- Email: [email protected]
Chromosomal and cardiovascular anomalies associated with congenital laryngeal web
International Journal of Pediatric Otorhinolaryngology 66 (2002) 23 /27 www.elsevier.com/locate/ijporl
Chromosomal and cardiovascular anomalies associated with congenital laryngeal web Doff B. McElhinney a,b,1, Ian Jacobs c,d, Donna M. McDonald-McGinn e, Elaine H. Zackai b,e, Elizabeth Goldmuntz a,b,* a
Division of Pediatric Cardiology, The Children’s Hospital of Philadelphia, Abramson Research Center 702A, 3516 Civic Center Blvd., Philadelphia, PA, 19104-4318, USA b Department of Pediatrics, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA c Division of Otorhinolaryngology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA d Department of Otolaryngology, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA e Division of Human Genetics and Molecular Biology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Received 5 February 2002; received in revised form 4 June 2002; accepted 5 June 2002
Abstract Objective: The purpose of this study was to estimate the frequency of chromosomal and cardiovascular anomalies associated with a congenital laryngeal web. Methods: We reviewed our experience with 25 patients who underwent intervention for a symptomatic congenital laryngeal web between 1988 and 2000, in order to investigate the frequency of associated chromosomal and cardiovascular anomalies. Twelve patients underwent cytogenetic evaluation, including seven that were tested for a chromosome 22q11 deletion by fluorescence in situ hybridization. Results: Chromosomal abnormalities were detected in seven of the 12 patients in whom cytogenetic evaluation was performed (28% of the entire cohort), including a chromosome 22q11 deletion in six and trisomy 21 in one. Associated cardiovascular anomalies were diagnosed in nine of the 25 patients, most commonly aortic arch anomalies. Of the patients with cardiovascular anomalies, 55% also had chromosomal alterations, and 71% of patients with chromosomal alterations also had a cardiovascular defect, of which four had the triad of a congenital laryngeal web, a chromosome 22q11 deletion, and congenital cardiovascular anomalies. Conclusions: Chromosomal and cardiovascular anomalies are common in patients with a congenital laryngeal web. A chromosome 22q11 deletion was particularly common, as were the cardiovascular anomalies associated with the chromosome 22q11 deletion syndrome. Accordingly, patients with a congenital laryngeal web should undergo genetic screening, including evaluation for a chromosome 22q11 deletion, and a thorough cardiovascular evaluation, including imaging of the aortic arch. Particular attention should be paid to identifying patients with the triad of a congenital laryngeal web, a chromosome 22q11 deletion, and cardiovascular anomalies, particularly a vascular ring. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: DiGeorge syndrome; Velocardiofacial syndrome; Vascular ring
* Corresponding author. Tel.: /1-215-590-5820; fax: /1-215-590-5454 E-mail address: [email protected] (E. Goldmuntz). 1 Present address: Department of Cardiology, Children’s Hospital, Boston, MA, USA. 0165-5876/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 5 8 7 6 ( 0 2 ) 0 0 1 8 4 - 2
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D.B. McElhinney et al. / Int. J. Pediatr. Otorhinolaryngol. 66 (2002) 23 /27
1. Introduction Congenital laryngeal webs are uncommon airway anomalies in which membranous tissue present at birth causes partial obstruction of the supraglottic, glottic, or subglottic region of the larynx, often causing significant airway obstruction early in life. An association between congenital glottic or subglottic webs and a chromosome 22q11 deletion (DiGeorge syndrome, velocardiofacial syndrome) has been noted in several reports [1 /5]. In series of patients with a chromosome 22q11 deletion, the incidence of a congenital laryngeal web has ranged from 1/5% [1,2], but the frequency of a chromosome 22q11 deletion and other genetic abnormalities in patients with a congenital laryngeal web is not known. Cardiovascular anomalies are common in patients with a chromosome 22q11 deletion and other chromosomal anomalies [1,2], and have been reported in association with a congenital laryngeal web [3 /9]. However, data on the frequency and types of cardiovascular anomalies seen in patients with a congenital laryngeal web are limited. Therefore, we reviewed our experience with patients who underwent intervention for a symptomatic congenital laryngeal web to estimate the frequency of chromosomal anomalies and associated cardiovascular malformations.
