Proportions with unilateral choanal atresia and stenosis (CA/S) in each diagnostic group. *Statistically significant P value of < .01 compared with isolated cases of CA/S. CHARGE indicates coloboma, heart defect, atresia choanae, retarded growth, genitourinary abnormalities, and ear anomalies; MCA, multiple congenital anomalies.
Proportions with left-sided unilateral choanal atresia and stenosis (CA/S) in each diagnostic group. *P value compared with isolated cases of CA/S; P value for statistical significance equals .08. The chromosomal diagnosis group was not included in statistical analyses of laterality because of the small sample size. CHARGE indicates coloboma, heart defect, atresia choanae, retarded growth, genitourinary abnormalities, and ear anomalies; MCA, multiple congenital anomalies.
Proportions of individuals with neurologic findings in each diagnostic group. *P value of < .01 compared with isolated cases of unilateral choanal atresia and stenosis (CA/S). †P value compared with CHARGE (coloboma, heart defect, atresia choanae, retarded growth, genitourinary abnormalities, and ear anomalies syndrome). P value for statistical significance equals .005. MCA indicates multiple congenital anomalies.
Burrow TA, Saal HM, de Alarcon A, Martin LJ, Cotton RT, Hopkin RJ. Characterization of Congenital Anomalies in Individuals With Choanal Atresia. Arch Otolaryngol Head Neck Surg. 2009;135(6):543-547. doi:10.1001/archoto.2009.53
To review a tertiary care pediatric hospital's experience with choanal atresia and stenosis (CA/S) related to associated congenital anomalies (birth defects, including minor abnormalities) and genetic disorders.
Retrospective case series.
Tertiary care pediatric hospital.
Individuals with CA/S.
Main Outcome Measures
Identification of congenital anomalies, neurologic abnormalities, and developmental disabilities in individuals with CA/S.
One hundred twenty-nine individuals with CA/S were evaluated between July 1, 1997, and July 1, 2007. Choanal atresia and stenosis was an isolated finding in 34 patients (26.4%) and was associated with other anomalies in 95 patients (73.6%). Specific conditions were diagnosed in 66 patients (51.2%); CHARGE (coloboma, heart defect, atresia choanae, retarded growth, genitourinary abnormalities, and ear anomalies) syndrome was the most common diagnosis (33 patients [25.6%]). Numerous conditions were seen, including chromosomal abnormalities, single-gene defects, deformations, and those caused by teratogens. Choanal atresia and stenosis was unilateral in 62 patients (48.1%) and was bilateral in 60 patients (46.5%). Unilateral cases were more likely to be isolated (30 patients [53.2%]). Bilateral cases were more likely to be associated with specific disorders or multiple congenital anomalies (60 patients [98.4%]). There was no difference in laterality among unilateral cases.
Choanal atresia and stenosis is associated with a wide range of disorders. Congenital anomalies, neurologic abnormalities, and developmental disabilities are commonly identified in affected individuals. Bilateral CA/S is more commonly seen in patients in whom specific diagnoses or other congenital anomalies are identified. Unilateral CA/S occurs more frequently in isolated cases. A comprehensive evaluation is recommended in individuals with CA/S to evaluate for other congenital anomalies, neurologic abnormalities, developmental delays, and evidence of a specific underlying disorder.
Choanal atresia is a common craniofacial defect and is characterized by obstruction of the posterior nasal passages. The incidence of choanal atresia is approximately 1 case in 8000 live births.1 Although it may occur up to twice as frequently in females as in males,2 an extensive review article1 suggests a 1:1 ratio of male to female frequency. A 2:1 ratio of unilateral to bilateral atresia has been reported,3 although more recent findings have demonstrated a 1:1 ratio.4 Additional malformations have been previously reported in up to 49% of individuals with choanal atresia and stenosis (CA/S).1,2 Although the pathogenesis is unknown, one theory attributes the cause of choanal atresia to persistence of the buccopharyngeal membranes or to failure of the oronasal membrane to rupture.3
Choanal atresia and stenosis is known to be a component of many disorders. The POSSUM Web,5 London Dysmorphology Database,6 and Online Mendelian Inheritance in Man7 databases record 88, 81, and 67 conditions, respectively, with CA/S as a related finding. CHARGE (coloboma, heart defect, atresia choanae, retarded growth, genitourinary abnormalities, and ear anomalies) syndrome is the most commonly reported disorder related to CA/S in the literature. Depending on the stringency of the diagnostic criteria and the way in which they are applied in diagnosing CHARGE syndrome, 7% to 29% of individuals with choanal atresia may meet diagnostic criteria for CHARGE syndrome.1,8
Studies1,9 have focused on the relationship between CA/S and CHARGE syndrome. Fewer have addressed the association of choanal atresia with other congenital anomalies (excluding CHARGE syndrome). Case reports have identified CA/S in individuals with other specific disorders or with multiple congenital anomalies (MCA).10
In the present study, we sought to further elucidate the relationship between CA/S and congenital anomalies (including CHARGE syndrome). We reviewed the congenital anomalies and specific conditions associated with CA/S in 129 patients treated for CA/S at a large tertiary care pediatric center over 10 years.
