Congenital foregut partitioning defect characterized by an abnormal posterior communication between the larynx/trachea and the esophagus.
Conditions with similar clinical presentations that must be differentiated from Laryngotracheoesophageal Cleft:
Pathophysiology description Laryngotracheoesophageal cleft is a congenital foregut partitioning defect in which the posterior larynx/trachea remain abnormally continuous with the esophagus. Current developmental evidence indicates that proper separation of the anterior foregut into respiratory (ventral) and esophageal (dorsal) lineages requires tightly coordinated dorsoventral patterning of endoderm and splanchnic mesenchyme, mediated by reciprocal signaling between SHH/GLI, WNT/β-catenin, BMP (and its antagonist NOG), FGF, and retinoic acid pathways, and executed by transcription factors that assign dorsal esophageal identity (SOX2) and ventral respiratory fate (NKX2-1/TTF1). Disruption of these networks alters epithelial–mesenchymal growth and septation, leading to a spectrum of tracheoesophageal malformations that includes LTEC, esophageal atresia, and tracheoesophageal fistula (TEF) (pfeifer2024trachealagenesisversus pages 1-2, eenjes2022lungepitheliumdevelopment pages 1-3, maj2024singlecellanalysisreveals pages 1-2).
Recent developments and latest research (2023–2024 priority) - Mechanistic synthesis distinguishing agenesis vs atresia. A 2024 rare-disease synthesis disentangles tracheal agenesis from atresia and re-emphasizes dorsoventral patterning/SOX2 vs NKX2-1 identity, BMP4/SMAD suppression of dorsal fate, and mesenchymal WNT2/2b induction of respiratory progenitors. It highlights compartmentalization via localized epithelial and mesenchymal proliferation along lateral mid-lines as a morphogenetic mechanism for separation (Orphanet J Rare Dis, Mar 2024, doi:10.1186/s13023-024-03106-z) (pfeifer2024trachealagenesisversus pages 1-2). - Single-cell resolution of risk loci and timing. A 2024 systems study maps 29 foregut malformation genes plus interactors, nominating FOXF1/FOXC1 and SOX2 across mouse/human datasets and pinpointing lateral plate mesoderm and early foregut endoderm as the most relevant lineages/stages (Sci Rep, Feb 2024, doi:10.1038/s41598-024-53098-w) (maj2024singlecellanalysisreveals pages 1-2). - Laryngeal epithelial/mesenchymal lineage dynamics. A 2024 cellular atlas of laryngeal/vocal fold development records prominent Shh/Wnt/RA activity in early laryngeal embryogenesis, Shh peak around E11.5, and Gli2/3 expression within neural crest–derived mesenchyme—supporting the cross-talk model at the laryngeal end of the foregut (2024 atlas) (lunga2024cellularatlasofb pages 92-96, lunga2024cellularatlasof pages 92-96).
Current applications and real-world implementations - Diagnostic framing and surgical planning leverage the shared developmental origin of LTEC with other foregut anomalies (TEF, atresia), informing comprehensive evaluation for associated malformations. In a 2023 case, recognition of aspiration and recurrent pneumonia prompted endoscopic diagnosis of a type III LTEC, guiding surgical timing and approach; histology of a concurrent gastric lesion confirmed ectopic respiratory (bronchial) tissue, underscoring global foregut patterning errors (Surgical Case Reports, May 2023, doi:10.1186/s40792-023-01650-7) (maj2024singlecellanalysisreveals pages 9-10). - Translational insight from patterning pathways. Clinical genetics increasingly screens patterning pathway genes and RA metabolism (e.g., ALDH1A2) in severe congenital anomaly syndromes; while not LTEC-specific, these data strengthen the rationale to consider RA–HH–WNT–BMP axes in diagnostic algorithms for complex foregut anomalies (contextualized in Front Cell Dev Biol 2022; Laryngeal atlas 2024) (eenjes2022lungepitheliumdevelopment pages 1-3, lunga2024cellularatlasofb pages 92-96, lunga2024cellularatlasof pages 92-96).
Expert opinions and analysis from authoritative sources - “Dorsal expression of SOX2 and ventral expression of NKX2-1 establish patterning; reduced SOX2 causes loss of dorsal identity … while reduced NKX2-1 causes loss of ventral identity” and separation requires “compartmentalization with local proliferation of epithelial and mesenchymal cells along lateral mid-lines,” synthesizing animal and human findings (Orphanet J Rare Dis, 2024, doi:10.1186/s13023-024-03106-z) (pfeifer2024trachealagenesisversus pages 1-2). - Reviews emphasize that mesodermal RA induces endodermal SHH, which signals via GLI2/3 to modulate mesenchymal WNT/BMP/FGF10 and thereby epithelial–mesenchymal coordination for foregut morphogenesis; perturbations reactivate these pathways in disease (Front Cell Dev Biol, 2022, doi:10.3389/fcell.2022.1022457) (eenjes2022lungepitheliumdevelopment pages 1-3). - Cross-atlas integrative analyses nominate FOXF1/FOXC1 and SOX2 as top regulators in the key lineages/time windows for esophageal malformations, providing a cell-type–specific and temporal framework for hypothesis generation in LTEC (Sci Rep, 2024, doi:10.1038/s41598-024-53098-w) (maj2024singlecellanalysisreveals pages 1-2).
Relevant statistics and data from recent studies - While LTEC incidence statistics were not reported in the retrieved 2023–2024 sources, the 2023 case report documents clinically relevant complications (frequent vomiting, aspiration pneumonia) and a confirmed type III LTEC on laryngoscopy at 30 days of life, with operative and histologic correlation (Surg Case Rep, May 2023, doi:10.1186/s40792-023-01650-7) (maj2024singlecellanalysisreveals pages 9-10).
Cellular processes affected: Endodermal fate specification, epithelial tube morphogenesis, epithelial–mesenchymal signaling, mesenchymal patterning (cartilage vs smooth muscle), localized proliferation at separation planes (Orphanet J Rare Dis 2024; Front Cell Dev Biol 2022) (pfeifer2024trachealagenesisversus pages 1-2, eenjes2022lungepitheliumdevelopment pages 1-3).
Key Molecular Players
Anatomical locations (UBERON): Anterior foregut (UBERON:0001040); larynx (UBERON:0001737); trachea (UBERON:0003126); esophagus (UBERON:0001043); tracheal mesenchyme; laryngeal mesenchyme (pfeifer2024trachealagenesisversus pages 1-2, eenjes2022lungepitheliumdevelopment pages 1-3, lunga2024cellularatlasofb pages 92-96, lunga2024cellularatlasof pages 92-96).
Biological Processes (for GO annotation)
Foregut morphogenesis; dorsal–ventral pattern specification; epithelial tube morphogenesis; epithelial cell fate commitment; regulation of Wnt signaling; Hedgehog signaling; retinoic acid biosynthetic process; epithelial–mesenchymal signaling; mesenchymal cell differentiation; trachea morphogenesis; larynx development (pfeifer2024trachealagenesisversus pages 1-2, eenjes2022lungepitheliumdevelopment pages 1-3, maj2024singlecellanalysisreveals pages 1-2, eenjes2022lungepitheliumdevelopment pages 11-11).
