Laryngeal clefts are rare congenital anomalies, first described in 1792 by Richter, that allow communication between the tracheal and esophageal axis. The incidence is 1 in 10,000 to 20,000 births, which represents approximately 1.5% of the laryngeal pathology in children. Laryngeal clefts result from a failure of fusion of the posterior cricoid lamina and development of the tracheoesophageal septum. Recent work has further refined our understanding of this complex development.
Several classification systems have been proposed, and the one currently in use by Benjamin and Inglis describes a hierarchy of four types of cleft, each more severe. Symptoms are a variable combination of airway and feeding difficulty. Severity of symptoms is generally in proportion to the inferior extent of the cleft.
A high index of suspicion is required for early diagnosis to prevent chronic pulmonary aspiration. An early diagnosis leads to a reduction in morbidity and mortality. Clefts are commonly seen with other congenital abnormalities in 60% of cases and are frequently associated with other syndromes. The two most commonly associated abnormalities are tracheoesophageal fistula (20%–37%) and tracheomalacia. Diagnosis of clefts requires suspension microlaryngoscopy under general anesthesia with spontaneous breathing. The arytenoids must be separated with a probe to fully visualize the cleft and its full extent. Before surgical intervention, medical stabilization is necessary. When medical treatment fails to control the situation, intubation, tracheotomy, gastrostomy, and Nissen fundoplication may be required. Surgical repair depends on the severity the cleft.
The laryngotracheal cleft is a fissure between the laryngotracheal and the pharyngoesophageal systems caused by a lack of separation between the laryngotracheal axis and the esophagus. First reported by Richter in 1792 in a newborn who presented with aspiration, it is a rare congenital anomaly whose origin remains unexplained. In 1955, Pettersson performed the first successful surgical reconstruction and described a classification system. In 1965, Blumberg and colleagues published the first global review of the literature. In 1983, Roth and colleagues reported the first large and well-documented series. Advances in knowledge, diagnosis, and treatment of laryngeal cleft have led to significant improvements in survival and quality of life of patients.
Embryology
Esophageal and tracheal embryology is controversial because the most recent research casts doubt on the traditional theory of development of a tracheoesophageal septum. The discovery of an experimental animal model has helped us understand the anomalies of embryology and led to new concepts explaining the development of esophageal and respiratory systems.
In the classic understanding first proposed by His, who was the first to describe the embryology of the respiratory system, the development of the larynx derives from two tissue sources evolving in parallel: the endoderm coming from the foregut and the mesenchymal elements from the fourth and sixth branchial arches . His suggested that the division of the foregut is the result of the fusion of lateral ridges that appear in the lateral walls of the foregut. This process starts caudally and ends cranially in the region of the larynx, thus forming a septum that divides the foregut into a ventral portion, the laryngotracheal tube, and a dorsal portion, the esophagus. This theory has been viewed with some skepticism for many years because it fails to explain the formation of commonly seen isolated tracheoesophageal fistula and many other tracheoesophageal abnormalities.
In 1987, while studying embryology of the foregut of chick embryos, Kluth and colleagues failed to identify discreet lateral ridges and suggested that the development of the trachea and esophagus results from a size reduction of the foregut caused by a system of folds that approximate but do not fuse. This system of folds appears in the foregut and involves the tracheoesophageal space cranially and caudally: the caudal fold has a cranial evolution and the two cranial folds have a caudal evolution. More recent findings complement this description by introducing the notion that the respiratory diverticulum develops from the ventral area of the foregut and continues to elongate to form the trachea.
O’Rahilly and Muller described the pulmonary primordium that appears in the foregut’s ventral mesenchyme as a paired structure that develops caudally. The portion of mesenchyme located between the digestive and respiratory tubes, defined as the tracheoesophageal septum, is initially present as a result of the separation of the two tracts. They also showed that the point of separation between the digestive and respiratory tube does not migrate and remains at a constant horizontal plane, whereas the tracheal bifurcation descends. Qi and Beasley highlighted apoptic epithelial cells at the tracheoesophageal separation point and found intense cellular activity in the ventral part of the foregut, whereas the dorsal part remains inactive, which suggests that a predetermined apoptotic phenomenon is responsible for tissue growth and involution.
