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Genetic factors in isolated and syndromic laryngeal cleft
Paediatric Respiratory Reviews xxx (xxxx) xxx
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Clinical usefulness
Genetic factors in isolated and syndromic laryngeal cleft Youjin Li a,⇑, Xiaoqing Rui a, Niu Li b a b
Department of Otorhinolaryngology-Head & Neck Surgery, Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
Educational Aims The reader will be able to appreciate: The importance of clinical features in patients with isolated and syndromic laryngotracheoesophageal clefts. No consistent pattern of inheritance has been identified. The underlying genetic etiology of LCs is currently unknown.
a r t i c l e
i n f o
Keywords: Congenital anomaly Genetics Laryngotracheoesophageal cleft
a b s t r a c t A laryngotracheoesophageal cleft (LC) is a rare congenital anomaly of the upper aerodigestive tract resulting from the absence of fusion of the posterior cricoid lamina, which affects an abnormal communication between the larynx, trachea and esophagus. The genetic etiology of LC remains elusive. The involvement of genetic factors in the development of LC is suggested by reports of familial occurrence, and the increased prevalence of component features among first-degree relatives of affected individuals and murine knockout models. No consistent pattern of inheritance has been found in nonsyndromic patients, except for cases associated with described syndromes. Once the syndrome related to the laryngeal cleft is considered, an active search for the cleft must be initiated. The genetic evaluation of patients with LCs should be guided by the type and location of the malformation, specific medical history and a detailed physical examination. The application of genetic approaches, such as microarrays and exome sequencing might lead to elucidating the etiology of LCs. Ó 2019 Elsevier Ltd. All rights reserved.
INTRODUCTION A laryngeal cleft or laryngotracheoesophageal cleft (LC) is a rare congenital abnormality of the upper aerodigestive tract characterized by failure of fusion of the posterior cricoid lamina or incomplete development of the tracheoesophageal septum. LCs are very uncommon, representing approximately 0.2–1.5% of congenital laryngeal airway anomalies [1]. From an epidemiological perspective, the incidence of LC is probably underestimated. The reported incidence ranges from 0.0001% to 7.6% [2–4]. Environmental exposure, deformation from an external physical force, or an underlying genetic abnormality may contribute to normal development disruption, which may cause congenital airway disorders. The embryology of the laryngotracheoesophageal anomalies is controversial. However, four processes described as intraembryonic ⇑ Corresponding author. E-mail address: [email protected] (Y. Li).
pressure, epithelial occlusion, vascular occlusion and differential cell growth have been proposed to explain the development of tracheoesophageal anomalies by numerous authors [5]. Four types of LC have been described based on the downward extension of the cleft, which typically correlates with the severity of symptoms. The Benjamin–Inglis classification is the most widely used classification system [6]. Over 50% of patients with LCs have an associated syndromic or nonsyndromic congenital abnormality. The severity of the cleft may correspond to the incidence of concurrent anomalies in 68% cases [7]. These are mainly malformations of the digestive tract (16–67%), including esophageal atresia (20–37%)and tracheoesophageal fistula (10–20%); and renal and genitourinary anomalies (14–44%). However, type I clefts may be observed in isolation. Other abnormalities include cardiac (16–33%), craniofacial (5–15%), and pulmonary (2–9%) [1,5,8,9]. Prenatal diagnosis of LC has never been reported, although an ultrasound assessment of abnormal levels of amniotic fluid may suggest an underlying malformation.
https://doi.org/10.1016/j.prrv.2019.09.004 1526-0542/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Y. Li, X. Rui and N. Li, Genetic factors in isolated and syndromic laryngeal cleft, Paediatric Respiratory Reviews, https://doi.org/ 10.1016/j.prrv.2019.09.004
2
Y. Li et al. / Paediatric Respiratory Reviews xxx (xxxx) xxx
The majority of LCs are sporadic although some familial cases with suspected autosomal dominant transmission have been reported [10]. In 1949, Dr. Crooks [11] reported the case of an infant with inspiratory stridor and feeding difficulty whose autopsy showed a cleft between the arytenoids. Three of his sisters in this family of five children had had a similar clinical presentation and died at approximately 3 or 4 months old from ulcerative tracheitis or unspecified lung infection. A laryngeal cleft was confirmed in one of the sisters. In 1961 two siblings with LCs were reported by Zachary and Emery [12]. In a familial occurrence of congenital LC, the authors suggested that the anomaly is inherited in an autosomal dominant manner given that the two sibling had 6 double first cousins with