Cellular Components
Sites of action include: apical/basolateral plasma membrane signaling hubs in endodermal epithelium (WNT/BMP/SHH reception), ciliary structures in mesenchymal cells transducing SHH–GLI signaling, extracellular space and ECM where morphogens distribute; mesenchymal niches adjacent to the foregut tube where FOXF1/FOXC1 and FGF10 operate (eenjes2022lungepitheliumdevelopment pages 1-3, lunga2024cellularatlasofb pages 92-96).
Disease Progression (sequence of events)
Disruption: Altered dosage of SOX2 or NKX2-1, aberrant BMP/RA/WNT/SHH/FGF signaling, or mesenchymal TF (FOXF1/FOXC1) dysfunction leaves persistent communication across laryngo-tracheo-esophageal compartments (LTEC) with downstream aspiration and feeding complications (Orphanet J Rare Dis 2024; Surg Case Rep 2023) (pfeifer2024trachealagenesisversus pages 1-2, maj2024singlecellanalysisreveals pages 9-10).
Phenotypic Manifestations
Gene/protein annotations with ontology terms (examples) - SOX2 (HGNC:11195): GO Biological Process: dorsal–ventral pattern formation; epithelial cell fate commitment; foregut morphogenesis. Cellular Component: nucleus; chromatin. Evidence: Orphanet J Rare Dis 2024; Sci Rep 2024 (pfeifer2024trachealagenesisversus pages 1-2, maj2024singlecellanalysisreveals pages 1-2). - NKX2-1 (HGNC:11825): GO Biological Process: respiratory system development; ventral foregut specification; epithelial differentiation. Cellular Component: nucleus. Evidence: Orphanet J Rare Dis 2024; Front Cell Dev Biol 2022 (pfeifer2024trachealagenesisversus pages 1-2, eenjes2022lungepitheliumdevelopment pages 1-3). - SHH/GLI2/GLI3 (HGNC:10848/4318/4319): GO Biological Process: Hedgehog signaling; mesenchymal cell differentiation; regulation of FGF signaling. Cellular Component: primary cilium (signal transduction), nucleus (GLI TFs). Evidence: Front Cell Dev Biol 2022; laryngeal atlas 2024 (eenjes2022lungepitheliumdevelopment pages 1-3, lunga2024cellularatlasofb pages 92-96, lunga2024cellularatlasof pages 92-96). - WNT2/WNT2B (HGNC:12784/12785): GO Biological Process: Wnt signaling; induction of respiratory progenitor fate. Cellular Component: extracellular region/plasma membrane. Evidence: Orphanet J Rare Dis 2024; Front Cell Dev Biol 2022 (pfeifer2024trachealagenesisversus pages 1-2, eenjes2022lungepitheliumdevelopment pages 1-3). - BMP4/NOG (HGNC:1071/7866): GO Biological Process: BMP signaling; negative regulation by NOG; epithelial patterning. Cellular Component: extracellular region. Evidence: compiled citations summarized in 2025 review and Front Cell Dev Biol 2022 (beuchat2025modélisationdelœsophage pages 73-76, eenjes2022lungepitheliumdevelopment pages 1-3). - FOXF1/FOXC1 (HGNC:3801/3811): GO Biological Process: mesenchyme development; response to SHH; smooth muscle/cartilage patterning. Cellular Component: nucleus. Evidence: Sci Rep 2024; Front Cell Dev Biol 2022 (maj2024singlecellanalysisreveals pages 1-2, eenjes2022lungepitheliumdevelopment pages 1-3). - BARX1 (HGNC:959): GO Biological Process: negative regulation of Wnt signaling; foregut septation; epithelial differentiation. Cellular Component: nucleus. Evidence: review citing PLoS One 2011 summarized in Front Cell Dev Biol 2022 (eenjes2022lungepitheliumdevelopment pages 11-11).
Phenotype associations (selected HPO terms) - Aspiration (HP:0002835), Recurrent pneumonia (HP:0002205), Feeding difficulties in infancy (HP:0008872), Laryngeal cleft (HP:0010574) and Tracheoesophageal fistula (HP:0002575) as a related malformation in the spectrum (Surg Case Rep 2023; 2024 atlas context) (maj2024singlecellanalysisreveals pages 9-10, lunga2024cellularatlasofb pages 92-96).
Cell type involvement (CL terms) - Foregut endodermal epithelial progenitor (CL:0002256, generalized), Respiratory epithelial progenitor, Splanchnic mesenchymal progenitor (generalized), Neural crest–derived mesenchyme of larynx (CL class; as characterized in the atlas) (lunga2024cellularatlasofb pages 92-96, lunga2024cellularatlasof pages 92-96, maj2024singlecellanalysisreveals pages 1-2).
Anatomical locations (UBERON terms) - Anterior foregut (UBERON:0001040), Larynx (UBERON:0001737), Trachea (UBERON:0003126), Esophagus (UBERON:0001043) (pfeifer2024trachealagenesisversus pages 1-2, eenjes2022lungepitheliumdevelopment pages 1-3, lunga2024cellularatlasofb pages 92-96).
Chemical entities (CHEBI terms) - Retinoic acid (CHEBI:26538), Vitamin A derivatives (RA pathway; ALDH1A2-mediated synthesis) (eenjes2022lungepitheliumdevelopment pages 1-3, beuchat2025modélisationdelœsophage pages 73-76).
Evidence items with PMIDs/DOIs/URLs and dates - Pfeifer et al. Tracheal agenesis versus tracheal atresia: anatomical conditions, pathomechanisms and causes with a possible link to a novel MAPK11 variant. Orphanet Journal of Rare Diseases. Mar 2024. doi:10.1186/s13023-024-03106-z; URL: https://doi.org/10.1186/s13023-024-03106-z (pfeifer2024trachealagenesisversus pages 1-2). - Maj et al. Single-cell analysis reveals the spatial-temporal expression of genes associated with esophageal malformations. Scientific Reports. Feb 2024. doi:10.1038/s41598-024-53098-w; URL: https://doi.org/10.1038/s41598-024-53098-w (maj2024singlecellanalysisreveals pages 1-2). - Eenjes et al. Lung epithelium development and airway regeneration. Frontiers in Cell and Developmental Biology. Oct 2022. doi:10.3389/fcell.2022.1022457; URL: https://doi.org/10.3389/fcell.2022.1022457 (eenjes2022lungepitheliumdevelopment pages 1-3, eenjes2022lungepitheliumdevelopment pages 11-11). - Lunga T. Cellular Atlas of Laryngeal and Vocal Fold Embryogenesis, Maturation and Aging. 2024 (prepublication/unknown journal); excerpts indicate Shh/Wnt/RA activity and Gli2/3 expression across epithelial and neural crest–derived mesenchymal compartments (lunga2024cellularatlasofb pages 92-96, lunga2024cellularatlasof pages 92-96). - Nakatani et al. Gastric tumor mimicking bronchial tissue associated with a laryngotracheoesophageal cleft: a case report. Surgical Case Reports. May 2023. doi:10.1186/s40792-023-01650-7; URL: https://doi.org/10.1186/s40792-023-01650-7 (maj2024singlecellanalysisreveals pages 9-10). - Beuchat S. Modélisation de l'œsophage de Barrett à l'aide de cellules souches pluripotentes induites. 2025. The excerpt compiles primary sources on SHH, BMP/Noggin, WNT2/2b/β-catenin, and NKX2-1 regulation during foregut partitioning (e.g., Goss 2009 Dev Cell; Kim 2019 Dev Cell), providing DOIs and context (beuchat2025modélisationdelœsophage pages 73-76).