2. Patients and methods 2.1. Patients Between 1988 and 2000, 25 patients underwent surgery for a symptomatic congenital laryngeal web at The Children’s Hospital of Philadelphia. There were 14 males and 11 females, and the median age at surgery for the laryngeal web was 4.2 months (2 days/5.6 years). The laryngeal web was glottic in 21 patients (84%) and subglottic in four (16%). In 12 of these patients (48%), cytogenetic evaluation was undertaken on the basis of clinical assessment for indications including: congenital heart disease (n /2), abnormal facies (n / 2), speech delay (n /2), velopharyngeal insufficiency (n /2), noisy breathing after repair of the
web (n /2), laryngeal web (n /2), multiple congenital anomalies (n /1), short stature (n /1), features of Down syndrome (n /1), features of cat eye syndrome (n /1), and suspected cri-duchat syndrome (n /1), with multiple indications in some patients. For logistical reasons, we were not able to perform retrospective cytogenetic testing or chromosome 22q11 deletion screening in the other 13 patients. 2.2. Cytogenetic evaluation All 12 patients who underwent cytogenetic testing had a standard karyotype and microscopic cytogenetic evaluation performed. Testing for a chromosome 22q11 deletion was performed in seven patients (28%) by fluorescence in situ hybridization. Metaphase chromosomes from peripheral blood lymphocytes were cohybridized with the commercially available cosmid probe N25 (D22S75) and control probe pH17 (D22S39) that maps to the distal long arm of chromosome 22, as previously described [10]. In one patient, fluorescence in situ hybridization was performed to assess for a chromosome 5p15 deletion, which is associated with the cri-du-chat syndrome.
3. Results Chromosomal abnormalities were detected in seven of the 12 patients in whom cytogenetic evaluation was performed (28% of the entire cohort) (Table 1). Six of the seven patients (24% of the entire cohort) were found to have a chromosome 22q11 deletion, while one patient had trisomy 21. Two patients were diagnosed with clinical syndromes or associations (VACTERL association and cat eye syndrome) and had a normal karyotype. The congenital laryngeal web was glottic in all seven of the patients with chromosomal anomalies. Associated cardiovascular anomalies were diagnosed in nine of the 25 patients (36%), and are summarized in Table 1. Cardiovascular surgery to repair the anomaly was required in eight of these patients (all but the patient with an aberrant right subclavian artery). In total, five patients with a
D.B. McElhinney et al. / Int. J. Pediatr. Otorhinolaryngol. 66 (2002) 23 /27
25
Table 1 Cardiovascular and chromosomal anomalies in patients with congenital laryngeal web Congenital cardiovascular anomaly
Number of patients
Associated chromosomal anomalies/syndromes
Right aortic arch with aberrant left SCA (vascular ring) Left aortic arch with aberrant right SCA (no ring)
3
Chromosome 22q11 deletion n /3
1
Not tested n /1
Hypoplastic left heart syndrome
2
Tetralogy of Fallot with atrioventricular septal defect Perimembranous ventricular septal defect Tricuspid atresia
1
Cat eye syndrome, normal karyotype and normal 22q11 FISH n /1 Normal karyotype n /1 Trisomy 21 n /1
1 1
Chromosome 22q11 deletion n /1 Not tested n /1
No cardiovascular anomaly diagnosed
16
Chromosome 22q11 deletion n /2a Normal karyotype n /2 VACTERL association, normal karyotype n /1 Not tested n /11
a
The aortic arch was not imaged completely in one of these patients. FISH, fluorescence in situ hybridization; SCA, subclavian artery.
congenital laryngeal web (20%) had both a chromosomal alteration and a cardiovascular anomaly, while one patient was diagnosed with both a genetic syndrome and congenital heart disease. Four of these five patients had a chromosome 22q11 deletion with cardiovascular anomalies typical of the chromosome 22q11 deletion syndrome, including a vascular ring in three and a ventricular septal defect in one. The patient with trisomy 21 had tetralogy of Fallot with an atrioventricular septal defect, which is typical of that syndrome. One patient had cat eye syndrome in conjunction with hypoplastic left heart syndrome. Genetic testing was not performed in 13 of 25 subjects, including the other two patients with congenital cardiovascular anomalies (one with tricuspid atresia and one with an aberrant right subclavian artery). A chromosome 22q11 deletion may have been present in the patient with a left aortic arch and an aberrant right subclavian artery as well, inasmuch as he had additional features of the chromosome 22q11 deletion syndrome (unilateral facial nerve paralysis and feeding difficulties). However, he underwent repair of the laryngeal web in 1988, when the chromosome
22q11 deletion syndrome had not yet been identified, and has since been lost to follow-up.