congenital laryngeal anomalies. Three had a proven congenital posterior LC, one subglottic stenosis coexisting with a deformed cricoid cartilage, and the other two likely had posterior LC [13]. In 1984, the clinical presentation of a cleft larynx was described in a mother and her first-born child [14]. The first-born child was found at autopsy to have a complete laryngotracheoesophageal cleft. The mother had a history of persistent hoarseness and recurrent respiratory infections. Her laryngeal exam showed absence of the interarytenoid muscles and intact cricoid cartilage. Physicians concluded that she likely had a minor laryngotracheoesophageal cleft. It is important to determine the mode of inheritance in familial cases with apparently unaffected parents who have been examined adequately. However, identifying the LC with a laryngoscope under general anesthesia in a symptom-free person may not be practical. NONSYNDROMIC LC A slightly higher incidence has been reported in boys than in girls with a ratio of 1.2–1.8. No specific geographic distribution and racial predominance have been found. The causes of the embryological developmental anomalies leading to LC are not known but are thought to be multifactorial. During fetal development, a wall of tissue known as the tracheoesophageal septum fails to form causing abnormalities such as LC. However, its exact mechanism is unknown. It is estimated that the defect occurs at approximately day 35 of gestation. Alcohol and/or drug abuse during pregnancy, multiple miscarriages, hydramnios, and prematurity are frequently reported, but none have been identified as a specific risk factor [2,5] Most of these malformations are probably linked to not-yet identified syndromes. However, a purely isolated LC is also possible. An animal model of laryngotracheal malformations has been described in rat embryos exposed to doxorubicin (AdriamycinÒ) [15], which is similar to those described in the VACTERL association (esophageal atresia and tracheo-esophageal fistula) [16]. A lacZ knockout mouse model for classifying LC in which the loss of ephrin-B2 signaling has disrupted normal midline fusion of the posterior laryngotracheal wall was reported [17]. No consistent pattern of inheritance appears to be demonstrated by nonsyndromic patients, except for cases associated with described syndromes.
associated with significant LCs are discussed below. In addition, other low incidences associated with LC in specific syndrome are also briefly described. ANEUPLOIDY SYNDROMES Aneuploidy refers to the presence of an abnormal number of chromosomes and includes important syndromes, such as trisomy 18 and 21, both of which have been associated with significant airway anomalies including LC. The 22q11 monosomy including chromosome 22q11.2 deletion syndrome (OMIM #192430) and DiGeorge syndrome (OMIM #188400) may include numerous malformations, especially hypoplastic thymus and parathyroid glands, cardiopathy, velopharyngeal insufficiency with or without cleft palate, and sometimes LC. The clinical course mainly depends on the malformations involved. Its overall incidence is estimated at 1/5000 births but is much lower when associated with LC. In addition, LC is predicted to occur with increased frequency in aneuploidy syndromes. OPITZ G/BBB SYNDROME (GBBB) (GBBB II: OMIM#145410; GBBB I: OMIM# 300000) Forty-four percent of laryngotracheal clefts were described in 5 subjects of 3 families, and 23 published cases of G syndrome were reviewed [18]. G syndrome is a multiple congenital anomaly syndrome of hypertelorism, hypospadias, stridor, and swallowing difficulties. Pedigrees of families with G syndrome have suggested either X-linked or autosomal dominant transmission. Males in general, have been reported to be more severely affected than females. One family with G syndrome had a lethal case with a laryngotracheoesophageal cleft, while the other showed only a relatively mild expression of the syndrome in both sexes [19]. Howell and Smith reported 2 additional cases of G syndrome with LCs in 1989 [20]. Opitz reported the presence of LC in the BBB syndrome and a young child with the G syndrome phenotype with a large family who clearly had BBB syndrome. However, laryngotracheoesophageal clefts in general are not as rare as the few published causes suggest and the same is certainly true for the Opitz G syndrome as several teams have gradually diagnosed two or three affected families [21– 23]. Although phenotypic overlap between BBB and G syndromes has long been recognized, many still consider them to be different expressions of the same mutant gene [24]. Verloes et al. reported a family in which the proband had G syndrome, including laryngeal cleft, and another relative had facial anomalies typical of BBB syndrome [25]. Autosomal dominant inheritance and X-linked inheritance both served as the heredity pattern for GBBB II. Heterozygous mutation in the SPECC1L gene (614140) on chromosome 22q11.23 is responsible for GBBB II. The phenotype can also result from heterozygous deletion at chromosome 22q11.2. The X-linked form of GBBB II is caused by the mutation in the MID1 gene (300552) on Xp22. PALLISTER–HALL SYNDROME (PHS) (OMIM#146510)