Pathophysiology
The embryology of the laryngotracheoesophageal anomalies is also controversial, mainly because of a lack of embryos with anomalies at different stages available for histologic studies. The recent discovery of an experimental rat model provided a better understanding of these anomalies. Rat embryos exposed to Adriamycin (doxorubicin) present with major tracheoesophageal anomalies described in the VATER and VACTERL associations—mostly esophageal atresia and tracheoesophageal fistula .
Numerous theories that have been proposed to explain the development of tracheoesophageal anomalies can be divided into four groups:
- 1.
Intraembryonic pressure. The development of the heart and the marked curvature of the cervical region cause a displacement of the esophagus under tension, which results in the origin of the anomalies.
- 2.
Epithelial occlusion. During cell proliferation there is a solid esophageal stage that eventually recanalizes. The lack of recanilization of the esophagus results in the origin of the anomalies.
- 3.
Vascular occlusion. The abnormal persistence of an aberrant vessel leads to vascular insufficiency in the foregut, which results in the origin of the anomalies.
- 4.
Differential cell growth. Cell development dysfunction in either the ventral or dorsal part of the developing tracheoesophagus results in esophageal abnormalities and tracheal defects, respectively.
Blumberg and colleagues originally suggested that the premature arrest of development of the tracheoesophageal septum and eventually the lack of fusion of the two lateral centers of chondrification of the cricoid cartilage at the eighth week would be responsible, depending on the height reached at the arrest, for a laryngeal cleft. Significantly, this does not explain the frequent abnormalities associated with laryngeal cleft, such as atresia and especially tracheoesophageal fistula. The Kluth system of folds in chick embryos proposed that excessive growth of the dorsal fold explains esophageal atresia and esophageotracheal fistula, whereas a lack of growth of the laryngeal fold results in laryngeal cleft.
Merei and Hutson proposed a dynamic theory for laryngo-tracheo-esophageal abnormalities based on anomalies occurring in rat embryos exposed to doxorubicin. The respiratory diverticulum grows normally in the ventral portion of the foregut before the development or growth of the trachea. This event induces foregut overgrowth and the development of a dorsal upper foregut pouch. The process of differentiation that follows this event leads to the differentiation of the ventral elements into respiratory tract (respiratory epithelium and cartilaginous rings) and the dorsal elements into digestive tract.
In case of esophageal atresia with fistula, the pouch develops dorsally and differentiates into a blind-nding esophagus. The development of the trachea depends on the level of the fistula, which determines the transformation of a smaller or larger part of the foregut into false trachea. In the case of tracheal atresia, the pouch develops ventrally and differentiates into a blind-ending trachea, whereas the foregut differentiates into the esophagus. Laryngeal clefts have not been experimentally observed in this model, but presumably, in the absence of pouch, the anterior part of the foregut differentiates into trachea and the posterior part into esophagus, leading to a laryngeal cleft.
Pathophysiology
The embryology of the laryngotracheoesophageal anomalies is also controversial, mainly because of a lack of embryos with anomalies at different stages available for histologic studies. The recent discovery of an experimental rat model provided a better understanding of these anomalies. Rat embryos exposed to Adriamycin (doxorubicin) present with major tracheoesophageal anomalies described in the VATER and VACTERL associations—mostly esophageal atresia and tracheoesophageal fistula .
Numerous theories that have been proposed to explain the development of tracheoesophageal anomalies can be divided into four groups:
- 1.
Intraembryonic pressure. The development of the heart and the marked curvature of the cervical region cause a displacement of the esophagus under tension, which results in the origin of the anomalies.
- 2.
Epithelial occlusion. During cell proliferation there is a solid esophageal stage that eventually recanalizes. The lack of recanilization of the esophagus results in the origin of the anomalies.
- 3.
Vascular occlusion. The abnormal persistence of an aberrant vessel leads to vascular insufficiency in the foregut, which results in the origin of the anomalies.
- 4.
Differential cell growth. Cell development dysfunction in either the ventral or dorsal part of the developing tracheoesophagus results in esophageal abnormalities and tracheal defects, respectively.
Blumberg and colleagues originally suggested that the premature arrest of development of the tracheoesophageal septum and eventually the lack of fusion of the two lateral centers of chondrification of the cricoid cartilage at the eighth week would be responsible, depending on the height reached at the arrest, for a laryngeal cleft. Significantly, this does not explain the frequent abnormalities associated with laryngeal cleft, such as atresia and especially tracheoesophageal fistula. The Kluth system of folds in chick embryos proposed that excessive growth of the dorsal fold explains esophageal atresia and esophageotracheal fistula, whereas a lack of growth of the laryngeal fold results in laryngeal cleft.