4. Discussion The association of a congenital laryngeal web with a chromosome 22q11 deletion was first reported by Driscoll et al. [11]. In subsequent series, a congenital laryngeal web has been found in anywhere from 1 to 5% of patients with a chromosome 22q11 deletion [1,2]. Although congenital glottic and subglottic webs have been reported in patients with a chromosome 22q11 deletion [1 /5], the frequency of this chromosomal abnormality in patients with a congenital laryngeal web was not known prior to the present study. This study demonstrates that chromosomal anomalies, as well as congenital malformations/ syndromes, are common in patients with a congenital laryngeal web. The chromosome 22q11 deletion syndrome is particularly common: six of 25 patients (24%) who underwent intervention for a congenital laryngeal web at our center during the study period were diagnosed with a chromosome 22q11 deletion. Our study almost certainly under-
26
D.B. McElhinney et al. / Int. J. Pediatr. Otorhinolaryngol. 66 (2002) 23 /27
estimates the prevalence of chromosomal anomalies in patients with a congenital laryngeal web, as all patients who might be considered to warrant genetic testing in the current era did not undergo cytogenetic or chromosome 22q11 screening. The association between a congenital laryngeal web and cardiovascular anomalies has also been noted previously [3 /9]. As was the case in our study, previous reports have documented a variety of cardiovascular defects in patients with laryngeal webs. In a review of 51 patients with a congenital glottic web, Cohen reported seven with associated cardiovascular anomalies, including tetralogy of Fallot, ventricular septal defect, aortic arch anomalies (double aortic arch, aberrant subclavian artery), pulmonary arterial stenosis, and patent ductus arteriosus [6]. Shearer et al. reported a congenital glottic web associated with a ventricular septal defect in three patients [8]. Gay et al. described a family in which four members had a laryngeal web (subglottic in three, glottic in one), three of whom also had a ventricular septal defect [9]. Consistent with previous findings, this study identified a high frequency of congenital cardiovascular malformations among patients with a congenital laryngeal web. Of 25 patients with a laryngeal web, at least nine had congenital cardiovascular anomalies (36%), which ranged extensively in type and severity. Cardiovascular imaging was not performed in all patients, and in one of the patients with a web and a chromosome 22q11 deletion, the aortic arch was not completely evaluated during the echocardiographic examination. Accordingly, the frequency of cardiovascular anomalies, particularly abnormalities of aortic arch anatomy (sidedness and/or branching), may be underestimated in this study. Among patients with congenital laryngeal web, we found that a significant number have a diagnostic triad consisting of the web, congenital cardiovascular disease, and a chromosome 22q11 deletion, which has been noted in prior case reports (among the seven previously reported patients with a congenital laryngeal web and a chromosome 22q11 deletion, cardiovascular anomalies were noted in six, including ventricular septal defect, atrial septal defect, and interrupted
aortic arch [3 /5]). This triad was present in at least four of 25 patients in our series, and possibly a fifth, in whom chromosomal testing was not performed. Three of these patients had a vascular ring, and in all cases the diagnosis of the ring was delayed because of the history of a laryngeal web. The frequency of aortic arch anomalies in this patient population highlights the importance of excluding a vascular ring in patients with a congenital laryngeal web, especially if symptoms persist after repair of the web or if a chromosome 22q11 deletion has been identified. In particular, airway symptoms may persist after repair of a congenital laryngeal web, but in some cases may actually be due to an associated vascular ring. If the symptoms are attributed to residual glottic pathology, however, diagnosis of the vascular ring may be delayed. On the basis of these findings, we recommend that genetic screening, especially testing for a chromosome 22q11 deletion, should be considered in patients with a congenital laryngeal web, particularly in those with associated cardiovascular anomalies. Similarly, if