SYNDROMIC LARYNGEAL CLEFT A recurrent pattern of malformation identified as a syndrome likely derives from a single underlying etiology. However, a pattern of anomalies that occur together more frequently than expected by chance are identified as an association because of no unifying etiology can be established. The syndromes most frequently associated with an LC are aneuploidy syndrome, Opitz/BBB syndrome, Pallister–Hall syndrome, CHARGE syndrome and VACTERL/VATER association, which exhibit significant airway anomalies such as those in an LC. The genetics of identifiable syndromes commonly
PHS is caused by a heterozygous mutation in the GLI3 gene (165240) on chromosome 7p14 involved in frameshift mutations and various abnormal fragments of mitochondrial DNA [26,27]. PHS is inherited in autosomal dominant pattern with variable expression. Most cases are sporadic and the result of a de novo mutation. PHS is characterized by laryngeal anomalies, congenital hypothalamic hamartoblastoma, hypopituitarism, postaxial polydactyly and syndactyly. It may also be associated with gastrointestinal, cardiac, pulmonary and renal malformations. Posterior laryngeal clefts are an uncommon manifestation of Pallister–Hall
Please cite this article as: Y. Li, X. Rui and N. Li, Genetic factors in isolated and syndromic laryngeal cleft, Paediatric Respiratory Reviews, https://doi.org/ 10.1016/j.prrv.2019.09.004
Y. Li et al. / Paediatric Respiratory Reviews xxx (xxxx) xxx
syndrome (PHS), identified only in severely affected patients [28]. In the original description of PHS, the first three patients were found to have LCs at the time of autopsy [29]. CHARGE SYNDROME (OMIM#214800) The CHARGE syndrome is due to mutations in the chromodomain helicase DNA binding protein 7 (CHD7) gene (608892). CHARGE syndrome is a multiple congenital anomalies which are frequently present by colobama, heart anomalies, atresia of the choanae, retardation of growth and development, genital anomalies and ear anomalies (including deafness and vestibular disorders, can be life-threatening in the neonatal period. Swallowing difficulties that may lead to aspiration, gastroesophageal reflux disease, and postoperative airway events are important contributors to post-neonatal death in CHARGE syndrome [30]. Stack [31] reported that one infant had a first-degree LC with an incompetent larynx in all 50 retrospective patients with CHARGE syndrome. An LC may also be associated with many other cranial malformations (cleft lip and palate, laryngomalacia, laryngeal webs) [1]. Personal experience with airway problems in patients with CHARGE syndrome led us to believe that the incidence and variety of airway abnormalities were higher than previously reported. VACTERL/VATER ASSOCIATION (OMIM#192350) VACTERL association is typically described by an expanded definition of the association that includes vertebral anomalies, anal atresia, cardiac malformation, tracheo-esophageal fistula (TEF) (including LC) and/or esophageal atresia, renal anomalies and/or limb abnormalities. Thirty-two percent of patients with TEF are often included as part of the ‘‘T” in VACTERL. Approximately 12% of patients with LC have a concurrent TEF [32]. The symptoms of chronic cough, aspirations, recurrent pneumonias and respiratory distress will be most common in patients suspected to be LC. Though the exact cause is unknown, VACTERL is thought to be multifactorial in etiology, one of which is interacting with a genetically susceptible genome. The mutant Gli genes (165220) which encode transcription factors mediating Sonic hedgehog signal transduction could lead to a spectrum of developmental anomalies in mice similar to those of VACTERL [33]. AURICULOCONDYLAR SYNDROME 3 (ARCND3) (OMIM#615706) Patients with auriculocondylar syndrome (ARCND) present defects in ear and mandible development. Affected structures arise from cranial neural crest cells, a population of embryonic cells that reside in the pharyngeal arches and give rise to most of the bone, cartilage and connective tissue of the face [34]. Gordon et al. studied a brother and sister, born to healthy first-cousin parents, who had ARCND. Only the brother displayed typical clinical features in comorbidity with bifid uvula and LC [35]. ARCND3 is a rare autosomal recessive disorder caused by a homozygous mutation in the EDN1 gene (131240) on chromosome 6p24.1. CHITAYAT–HALL SYNDROME (OMIM#208080) Chitayat–Hall syndrome is a rare, severe disorder with heterogeneous clinical traits. Respiratory system anomalies, neurological anomalies, intellectual disability, and distal joint contractures are the most important characteristics. Rao et al. reported a 3-yearold girl with congenital stridor and a laryngeal cleft, vocal cord palsy on the left, and partial vocal cord palsy on the right. Her presentation was attributed to consanguinity in their family and supported an autosomal recessive inheritance of the disorder [36].