Embedded quick-reference table | Gene/Protein (HGNC) | Pathway (GO/Reactome label) | Mechanistic role in foregut/laryngotracheal separation (1–2 sentences) | Principal cell types (CL, brief) | Key anatomy (UBERON, brief) | Evidence and recent source (journal, year, DOI/URL) | Suggested GO Biological Processes | |---|---|---|---|---|---|---| | SOX2 | Transcriptional regulation / Dorsal foregut patterning (TF activity) | Establishes dorsal (esophageal) identity in anterior foregut; dose-dependent loss disrupts dorsal fate and contributes to esophageal/tracheal malformations. | Foregut endoderm epithelial progenitors; basal/progenitor epithelial cells (CL: foregut endoderm, epithelial progenitors) | Larynx, trachea, esophagus (UBERON: larynx, trachea, esophagus) | Maj et al., Scientific Reports 2024 (doi:10.1038/s41598-024-53098-w); Pfeifer et al., Orphanet J Rare Dis 2024 (doi:10.1186/s13023-024-03106-z); Eenjes et al., Front Cell Dev Biol 2022 (doi:10.3389/fcell.2022.1022457) (maj2024singlecellanalysisreveals pages 1-2, pfeifer2024trachealagenesisversus pages 1-2, eenjes2022lungepitheliumdevelopment pages 1-3) | Foregut morphogenesis; dorsal-ventral pattern specification; epithelial cell fate commitment | | NKX2-1 (TTF1) | Ventral respiratory fate TF / WNT-induced respiratory progenitor program | Specifies ventral respiratory identity (trachea/lung); loss reduces ventral identity leading to tracheal agenesis or failed separation. | Ventral foregut endoderm respiratory progenitors (CL: respiratory epithelial progenitors) | Trachea, larynx, lung primordium (UBERON: trachea, larynx, lung) | Pfeifer et al., Orphanet J Rare Dis 2024 (doi:10.1186/s13023-024-03106-z); Eenjes et al., Front Cell Dev Biol 2022 (doi:10.3389/fcell.2022.1022457); Maj et al., Sci Rep 2024 (doi:10.1038/s41598-024-53098-w) (pfeifer2024trachealagenesisversus pages 1-2, eenjes2022lungepitheliumdevelopment pages 1-3, maj2024singlecellanalysisreveals pages 1-2) | Ventral foregut patterning; respiratory system development; epithelial cell differentiation | | SHH / GLI2 / GLI3 axis | Hedgehog signaling pathway (SHH → GLI transcriptional effectors) | Endoderm-derived SHH signals to surrounding mesenchyme activating GLI2/3, which regulate mesenchymal factors (WNT, BMP, FGF10) that coordinate epithelial–mesenchymal interactions required for septation and cartilage/smooth muscle patterning. | Foregut endoderm (SHH-expressing) and splanchnic mesenchyme (CL: splanchnic mesoderm, mesenchymal progenitors) | Anterior foregut, tracheal mesenchyme, laryngeal mesenchyme (UBERON: anterior foregut, trachea) | Eenjes et al., Front Cell Dev Biol 2022 (doi:10.3389/fcell.2022.1022457); Lunga 2024 (cellular atlas) (eenjes2022lungepitheliumdevelopment pages 1-3, lunga2024cellularatlasofb pages 92-96) | Hedgehog-activated signaling; regulation of mesenchymal cell proliferation; epithelial–mesenchymal signaling during foregut development | | WNT2 / WNT2B - β-catenin | WNT signaling / canonical β-catenin pathway | Mesenchymal WNT2/2b induce Nkx2-1+ respiratory progenitors and promote ventral respiratory fate; WNT activity interacts with BMP/RA/SHH to sculpt dorsal–ventral identity. | Splanchnic mesoderm and foregut endoderm progenitors (CL: splanchnic mesenchyme, endodermal progenitors) | Anterior foregut, prospective trachea (UBERON: anterior foregut, trachea) | Pfeifer et al., Orphanet J Rare Dis 2024; Eenjes et al., Front Cell Dev Biol 2022 (pfeifer2024trachealagenesisversus pages 1-2, eenjes2022lungepitheliumdevelopment pages 1-3) | Regulation of canonical Wnt signaling; induction of respiratory progenitor fate; epithelial tube morphogenesis | | BMP4 / NOG (Noggin) | BMP signaling (BMP4) and antagonist Noggin (TGF-β superfamily) | Ventral BMP4/SMAD signaling contributes to suppression of SOX2 ventrally; Noggin (BMP antagonist) misexpression perturbs foregut progenitor programming and can lead to atresia/failure of proper separation. | Foregut epithelium and adjacent mesenchyme (CL: foregut epithelium, mesenchymal progenitors) | Anterior foregut, esophagus/trachea junction (UBERON: anterior foregut, esophagus, trachea) | Literature syntheses and experimental reports cited in Beuchat/compiled review and Eenjes 2022 noting BMP4 effects and Noggin misexpression links (beuchat2025modélisationdelœsophage pages 73-76, eenjes2022lungepitheliumdevelopment pages 1-3) | Regulation of BMP-mediated signaling; negative regulation of epithelial differentiation; epithelial cell fate specification | | FOXF1 / FOXC1 | Forkhead-box transcription factors / SHH downstream targets | FOXF1 is a mesenchymal SHH-responsive TF required for proper mesenchymal patterning of foregut derivatives; haploinsufficiency associates with lung/foregut malformations in humans/animals. | Splanchnic mesenchyme, mesenchymal progenitors (CL: splanchnic mesoderm, mesenchymal progenitors) | Lung/foregut mesenchyme, tracheal/bronchial supporting tissues (UBERON: lung, trachea) | Maj et al., Scientific Reports 2024 (single-cell enrichment of FOXF1/FOXC1 in EM-associated gene sets); Eenjes et al., 2022 (maj2024singlecellanalysisreveals pages 1-2, eenjes2022lungepitheliumdevelopment pages 1-3) | Regulation of mesenchyme development; response to SHH signaling; regulation of mesenchymal cell differentiation | | Retinoic Acid (ALDH1A2 / RA signaling) | Retinoic acid biosynthesis / RA signaling pathway | Mesodermal RA regulates SHH expression in endoderm and modulates WNT/BMP/FGF cross-talk; perturbation of RA synthesis (e.g., ALDH1A2 variants) disrupts foregut and cardiopulmonary morphogenesis. | Mesodermal cells (ALDH1A2-expressing mesenchyme) and foregut endoderm responding cells (CL: splanchnic mesoderm, endoderm) | Anterior foregut, developing lung/diaphragm regions (UBERON: anterior foregut, lung, diaphragm) | Beecroft et al. (ALDH1A2 variants) and reviews on RA→SHH interactions; Eenjes et al., 2022; Lunga 2024 (eenjes2022lungepitheliumdevelopment pages 1-3, lunga2024cellularatlasofb pages 92-96, beuchat2025modélisationdelœsophage pages 73-76) | Retinoic acid biosynthetic process; regulation of epithelial–mesenchymal signaling; morphogen-mediated pattern specification | | BARX1 | Transcriptional regulator that modulates WNT signaling in foregut | BARX1 in thoracic foregut mesenchyme inhibits WNT signaling locally to control tracheo-esophageal septation and epithelial differentiation; loss alters septation dynamics. | Foregut mesenchyme (CL: thoracic mesenchymal progenitors) | Thoracic foregut / esophagus region adjacent to prospective trachea (UBERON: thoracic foregut, esophagus) | Cited experimental evidence of BARX1 inhibition of WNT in mouse thoracic foregut controlling septation (reviewed in Eenjes 2022 referencing PLoS One 2011) (eenjes2022lungepitheliumdevelopment pages 1-3, eenjes2022lungepitheliumdevelopment pages 11-11) | Negative regulation of Wnt signaling; regulation of foregut epithelial differentiation; foregut septation |
Table: Compact reference table summarizing principal genes/pathways implicated in foregut partitioning and LTEC-related anomalies, with mechanistic roles, affected cell types and anatomical sites, evidence (recent sources/DOIs), and suggested GO biological processes for ontology mapping.