a chromosome 22q11 deletion is detected in a patient with a congenital laryngeal web, cardiovascular evaluation should be performed, including complete examination by echocardiography or magnetic resonance imaging to define the sidedness and branching pattern of the aortic arch. Congenital cardiovascular anomalies, including vascular rings, are among the most common phenotypic features of the chromosome 22q11 deletion syndrome, occurring in over 75% of patients [1,12,13]. However, it is not uncommon for delay in the diagnosis of aortic arch anomalies in patients with a chromosome 22q11 deletion, especially those with additional respiratory/feeding symptoms [14]. There are two significant limitations to this study. First, we only included patients who underwent surgery for a symptomatic laryngeal web. The severity of congenital laryngeal webs can vary considerably, and patients with a web covering B/ 35% of the glottic opening may be entirely asymptomatic [6]. Thus, our analysis is limited to patients with more severe forms of congenital laryngeal web. Second, the study is limited by the fact that only 12 of the 25 patients (48%) under-
D.B. McElhinney et al. / Int. J. Pediatr. Otorhinolaryngol. 66 (2002) 23 /27
went cytogenetic evaluation, and only seven (28%) underwent chromosome 22q11 deletion testing. In all cases, genetic analysis was performed for clinical indications. For logistical reasons, it was not possible to perform cytogenetic evaluation in the remaining patients. Thus, our findings represent only a minimum incidence of genetic anomalies. Despite this shortcoming of the study, the frequency of chromosomal anomalies in patients with a symptomatic congenital laryngeal web is high (28%) and supports our recommendation that patients with a congenital laryngeal web, especially those with persistent respiratory symptoms after repair of the web, undergo testing for a chromosome 22q11 deletion and cardiovascular evaluation to exclude the possibility of a vascular ring. Other characteristic features of a chromosome 22q11 deletion, such as facial features and speech and learning disabilities, may not become apparent until later in childhood, and early identification of a deletion can facilitate complete evaluation and counseling, as well as allow for early intervention, all of which are likely to benefit both the patient and the family.
Acknowledgements This study was supported in part by grants from the NIH (P50HL62177 and DC02027).
References [1] A.K. Ryan, J.A. Goodship, D.I. Wilson, et al., Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study, J. Med. Genet. 34 (1997) 798 /804. [2] E.A. Lindsay, R. Goldberg, V. Jurecic, B. Morrow, C. Carlson, R.S. Kucherlapati, R.J. Shprintzen, A. Baldini, Velo-cardio-facial syndrome: frequency and extent of 22q11 deletions, Am. J. Med. Genet. 57 (1995) 514 /522.
27
[3] M. Marble, E. Morava, F. Tsien, R. Amedee, M. Pierce, Subglottic web in a mother and son with 22q11.2 deletion, Am. J. Med. Genet. 75 (1998) 537. [4] S. Fokstuen, A. Bottani, P.F. Medeiros, S.E. Antonarakis, C. Stoll, A. Schinzel, Laryngeal atresia type III (glottic web) with 22q11.2 microdeletion: report of three patients, Am. J. Med. Genet. 70 (1997) 130 /133. [5] J.M. Stoler, M. Ladoulis, L.B. Holmes, Anterior laryngeal webs and 22q11 deletions, Am. J. Med. Genet. 79 (1998) 152. [6] S.R. Cohen, Congenital glottic webs in children: a retrospective review of 51 patients, Ann. Otol. Rhinol. Laryngol. 121 (1985) 2 /16. [7] H.A. Milczuk, J.D. Smith, E.C. Everts, Congenital laryngeal webs: surgical management and clinical embryology, Int. J. Pediatr. Otorhinolaryngol. 52 (1) (2000) 1 /9. [8] W.T. Shearer, H.F. Biller, J.H. Ogura, D. Goldring, Congenital laryngeal web and interventricular septal defect. First reported cases, Am. J. Dis. Child 123 (1972) 605 /607. [9] I. Gay, R. Feinmesser, T. Cohen, Laryngeal web, congenital heart disease and low stature. A syndrome?, Arch. Otolaryngol. 107 (1981) 510 /512. [10] E. Goldmuntz, B.J. Clark, L.E. Mitchell, A.F. Jawad, B.F. Cuneo, L. Reed, D. McDonald-McGinn, P. Chien, J. Feuer, E.H. Zackai, B.S. Emanuel, D.A. Driscoll, Frequency of 22q11 deletions in patients with conotruncal defects, J. Am. Coll. Cardiol. 32 (1998) 492 /498. [11] D.A. Driscoll, N.B. Spinner, M.L. Budarf, D.M. McDonald-McGinn, E.H. Zackai, R.B. Goldberg, R.J. Shprintzen, H.M. Saal, J. Zonana, M.C. Jones, T.J. Mascarello, B.S. Emmanuel, Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome, Am. J. Med. Genet. 