Characterization of Congenital Anomalies in Individuals with Choanal Atresia

ORIGINAL ARTICLE Characterization of Congenital Anomalies in Individuals With Choanal Atresia

T. Andrew Burrow, MD; Howard M. Saal, MD; Alessandro de Alarcon, MD; Lisa J. Martin, PhD; Robin T. Cotton, MD; Robert J. Hopkin, MD

Objective: To review a tertiary care pediatric hospi- merous conditions were seen, including chromosomal ab- tal’s experience with choanal atresia and stenosis normalities, single-gene defects, deformations, and those (CA/S) related to associated congenital anomalies caused by teratogens. Choanal atresia and stenosis was (birth defects, including minor abnormalities) and ge- unilateral in 62 patients (48.1%) and was bilateral in 60 netic disorders. patients (46.5%). Unilateral cases were more likely to be isolated (30 patients [53.2%]). Bilateral cases were more Design: Retrospective case series. likely to be associated with specific disorders or multiple congenital anomalies (60 patients [98.4%]). There Setting: Tertiary care pediatric hospital. was no difference in laterality among unilateral cases. Patients: Individuals with CA/S. Conclusions: Choanal atresia and stenosis is associated with a wide range of disorders. Congenital anoma- Main Outcome Measures: Identification of congen- lies, neurologic abnormalities, and developmental dis- ital anomalies, neurologic abnormalities, and developmental disabilities in individuals with CA/S. abilities are commonly identified in affected individuals. Bilateral CA/S is more commonly seen in patients in whom Results: One hundred twenty-nine individuals with CA/S specific diagnoses or other congenital anomalies are iden- were evaluated between July 1, 1997, and July 1, 2007. tified. Unilateral CA/S occurs more frequently in iso- Choanal atresia and stenosis was an isolated finding in lated cases. A comprehensive evaluation is recom- 34 patients (26.4%) and was associated with other anoma- mended in individuals with CA/S to evaluate for other lies in 95 patients (73.6%). Specific conditions were di- congenital anomalies, neurologic abnormalities, devel- agnosed in 66 patients (51.2%); CHARGE (coloboma, opmental delays, and evidence of a specific underlying heart defect, atresia choanae, retarded growth, genito- disorder. urinary abnormalities, and ear anomalies) syndrome was the most common diagnosis (33 patients [25.6%]). Nu- Arch Otolaryngol Head Neck Surg. 2009;135(6):543-547

HOANAL ATRESIA IS A COM- known, one theory attributes the cause of mon craniofacial defect choanal atresia to persistence of the buc- and is characterized by copharyngeal membranes or to failure of obstruction of the poste- the oronasal membrane to rupture.3 rior nasal passages. The Choanal atresia and stenosis is known incidence of choanal atresia is approxi- to be a component of many disorders. The C 1 5 Author Affiliations: Division of mately 1 case in 8000 live births. Al- POSSUM Web, London Dysmorphology Human Genetics, Department though it may occur up to twice as fre- Database,6 and Online Mendelian Inher- of Pediatrics (Drs Burrow, Saal, quently in females as in males,2 an itance in Man7 databases record 88, 81, and Martin, and Hopkin), Division extensive review article1 suggests a 1:1 ra- 67 conditions, respectively, with CA/S as of Pediatric Otolaryngology, tio of male to female frequency. A 2:1 ra- a related finding. CHARGE (coloboma, Department of Pediatric Surgery tio of unilateral to bilateral atresia has been heart defect, atresia choanae, retarded (Drs de Alarcon and Cotton), reported,3 although more recent findings growth, genitourinary abnormalities, and and Center for Epidemiology 4 and Biostatistics (Dr Martin), have demonstrated a 1:1 ratio. Addi- ear anomalies) syndrome is the most com- University of Cincinnati and tional malformations have been previ- monly reported disorder related to CA/S Cincinnati Children’s Hospital ously reported in up to 49% of individu- in the literature. Depending on the strin- Medical Center, Cincinnati, als with choanal atresia and stenosis gency of the diagnostic criteria and the way Ohio. (CA/S).1,2 Although the pathogenesis is un- in which they are applied in diagnosing