Notes and limitations - Human genotype–phenotype correlations specifically for LTEC remain sparse in the 2023–2024 sources retrieved here; however, the convergent developmental model and shared foregut field defects strongly support mechanistic extrapolation from TEF/EA and tracheal agenesis/atresia to LTEC. Where direct LTEC molecular pathology data are unavailable, we cite adjacent high-confidence mechanisms and cell-level atlases with explicit scope statements (pfeifer2024trachealagenesisversus pages 1-2, eenjes2022lungepitheliumdevelopment pages 1-3, maj2024singlecellanalysisreveals pages 1-2).
References
(pfeifer2024trachealagenesisversus pages 1-2): Mateja Pfeifer, Helga Rehder, Maria Gerykova Bujalkova, Christine Bartsch, Barbara Fritz, Cordula Knopp, Björn Beckers, Frank Dohle, Matthias Meyer-Wittkopf, Roland Axt-Fliedner, Alexander V. Beribisky, Manuel Hofer, Franco Laccone, and Katharina Schoner. Tracheal agenesis versus tracheal atresia: anatomical conditions, pathomechanisms and causes with a possible link to a novel mapk11 variant in one case. Orphanet Journal of Rare Diseases, Mar 2024. URL: https://doi.org/10.1186/s13023-024-03106-z, doi:10.1186/s13023-024-03106-z. This article has 2 citations and is from a peer-reviewed journal.
(eenjes2022lungepitheliumdevelopment pages 1-3): Evelien Eenjes, Dick Tibboel, Rene M.H. Wijnen, and Robbert J. Rottier. Lung epithelium development and airway regeneration. Frontiers in Cell and Developmental Biology, Oct 2022. URL: https://doi.org/10.3389/fcell.2022.1022457, doi:10.3389/fcell.2022.1022457. This article has 37 citations and is from a poor quality or predatory journal.
(maj2024singlecellanalysisreveals pages 1-2): Carlo Maj, Antonia Eberts, Johannes Schumacher, and Pouria Dasmeh. Single-cell analysis reveals the spatial-temporal expression of genes associated with esophageal malformations. Scientific Reports, Feb 2024. URL: https://doi.org/10.1038/s41598-024-53098-w, doi:10.1038/s41598-024-53098-w. This article has 1 citations and is from a peer-reviewed journal.
(lunga2024cellularatlasofb pages 92-96): T Lunga. Cellular atlas of laryngeal and vocal fold embryogenesis, maturation and aging. Unknown journal, 2024.
(lunga2024cellularatlasof pages 92-96): T Lunga. Cellular atlas of laryngeal and vocal fold embryogenesis, maturation and aging. Unknown journal, 2024.
(maj2024singlecellanalysisreveals pages 9-10): Carlo Maj, Antonia Eberts, Johannes Schumacher, and Pouria Dasmeh. Single-cell analysis reveals the spatial-temporal expression of genes associated with esophageal malformations. Scientific Reports, Feb 2024. URL: https://doi.org/10.1038/s41598-024-53098-w, doi:10.1038/s41598-024-53098-w. This article has 1 citations and is from a peer-reviewed journal.
(beuchat2025modélisationdelœsophage pages 73-76): S Beuchat. Modélisation de l'œsophage de barrett à l'aide de cellules souches pluripotentes induites. Unknown journal, 2025.
(eenjes2022lungepitheliumdevelopment pages 11-11): Evelien Eenjes, Dick Tibboel, Rene M.H. Wijnen, and Robbert J. Rottier. Lung epithelium development and airway regeneration. Frontiers in Cell and Developmental Biology, Oct 2022. URL: https://doi.org/10.3389/fcell.2022.1022457, doi:10.3389/fcell.2022.1022457. This article has 37 citations and is from a poor quality or predatory journal.
name: Laryngotracheoesophageal Cleft
creation_date: '2026-02-03T18:21:46Z'
updated_date: '2026-02-17T21:53:14Z'
category: Complex
synonyms:
- Laryngeal cleft
- Laryngotracheoesophageal cleft
- Laryngotracheal cleft
description: >-
Congenital foregut partitioning defect characterized by an abnormal posterior
communication between the larynx/trachea and the esophagus.
disease_term:
preferred_term: laryngotracheoesophageal cleft
term:
id: MONDO:0016060
label: laryngotracheoesophageal cleft
parents:
- tracheal disorder
- esophageal disorder
prevalence:
- population: Infants undergoing flexible endoscopy at a tertiary care center
percentage: 0.28
notes: Proportion of infants diagnosed with laryngeal cleft among those
undergoing flexible endoscopy at a single institution.
evidence:
- reference: PMID:35596199
reference_title: "Early detection of laryngeal cleft in infants by novel technique of flexible endoscopy with sustained pharyngeal inflation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This equates to a prevalence of 0.28% in all the children who underwent
flexible endoscopy at our institution."
explanation: Study reports a 0.28% prevalence among children undergoing
flexible endoscopy.
has_subtypes:
- name: Type 0 (interarytenoid cleft)
description: Interarytenoid notch above the vocal folds without extension into
the cricoid cartilage.
subtype_term:
preferred_term: laryngotracheoesophageal cleft type 0
term:
id: MONDO:0017220
label: laryngotracheoesophageal cleft type 0
- name: Type I
description: Supraglottic cleft extending to, but not through, the cricoid
cartilage.
subtype_term:
preferred_term: laryngotracheoesophageal cleft type 1
term:
id: MONDO:0019761
label: laryngotracheoesophageal cleft type 1
- name: Type II
description: Cleft extends through the cricoid cartilage into the cervical
trachea.
subtype_term:
preferred_term: laryngotracheoesophageal cleft type 2
term:
id: MONDO:0019762
label: laryngotracheoesophageal cleft type 2
- name: Type III
description: Cleft extends into the thoracic trachea.
subtype_term:
preferred_term: laryngotracheoesophageal cleft type 3
term:
id: MONDO:0019763
label: laryngotracheoesophageal cleft type 3
- name: Type IV
description: Cleft extends to the carina and may involve a mainstem bronchus.
subtype_term:
preferred_term: laryngotracheoesophageal cleft type 4
term:
id: MONDO:0019764
label: laryngotracheoesophageal cleft type 4
pathophysiology:
- name: Failed foregut partitioning
description: Abnormal separation of the anterior foregut permits persistent
communication between airway and esophagus.
locations:
- preferred_term: foregut
term:
id: UBERON:0001041
label: foregut
biological_processes:
- preferred_term: digestive tract development
term:
id: GO:0048565
label: digestive tract development
modifier: DYSREGULATED
- preferred_term: respiratory system development
term:
id: GO:0060541
label: respiratory system development
modifier: DYSREGULATED
evidence:
- reference: DOI:10.1186/s40792-023-01650-7
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "LTEC occurs because of foregut maldevelopment"
explanation: Case report links LTEC to foregut maldevelopment, supporting
failed partitioning.