44 (1992) 261 /268. [12] D.M. McDonald-McGinn, D. LaRossa, E. Goldmuntz, et al., The 22q11.2 deletion: screening, diagnostic workup, and outcome of results; report on 181 patients, Genet. Test. 1 (1997) 99 /108. [13] D.B. McElhinney, B.J. Clark, P.M. Weinberg, M.L. Kenton, D. McDonald-McGinn, D.A. Driscoll, E.H. Zackai, E. Goldmuntz, Chromosome 22q11 deletions in patients with isolated anomalies of aortic arch sidedness or branching, J. Am. Coll. Cardiol. 37 (2001) 2114 /2119. [14] D.B. McElhinney, D. McDonald-McGinn, E.H. Zackai, E. Goldmuntz, Cardiovascular anomalies in patients diagnosed with a chromosome 22q11 deletion beyond six months of age, Pediatrics 108 (2001) e104.
Chromosomal and cardiovascular anomalies associated with congenital laryngeal web Doff B. McElhinney a,b,1, Ian Jacobs c,d, Donna M. McDonald-McGinn e, Elaine H. Zackai b,e, Elizabeth Goldmuntz a,b,* a
Division of Pediatric Cardiology, The Children’s Hospital of Philadelphia, Abramson Research Center 702A, 3516 Civic Center Blvd., Philadelphia, PA, 19104-4318, USA b Department of Pediatrics, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA c Division of Otorhinolaryngology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA d Department of Otolaryngology, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA e Division of Human Genetics and Molecular Biology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Received 5 February 2002; received in revised form 4 June 2002; accepted 5 June 2002
Abstract Objective: The purpose of this study was to estimate the frequency of chromosomal and cardiovascular anomalies associated with a congenital laryngeal web. Methods: We reviewed our experience with 25 patients who underwent intervention for a symptomatic congenital laryngeal web between 1988 and 2000, in order to investigate the frequency of associated chromosomal and cardiovascular anomalies. Twelve patients underwent cytogenetic evaluation, including seven that were tested for a chromosome 22q11 deletion by fluorescence in situ hybridization. Results: Chromosomal abnormalities were detected in seven of the 12 patients in whom cytogenetic evaluation was performed (28% of the entire cohort), including a chromosome 22q11 deletion in six and trisomy 21 in one. Associated cardiovascular anomalies were diagnosed in nine of the 25 patients, most commonly aortic arch anomalies. Of the patients with cardiovascular anomalies, 55% also had chromosomal alterations, and 71% of patients with chromosomal alterations also had a cardiovascular defect, of which four had the triad of a congenital laryngeal web, a chromosome 22q11 deletion, and congenital cardiovascular anomalies. Conclusions: Chromosomal and cardiovascular anomalies are common in patients with a congenital laryngeal web. A chromosome 22q11 deletion was particularly common, as were the cardiovascular anomalies associated with the chromosome 22q11 deletion syndrome. Accordingly, patients with a congenital laryngeal web should undergo genetic screening, including evaluation for a chromosome 22q11 deletion, and a thorough cardiovascular evaluation, including imaging of the aortic arch. Particular attention should be paid to identifying patients with the triad of a congenital laryngeal web, a chromosome 22q11 deletion, and cardiovascular anomalies, particularly a vascular ring. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: DiGeorge syndrome; Velocardiofacial syndrome; Vascular ring
* Corresponding author. Tel.: /1-215-590-5820; fax: /1-215-590-5454 E-mail address: [email protected] (E. Goldmuntz). 1 Present address: Department of Cardiology, Children’s Hospital, Boston, MA, USA. 0165-5876/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 5 8 7 6 ( 0 2 ) 0 0 1 8 4 - 2
24
D.B. McElhinney et al. / Int. J. Pediatr. Otorhinolaryngol. 66 (2002) 23 /27