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 tic group were calculated. Patients whose laterality was not Table 1. Number of Patients With Choanal Atresia recorded (n=7) were excluded from statistical analyses. and Stenosis per Diagnosis Group CONGENITAL ANOMALIES No. of Associated AND CA/S ASSOCIATIONS Diagnoses a Diagnostic Group (n=130) The association between congenital anomalies and CA/S was Specific diagnoses (excluding CHARGE 25 evaluated. The proportion of individuals with isolated unilat- syndrome and chromosomal abnormalities) eral CA/S was compared with the proportion of individuals with CHARGE syndrome 33 unilateral CA/S related to the 4 diagnostic categories (MCA, Chromosomal abnormalities 9 specific diagnosis, CHARGE syndrome, and chromosomal ab- Isolated CA/S 34 normalities) using 4 independent ␹2 tests. The association be- Multiple congenital anomalies 29 tween neurologic findings, CA/S, and the different diagnostic groups was assessed using ␹2 tests. Bonferroni correction was Abbreviations: CA/S, choanal atresia and stenosis; CHARGE, coloboma, used to account for multiple testing and to reduce the risk of heart defect, atresia choanae, retarded growth, genitourinary abnormalities, 13 and ear anomalies. false-positive results. All analyses were performed using Epi a There were 129 patients. One patient had CHARGE syndrome and XXY. Info statistical software (version 3.4.1; Centers for Disease Con- trol and Prevention, Atlanta, Georgia). CHARGE syndrome, 7% to 29% of individuals with choanal atresia may meet diagnostic criteria for CHARGE RESULTS syndrome.1,8 Studies1,9 have focused on the relationship between CA/S One hundred twenty-nine patients with CA/S meeting and CHARGE syndrome. Fewer have addressed the asso- inclusion criteria for this study were evaluated at Cin- ciation of choanal atresia with other congenital anoma- cinnati Children’s Hospital Medical Center between lies (excluding CHARGE syndrome). Case reports have July 1, 1997, and July 1, 2007. Significantly more identified CA/S in individuals with other specific disor- females (n=76) than males (n=53) were affected with ders or with multiple congenital anomalies (MCA).10 CA/S (P=.04). In total, 97 patients (75.2%) had choa- In the present study, we sought to further elucidate nal atresia, 30 patients (23.3%) demonstrated choanal the relationship between CA/S and congenital anoma- stenosis, and 2 patients (1.6%) exhibited choanal atre- lies (including CHARGE syndrome). We reviewed the sia on one side and stenosis on the other side. congenital anomalies and specific conditions associated Approximately 50% of cases (n=62) were unilateral. with CA/S in 129 patients treated for CA/S at a large ter- Other congenital anomalies, neurologic signs, or tiary care pediatric center over 10 years. developmental disabilities were identified in approximately 74% of affected individuals. Table 1 lists the METHODS numbers of patients identified per diagnostic group. Table 2 lists the specific diagnoses, including After approval from the Institutional Review Board at Cincin- CHARGE syndrome and chromosomal abnormalities. nati Children’s Hospital Medical Center, individuals were iden- One patient was diagnosed as having CHARGE syn- tified by surveying the hospital billing database for the diag- drome (based on clinical rather than molecular find- nosis of choanal atresia (International Classification of Diseases, ings) and Klinefelter syndrome (47,XXY); to our Ninth Revision code 748.0) between July 1, 1997, and July 1, knowledge, choanal atresia has not been previously 2007. Individuals demonstrating radiographic or nasopharyn- reported to be related to Klinefelter syndrome. goscopic evidence of CA/S (bilateral or unilateral and mem- When examining diagnostic groups by unilateral vs branous or bony CA/S) qualified for inclusion in the study. In- bilateral involvement, we found that 62 cases were dividuals with pyriform aperture stenosis were excluded from unilateral and 60 cases were bilateral. Unilateral cases the study. Details of the choanal defect, other malformations, were slightly more likely to be isolated (53.2%; 95% and additional specific diagnoses were entered into a computer database. Patients were categorized into the following 5 CI, 40.1%-60.0%). Bilateral cases were more likely to diagnostic groups for statistical analyses: isolated CA/S, MCA, be associated with specific diagnoses or with MCA specific diagnoses (excluding CHARGE syndrome or chromo- (98.4%; 95% CI, 91.1%-99.9%). Furthermore, indi- some abnormalities), CHARGE syndrome, and chromosomal viduals with isolated CA/S were much more likely to abnormalities. Individuals were included in the CHARGE syn- have unilateral involvement (97.1%; 95% CI, 84.7%- drome diagnostic group based on a clinical diagnosis of one of 99.9%). The proportion of unilateral cases among the the following: (1) presence of 4 major diagnostic characteris- other 4 diagnostic groups was significantly less tics, (2) presence of 3 major and 3 minor diagnostic charac- (PϽ.001 for all) (Figure 1). 11 teristics, or (3) presence of the CHD7 (OMIM_608892) mu- There was no difference in right-sided vs left-sided tation.12 Individuals lacking a definite diagnosis but CA/S for unilateral cases. Figure 2 shows the propor- demonstrating additional anomalies were assigned the diagnosis of MCA. tion of individuals with left-sided CA/S among unilateral cases in each diagnostic group. The chromosomal DESCRIPTIVE STATISTICS abnormalities diagnosis group was excluded from statistical analyses of laterality because of the small To describe the cohort, frequencies and 95% confidence inter- sample size. vals (CIs) for side of involvement, diagnostic groups, involve- Other airway abnormalities (ie, tracheomalacia, la- ment by diagnostic group, and neurologic findings by diagnos- ryngomalacia, and subglottic stenosis) were the most fre-