- reference: PMID:38380453
reference_title: "Laryngotracheoesophageal Cleft Type IV in a Preterm Neonate. A Case Report and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "failure of separation of the trachea and the oesophagus during fetal
development"
explanation: Case report reiterates fetal failure of trachea-esophagus
separation in LTEC.
- name: Disrupted BMP4 signaling during larynx development
description: Disruption of BMP4 signaling perturbs laryngeal development and
is associated with laryngeal cleft in a mouse model.
biological_processes:
- preferred_term: BMP signaling pathway
term:
id: GO:0030509
label: BMP signaling pathway
modifier: DYSREGULATED
- preferred_term: larynx development
term:
id: GO:0120224
label: larynx development
modifier: DYSREGULATED
evidence:
- reference: PMID:37230380
reference_title: "Disruption of BMP4 signaling is associated with laryngeal birth defects in a mouse model."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Disruption of BMP4 signaling is associated with laryngeal birth defects
in a mouse model."
explanation: Mouse model demonstrates association of disrupted BMP4
signaling with laryngeal cleft.
- name: Posterior communication between larynx/trachea and esophagus
description: Abnormal posterior cleft connects the larynx/trachea with the
esophagus.
locations:
- preferred_term: larynx
term:
id: UBERON:0001737
label: larynx
- preferred_term: trachea
term:
id: UBERON:0003126
label: trachea
- preferred_term: esophagus
term:
id: UBERON:0001043
label: esophagus
evidence:
- reference: DOI:10.1186/s40792-023-01650-7
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Laryngotracheoesophageal cleft (LTEC) is a rare disease in which the
larynx and trachea communicate posteriorly to the esophagus."
explanation: Case report defines LTEC as a posterior larynx/trachea
communication with the esophagus.
- name: Foregut maldevelopment during respiratory and digestive tract
development
description: Disrupted foregut development underlies formation of the cleft.
locations:
- preferred_term: foregut
term:
id: UBERON:0001041
label: foregut
biological_processes:
- preferred_term: digestive tract development
term:
id: GO:0048565
label: digestive tract development
modifier: DYSREGULATED
- preferred_term: respiratory system development
term:
id: GO:0060541
label: respiratory system development
modifier: DYSREGULATED
evidence:
- reference: DOI:10.1186/s40792-023-01650-7
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "LTEC occurs because of foregut maldevelopment"
explanation: Case report links LTEC to foregut maldevelopment.
- name: Enriched esophageal malformation gene expression in lateral plate
mesoderm
description: Esophageal malformation genes show highest expression in lateral
plate mesoderm during early development, implicating this tissue in
maldevelopment.
locations:
- preferred_term: lateral plate mesoderm
term:
id: UBERON:0003081
label: lateral plate mesoderm
evidence:
- reference: DOI:10.1038/s41598-024-53098-w
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "the genes associated with esophageal malformations show their highest
cell-type specific expression in lateral plate mesoderm cells and at the developmental
stage of E8.75–E9.0 days."
explanation: Single-cell atlas analysis highlights lateral plate mesoderm
enrichment of esophageal malformation genes.
phenotypes:
- name: Vomiting
category: Gastrointestinal
frequency: OCCASIONAL
phenotype_term:
preferred_term: Vomiting
term:
id: HP:0002013
label: Vomiting
evidence:
- reference: DOI:10.1186/s40792-023-01650-7
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient experienced frequent vomiting and aspiration pneumonia"
explanation: Case report describes frequent vomiting in LTEC.
- name: Pneumonia
category: Respiratory
frequency: OCCASIONAL
phenotype_term:
preferred_term: Pneumonia
term:
id: HP:0002090
label: Pneumonia
evidence:
- reference: DOI:10.1186/s40792-023-01650-7
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient experienced frequent vomiting and aspiration pneumonia"
explanation: Case report documents aspiration pneumonia in LTEC.
- reference: PMID:32593610
reference_title: "Not Just for Kids: A Rare Case of Congenital Laryngeal Cleft in an Adult."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He had chronic aspiration, recurrent pneumonia, and a hoarse voice for
his entire life."
explanation: Adult case report documents recurrent pneumonia in a laryngeal
cleft patient.
- reference: PMID:40227884
reference_title: "Pulmonary and Radiographic Findings in Pediatric Type 1 Laryngeal Cleft."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "nearly half (44%) had a history of pneumonia"
explanation: Cohort study reports frequent pneumonia history in type 1
laryngeal cleft.
- reference: PMID:6873110
reference_title: "Laryngo-tracheo-oesophageal cleft. Clinical features, diagnosis and therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "life-threatening disturbances in the form of asphyxia and aspiration
pneumonia."
explanation: Review highlights aspiration pneumonia as a major clinical
complication.
- name: Aspiration pneumonia
category: Respiratory
frequency: OCCASIONAL
description: Aspiration pneumonia due to airway-esophageal communication.
phenotype_term:
preferred_term: Aspiration pneumonia
term:
id: HP:0011951
label: Aspiration pneumonia
evidence:
- reference: PMID:6873110
reference_title: "Laryngo-tracheo-oesophageal cleft. Clinical features, diagnosis and therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "life-threatening disturbances in the form of asphyxia and aspiration
pneumonia."
explanation: Review describes aspiration pneumonia as a key clinical
disturbance.
- name: Cough
category: Respiratory
frequency: OCCASIONAL
severity: Severe
description: Chronic or severe cough related to airway communication and
aspiration.
phenotype_term:
preferred_term: Cough
term:
id: HP:0012735
label: Cough
evidence:
- reference: PMID:32593610
reference_title: "Not Just for Kids: A Rare Case of Congenital Laryngeal Cleft in an Adult."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a 56-year-old male referred for hoarseness and chronic cough that was
discovered to have a type 2 laryngeal cleft."
explanation: Adult case report documents chronic cough in laryngeal cleft.
- reference: PMID:39543566
reference_title: "The Breathing Struggle: A Case Study of Congenital Lung Malformation in a Young Child."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "severe coughing"
explanation: Case report describes severe coughing in a child with a
posterior laryngeal cleft.
- reference: PMID:40330935
reference_title: "Type 1 laryngeal cleft management: a pediatric tertiary care center case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients experienced cough and choking with feeding."
explanation: Case series reports cough as a common presenting symptom in
type 1 laryngeal cleft.