After approval from the Institutional Review Board at Cincinnati Children's Hospital Medical Center, individuals were identified by surveying the hospital billing database for the diagnosis of choanal atresia (International Classification of Diseases, Ninth Revision code 748.0) between July 1, 1997, and July 1, 2007. Individuals demonstrating radiographic or nasopharyngoscopic evidence of CA/S (bilateral or unilateral and membranous or bony CA/S) qualified for inclusion in the study. Individuals with pyriform aperture stenosis were excluded from the study. Details of the choanal defect, other malformations, and additional specific diagnoses were entered into a computer database. Patients were categorized into the following 5 diagnostic groups for statistical analyses: isolated CA/S, MCA, specific diagnoses (excluding CHARGE syndrome or chromosome abnormalities), CHARGE syndrome, and chromosomal abnormalities. Individuals were included in the CHARGE syndrome diagnostic group based on a clinical diagnosis of one of the following: (1) presence of 4 major diagnostic characteristics, (2) presence of 3 major and 3 minor diagnostic characteristics,11 or (3) presence of the CHD7 (OMIM_ 608892) mutation.12 Individuals lacking a definite diagnosis but demonstrating additional anomalies were assigned the diagnosis of MCA.
To describe the cohort, frequencies and 95% confidence intervals (CIs) for side of involvement, diagnostic groups, involvement by diagnostic group, and neurologic findings by diagnostic group were calculated. Patients whose laterality was not recorded (n = 7) were excluded from statistical analyses.
The association between congenital anomalies and CA/S was evaluated. The proportion of individuals with isolated unilateral CA/S was compared with the proportion of individuals with unilateral CA/S related to the 4 diagnostic categories (MCA, specific diagnosis, CHARGE syndrome, and chromosomal abnormalities) using 4 independent χ2 tests. The association between neurologic findings, CA/S, and the different diagnostic groups was assessed using χ2 tests. Bonferroni correction was used to account for multiple testing and to reduce the risk of false-positive results.13 All analyses were performed using Epi Info statistical software (version 3.4.1; Centers for Disease Control and Prevention, Atlanta, Georgia).
One hundred twenty-nine patients with CA/S meeting inclusion criteria for this study were evaluated at Cincinnati Children's Hospital Medical Center between July 1, 1997, and July 1, 2007. Significantly more females (n = 76) than males (n = 53) were affected with CA/S (P = .04). In total, 97 patients (75.2%) had choanal atresia, 30 patients (23.3%) demonstrated choanal stenosis, and 2 patients (1.6%) exhibited choanal atresia on one side and stenosis on the other side. Approximately 50% of cases (n = 62) were unilateral. Other congenital anomalies, neurologic signs, or developmental disabilities were identified in approximately 74% of affected individuals. Table 1 lists the numbers of patients identified per diagnostic group. Table 2 lists the specific diagnoses, including CHARGE syndrome and chromosomal abnormalities. One patient was diagnosed as having CHARGE syndrome (based on clinical rather than molecular findings) and Klinefelter syndrome (47,XXY); to our knowledge, choanal atresia has not been previously reported to be related to Klinefelter syndrome.
When examining diagnostic groups by unilateral vs bilateral involvement, we found that 62 cases were unilateral and 60 cases were bilateral. Unilateral cases were slightly more likely to be isolated (53.2%; 95% CI, 40.1%-60.0%). Bilateral cases were more likely to be associated with specific diagnoses or with MCA (98.4%; 95% CI, 91.1%-99.9%). Furthermore, individuals with isolated CA/S were much more likely to have unilateral involvement (97.1%; 95% CI, 84.7%-99.9%). The proportion of unilateral cases among the other 4 diagnostic groups was significantly less (P < .001 for all) (Figure 1).
There was no difference in right-sided vs left-sided CA/S for unilateral cases. Figure 2 shows the proportion of individuals with left-sided CA/S among unilateral cases in each diagnostic group. The chromosomal abnormalities diagnosis group was excluded from statistical analyses of laterality because of the small sample size.
Other airway abnormalities (ie, tracheomalacia, laryngomalacia, and subglottic stenosis) were the most frequently identified anomalies in individuals within the MCA diagnosis group (Table 3), followed by mental retardation or developmental delay and brain abnormalities. However, combining brain abnormalities, developmental delay, and mental retardation, 55.2% of individuals in the MCA diagnostic group had a neurologic abnormality. Altogether, 64 individuals (49.6%) exhibited developmental disabilities or mental retardation, neurologic signs, or brain abnormalities.
By definition, individuals with isolated CA/S did not demonstrate neurologic abnormalities. Neurologic abnormalities were significantly more common among the other 4 diagnostic groups (P < .001) (Figure 3). Individuals with CHARGE syndrome were much more frequently diagnosed as having neurologic abnormalities compared with the MCA and specific diagnoses diagnostic groups (P < .001 and P = .002, respectively). The difference in proportions of neurologic findings between the CHARGE syndrome and chromosomal abnormalities diagnostic groups was not statistically significant (P = .001).