1. Introduction Congenital laryngeal webs are uncommon airway anomalies in which membranous tissue present at birth causes partial obstruction of the supraglottic, glottic, or subglottic region of the larynx, often causing significant airway obstruction early in life. An association between congenital glottic or subglottic webs and a chromosome 22q11 deletion (DiGeorge syndrome, velocardiofacial syndrome) has been noted in several reports [1 /5]. In series of patients with a chromosome 22q11 deletion, the incidence of a congenital laryngeal web has ranged from 1/5% [1,2], but the frequency of a chromosome 22q11 deletion and other genetic abnormalities in patients with a congenital laryngeal web is not known. Cardiovascular anomalies are common in patients with a chromosome 22q11 deletion and other chromosomal anomalies [1,2], and have been reported in association with a congenital laryngeal web [3 /9]. However, data on the frequency and types of cardiovascular anomalies seen in patients with a congenital laryngeal web are limited. Therefore, we reviewed our experience with patients who underwent intervention for a symptomatic congenital laryngeal web to estimate the frequency of chromosomal anomalies and associated cardiovascular malformations.
2. Patients and methods 2.1. Patients Between 1988 and 2000, 25 patients underwent surgery for a symptomatic congenital laryngeal web at The Children’s Hospital of Philadelphia. There were 14 males and 11 females, and the median age at surgery for the laryngeal web was 4.2 months (2 days/5.6 years). The laryngeal web was glottic in 21 patients (84%) and subglottic in four (16%). In 12 of these patients (48%), cytogenetic evaluation was undertaken on the basis of clinical assessment for indications including: congenital heart disease (n /2), abnormal facies (n / 2), speech delay (n /2), velopharyngeal insufficiency (n /2), noisy breathing after repair of the
web (n /2), laryngeal web (n /2), multiple congenital anomalies (n /1), short stature (n /1), features of Down syndrome (n /1), features of cat eye syndrome (n /1), and suspected cri-duchat syndrome (n /1), with multiple indications in some patients. For logistical reasons, we were not able to perform retrospective cytogenetic testing or chromosome 22q11 deletion screening in the other 13 patients. 2.2. Cytogenetic evaluation All 12 patients who underwent cytogenetic testing had a standard karyotype and microscopic cytogenetic evaluation performed. Testing for a chromosome 22q11 deletion was performed in seven patients (28%) by fluorescence in situ hybridization. Metaphase chromosomes from peripheral blood lymphocytes were cohybridized with the commercially available cosmid probe N25 (D22S75) and control probe pH17 (D22S39) that maps to the distal long arm of chromosome 22, as previously described [10]. In one patient, fluorescence in situ hybridization was performed to assess for a chromosome 5p15 deletion, which is associated with the cri-du-chat syndrome.
3. Results Chromosomal abnormalities were detected in seven of the 12 patients in whom cytogenetic evaluation was performed (28% of the entire cohort) (Table 1). Six of the seven patients (24% of the entire cohort) were found to have a chromosome 22q11 deletion, while one patient had trisomy 21. Two patients were diagnosed with clinical syndromes or associations (VACTERL association and cat eye syndrome) and had a normal karyotype. The congenital laryngeal web was glottic in all seven of the patients with chromosomal anomalies. Associated cardiovascular anomalies were diagnosed in nine of the 25 patients (36%), and are summarized in Table 1. Cardiovascular surgery to repair the anomaly was required in eight of these patients (all but the patient with an aberrant right subclavian artery). In total, five patients with a
D.B. McElhinney et al. / Int. J. Pediatr. Otorhinolaryngol. 66 (2002) 23 /27
25
Table 1 Cardiovascular and chromosomal anomalies in patients with congenital laryngeal web Congenital cardiovascular anomaly
Number of patients
Associated chromosomal anomalies/syndromes
Right aortic arch with aberrant left SCA (vascular ring) Left aortic arch with aberrant right SCA (no ring)
3
Chromosome 22q11 deletion n /3
1
Not tested n /1
Hypoplastic left heart syndrome
2
Tetralogy of Fallot with atrioventricular septal defect Perimembranous ventricular septal defect Tricuspid atresia
1
Cat eye syndrome, normal karyotype and normal 22q11 FISH n /1 Normal karyotype n /1 Trisomy 21 n /1
1 1
Chromosome 22q11 deletion n /1 Not tested n /1
No cardiovascular anomaly diagnosed
16
Chromosome 22q11 deletion n /2a Normal karyotype n /2 VACTERL association, normal karyotype n /1 Not tested n /11
a
The aortic arch was not imaged completely in one of these patients. FISH, fluorescence in situ hybridization; SCA, subclavian artery.