- name: Choking episodes
category: Respiratory
frequency: OCCASIONAL
description: Choking during feeding due to abnormal airway-esophageal
communication.
phenotype_term:
preferred_term: Choking episodes
term:
id: HP:0030842
label: Choking episodes
evidence:
- reference: PMID:40330935
reference_title: "Type 1 laryngeal cleft management: a pediatric tertiary care center case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients experienced cough and choking with feeding."
explanation: Case series documents choking with feeding in type 1 laryngeal
cleft.
- name: Upper airway obstruction
category: Respiratory
frequency: RARE
description: Obstructive upper airway symptoms can occur even without
aspiration.
phenotype_term:
preferred_term: Upper airway obstruction
term:
id: HP:0002781
label: Upper airway obstruction
evidence:
- reference: PMID:37436152
reference_title: "Type 3 Laryngeal Clefts Presenting with Upper Airway Obstruction without Aspiration."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the sole presenting feature may be airway obstruction."
explanation: Case report notes upper airway obstruction as the presenting
feature in type III clefts without aspiration.
- name: Dysphagia
category: Gastrointestinal
frequency: OCCASIONAL
description: Swallowing dysfunction requiring thickened feeds in some
patients.
phenotype_term:
preferred_term: Dysphagia
term:
id: HP:0002015
label: Dysphagia
evidence:
- reference: PMID:37441989
reference_title: "Timeline to dysphagia resolution after endoscopic intervention of an interarytenoid defect based on Video Fluoroscopic Swallow Study dysphagia severity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "children with dysphagia found to have a LC-1 or DIG on endoscopic exam"
explanation: Study cohort with LC-1/DIG demonstrates dysphagia assessed by
VFSS.
- name: Stridor
category: Respiratory
frequency: RARE
description: Noisy breathing due to upper airway involvement.
phenotype_term:
preferred_term: Stridor
term:
id: HP:0010307
label: Stridor
evidence:
- reference: PMID:40330935
reference_title: "Type 1 laryngeal cleft management: a pediatric tertiary care center case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "one had a stridor"
explanation: Case series reports stridor in a subset of type 1 laryngeal
cleft patients.
- name: Hoarse voice
category: Head and Neck
frequency: OCCASIONAL
description: Voice changes due to abnormal laryngeal communication.
phenotype_term:
preferred_term: Hoarse voice
term:
id: HP:0001609
label: Hoarse voice
evidence:
- reference: PMID:32593610
reference_title: "Not Just for Kids: A Rare Case of Congenital Laryngeal Cleft in an Adult."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "referred for hoarseness and chronic cough"
explanation: Adult case report lists hoarseness as a presenting symptom.
- reference: PMID:39543566
reference_title: "The Breathing Struggle: A Case Study of Congenital Lung Malformation in a Young Child."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He presented with hoarseness"
explanation: Pediatric case report notes hoarseness with posterior laryngeal
cleft.
- name: Dyspnea
category: Respiratory
frequency: OCCASIONAL
severity: Severe
description: Shortness of breath during feeding or respiratory distress.
phenotype_term:
preferred_term: Dyspnea
term:
id: HP:0002094
label: Dyspnea
evidence:
- reference: PMID:30783751
reference_title: "Repair of type IV laryngotracheoesophageal cleft (LTEC) on ECMO."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "showed severe dyspnea and dysphagia"
explanation: Case report documents severe dyspnea in type IV LTEC.
- reference: PMID:39543566
reference_title: "The Breathing Struggle: A Case Study of Congenital Lung Malformation in a Young Child."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "shortness of breath"
explanation: Case report describes shortness of breath in a child with
posterior laryngeal cleft.
- name: Wheezing
category: Respiratory
frequency: OCCASIONAL
severity: Severe
description: Audible wheeze due to airway compromise.
phenotype_term:
preferred_term: Wheezing
term:
id: HP:0030828
label: Wheezing
evidence:
- reference: PMID:39543566
reference_title: "The Breathing Struggle: A Case Study of Congenital Lung Malformation in a Young Child."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "severe wheezing"
explanation: Case report notes severe wheezing in a child with posterior
laryngeal cleft.
- name: Aspiration
category: Respiratory
frequency: OCCASIONAL
description: Microaspiration due to abnormal communication between airway and
esophagus.
phenotype_term:
preferred_term: Aspiration
term:
id: HP:0002835
label: Aspiration
evidence:
- reference: PMID:40227884
reference_title: "Pulmonary and Radiographic Findings in Pediatric Type 1 Laryngeal Cleft."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "can result in chronic microaspiration and subsequent lung disease"
explanation: Cohort study highlights chronic microaspiration in type 1
laryngeal cleft.
- name: Atelectasis
category: Respiratory
frequency: FREQUENT
description: Collapse of lung segments noted on chest imaging.
phenotype_term:
preferred_term: Atelectasis
term:
id: HP:0100750
label: Atelectasis
evidence:
- reference: PMID:40227884
reference_title: "Pulmonary and Radiographic Findings in Pediatric Type 1 Laryngeal Cleft."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "atelectasis (56%)"
explanation: Cohort study reports atelectasis as a common radiographic
finding in type 1 laryngeal cleft.
- name: Bronchial wall thickening
category: Respiratory
frequency: FREQUENT
description: Bronchial wall thickening observed on chest imaging.
phenotype_term:
preferred_term: Bronchial wall thickening
term:
id: HP:0033542
label: Bronchial wall thickening
evidence:
- reference: PMID:40227884
reference_title: "Pulmonary and Radiographic Findings in Pediatric Type 1 Laryngeal Cleft."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "bronchial wall thickening (59%)"
explanation: Cohort study reports bronchial wall thickening as a prevalent
radiographic finding.
diagnosis:
- name: Direct laryngoscopy
description: Direct laryngoscopy visualizes the interarytenoid region and
cleft extent.
diagnosis_term:
preferred_term: laryngoscopy
term:
id: MAXO:0001189
label: laryngoscopy
evidence:
- reference: PMID:38380453
reference_title: "Laryngotracheoesophageal Cleft Type IV in a Preterm Neonate. A Case Report and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "direct laryngoscopy/bronchoscopy finally depicts the exact extension
of the medical condition"
explanation: Case report highlights direct laryngoscopy as definitive for
delineating cleft extent.
- reference: PMID:6873110
reference_title: "Laryngo-tracheo-oesophageal cleft. Clinical features, diagnosis and therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The diagnosis is made through direct laryngoscopy."
explanation: Review states that direct laryngoscopy establishes the
diagnosis.
- reference: PMID:37816841
reference_title: "Congenital laryngo-tracheo-esophageal clefts: updates from a quaternary care pediatric airway unit."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Every patient underwent a diagnostic endoscopy under general anesthesia"
explanation: Surgical series reports diagnostic endoscopy as a standard
evaluation step.
- name: Bronchoscopy
description: Bronchoscopy evaluates the airway and defines the extent of the
cleft.
diagnosis_term:
preferred_term: bronchoscopy
term:
id: MAXO:0001183
label: bronchoscopy
evidence:
- reference: PMID:38380453
reference_title: "Laryngotracheoesophageal Cleft Type IV in a Preterm Neonate. A Case Report and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "direct laryngoscopy/bronchoscopy finally depicts the exact extension
of the medical condition"
explanation: Case report notes bronchoscopy as part of definitive
evaluation.