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WORK UP Once a syndrome related to a laryngeal cleft is considered, an active search for the cleft must be initiated. Given the associated malformations and potential for syndromic association, some standard workup should be performed in all cases. This includes genetic evaluation with karyotype, echocardiogram and renal ultrasounds, spine radiographs, hearing screen and chest radiograph [1,9]. It is important to consider that most associated malformations with LCs are linked to not-yet identified syndromes. Hence, the genetic evaluation of a patient with LCs should be guided by the type and location of the malformation, specific medical history and a detailed physical examination. The consideration of seemingly unrelated birth defects in other family members may provide a clue to the proband’s diagnosis. Systematic evaluation of the associated defects that may be nonspecifically associated with LCs should be suggested. Other anomalies are commonly present in association with LC. These include subglottic stenosis, esophageal anomalies, laryngomalacia, cleft lip and cleft palate, congenital heart defect, and congenital pulmonary malformation. The association of subglottic stenosis and LC suggests that the anomaly is most likely a result of dysplasia of the cricoid cartilage. Some authors have suggested that LCs result from failure of posterior fusion of the two wings of the cricoid cartilage, which arise in the sixth branchial arch. Further disturbance in the development of the cricoid cartilage and associated tissues probably results in the subglottic stenosis [13]. the most commonly associated defect with LC is tracheoesophageal fistula (TEF). Nineteen percent of TEF below the cleft has been described [14]. Lim et al. [37] noted that the incidence of LC in patients with TEF is low, but physicians caring for TEF patients should be aware of the possibility of LC, which is specific to patients with stridor, esophageal reflux, and esophageal atresia. Many of these type 1 LCs are not diagnosed because laryngomalacia is assumed and endoscopists fail to precisely measure the depth of the interarytenoid cleft. The rate of association of cleft larynx with congenital heart defects is greater than that in noncleft larynx infants. However, no consistent type of congenital heart anomaly has been associated with LC. In addition, small, misshapen or incompletely fissured lung-associated defects were reported in patients with LC. Airway development and a functional respiratory system in young children are significantly impacted by genetic disorders. Despite this, the underlying genetic etiology of LCs is currently unknown. The development of diverse structures in the airway must be carefully coordinated and guided by thousands of genes. Airway malformations can be part of a constellation of findings that result from a mutation in a single gene. New genetic approaches, such as microarrays and exome sequencing, will likely contribute to elucidating the etiology of LCs. However, all syndromes associated with LCs are not yet well described.
DIRECTIONS FOR FUTURE RESEARCH Research efforts should focus on the evidence for the genetic effects on LCs to highlight the requirement of advanced airway management. Strategies for the application of genetic approaches are needed to elucidate the etiology of LCs.
References [1] Leboulanger N, Garabedian EN. Laryngo-tracheo-oesophageal clefts. Orphanet J Rare Dis 2011;6:81. [2] Moungthong G, Holinger LD. Laryngotracheoesophageal clefts. Ann Otol Rhinol Laryngol 1997;106:1002–11.
Please cite this article as: Y. Li, X. Rui and N. Li, Genetic factors in isolated and syndromic laryngeal cleft, Paediatric Respiratory Reviews, https://doi.org/ 10.1016/j.prrv.2019.09.004
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[3] Chien W, Ashland J, Haver K, et al. Type 1 laryngeal cleft: establishing a functional diagnostic and management algorithm. Int J Pediatr Otorhinolaryngol 2006;70:2073–9. [4] Thiel G, Clement WA, Kubba H. The management of laryngeal clefts. Int J Pediatr Otorhinolaryngol 2011;75:1525–8. [5] Pezzettigotta SM, Leboulanger N, Roger G, et al. Laryngeal cleft. Otolaryngol Clin North Am 2008;41(913–933):ix. [6] Benjamin B, Inglis A. Minor congenital laryngeal clefts: diagnosis and classification. Ann Otol Rhinol Laryngol 1989;98:417–20. [7] Rahbar R, Rouillon I, Roger G, et al. The presentation and management of laryngeal cleft: a 10-year experience. Arch Otolaryngol Head Neck Surg 2006;132:1335–41. [8] Leishman C, Monnier P, Jaquet Y. Endoscopic repair of laryngotracheoesophageal clefts: experience in 17 cases. Int J Pediatr Otorhinolaryngol 2014;78:227–31. [9] Johnston DR, Watters K, Ferrari LR, Rahbar R. Laryngeal cleft: evaluation and management. Int J Pediatr Otorhinolaryngol 2014;78:905–11. [10] Phelan PD, Williams H, Danks D. Familial occurrence of congenital laryngeal clefts. Arch Dis Child 1995;72:98. [11] Crooks J. Non-inflammatory laryngeal stridor in infants. Arch Dis Child 1954;29:12–7. [12] Zachary RB, Emery JL. Failure of separation of larynx and trachea from the esophagus: persistent esophagotrachea. Surgery 1961;49:525–9. [13] Phelan PD, Stocks JG, Williams HE, Danks DM. Familial occurrence of congenital laryngeal clefts. Arch Dis Child 1973;48:275–8. [14] Armitage EN. Laryngotracheo-oesophageal cleft. A report of three cases. Anaesthesia 1984;39:706–13. [15] Qi BQ MJ, Farmer P, Hasthorpe S. Cardiovascular malformations in rat fetuses with oesophageal atresia and tracheo-oesophageal fistula induced by adriamycin. Pediatr Surg Int 1997;12:556–64. [16] Merei J, Hasthorpe S, Farmer P, Hutson JM. Visceral anomalies in prenatally adriamycin-exposed rat fetuses: a model for the VATER association. Pediatr Surg Int 1999;15:11–6. [17] Neilan RE, Shao D, Dravis C, et al. Characterization of the larynx in ephrin-B2 knockout mice: a novel animal model for laryngeal clefts. Arch Otolaryngol Head Neck Surg 2012;138:969–72. [18] Wilson GN, Oliver WJ. Further delineation of the G syndrome: a manageable genetic cause of infantile dysphagia. J Med Genet 1988;25:157–63. [19] Greenberg CR, Schraufnagel D. The G syndrome: a case report. Am J Med Genet 1979;3:59–64.
