniela Falkenstein, Christian Beetz, Elisabeth Graf, Thomas Schwarzmayr, Sofia Douzgou, Jill Clayton-Smith, Sarah B. Daly, Simon G. Williams, Sanjeev S. Bhaskar, Jill E. Urquhart, Beverley Anderson, James O’Sullivan, Odile Boute, Jasmin Gundlach, Johanna Christina Czeschik, Anthonie J. van Essen, Filiz Hazan, Sarah Park, Anne Hing, Alma Kuechler, Dietmar R. Lohmann, Kerstin U. Ludwig, Elisabeth Mangold, Laura Steenpaß, Michael Zeschnigk, Johannes R. Lemke, Charles Marques Lourenco, Ute Hehr, Eva-Christina Prott, Melanie Waldenberger, Anne C. Böhmer, Bernhard Horsthemke, Raymond T. O’Keefe, Thomas Meitinger, John Burn, Hermann-Josef Lüdecke, and Tim M. Strom. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in txnl4a causes burn-mckeown syndrome. American journal of human genetics, 95 6:698-707, Dec 2014. URL: https://doi.org/10.1016/j.ajhg.2014.10.014, doi:10.1016/j.ajhg.2014.10.014. This article has 78 citations and is from a highest quality peer-reviewed journal.

  3. (wieczorek2014compoundheterozygosityof pages 7-8): Dagmar Wieczorek, William G. Newman, Thomas Wieland, Tea Berulava, Maria Kaffe, Daniela Falkenstein, Christian Beetz, Elisabeth Graf, Thomas Schwarzmayr, Sofia Douzgou, Jill Clayton-Smith, Sarah B. Daly, Simon G. Williams, Sanjeev S. Bhaskar, Jill E. Urquhart, Beverley Anderson, James O’Sullivan, Odile Boute, Jasmin Gundlach, Johanna Christina Czeschik, Anthonie J. van Essen, Filiz Hazan, Sarah Park, Anne Hing, Alma Kuechler, Dietmar R. Lohmann, Kerstin U. Ludwig, Elisabeth Mangold, Laura Steenpaß, Michael Zeschnigk, Johannes R. Lemke, Charles Marques Lourenco, Ute Hehr, Eva-Christina Prott, Melanie Waldenberger, Anne C. Böhmer, Bernhard Horsthemke, Raymond T. O’Keefe, Thomas Meitinger, John Burn, Hermann-Josef Lüdecke, and Tim M. Strom. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in txnl4a causes burn-mckeown syndrome. American journal of human genetics, 95 6:698-707, Dec 2014. URL: https://doi.org/10.1016/j.ajhg.2014.10.014, doi:10.1016/j.ajhg.2014.10.014. This article has 78 citations and is from a highest quality peer-reviewed journal.

  4. (wood2020modellingthedevelopmental pages 37-41): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.

  5. (park2022thecoresplicing pages 7-10): Byung-Yong Park, Melanie Tachi-Duprat, Chibuike Ihewulezi, Arun Devotta, and Jean-Pierre Saint-Jeannet. The core splicing factors eftud2, snrpb and txnl4a are essential for neural crest and craniofacial development. Journal of Developmental Biology, 10:29, Jul 2022. URL: https://doi.org/10.3390/jdb10030029, doi:10.3390/jdb10030029. This article has 27 citations.

  6. (wieczorek2014compoundheterozygosityof pages 4-6): Dagmar Wieczorek, William G. Newman, Thomas Wieland, Tea Berulava, Maria Kaffe, Daniela Falkenstein, Christian Beetz, Elisabeth Graf, Thomas Schwarzmayr, Sofia Douzgou, Jill Clayton-Smith, Sarah B. Daly, Simon G. Williams, Sanjeev S. Bhaskar, Jill E. Urquhart, Beverley Anderson, James O’Sullivan, Odile Boute, Jasmin Gundlach, Johanna Christina Czeschik, Anthonie J. van Essen, Filiz Hazan, Sarah Park, Anne Hing, Alma Kuechler, Dietmar R. Lohmann, Kerstin U. Ludwig, Elisabeth Mangold, Laura Steenpaß, Michael Zeschnigk, Johannes R. Lemke, Charles Marques Lourenco, Ute Hehr, Eva-Christina Prott, Melanie Waldenberger, Anne C. Böhmer, Bernhard Horsthemke, Raymond T. O’Keefe, Thomas Meitinger, John Burn, Hermann-Josef Lüdecke, and Tim M. Strom. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in txnl4a causes burn-mckeown syndrome. American journal of human genetics, 95 6:698-707, Dec 2014. URL: https://doi.org/10.1016/j.ajhg.2014.10.014, doi:10.1016/j.ajhg.2014.10.014. This article has 78 citations and is from a highest quality peer-reviewed journal.