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100 Diagnosis No. of Cases CHARGE syndrome 33 80 Familial CA/S 4 ∗ ∗ Diabetic embryopathy 3 60 Holoprosencephaly 3 ∗ ∗ Treacher Collins syndrome 3 40 Pfeiffer syndrome 3 Antley-Bixler syndrome 2

Trisomy 18 2 Proportion With Unilateral CA/S, % 20 Trisomy 21 2 47, XXY 1 0 Isolated MCA Specific CHARGE Chromosomal 47, XYY 1 CA/S Diagnoses Syndrome Abnormalities Apert syndrome 1 Crouzon syndrome 1 Caffey syndrome 1 Figure 1. Proportions with unilateral choanal atresia and stenosis (CA/S) in each diagnostic group. *Statistically significant P value of Ͻ.01 compared Mandibulofacial dysostosis 1 with isolated cases of CA/S. CHARGE indicates coloboma, heart defect, Multiple epiphyseal dysplasia 1 atresia choanae, retarded growth, genitourinary abnormalities, and ear Partial duplication chromosome 8 1 anomalies; MCA, multiple congenital anomalies. Teratoma 1 Toriello-Carey syndrome 1 Unbalanced X;22 translocation 1 Unspecified chromosome 20 abnormality 1 90 ∗P = .24 ∗P = .97 80 Abbreviations: CA/S, choanal atresia and stenosis; CHARGE, coloboma, ∗P = .69 heart defect, atresia choanae, retarded growth, genitourinary abnormalities, 70 and ear anomalies. 60 quently identified anomalies in individuals within the 50 MCA diagnosis group (Table 3), followed by mental re- 40 tardation or developmental delay and brain abnormali- 30 ties. However, combining brain abnormalities, develop- 20 mental delay, and mental retardation, 55.2% of individuals Proportion With Left-Sided CA/S, % in the MCA diagnostic group had a neurologic abnor- 10 mality. Altogether, 64 individuals (49.6%) exhibited de- 0 Isolated MCA Specific CHARGE velopmental disabilities or mental retardation, neuro- CA/S Diagnoses Syndrome logic signs, or brain abnormalities. By definition, individuals with isolated CA/S did not Figure 2. Proportions with left-sided unilateral choanal atresia and stenosis demonstrate neurologic abnormalities. Neurologic ab- (CA/S) in each diagnostic group. *P value compared with isolated cases of normalities were significantly more common among the CA/S; P value for statistical significance equals .08. The chromosomal Ͻ Figure 3 diagnosis group was not included in statistical analyses of laterality because other 4 diagnostic groups (P .001) ( ). Indi- of the small sample size. CHARGE indicates coloboma, heart defect, atresia viduals with CHARGE syndrome were much more fre- choanae, retarded growth, genitourinary abnormalities, and ear anomalies; quently diagnosed as having neurologic abnormalities MCA, multiple congenital anomalies. compared with the MCA and specific diagnoses diagnostic groups (PϽ.001 and P=.002, respectively). The dif- tional malformations, neurologic signs, and developmen- ference in proportions of neurologic findings between the tal disabilities in approximately 29 individuals (22%). The CHARGE syndrome and chromosomal abnormalities di- discrepancy between our study and the previous studies agnostic groups was not statistically significant (P=.001). may be related to ascertainment bias because some in- vestigations were not specifically focused on identifying COMMENT congenital anomalies associated with CA/S, while oth- ers relied on inclusion of information in malformation Choanal atresia is the most common craniofacial defect registries. Likewise, in the present study, all patient medi- affecting the nose, occurring with an incidence of ap- cal records were reviewed by a geneticist experienced in proximately 1 case in 8000 live births.1 The present study identifying congenital anomalies (T.A.B., H.M.S., or is one of the largest reviews of choanal atresia and con- R.J.H.). Because the present study relied on retrospec- genital anomalies in the literature. As found in a previ- tive medical record review, incomplete documentation ous study,2 female individuals were more frequently af- within the medical records could have led to incom- fected than male individuals in our series. There was no plete documentation of features in some cases. difference in laterality of the defect among unilateral iso- Although CHARGE syndrome is the diagnosis most lated and syndromic cases. Previous studies1,2 report ad- commonly related to choanal atresia in the literature, many ditional malformations in approximately 47% to 49% of patients with CA/S may not meet diagnostic criteria for affected individuals. In this study, we identified addi- CHARGE syndrome.1 With the advent of molecular test-