[20] Howell L, Smith JD. G syndrome and its otolaryngologic manifestations. Ann Otol Rhinol Laryngol 1989;98:185–90. [21] Little JRJMO. The G syndrome. Am. J. Dis. Child. 1971;121:505–7. [22] Frias JL, Rosenbloom AL. Two new familial cases of the G syndrome. Birth Defects Original Article Series 1975;11:54–7. [23] Funderburk SJ, Stewart R. The G and BBB syndromes: case presentations, genetics, and nosology. Am J Med Genet. 1978;2:131–44. [24] Allanson JE. G syndrome: an unusual family. Am J Med Genet 1988;31:637–42. [25] Verloes A, Le Merrer M, Briard ML. BBBG syndrome or Opitz syndrome: new family. Am J Med Genet 1989;34:313–6. [26] Turner C, Killoran C, Thomas NS, et al. Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer. Hum Genet 2003;112:303–9. [27] Woischnik M, Moraes CT. Pattern of organization of human mitochondrial pseudogenes in the nuclear genome. Genome Res 2002;12:885–93. [28] Frank Ondrey AG, Van Waes Carter, Rudy Susan. Asymptomatic laryngeal malformations are common in patients with Pallister-Hall syndrome. Am J Med Genet 2000;94:64–7. [29] Hall JG, Pallister PD, Clarren SK, et al. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly–a new syndrome? Part I: clinical, causal, and pathogenetic considerations. Am J Med Genet 1980;7:47–74. [30] Bergman JE, Blake KD, Bakker MK, et al. Death in CHARGE syndrome after the neonatal period. Clin Genet 2010;77:232–40. [31] Stack CGWR. Incidence and management of airway problems in the CHARGE Association. Anaesthesia 1991;46:582–5. [32] Fraga JC, Adil EA, Kacprowicz A, et al. The association between laryngeal cleft and tracheoesophageal fistula: myth or reality? Laryngoscope 2015;125:469–74. [33] Killoran CE, Abbott M, McKusick VA, Biesecker LG. Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis. Clin Genet 2000;58:28–30. [34] Clouthier DE, Passos-Bueno MR, Tavares AL, et al. Understanding the basis of auriculocondylar syndrome: Insights from human, mouse and zebrafish genetic studies. Am J Med Genet Part C, Semin Med Genet 2013;163C:306–17. [35] Gordon CT, Vuillot A, Marlin S, et al. Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome. J Med Genet 2013;50:174–86. [36] Rao V, El-Alem T, Aminu K, et al. Chitayat-Hall syndrome: extending the clinical phenotype. Clin Dysmorphol 2013;22:156–60. [37] Lim TA, Spanier SS, Kohut RI. Laryngeal clefts: a histopathologic study and review. Ann Otol Rhinol Laryngol 1979;88:837–45.
Please cite this article as: Y. Li, X. Rui and N. Li, Genetic factors in isolated and syndromic laryngeal cleft, Paediatric Respiratory Reviews, https://doi.org/ 10.1016/j.prrv.2019.09.004
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Clinical usefulness
Genetic factors in isolated and syndromic laryngeal cleft Youjin Li a,⇑, Xiaoqing Rui a, Niu Li b a b
Department of Otorhinolaryngology-Head & Neck Surgery, Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
Educational Aims The reader will be able to appreciate: The importance of clinical features in patients with isolated and syndromic laryngotracheoesophageal clefts. No consistent pattern of inheritance has been identified. The underlying genetic etiology of LCs is currently unknown.
a r t i c l e
i n f o
Keywords: Congenital anomaly Genetics Laryngotracheoesophageal cleft
a b s t r a c t A laryngotracheoesophageal cleft (LC) is a rare congenital anomaly of the upper aerodigestive tract resulting from the absence of fusion of the posterior cricoid lamina, which affects an abnormal communication between the larynx, trachea and esophagus. The genetic etiology of LC remains elusive. The involvement of genetic factors in the development of LC is suggested by reports of familial occurrence, and the increased prevalence of component features among first-degree relatives of affected individuals and murine knockout models. No consistent pattern of inheritance has been found in nonsyndromic patients, except for cases associated with described syndromes. Once the syndrome related to the laryngeal cleft is considered, an active search for the cleft must be initiated. The genetic evaluation of patients with LCs should be guided by the type and location of the malformation, specific medical history and a detailed physical examination. The application of genetic approaches, such as microarrays and exome sequencing might lead to elucidating the etiology of LCs. Ó 2019 Elsevier Ltd. All rights reserved.
