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Katherine JohnsonUniversity of Nebraska Medical CenterDepartment of Otolaryngology, Head and Neck SurgeryEmail: katherine_johnson13@msn.comPhone: 402-559-7777

Stridor in the newborn is a common cause for referral to the otolaryngologist. Though extremely rare, findings such as posterior glottic clefts, anterior laryngeal webs, and bifid epiglottis are associated with documented genetic syndromes. Pallister Hall Syndrome is a rare genetic syndrome with findings that include bifid epiglottis, hypothalamic hamartoma, pituitary dysfunction, and central polydactyly. Posterior glottic clefts are associated with Opitz-Frias Syndrome. In addition, this syndrome also has findings of cleft palate, tracheoesophageal fistula, and congenital heart defects. CHARGE Syndrome is characterized by colobomas, heart defects, choanal atresia, growth and development retardation, genitourinary and ear anomalies; however anterior laryngeal webs are also associated with this syndrome. These three syndromes are all diagnosed with genetic testing.

Though rare, Pallister-Hall Syndrome, Opitz-Frias Syndrome, and Velocardiofacial Syndrome can present with laryngeal findings. Understanding the clinical features associated with these syndromes will help the otolaryngologist make accurate diagnosis for improved patient care.

Laryngeal Manifestations of Common Genetic SyndromesKatherine Johnson, MD1; Allison Rasband-Lindquist, BS2; Rodney Lusk, MD3

1University of Nebraska Medical Center, 2Creighton University School of Medicine, 3Boystown National Research Institute

Opitz-Frias Syndrome:•Exceptionally rare with an incidence of 1:4,000 in the autosomal dominant form and 1:50,000-100,000 in the X-linked form•Autosomal dominant or X-linked transmission•Diagnosed clinically•Most common abnormalities include:

• Posterior laryngeal clefts (90%)• Anorectal malformations• Esophageal atresia•Hypospadias•Cardiovascular abnormalities•Tracheoesophageal fistula•Developmental abnormalities•Additional less common craniofacial abnormalities include: hypertelorism, cleft lip, and/or cleft palate

Pathophysiology of Posterior Glottic Clefts:•Posterior glottic clefts are cause by failure of posterior cricoid lamina to fuse•This causes an incomplete development of the tracheoesophageal septum•Posterior glottic clefts are classified according to their location

•Type 1: limited to the supraglottis•Type 2: extend below the cords causing a partial cleft of the cricoid•Type 3: extend through the entire length of the cricoid and into the cervical/esophageal esophagus•Type 4: extend to or below the carina

Signs & Symptoms of Posterior Glottic Clefts:•Hoarse cry•Stridor•Choking•Recurrent aspiration pneumonia

Recommended Evaluation for Posterior Glottic Clefts:•Because over 90% of patients with Opitz-Frias Syndrome suffer from posterior laryngeal clefts, it is vital to evaluation these patients for other anomalies associated with the syndrome

•It is recommended that these patients undergo intensive cardiologic , upper gastrointestinal and genitourinary evaluation

Although rare, laryngeal abnormalities are often found with Pallister-Hall Syndrome, Opitz-Frias Syndrome, and 22q11 Deletion Syndrome. Pallister-Hall Syndrome is associated with bifid epiglottis. Opitz-Frias Syndrome is related to posterior glottic clefts. 22q11 Deletion Syndrome is connected with anterior glottic webs.

Understanding the clinical features associated with these three syndromes will help the otolaryngologist make early and accurate and timely diagnosis, which will improve patient care.

Pallister-Hall Syndrome: •Extremely rare syndrome with less than 100 cases clinically recognized before the year 2000•Sporadic or autosomal dominant transmission•Diagnosed clinically•Most common abnormalities include:

• Bifid epiglottis (40-50%)• Hypothalamic hamartoma• Pituitary dysfunction• Central polydactyly• Imperforate anus• Renal abnormalities• Additional less common craniofacial abnormalities include: laryngeal clefting, tracheoesophageal fistula, micrognathia, and hard palate malformations

•Symptoms range from life-threatening to asymptomatic

Pathophysiology of Bifid Epiglottis:•Epiglottis develops as a median swelling of the fourth brachial arch•Normally, these swellings fuse completely leading to a common epiglottis•Bifid epiglottis results when the mesenchyme fails to fuse properly

Signs & Symptoms of Bifid Epiglottis: •Choking during feeding•Chronic aspiration•Stridor •Respiratory distress•Asymptomatic

Recommended Evaluation for Bifid Epiglottis:•Early diagnosis of Pallister-Hall Syndrome will prevent significant morbidity and mortality for these patients including:

•Hypothalamic dysfunction•Seizure activity

•Patients found to have a bifid epiglottis should undergo evaluation for other congenital anomalies, particularly those associated with Pallister-Hall Syndrome

•These patients should undergo intensive endocrine and ophthalmologic evaluation, serial MRIs to monitor hypothalamic hamartoma formation, and a dedicated search for associated visceral abnormalities

Posterior Glottic Clefts:Opitz-Frias Syndrome CONCLUSIONS

Anterior Laryngeal Webs:22q11 Deletion Syndrome

REFERENCES

Figure 3. A photograph demonstrates an anterior laryngeal web. This malformation is commonly associated with 22q11 Deletion Syndrome.