- reference: PMID:30783751
reference_title: "Repair of type IV laryngotracheoesophageal cleft (LTEC) on ECMO."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We also performed observations with a rigid bronchoscope to assess extent
of the cleft"
explanation: Type IV LTEC case used rigid bronchoscopy to assess cleft
extent.
- name: Chest radiograph imaging
description: Chest radiographs show pulmonary complications that support
diagnosis and guide repair.
diagnosis_term:
preferred_term: chest radiograph procedure
term:
id: MAXO:0010356
label: chest radiograph procedure
evidence:
- reference: PMID:40227884
reference_title: "Pulmonary and Radiographic Findings in Pediatric Type 1 Laryngeal Cleft."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Abnormal CXR findings were common (80%), with atelectasis (56%) and
bronchial wall thickening (59%) being most prevalent."
explanation: Cohort study documents common abnormal chest radiograph
findings in type 1 laryngeal cleft.
- name: Flexible endoscopy with sustained pharyngeal inflation
description: Flexible endoscopy with sustained pharyngeal inflation can
improve visualization of laryngeal clefts in infants.
diagnosis_term:
preferred_term: laryngoscopy
term:
id: MAXO:0001189
label: laryngoscopy
evidence:
- reference: PMID:35596199
reference_title: "Early detection of laryngeal cleft in infants by novel technique of flexible endoscopy with sustained pharyngeal inflation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "flexible endoscopy with noninvasive ventilation (NIV) and sustained
pharyngeal inflation (FE-NIV-SPI) in assessing aeroesophageal tracts (AET) to
facilitate early detection of laryngeal clefts in infants."
explanation: Study reports FE-NIV-SPI as a technique for early detection of
laryngeal clefts.
- name: Video fluoroscopic swallow study
description: Video fluoroscopic swallow study evaluates dysphagia severity and
guides management of interarytenoid defects.
diagnosis_term:
preferred_term: barium swallow radiograph procedure
term:
id: MAXO:0035082
label: barium swallow radiograph procedure
evidence:
- reference: PMID:37441989
reference_title: "Timeline to dysphagia resolution after endoscopic intervention of an interarytenoid defect based on Video Fluoroscopic Swallow Study dysphagia severity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Video Fluoroscopic Swallow Study dysphagia severity"
explanation: Study uses VFSS to characterize dysphagia severity in LC1/DIG
patients undergoing endoscopic intervention.
- reference: PMID:6873110
reference_title: "Laryngo-tracheo-oesophageal cleft. Clinical features, diagnosis and therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Radiological demonstration of swallowing and tracheo-oesophagoscopy
are necessary additional investigations."
explanation: Review notes radiologic swallow studies as key additional
investigations.
- name: Computed tomography imaging
description: Chest CT may be obtained during evaluation but can miss laryngeal
clefts without targeted endoscopic assessment.
diagnosis_term:
preferred_term: computed tomography procedure
term:
id: MAXO:0000571
label: computed tomography procedure
evidence:
- reference: PMID:35596199
reference_title: "Early detection of laryngeal cleft in infants by novel technique of flexible endoscopy with sustained pharyngeal inflation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "missed by 11 prior bronchoscopy and 5 computer tomography examinations."
explanation: Case series notes that CT examinations can miss laryngeal
clefts, underscoring need for targeted endoscopy.
differential_diagnoses:
- name: Esophageal atresia
description: Prenatal imaging features of LTEC can mimic esophageal atresia.
disease_term:
preferred_term: esophageal atresia
term:
id: MONDO:0001044
label: esophageal atresia
evidence:
- reference: PMID:30232040
reference_title: "Laryngotracheoesophageal cleft, a rare differential diagnosis of esophageal atresia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Laryngotracheoesophageal cleft, a rare differential diagnosis of esophageal
atresia."
explanation: Case report highlights LTEC as a differential diagnosis for
esophageal atresia.
- name: Tracheo-esophageal fistula
description: Fistulous communication can resemble LTEC and must be
distinguished.
disease_term:
preferred_term: isolated tracheo-esophageal fistula
term:
id: MONDO:0018694
label: isolated tracheo-esophageal fistula
evidence:
- reference: PMID:22151899
reference_title: "Laryngo-tracheo-oesophageal clefts."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Differential diagnoses include tracheo-bronchial fistula, gastro-esophageal
reflux disease and neurological swallowing disorders, as well as laryngomalacia
and laryngeal palsy."
explanation: Review lists tracheo-bronchial fistula among LTEC
differentials.
- name: Gastroesophageal reflux disease
description: GERD can present with aspiration and feeding symptoms that
overlap with LTEC.
disease_term:
preferred_term: gastroesophageal reflux disease
term:
id: MONDO:0007186
label: gastroesophageal reflux disease
evidence:
- reference: PMID:22151899
reference_title: "Laryngo-tracheo-oesophageal clefts."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Differential diagnoses include tracheo-bronchial fistula, gastro-esophageal
reflux disease and neurological swallowing disorders, as well as laryngomalacia
and laryngeal palsy."
explanation: Review lists GERD among LTEC differential diagnoses.
- name: Congenital laryngomalacia
description: Laryngomalacia can cause stridor and aspiration symptoms
resembling LTEC.
disease_term:
preferred_term: congenital laryngomalacia
term:
id: MONDO:0007878
label: congenital laryngomalacia
evidence:
- reference: PMID:22151899
reference_title: "Laryngo-tracheo-oesophageal clefts."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Differential diagnoses include tracheo-bronchial fistula, gastro-esophageal
reflux disease and neurological swallowing disorders, as well as laryngomalacia
and laryngeal palsy."
explanation: Review lists laryngomalacia among LTEC differential diagnoses.
treatments:
- name: Endoscopic laser repair (type 1)
description: Endoscopic laser repair used for type 1 laryngeal clefts.
evidence:
- reference: PMID:40330935
reference_title: "Type 1 laryngeal cleft management: a pediatric tertiary care center case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "endoscopic laser repair remains the gold standard treatment for type
1 LC."
explanation: Case series identifies endoscopic laser repair as the standard
treatment for type 1 laryngeal cleft.
treatment_term:
preferred_term: laser surgical procedure
term:
id: MAXO:0001578
label: laser surgical procedure
qualifiers:
- predicate:
preferred_term: surgical procedure
term:
id: NCIT:C15329
label: Surgical Procedure
value:
preferred_term: laser surgery
term:
id: NCIT:C15268
label: Laser Surgery
- name: Endoscopic CO2 laser repair (type 3)
description: Staged endoscopic CO2 laser-assisted repair for type 3 clefts.
evidence:
- reference: PMID:40579891
reference_title: "Minimally Invasive Staged Endoscopic CO2 Laser Repair of Type III Laryngo-Tracheo-Esophageal Clefts: When and How."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Nineteen patients with Type III laryngeal clefts who were treated with
endoscopic carbon dioxide laser-assisted repair were included."
explanation: Case series reports staged endoscopic CO2 laser repair for type
3 clefts.
treatment_term:
preferred_term: laser surgical procedure
term:
id: MAXO:0001578
label: laser surgical procedure
qualifiers:
- predicate:
preferred_term: surgical procedure
term:
id: NCIT:C15329
label: Surgical Procedure
value:
preferred_term: laser surgery
term:
id: NCIT:C15268
label: Laser Surgery
- predicate:
preferred_term: therapeutic agent
term:
id: NCIT:C2259
label: Therapeutic Agent
value:
preferred_term: carbon dioxide
term:
id: NCIT:C65288
label: Carbon Dioxide
- name: Injection laryngoplasty
description: Injection laryngoplasty used as a diagnostic or temporizing
intervention in laryngeal cleft.
evidence:
- reference: PMID:39260330
reference_title: "International perspective of injection laryngoplasty for laryngeal cleft - A survey study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "LC can be treated surgically by performing suture repair or by Injection
Laryngoplasty (IL)."
explanation: Survey study identifies injection laryngoplasty as a treatment
option for laryngeal cleft.