INTRODUCTION A laryngeal cleft or laryngotracheoesophageal cleft (LC) is a rare congenital abnormality of the upper aerodigestive tract characterized by failure of fusion of the posterior cricoid lamina or incomplete development of the tracheoesophageal septum. LCs are very uncommon, representing approximately 0.2–1.5% of congenital laryngeal airway anomalies [1]. From an epidemiological perspective, the incidence of LC is probably underestimated. The reported incidence ranges from 0.0001% to 7.6% [2–4]. Environmental exposure, deformation from an external physical force, or an underlying genetic abnormality may contribute to normal development disruption, which may cause congenital airway disorders. The embryology of the laryngotracheoesophageal anomalies is controversial. However, four processes described as intraembryonic ⇑ Corresponding author. E-mail address: [email protected] (Y. Li).
pressure, epithelial occlusion, vascular occlusion and differential cell growth have been proposed to explain the development of tracheoesophageal anomalies by numerous authors [5]. Four types of LC have been described based on the downward extension of the cleft, which typically correlates with the severity of symptoms. The Benjamin–Inglis classification is the most widely used classification system [6]. Over 50% of patients with LCs have an associated syndromic or nonsyndromic congenital abnormality. The severity of the cleft may correspond to the incidence of concurrent anomalies in 68% cases [7]. These are mainly malformations of the digestive tract (16–67%), including esophageal atresia (20–37%)and tracheoesophageal fistula (10–20%); and renal and genitourinary anomalies (14–44%). However, type I clefts may be observed in isolation. Other abnormalities include cardiac (16–33%), craniofacial (5–15%), and pulmonary (2–9%) [1,5,8,9]. Prenatal diagnosis of LC has never been reported, although an ultrasound assessment of abnormal levels of amniotic fluid may suggest an underlying malformation.
https://doi.org/10.1016/j.prrv.2019.09.004 1526-0542/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Y. Li, X. Rui and N. Li, Genetic factors in isolated and syndromic laryngeal cleft, Paediatric Respiratory Reviews, https://doi.org/ 10.1016/j.prrv.2019.09.004
2
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The majority of LCs are sporadic although some familial cases with suspected autosomal dominant transmission have been reported [10]. In 1949, Dr. Crooks [11] reported the case of an infant with inspiratory stridor and feeding difficulty whose autopsy showed a cleft between the arytenoids. Three of his sisters in this family of five children had had a similar clinical presentation and died at approximately 3 or 4 months old from ulcerative tracheitis or unspecified lung infection. A laryngeal cleft was confirmed in one of the sisters. In 1961 two siblings with LCs were reported by Zachary and Emery [12]. In a familial occurrence of congenital LC, the authors suggested that the anomaly is inherited in an autosomal dominant manner given that the two sibling had 6 double first cousins with congenital laryngeal anomalies. Three had a proven congenital posterior LC, one subglottic stenosis coexisting with a deformed cricoid cartilage, and the other two likely had posterior LC [13]. In 1984, the clinical presentation of a cleft larynx was described in a mother and her first-born child [14]. The first-born child was found at autopsy to have a complete laryngotracheoesophageal cleft. The mother had a history of persistent hoarseness and recurrent respiratory infections. Her laryngeal exam showed absence of the interarytenoid muscles and intact cricoid cartilage. Physicians concluded that she likely had a minor laryngotracheoesophageal cleft. It is important to determine the mode of inheritance in familial cases with apparently unaffected parents who have been examined adequately. However, identifying the LC with a laryngoscope under general anesthesia in a symptom-free person may not be practical. NONSYNDROMIC LC A slightly higher incidence has been reported in boys than in girls with a ratio of 1.2–1.8. No specific geographic distribution and racial predominance have been found. The causes of the embryological developmental anomalies leading to LC are not known but are thought to be multifactorial. During fetal development, a wall of tissue known as the tracheoesophageal septum fails to form causing abnormalities such as LC. However, its exact mechanism is unknown. It is estimated that the defect occurs at approximately day 35 of gestation. Alcohol and/or drug abuse during pregnancy, multiple miscarriages, hydramnios, and prematurity are frequently reported, but none have been identified as a specific risk factor [2,5] Most of these malformations are probably linked to not-yet identified syndromes. However, a purely isolated LC is also possible. An animal model of laryngotracheal malformations has been described in rat embryos exposed to doxorubicin (AdriamycinÒ) [15], which is similar to those described in the VACTERL association (esophageal atresia and tracheo-esophageal fistula) [16]. A lacZ knockout mouse model for classifying LC in which the loss of ephrin-B2 signaling has disrupted normal midline fusion of the posterior laryngotracheal wall was reported [17]. No consistent pattern of inheritance appears to be demonstrated by nonsyndromic patients, except for cases associated with described syndromes.