congenital laryngeal web (20%) had both a chromosomal alteration and a cardiovascular anomaly, while one patient was diagnosed with both a genetic syndrome and congenital heart disease. Four of these five patients had a chromosome 22q11 deletion with cardiovascular anomalies typical of the chromosome 22q11 deletion syndrome, including a vascular ring in three and a ventricular septal defect in one. The patient with trisomy 21 had tetralogy of Fallot with an atrioventricular septal defect, which is typical of that syndrome. One patient had cat eye syndrome in conjunction with hypoplastic left heart syndrome. Genetic testing was not performed in 13 of 25 subjects, including the other two patients with congenital cardiovascular anomalies (one with tricuspid atresia and one with an aberrant right subclavian artery). A chromosome 22q11 deletion may have been present in the patient with a left aortic arch and an aberrant right subclavian artery as well, inasmuch as he had additional features of the chromosome 22q11 deletion syndrome (unilateral facial nerve paralysis and feeding difficulties). However, he underwent repair of the laryngeal web in 1988, when the chromosome
22q11 deletion syndrome had not yet been identified, and has since been lost to follow-up.
4. Discussion The association of a congenital laryngeal web with a chromosome 22q11 deletion was first reported by Driscoll et al. [11]. In subsequent series, a congenital laryngeal web has been found in anywhere from 1 to 5% of patients with a chromosome 22q11 deletion [1,2]. Although congenital glottic and subglottic webs have been reported in patients with a chromosome 22q11 deletion [1 /5], the frequency of this chromosomal abnormality in patients with a congenital laryngeal web was not known prior to the present study. This study demonstrates that chromosomal anomalies, as well as congenital malformations/ syndromes, are common in patients with a congenital laryngeal web. The chromosome 22q11 deletion syndrome is particularly common: six of 25 patients (24%) who underwent intervention for a congenital laryngeal web at our center during the study period were diagnosed with a chromosome 22q11 deletion. Our study almost certainly under-
26
D.B. McElhinney et al. / Int. J. Pediatr. Otorhinolaryngol. 66 (2002) 23 /27
estimates the prevalence of chromosomal anomalies in patients with a congenital laryngeal web, as all patients who might be considered to warrant genetic testing in the current era did not undergo cytogenetic or chromosome 22q11 screening. The association between a congenital laryngeal web and cardiovascular anomalies has also been noted previously [3 /9]. As was the case in our study, previous reports have documented a variety of cardiovascular defects in patients with laryngeal webs. In a review of 51 patients with a congenital glottic web, Cohen reported seven with associated cardiovascular anomalies, including tetralogy of Fallot, ventricular septal defect, aortic arch anomalies (double aortic arch, aberrant subclavian artery), pulmonary arterial stenosis, and patent ductus arteriosus [6]. Shearer et al. reported a congenital glottic web associated with a ventricular septal defect in three patients [8]. Gay et al. described a family in which four members had a laryngeal web (subglottic in three, glottic in one), three of whom also had a ventricular septal defect [9]. Consistent with previous findings, this study identified a high frequency of congenital cardiovascular malformations among patients with a congenital laryngeal web. Of 25 patients with a laryngeal web, at least nine had congenital cardiovascular anomalies (36%), which ranged extensively in type and severity. Cardiovascular imaging was not performed in all patients, and in one of the patients with a web and a chromosome 22q11 deletion, the aortic arch was not completely evaluated during the echocardiographic examination. Accordingly, the frequency of cardiovascular anomalies, particularly abnormalities of aortic arch anatomy (sidedness and/or branching), may be underestimated in this study. Among patients with congenital laryngeal web, we found that a significant number have a diagnostic triad consisting of the web, congenital cardiovascular disease, and a chromosome 22q11 deletion, which has been noted in prior case reports (among the seven previously reported patients with a congenital laryngeal web and a chromosome 22q11 deletion, cardiovascular anomalies were noted in six, including ventricular septal defect, atrial septal defect, and interrupted