Merei and Hutson proposed a dynamic theory for laryngo-tracheo-esophageal abnormalities based on anomalies occurring in rat embryos exposed to doxorubicin. The respiratory diverticulum grows normally in the ventral portion of the foregut before the development or growth of the trachea. This event induces foregut overgrowth and the development of a dorsal upper foregut pouch. The process of differentiation that follows this event leads to the differentiation of the ventral elements into respiratory tract (respiratory epithelium and cartilaginous rings) and the dorsal elements into digestive tract.
In case of esophageal atresia with fistula, the pouch develops dorsally and differentiates into a blind-nding esophagus. The development of the trachea depends on the level of the fistula, which determines the transformation of a smaller or larger part of the foregut into false trachea. In the case of tracheal atresia, the pouch develops ventrally and differentiates into a blind-ending trachea, whereas the foregut differentiates into the esophagus. Laryngeal clefts have not been experimentally observed in this model, but presumably, in the absence of pouch, the anterior part of the foregut differentiates into trachea and the posterior part into esophagus, leading to a laryngeal cleft.
Epidemiology
The laryngeal cleft is a rare pathology whose incidence is most likely underestimated for three reasons: (1) minor laryngeal cleft may be asymptomatic, (2) the endoscopic diagnosis is difficult and the lesion is easily missed, and (3) severe clefts can lead to a child’s death before a diagnosis can be made.
The abnormalities of the larynx have an incidence between 1 per 2000 live births and 1 in 10,000 to 50,000 live births , and laryngeal clefts represent 0.5% to 1.6% of these abnormalities. From 1990 to 1995, 2338 endoscopies were performed in the ENT department of Children’s Memorial Hospital in Chicago, and only seven cases of laryngeal cleft were diagnosed (0.3%) . In a review of 433 cases of laryngeal anomalies, Fearon and Ellis found two cases of cleft (0.5%). Moungthong and Hollinger reported eight cases of submucous laryngeal cleft (7%) and three cases of laryngotracheoesophageal cleft (2.6%) in 115 cases of larynx acquired after postmortem examination. Cameron and Willians reported four cases of cleft (0.2%) in a series of 2000 pediatric autopsies. In a review of 660 endoscopies performed from 1987 to 1996, Parsons and colleagues found 41 cases of cleft type I (for an incidence of 6.2%). Similarly, in a prospective study conducted from 2002 to 2005, Chien and colleagues described 20 cases of cleft type I (7.6%) among 264 patients evaluated for cough or chronic aspiration. This incidence, far greater than those previously cited, seems to be more in line with reality because of a better understanding of the disease and its diagnosis.
Males have a slightly higher incidence than females, with a sex ratio of 1.2:1 to 1.8:1 . Although Myer and colleagues series of 14 patients included 13 white infants and 1 black infant, not enough data exist to specify racial predominance. The cases seem to be mostly sporadic; however, several articles have reported families with multiple children presenting a cleft. In these cases, the possibility of an autosomal dominant transmission is mentioned. Alcohol or drug abuse during pregnancy, multiple miscarriages, hydramnios, and prematurity are frequently reported but remained nonspecific markers.
Classification
All classification systems of laryngotracheoesophageal cleft are based on the length of the cleft. Having an accurate system is important for three reasons: (1) Descriptive—it provides a consistent comparison of the literature; (2) Therapeutic—it influences the choice of reconstructive technique; (3) Prognostic—surgical success and survival depend highly on the type. Over the past 50 years, many classifications have been proposed ; however, the one proposed by Benjamin and Inglis ( Fig. 1 ) in 1989 seems to be the most suitable and the most used. It is the only one to differentiate partial and total cleft of the cricoid cartilage and cervical and tracheothoracic cleft, which represents essential elements in the choice of therapy and prognosis.
Benjamin and Inglis classification
Type 1—supraglottic interarytenoid cleft is located above the vocal cord level
Type 2—cleft extends below the vocal cords into the upper cricoid cartilage
Type 3—cleft extends through the cricoid cartilage and possibly into the cervical trachea
Type 4—cleft extends into the thoracic trachea and extends variably toward the carina
The submucosal laryngeal cleft was initially described by Tucker and Maddalozzo in 1987 as a posterior midline submucous cartilage defect with intact soft tissue, including mucosa and interarytenoid muscle. Although this is a histologic diagnosis, it can have clinical relevance because it is seen in combination with other anomalies of the cricoid cartilage, including congenital subglottic stenosis .