  7. (wieczorek2014compoundheterozygosityof pages 3-4): Dagmar Wieczorek, William G. Newman, Thomas Wieland, Tea Berulava, Maria Kaffe, Daniela Falkenstein, Christian Beetz, Elisabeth Graf, Thomas Schwarzmayr, Sofia Douzgou, Jill Clayton-Smith, Sarah B. Daly, Simon G. Williams, Sanjeev S. Bhaskar, Jill E. Urquhart, Beverley Anderson, James O’Sullivan, Odile Boute, Jasmin Gundlach, Johanna Christina Czeschik, Anthonie J. van Essen, Filiz Hazan, Sarah Park, Anne Hing, Alma Kuechler, Dietmar R. Lohmann, Kerstin U. Ludwig, Elisabeth Mangold, Laura Steenpaß, Michael Zeschnigk, Johannes R. Lemke, Charles Marques Lourenco, Ute Hehr, Eva-Christina Prott, Melanie Waldenberger, Anne C. Böhmer, Bernhard Horsthemke, Raymond T. O’Keefe, Thomas Meitinger, John Burn, Hermann-Josef Lüdecke, and Tim M. Strom. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in txnl4a causes burn-mckeown syndrome. American journal of human genetics, 95 6:698-707, Dec 2014. URL: https://doi.org/10.1016/j.ajhg.2014.10.014, doi:10.1016/j.ajhg.2014.10.014. This article has 78 citations and is from a highest quality peer-reviewed journal.

  8. (wieczorek2014compoundheterozygosityof pages 2-3): Dagmar Wieczorek, William G. Newman, Thomas Wieland, Tea Berulava, Maria Kaffe, Daniela Falkenstein, Christian Beetz, Elisabeth Graf, Thomas Schwarzmayr, Sofia Douzgou, Jill Clayton-Smith, Sarah B. Daly, Simon G. Williams, Sanjeev S. Bhaskar, Jill E. Urquhart, Beverley Anderson, James O’Sullivan, Odile Boute, Jasmin Gundlach, Johanna Christina Czeschik, Anthonie J. van Essen, Filiz Hazan, Sarah Park, Anne Hing, Alma Kuechler, Dietmar R. Lohmann, Kerstin U. Ludwig, Elisabeth Mangold, Laura Steenpaß, Michael Zeschnigk, Johannes R. Lemke, Charles Marques Lourenco, Ute Hehr, Eva-Christina Prott, Melanie Waldenberger, Anne C. Böhmer, Bernhard Horsthemke, Raymond T. O’Keefe, Thomas Meitinger, John Burn, Hermann-Josef Lüdecke, and Tim M. Strom. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in txnl4a causes burn-mckeown syndrome. American journal of human genetics, 95 6:698-707, Dec 2014. URL: https://doi.org/10.1016/j.ajhg.2014.10.014, doi:10.1016/j.ajhg.2014.10.014. This article has 78 citations and is from a highest quality peer-reviewed journal.

  9. (wood2020modellingthedevelopmental pages 24-27): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.

  10. (wood2020modellingthedevelopmental pages 27-31): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.

  11. (wood2020modellingthedevelopmental pages 69-74): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.

  12. (wood2020modellingthedevelopmental pages 34-37): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.

  13. (wood2020modellingthedevelopmental pages 21-24): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.

  14. (park2022thecoresplicing pages 4-7): Byung-Yong Park, Melanie Tachi-Duprat, Chibuike Ihewulezi, Arun Devotta, and Jean-Pierre Saint-Jeannet. The core splicing factors eftud2, snrpb and txnl4a are essential for neural crest and craniofacial development. Journal of Developmental Biology, 10:29, Jul 2022. URL: https://doi.org/10.3390/jdb10030029, doi:10.3390/jdb10030029. This article has 27 citations.

  15. (park2022thecoresplicing pages 1-2): Byung-Yong Park, Melanie Tachi-Duprat, Chibuike Ihewulezi, Arun Devotta, and Jean-Pierre Saint-Jeannet. The core splicing factors eftud2, snrpb and txnl4a are essential for neural crest and craniofacial development. Journal of Developmental Biology, 10:29, Jul 2022. URL: https://doi.org/10.3390/jdb10030029, doi:10.3390/jdb10030029. This article has 27 citations.

  16. (wood2020modellingthedevelopmental pages 45-49): Katherine A. Wood, Charlie F. Rowlands, Huw B. Thomas, Steven Woods, Julieta O’Flaherty, Sofia Douzgou, Susan J. Kimber, William G. Newman, and Raymond T. O’Keefe. Modelling the developmental spliceosomal craniofacial disorder burn-mckeown syndrome using induced pluripotent stem cells. BioRxiv, May 2020. URL: https://doi.org/10.1101/2020.05.13.094029, doi:10.1101/2020.05.13.094029. This article has 30 citations.

  17. (park2022thecoresplicing pages 2-4): Byung-Yong Park, Melanie Tachi-Duprat, Chibuike Ihewulezi, Arun Devotta, and Jean-Pierre Saint-Jeannet. The core splicing factors eftud2, snrpb and txnl4a are essential for neural crest and craniofacial development. Journal of Developmental Biology, 10:29, Jul 2022. URL: https://doi.org/10.3390/jdb10030029, doi:10.3390/jdb10030029. This article has 27 citations.

Artifacts