Choanal atresia is the most common craniofacial defect affecting the nose, occurring with an incidence of approximately 1 case in 8000 live births.1 The present study is one of the largest reviews of choanal atresia and congenital anomalies in the literature. As found in a previous study,2 female individuals were more frequently affected than male individuals in our series. There was no difference in laterality of the defect among unilateral isolated and syndromic cases. Previous studies1,2 report additional malformations in approximately 47% to 49% of affected individuals. In this study, we identified additional malformations, neurologic signs, and developmental disabilities in approximately 29 individuals (22%). The discrepancy between our study and the previous studies may be related to ascertainment bias because some investigations were not specifically focused on identifying congenital anomalies associated with CA/S, while others relied on inclusion of information in malformation registries. Likewise, in the present study, all patient medical records were reviewed by a geneticist experienced in identifying congenital anomalies (T.A.B., H.M.S., or R.J.H.). Because the present study relied on retrospective medical record review, incomplete documentation within the medical records could have led to incomplete documentation of features in some cases.
Although CHARGE syndrome is the diagnosis most commonly related to choanal atresia in the literature, many patients with CA/S may not meet diagnostic criteria for CHARGE syndrome.1 With the advent of molecular testing for CHARGE syndrome, the phenotype has expanded. Consequently, individuals having CA/S, other congenital anomalies, and identified CHD7 mutations but not meeting diagnostic criteria for CHARGE syndrome have been recognized. Many individuals in this retrospective study were evaluated before the availability of molecular genetic testing for CHARGE syndrome. Consequently, it is conceivable that the actual number of individuals with CHARGE syndrome in this cohort is higher than that reported.
Our data indicate that unilateral CA/S occurs more frequently in individuals with isolated presentation, whereas bilateral CA/S occurs more frequently in individuals with specific diagnoses or other MCA. This is not surprising considering that genetic factors are likely to result in perturbations of embryogenesis with symmetric involvement. Our findings indicate that most patients with bilateral CA/S will have other anomalies and many will have identifiable disorders. The associated conditions identified in this study were varied, falling into several causative categories such as teratogenic exposures, chromosomal anomalies, single-gene disorders, and deformations. One of the more frequent associations was with craniosynostosis syndromes. Specifically, CA/S was identified in individuals with Pfeiffer, Antley-Bixler, Apert, and Crouzon syndromes. However, most (if not all) causes of craniosynostosis may be associated with an increased risk for CA/S.
Children with CA/S, especially bilateral disease, should be evaluated for further evidence of a congenital anomaly. A broad range of associated congenital anomalies may be identified in individuals with CA/S, particularly brain abnormalities, developmental delays, and other airway abnormalities. These should be considered in individuals with CA/S.
Physicians caring for individuals with CA/S, especially those with bilateral presentation, should consider enlisting the help of a multidisciplinary team that includes developmental pediatricians and geneticists or dysmorphologists to perform comprehensive evaluations to identify further congenital anomalies and to aid in establishing the correct diagnosis. This should include obtaining a detailed prenatal medical history, particularly focusing on maternal diabetes mellitus and medication exposures, and a 3-generation pedigree. Because chromosomal abnormalities are commonly identified in individuals with CA/S, especially in patients with bilateral disease and other congenital anomalies, high-resolution chromosome analysis is recommended, with consideration of comparative genomic hybridization microarray analysis if no abnormality is identified. Testing for other diagnoses will depend on the specific findings associated with each patient. In addition, considering the high frequency of developmental delays and brain abnormalities in these individuals, we suggest that close developmental monitoring and brain imaging should be considered in all patient with CA/S, particularly if additional anomalies are identified.
Correspondence: Robert J. Hopkin, MD, Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Mail Location Code 4006, Cincinnati, OH 45229-3039 (Rob.Hopkin@CCHMC.org).
Submitted for Publication: September 30, 2008; final revision received November 5, 2008; accepted November 15, 2008.
Author Contributions: Dr Hopkin had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Burrow and Hopkin. Acquisition of data: Burrow and de Alarcon. Analysis and interpretation of data: Burrow, Saal, de Alarcon, Martin, Cotton, and Hopkin. Drafting of the manuscript: Burrow. Critical revision of the manuscript for important intellectual content: Burrow, Saal, de Alarcon, Martin, Cotton, and Hopkin. Statistical analysis: Martin. Study supervision: Saal, de Alarcon, Cotton, and Hopkin.
Financial Disclosure: None reported.
Previous Presentations: This study was presented in part at the 28th Annual D. W. Smith Workshop of Malformations and Morphogenesis; August 10, 2007; Williamsburg, Virginia; and at the 57th Annual Meeting of the American Society of Human Genetics; October 25, 2007; San Diego, California.