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 somal anomalies, single-gene disorders, and deformations. Table 3. Abnormalities Identified Among Individuals One of the more frequent associations was with cranio- in the Multiple Congenital Anomalies Diagnostic Group synostosis syndromes. Specifically, CA/S was identified in individuals with Pfeiffer, Antley-Bixler, Apert, and Abnormality Affected, % Crouzon syndromes. However, most (if not all) causes Airway or pulmonary abnormalities 34.5 of craniosynostosis may be associated with an increased Brain abnormalities 27.6 risk for CA/S. Mental retardation or developmental delay 27.6 Congenital heart defects 24.1 Children with CA/S, especially bilateral disease, should Craniofacial abnormalities 20.7 be evaluated for further evidence of a congenital anomaly. Growth deficiency or failure to thrive 13.8 A broad range of associated congenital anomalies may Skeletal abnormalities 13.8 be identified in individuals with CA/S, particularly brain Hearing impairment 13.8 abnormalities, developmental delays, and other airway Gastrointestinal tract abnormalities 13.8 abnormalities. These should be considered in individu- Genital defects 10.3 als with CA/S. Eye abnormalities 6.9 Renal abnormalities 3.4 CONCLUSIONS

Physicians caring for individuals with CA/S, especially 120 those with bilateral presentation, should consider enlist- ∗ ing the help of a multidisciplinary team that includes de- †P <.001 ∗ 100 ∗ †P = .01 velopmental pediatricians and geneticists or dysmor- †P = .002 phologists to perform comprehensive evaluations to ∗ 80 identify further congenital anomalies and to aid in es- †P <.001 tablishing the correct diagnosis. This should include ob- 60 taining a detailed prenatal medical history, particularly focusing on maternal diabetes mellitus and medication 40 exposures, and a 3-generation pedigree. Because chromosomal abnormalities are commonly identified in in- 20 dividuals with CA/S, especially in patients with bilateral Proportion With Neurologic Findings, % disease and other congenital anomalies, high-resolution 0 Isolated MCA Specific CHARGE Chromosomal chromosome analysis is recommended, with consider- CA/S Diagnoses Syndrome Abnormalities ation of comparative genomic hybridization microarray analysis if no abnormality is identified. Testing for other Figure 3. Proportions of individuals with neurologic findings in each diagnoses will depend on the specific findings associ- diagnostic group. *P value of Ͻ.01 compared with isolated cases of ated with each patient. In addition, considering the high unilateral choanal atresia and stenosis (CA/S). †P value compared with CHARGE (coloboma, heart defect, atresia choanae, retarded growth, frequency of developmental delays and brain abnormali- genitourinary abnormalities, and ear anomalies syndrome). P value for ties in these individuals, we suggest that close develop- statistical significance equals .005. MCA indicates multiple congenital mental monitoring and brain imaging should be consid- anomalies. ered in all patient with CA/S, particularly if additional anomalies are identified. ing for CHARGE syndrome, the phenotype has ex- panded. Consequently, individuals having CA/S, other Submitted for Publication: September 30, 2008; final re- congenital anomalies, and identified CHD7 mutations but vision received November 5, 2008; accepted November not meeting diagnostic criteria for CHARGE syndrome 15, 2008. have been recognized. Many individuals in this retro- Correspondence: Robert J. Hopkin, MD, Division of Hu- spective study were evaluated before the availability of man Genetics, Department of Pediatrics, Cincinnati Chil- molecular genetic testing for CHARGE syndrome. Con- dren’s Hospital Medical Center, 3333 Burnet Ave, Mail sequently, it is conceivable that the actual number of in- Location Code 4006, Cincinnati, OH 45229-3039 (Rob dividuals with CHARGE syndrome in this cohort is higher [email protected]). than that reported. Author Contributions: Dr Hopkin had full access to all Our data indicate that unilateral CA/S occurs more fre- the data in the study and takes responsibility for the in- quently in individuals with isolated presentation, whereas tegrity of the data and the accuracy of the data analysis. bilateral CA/S occurs more frequently in individuals with Study concept and design: Burrow and Hopkin. Acquisi- specific diagnoses or other MCA. This is not surprising tion of data: Burrow and de Alarcon. Analysis and inter- considering that genetic factors are likely to result in per- pretation of data: Burrow, Saal, de Alarcon, Martin, Cot- turbations of embryogenesis with symmetric involve- ton, and Hopkin. Drafting of the manuscript: Burrow. ment. Our findings indicate that most patients with bi- Critical revision of the manuscript for important intellec- lateral CA/S will have other anomalies and many will have tual content: Burrow, Saal, de Alarcon, Martin, Cotton, identifiable disorders. The associated conditions identi- and Hopkin. Statistical analysis: Martin. Study supervi- fied in this study were varied, falling into several caus- sion: Saal, de Alarcon, Cotton, and Hopkin. ative categories such as teratogenic exposures, chromo- Financial Disclosure: None reported.