- reference: PMID:40330935
reference_title: "Type 1 laryngeal cleft management: a pediatric tertiary care center case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we initially managed patients with type 1 LC with hyaluronic acid injections
for a few months"
explanation: Case series documents injection laryngoplasty used in initial
management.
- reference: PMID:35236684
reference_title: "Injection laryngoplasty for laryngeal cleft type I in an 8-week-old infant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "injection laryngoplasty is performed safely on an 8-week-old child"
explanation: Case report supports injection laryngoplasty as a feasible
intervention in infants.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
qualifiers:
- predicate:
preferred_term: therapeutic agent
term:
id: NCIT:C2259
label: Therapeutic Agent
value:
preferred_term: hyaluronic acid
term:
id: CHEBI:16336
label: hyaluronic acid
- name: Surgical repair of laryngeal cleft
description: Operative repair of laryngeal cleft improves aspiration symptoms.
evidence:
- reference: PMID:40629707
reference_title: "Familial Laryngeal Cleft: Pediatric Detection Leads to Adult Diagnosis and Intervention."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All showed marked improvement after surgical repair."
explanation: Familial case report shows symptom improvement after surgical
repair.
- reference: PMID:6873110
reference_title: "Laryngo-tracheo-oesophageal cleft. Clinical features, diagnosis and therapy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "an early operative correction of the defect is required."
explanation: Review emphasizes early operative correction for
laryngotracheoesophageal cleft.
- reference: PMID:30783751
reference_title: "Repair of type IV laryngotracheoesophageal cleft (LTEC) on ECMO."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "repair of the cleft was performed by an anterior approach via median
sternotomy"
explanation: Type IV case report documents surgical repair of LTEC with an
anterior approach under ECMO.
- reference: PMID:35039336
reference_title: "Simultaneous anterior cervical repair of type IV laryngeal cleft and tracheo-oesophageal fistula."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Simultaneous anterior cervical repair of type IV laryngeal cleft and
tracheo-oesophageal fistula."
explanation: Case report demonstrates surgical repair for type IV laryngeal
cleft with TEF.
- reference: PMID:32593610
reference_title: "Not Just for Kids: A Rare Case of Congenital Laryngeal Cleft in an Adult."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "successfully treated with an endoscopic approach using absorbable suture"
explanation: Adult case report supports endoscopic surgical repair.
- reference: PMID:37073597
reference_title: "Repair of posterior laryngeal cleft: a 10-year experience in a tertiary referral hospital."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Surgical management in the form of endoscopic Coblation-assisted or
an open approach is indicated"
explanation: Tertiary center series supports endoscopic or open surgical
management for laryngeal cleft.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
qualifiers:
- predicate:
preferred_term: surgical procedure
term:
id: NCIT:C15329
label: Surgical Procedure
value:
preferred_term: endoscopic procedure
term:
id: NCIT:C16546
label: Endoscopic Procedure
- name: Anterior laryngofissure repair with posterior cartilage grafting
description: Anterior approach surgical repair with posterior cartilage
grafting for type III/IV LTEC.
evidence:
- reference: PMID:38761217
reference_title: "Outcomes of surgical repair of Type III and IV laryngotracheoesophageal clefts with posterior cartilage grafting."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "an anterior approach that involved interposition a posterior cartilage
for Type III or Type IV laryngotracheoesophageal cleft (LTEC)."
explanation: Surgical series supports anterior laryngofissure repair with
posterior cartilage grafting for type III/IV LTEC.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
- name: Combined open and endoscopic repair for long clefts
description: Combined open and endoscopic approaches may be required for long
clefts with tracheal extension.
evidence:
- reference: PMID:37816841
reference_title: "Congenital laryngo-tracheo-esophageal clefts: updates from a quaternary care pediatric airway unit."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Primary and revision repair of long clefts with tracheal extension may
require a combined approach."
explanation: Series reports use of combined open and endoscopic approaches
for long clefts.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
biochemical: []
genetic:
- name: SOX2
association: Associated
evidence:
- reference: DOI:10.1038/s41598-024-53098-w
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "FOXF1, FOXC1, and FOXD1, as well as the SRY-box transcription factor,
SOX2, demonstrate the most significant preferential expression in both mouse
and human embryos."
explanation: Single-cell analysis links SOX2 to esophageal malformation gene
expression patterns.
gene_term:
preferred_term: SOX2
term:
id: hgnc:11195
label: SOX2
- name: FOXF1
association: Associated
evidence:
- reference: DOI:10.1038/s41598-024-53098-w
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "FOXF1, FOXC1, and FOXD1, as well as the SRY-box transcription factor,
SOX2, demonstrate the most significant preferential expression in both mouse
and human embryos."
explanation: Single-cell analysis highlights FOXF1 among genes enriched in
esophageal malformation contexts.
gene_term:
preferred_term: FOXF1
term:
id: hgnc:3809
label: FOXF1
- name: FOXC1
association: Associated
evidence:
- reference: DOI:10.1038/s41598-024-53098-w
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "FOXF1, FOXC1, and FOXD1, as well as the SRY-box transcription factor,
SOX2, demonstrate the most significant preferential expression in both mouse
and human embryos."
explanation: Single-cell analysis highlights FOXC1 among genes enriched in
esophageal malformation contexts.
gene_term:
preferred_term: FOXC1
term:
id: hgnc:3800
label: FOXC1
- name: RERE
association: Associated
evidence:
- reference: PMID:30245899
reference_title: "Type IV Laryngotracheoesophageal Cleft Associated with Type III Esophageal Atresia in 1p36 Deletions Containing the RERE Gene: Is There a Causal Role for the Genetic Alteration?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a 1p36 deletion including the RERE gene was detected."
explanation: Case report identifies a 1p36 deletion including RERE in a
neonate with type IV LTEC.
gene_term:
preferred_term: RERE
term:
id: hgnc:9965
label: RERE
environmental: []
datasets: []
clinical_trials: []
references:
- reference: DOI:10.1186/s13023-024-03106-z
title: 'Tracheal agenesis versus tracheal atresia: anatomical conditions, pathomechanisms
and causes with a possible link to a novel MAPK11 variant in one case'
findings: []
- reference: DOI:10.3389/fcell.2022.1022457
title: Lung epithelium development and airway regeneration
findings: []