associated with significant LCs are discussed below. In addition, other low incidences associated with LC in specific syndrome are also briefly described. ANEUPLOIDY SYNDROMES Aneuploidy refers to the presence of an abnormal number of chromosomes and includes important syndromes, such as trisomy 18 and 21, both of which have been associated with significant airway anomalies including LC. The 22q11 monosomy including chromosome 22q11.2 deletion syndrome (OMIM #192430) and DiGeorge syndrome (OMIM #188400) may include numerous malformations, especially hypoplastic thymus and parathyroid glands, cardiopathy, velopharyngeal insufficiency with or without cleft palate, and sometimes LC. The clinical course mainly depends on the malformations involved. Its overall incidence is estimated at 1/5000 births but is much lower when associated with LC. In addition, LC is predicted to occur with increased frequency in aneuploidy syndromes. OPITZ G/BBB SYNDROME (GBBB) (GBBB II: OMIM#145410; GBBB I: OMIM# 300000) Forty-four percent of laryngotracheal clefts were described in 5 subjects of 3 families, and 23 published cases of G syndrome were reviewed [18]. G syndrome is a multiple congenital anomaly syndrome of hypertelorism, hypospadias, stridor, and swallowing difficulties. Pedigrees of families with G syndrome have suggested either X-linked or autosomal dominant transmission. Males in general, have been reported to be more severely affected than females. One family with G syndrome had a lethal case with a laryngotracheoesophageal cleft, while the other showed only a relatively mild expression of the syndrome in both sexes [19]. Howell and Smith reported 2 additional cases of G syndrome with LCs in 1989 [20]. Opitz reported the presence of LC in the BBB syndrome and a young child with the G syndrome phenotype with a large family who clearly had BBB syndrome. However, laryngotracheoesophageal clefts in general are not as rare as the few published causes suggest and the same is certainly true for the Opitz G syndrome as several teams have gradually diagnosed two or three affected families [21– 23]. Although phenotypic overlap between BBB and G syndromes has long been recognized, many still consider them to be different expressions of the same mutant gene [24]. Verloes et al. reported a family in which the proband had G syndrome, including laryngeal cleft, and another relative had facial anomalies typical of BBB syndrome [25]. Autosomal dominant inheritance and X-linked inheritance both served as the heredity pattern for GBBB II. Heterozygous mutation in the SPECC1L gene (614140) on chromosome 22q11.23 is responsible for GBBB II. The phenotype can also result from heterozygous deletion at chromosome 22q11.2. The X-linked form of GBBB II is caused by the mutation in the MID1 gene (300552) on Xp22. PALLISTER–HALL SYNDROME (PHS) (OMIM#146510)
SYNDROMIC LARYNGEAL CLEFT A recurrent pattern of malformation identified as a syndrome likely derives from a single underlying etiology. However, a pattern of anomalies that occur together more frequently than expected by chance are identified as an association because of no unifying etiology can be established. The syndromes most frequently associated with an LC are aneuploidy syndrome, Opitz/BBB syndrome, Pallister–Hall syndrome, CHARGE syndrome and VACTERL/VATER association, which exhibit significant airway anomalies such as those in an LC. The genetics of identifiable syndromes commonly
PHS is caused by a heterozygous mutation in the GLI3 gene (165240) on chromosome 7p14 involved in frameshift mutations and various abnormal fragments of mitochondrial DNA [26,27]. PHS is inherited in autosomal dominant pattern with variable expression. Most cases are sporadic and the result of a de novo mutation. PHS is characterized by laryngeal anomalies, congenital hypothalamic hamartoblastoma, hypopituitarism, postaxial polydactyly and syndactyly. It may also be associated with gastrointestinal, cardiac, pulmonary and renal malformations. Posterior laryngeal clefts are an uncommon manifestation of Pallister–Hall
Please cite this article as: Y. Li, X. Rui and N. Li, Genetic factors in isolated and syndromic laryngeal cleft, Paediatric Respiratory Reviews, https://doi.org/ 10.1016/j.prrv.2019.09.004
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syndrome (PHS), identified only in severely affected patients [28]. In the original description of PHS, the first three patients were found to have LCs at the time of autopsy [29]. CHARGE SYNDROME (OMIM#214800) The CHARGE syndrome is due to mutations in the chromodomain helicase DNA binding protein 7 (CHD7) gene (608892). CHARGE syndrome is a multiple congenital anomalies which are frequently present by colobama, heart anomalies, atresia of the choanae, retardation of growth and development, genital anomalies and ear anomalies (including deafness and vestibular disorders, can be life-threatening in the neonatal period. Swallowing difficulties that may lead to aspiration, gastroesophageal reflux disease, and postoperative airway events are important contributors to post-neonatal death in CHARGE syndrome [30]. Stack [31] reported that one infant had a first-degree LC with an incompetent larynx in all 50 retrospective patients with CHARGE syndrome. An LC may also be associated with many other cranial malformations (cleft lip and palate, laryngomalacia, laryngeal webs) [1]. Personal experience with airway problems in patients with CHARGE syndrome led us to believe that the incidence and variety of airway abnormalities were higher than previously reported. VACTERL/VATER ASSOCIATION (OMIM#192350) VACTERL association is typically described by an expanded definition of the association