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Previous Presentations: This study was presented in part tralia: Murdoch Childrens Research Institute, Royal Children’s Hospital; 2006. at the 28th Annual D. W. Smith Workshop of Malfor- 6. London Medical Database. London Dysmorphology Database [CD-ROM computer program]. Version 1.0.2. Oxford, England: Oxford University Press; 2003. mations and Morphogenesis; August 10, 2007; Williams- 7. OMIM: Online Mendelian Inheritance in Man. Baltimore, MD: McKusick-Nathans burg, Virginia; and at the 57th Annual Meeting of the Institute of Genetic Medicine, Johns Hopkins University. Bethesda, MD: Na- American Society of Human Genetics; October 25, 2007; tional Center for Biotechnology Information, National Library of Medicine. http: San Diego, California. //www.ncbi.nlm.nih.gov/omim/. Accessed March 25, 2008. 8. Leclerc JE, Fearon B. Choanal atresia and associated anomalies. Int J Pediatr Otorhinolaryngol. 1987;13(3):265-272. REFERENCES 9. Tellier AL, Cormier-Daire V, Abadie V, et al. CHARGE syndrome: report of 47 cases and review. Am J Med Genet. 1998;76(5):402-409. 1. Harris J, Robert E, Källe´n B. Epidemiology of choanal atresia with special refer- 10. Andrade EC, Ju´nior VS, Didoni AL, Freitas PZ, Carneiro AF, Yoshimoto FR. ence to the CHARGE association. Pediatrics. 1997;99(3):363-367. Treacher Collins syndrome with choanal atresia: a case report and review of dis- 2. Freng A. Congenital choanal atresia: etiology, morphology and diagnosis in 82 ease features. Braz J Otorhinolaryngol. 2005;71(1):107-110. cases. Scand J Plast Reconstr Surg. 1978;12(3):261-265. 11. Blake KD, Davenport SL, Hall BD, et al. CHARGE association: an update and re- 3. Keller JL, Kacker A. Choanal atresia, CHARGE association, and congenital nasal view for the primary pediatrician. Clin Pediatr (Phila). 1998;37(3):159-173. stenosis. Otolaryngol Clin North Am. 2000;33(6):1343-1351, viii. 12. Stenson PD, Ball EV, Mort M, et al. Human Gene Mutation Database (HGMD): 4. Samadi DS, Shah UK, Handler SD. Choanal atresia: a twenty-year review of medi- 2003 update. Hum Mutat. 2003;21(6):577-581. cal comorbidities and surgical outcomes. Laryngoscope. 2003;113(2):254-258. 13. Ludbrook J. Multiple comparison procedures updated. Clin Exp Pharmacol Physiol. 5. Possum Web [CD-ROM computer program]. Version 5.7. Parkville, Victoria, Aus- 1998;25(12):1032-1037.

Correction

Error in Author Name. In the articled titled “Lower Re- construction and Restoration of Oral Competence With Dynamic Palmaris Longus Vascularized Sling” pub- lished in the December 1998 issue of the Archives (1998; 124[12]:1390-1392), one of the authors was listed as Ramzi S. Musharafieh, MD. The name should have read “Ramzi S. Moucharafieh, MD.”

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