Clinical symptoms
The intensity of clinical symptoms of laryngeal clefts typically correlates with the type of the cleft . Type I clefts usually present with moderate symptoms, including stridor, toneless or hoarse cry, pharyngeal hypersecretions, swallowing disorders, such as cough, dyspnea, and cyanosis during feeding. The impact on the pulmonary tract is mild to none. For example, 21% of clefts in the series by Myer and colleagues had no symptoms in connection with a cleft and were diagnosed by accident. Cleft types II and III have more pronounced symptoms with aspiration and recurrent pneumonia that quickly bring a child to medical attention ( Fig. 2 ). Type IV clefts present with early respiratory distress associated with bronchial flooding and difficulty maintaining proper ventilation. They have a bad prognosis. Several cases of extended cleft with minimal clinical symptoms also were described; however, in these cases an excess of esophageal mucosa herniating into the cleft seemed to provide protection against aspiration. The herniation also caused problems with stridor and ventilatory obstruction. It is necessary to have a high degree of suspicion of laryngeal cleft in any infant with swallowing disorder, stridor, recurring pneumonia, or weak cry.
A review of the literature allows specifying three groups of symptoms displayed in Table 1 . There is a great variability of expression of these symptoms. In the series by Evans and colleagues , 59% of cleft type 1 and 100% of cleft types 2, 3, and 4 showed aspirations. In the series by Chien and colleagues , 90% of cleft type I presented aspiration during liquid ingestion.
| Swallowing —50% | Aspiration and cyanosis during feeding, 53%–80% |
| Chronic cough, 27%–35% | |
| Pharyngolaryngeal—43% | Stridor, 10%–60% |
| Toneless cry or weak voice, 16% | |
| Pharyngeal hypersecretions, 10%–23% | |
| Respiratory—37% | Recurrent pneumonia,16%–54% |
| Respiratory distress at birth, 33% |
Age at diagnosis also depends on the type of cleft, which influences the intensity of clinical symptoms and directs medical and surgical care. In the series by Andrieu-Guitrancourt and colleagues , type O clefts (submucosal) were diagnosed after age 6 months (five out of seven), type I clefts before age 6 months (six out of seven), and type II clefts before age 2 months. In the series by Rhabar and colleagues , the average age at diagnosis, regardless of the type of cleft, was 21 months; the youngest was 15 days and the oldest was 12 years. In the series by Parsons and Herr of type I clefts, a considerable delay at diagnosis (2 years and 10 months) was seen.
A broad differential diagnosis must be considered in the presence of laryngeal cleft symptoms, especially aspirations:
- •
Tracheoesophageal fistula
- •
Laryngomalacia
- •
Laryngeal mobility disorder
- •
Gastroesophageal reflux
- •
Central neurogenic swallowing disorders
Most of these possibilities are ruled out during laryngotracheal endoscopy under general anesthesia.
Associated malformations
Laryngotracheal clefts (all types combined) are associated with other congenital abnormalities in 58% to 68% of cases and are most commonly associated with gastrointestinal anomalies. It is essential to systematically look for these anomalies during the clinical evaluation ( Table 2 ).
| Malformation | Type of malformation |
|---|---|
| Digestive, 16%–67% | Atresia with esophageal fistula, 20%–37% |
| Tracheoesopahgeal fistula, 10%–20% | |
| Imperforate anus, 21% | |
| False rotation or failure in intestinal fixation, 13% | |
| Meconium ileus, 8% | |
| Microgastria | |
| Genitourinary, 14%–44% | Hypospadias, 7%–13% |
| Kidney malformation, 4% | |
| Inguinal hernia, testicular ectopy | |
| Cardiac, 16%–33% | Coarctation of the aorta, great vessels transposition |
| Patent ductus arteriosus, ventricular septal defect | |
| Craniofacial, 5%–15% | Cleft lip and palate, 5% |
| Choanal atresia | |
| Micrognathia, glossoptos | |
| Hypertelorism, dysmorphia | |
| Anomaly of the external ear | |
| Tracheal, bronchial, pulmonary, 2%–9% | Short trachea |
| Bronchial, tracheal stenosis | |
| Abnormal lung segmentation, hypoplasia |
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