that includes vertebral anomalies, anal atresia, cardiac malformation, tracheo-esophageal fistula (TEF) (including LC) and/or esophageal atresia, renal anomalies and/or limb abnormalities. Thirty-two percent of patients with TEF are often included as part of the ‘‘T” in VACTERL. Approximately 12% of patients with LC have a concurrent TEF [32]. The symptoms of chronic cough, aspirations, recurrent pneumonias and respiratory distress will be most common in patients suspected to be LC. Though the exact cause is unknown, VACTERL is thought to be multifactorial in etiology, one of which is interacting with a genetically susceptible genome. The mutant Gli genes (165220) which encode transcription factors mediating Sonic hedgehog signal transduction could lead to a spectrum of developmental anomalies in mice similar to those of VACTERL [33]. AURICULOCONDYLAR SYNDROME 3 (ARCND3) (OMIM#615706) Patients with auriculocondylar syndrome (ARCND) present defects in ear and mandible development. Affected structures arise from cranial neural crest cells, a population of embryonic cells that reside in the pharyngeal arches and give rise to most of the bone, cartilage and connective tissue of the face [34]. Gordon et al. studied a brother and sister, born to healthy first-cousin parents, who had ARCND. Only the brother displayed typical clinical features in comorbidity with bifid uvula and LC [35]. ARCND3 is a rare autosomal recessive disorder caused by a homozygous mutation in the EDN1 gene (131240) on chromosome 6p24.1. CHITAYAT–HALL SYNDROME (OMIM#208080) Chitayat–Hall syndrome is a rare, severe disorder with heterogeneous clinical traits. Respiratory system anomalies, neurological anomalies, intellectual disability, and distal joint contractures are the most important characteristics. Rao et al. reported a 3-yearold girl with congenital stridor and a laryngeal cleft, vocal cord palsy on the left, and partial vocal cord palsy on the right. Her presentation was attributed to consanguinity in their family and supported an autosomal recessive inheritance of the disorder [36].
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WORK UP Once a syndrome related to a laryngeal cleft is considered, an active search for the cleft must be initiated. Given the associated malformations and potential for syndromic association, some standard workup should be performed in all cases. This includes genetic evaluation with karyotype, echocardiogram and renal ultrasounds, spine radiographs, hearing screen and chest radiograph [1,9]. It is important to consider that most associated malformations with LCs are linked to not-yet identified syndromes. Hence, the genetic evaluation of a patient with LCs should be guided by the type and location of the malformation, specific medical history and a detailed physical examination. The consideration of seemingly unrelated birth defects in other family members may provide a clue to the proband’s diagnosis. Systematic evaluation of the associated defects that may be nonspecifically associated with LCs should be suggested. Other anomalies are commonly present in association with LC. These include subglottic stenosis, esophageal anomalies, laryngomalacia, cleft lip and cleft palate, congenital heart defect, and congenital pulmonary malformation. The association of subglottic stenosis and LC suggests that the anomaly is most likely a result of dysplasia of the cricoid cartilage. Some authors have suggested that LCs result from failure of posterior fusion of the two wings of the cricoid cartilage, which arise in the sixth branchial arch. Further disturbance in the development of the cricoid cartilage and associated tissues probably results in the subglottic stenosis [13]. the most commonly associated defect with LC is tracheoesophageal fistula (TEF). Nineteen percent of TEF below the cleft has been described [14]. Lim et al. [37] noted that the incidence of LC in patients with TEF is low, but physicians caring for TEF patients should be aware of the possibility of LC, which is specific to patients with stridor, esophageal reflux, and esophageal atresia. Many of these type 1 LCs are not diagnosed because laryngomalacia is assumed and endoscopists fail to precisely measure the depth of the interarytenoid cleft. The rate of association of cleft larynx with congenital heart defects is greater than that in noncleft larynx infants. However, no consistent type of congenital heart anomaly has been associated with LC. In addition, small, misshapen or incompletely fissured lung-associated defects were reported in patients with LC. Airway development and a functional respiratory system in young children are significantly impacted by genetic disorders. Despite this, the underlying genetic etiology of LCs is currently unknown. The development of diverse structures in the airway must be carefully coordinated and guided by thousands of genes. Airway malformations can be part of a constellation of findings that result from a mutation in a single gene. New genetic approaches, such as microarrays and exome sequencing, will likely contribute to elucidating the etiology of LCs. However, all syndromes associated with LCs are not yet well described.
DIRECTIONS FOR FUTURE RESEARCH Research efforts should focus on the evidence for the genetic effects on LCs to highlight the requirement of advanced airway management. Strategies for the application of genetic approaches are needed to elucidate the etiology of LCs.
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Please cite this article as: Y. Li, X. Rui and N. Li, Genetic factors in isolated and syndromic laryngeal cleft, Paediatric Respiratory Reviews, https://doi.org/ 10.1016/j.prrv.2019.09.004