aortic arch [3 /5]). This triad was present in at least four of 25 patients in our series, and possibly a fifth, in whom chromosomal testing was not performed. Three of these patients had a vascular ring, and in all cases the diagnosis of the ring was delayed because of the history of a laryngeal web. The frequency of aortic arch anomalies in this patient population highlights the importance of excluding a vascular ring in patients with a congenital laryngeal web, especially if symptoms persist after repair of the web or if a chromosome 22q11 deletion has been identified. In particular, airway symptoms may persist after repair of a congenital laryngeal web, but in some cases may actually be due to an associated vascular ring. If the symptoms are attributed to residual glottic pathology, however, diagnosis of the vascular ring may be delayed. On the basis of these findings, we recommend that genetic screening, especially testing for a chromosome 22q11 deletion, should be considered in patients with a congenital laryngeal web, particularly in those with associated cardiovascular anomalies. Similarly, if a chromosome 22q11 deletion is detected in a patient with a congenital laryngeal web, cardiovascular evaluation should be performed, including complete examination by echocardiography or magnetic resonance imaging to define the sidedness and branching pattern of the aortic arch. Congenital cardiovascular anomalies, including vascular rings, are among the most common phenotypic features of the chromosome 22q11 deletion syndrome, occurring in over 75% of patients [1,12,13]. However, it is not uncommon for delay in the diagnosis of aortic arch anomalies in patients with a chromosome 22q11 deletion, especially those with additional respiratory/feeding symptoms [14]. There are two significant limitations to this study. First, we only included patients who underwent surgery for a symptomatic laryngeal web. The severity of congenital laryngeal webs can vary considerably, and patients with a web covering B/ 35% of the glottic opening may be entirely asymptomatic [6]. Thus, our analysis is limited to patients with more severe forms of congenital laryngeal web. Second, the study is limited by the fact that only 12 of the 25 patients (48%) under-
D.B. McElhinney et al. / Int. J. Pediatr. Otorhinolaryngol. 66 (2002) 23 /27
went cytogenetic evaluation, and only seven (28%) underwent chromosome 22q11 deletion testing. In all cases, genetic analysis was performed for clinical indications. For logistical reasons, it was not possible to perform cytogenetic evaluation in the remaining patients. Thus, our findings represent only a minimum incidence of genetic anomalies. Despite this shortcoming of the study, the frequency of chromosomal anomalies in patients with a symptomatic congenital laryngeal web is high (28%) and supports our recommendation that patients with a congenital laryngeal web, especially those with persistent respiratory symptoms after repair of the web, undergo testing for a chromosome 22q11 deletion and cardiovascular evaluation to exclude the possibility of a vascular ring. Other characteristic features of a chromosome 22q11 deletion, such as facial features and speech and learning disabilities, may not become apparent until later in childhood, and early identification of a deletion can facilitate complete evaluation and counseling, as well as allow for early intervention, all of which are likely to benefit both the patient and the family.
Acknowledgements This study was supported in part by grants from the NIH (P50HL62177 and DC02027).
References [1] A.K. Ryan, J.A. Goodship, D.I. Wilson, et al., Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study, J. Med. Genet. 34 (1997) 798 /804. [2] E.A. Lindsay, R. Goldberg, V. Jurecic, B. Morrow, C. Carlson, R.S. Kucherlapati, R.J. Shprintzen, A. Baldini, Velo-cardio-facial syndrome: frequency and extent of 22q11 deletions, Am. J. Med. Genet. 57 (1995) 514 /522.
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