Figure 2. Photographs demonstrating posterior glottic cleft. This malformation is commonly associated with Opitz-Frias Syndrome.

ABSTRACT

CONTACT

22q11 Deletion Syndrome:•This gene mutation is associated with several syndromes including DiGeorge, Velocardiofacial, and CATCH 22q Deletion Syndromes•Extremely rare with a prevalence of 1:4,000•Most cases due to sporadic gene mutation with less than 5% of cases inherited•Diagnosed via fluorescent in situ hybridization (FISH)•Most common abnormalities seen include:

• Anterior laryngeal webs (65%) • Cardiac anomalies• Abnormal facies• Thymus hypoplasia and hypocalcemia• Cleft palate• Anterior laryngeal webs (65%)

Pathophysiology of Anterior Laryngeal Webs:•During normal fetal development, mesenchyme from the brachial arches proliferates and completely obstructs the laryngeal lumen•The lumen is reestablished via autolysis by the 10th week of fetal development•Anterior laryngeal webs result from incomplete canalization of the larynx•These webs are classified by the embryologic age at which arrest occurs:

•Type 1: laryngeal arrest occurs before week seven; characterized by complete laryngeal atresia•Type 2: laryngeal arrest occurs between weeks 8 and 9; characterized by supraglottic obstruction•Type 3: laryngeal arrest occurs after week 9; characterized by partial glottic obstruction

Signs & Symptoms of Anterior Laryngeal Webs:•Type 1 and 2 are fatal unless immediate tracheotomy is performed at birth

•Presents with airway obstruction and respiratory distress•Type 3 can present with mild dysphonia or considerable airway obstruction

Recommended Evaluation for Anterior Laryngeal Webs:•All children diagnosed with anterior glottic webs should be immediately evaluated for chromosome 22q11 deletion with fluorescent in situ hybridization (FISH)

Bifid Epiglottis:Pallister-Hall Syndrome

Figure 1. A photograph demonstrates a bifid epiglottis. This malformation is commonly associated with Pallister-Hall Syndrome.

1. Antao, B., Soccorso, G., Bateman, N., Shawls, R. 2007. H-type tracheoesophageal fistula with type III laryngotracheoesophageal cleft. European Archives of Otorhinolaryngology. 264:1373-1376.

2. Blake, K.D., Russell-Eggitt, I.M., Morgan, D.W., Ratcliffe, J.M., Wyse, R.K.H. 1990. Who’s in CHARGE? Multidisciplinary management of patients with CHARGE association. Archives of Diseases in Childhood. 65:217-223.

3. Dyce, O., McDonald-McGinn, D., Kirschner, R.E., Zackai, E., Young, K., Jacobs, I.N. 2002. Otolaryngologic manifestations of the 22q11.2 deletion syndrome. Archives of Otolaryngology Head and Neck Surgery. 128:1408-1412.

4. Fokstuen, S., Bottani, A., Medeiros, P.F.V., Stylianos, E.A., Stoll, C., Schinzel, A. 1997. Laryngeal atresia type III (glottic web) with 22q11.2 microdeletion: Report of three patients. American Journal of Medical Genetics. 70:130-133.

5. Funderburk, S.J., Stewart, R. 1978. The G and BBB syndromes: case presentations, genetics, and nosology. American Journal of Medical Genetics. 2(2): 131-144.

6. Horne, S.K., Michaelson, P.G., Weitzel, E. 2007. Bifid epiglottis. Ear Nose and Throat Journal. 86(11):660-661.

7. Kamata, S., Ihara, Y., Usui, N., Kamiyama, M., Soh, H., Fukuzawa, M. 2005. Surgical management for posterior laryngeal cleft developing subglottic airway obstruction. Journal of Pediatric Surgery.40:15-16.

8. Kuo, J.S., Casey, S.O., Thompson, L., Truwit, C.L. 1999. Pallister-Hall Syndrome: clinical and MR features. Am J Neuroradiol. 20:1839-1841.

9. Lipson, A.H., Yuille, D., Angel, M., Thompson, P.G., Vandercoord, J.G., Beckenham, E.J. 1991. Velocardiofacial (Shprintzen) syndrome: an important syndrome for the dysmorphologist to recognize. Journal of Medical Genetics. 28:596-604.

10. McClay, J.E., Wiatrak, B., Proud, V.K. 1997. Bifid epiglottis and polydactyly: a new genetic syndrome. Otolaryngology Head and Neck Surgery. 116:129-133.

11. McElhinney, D.B., Jacobs, I., McDonald-McGinn, D.M., Zacki, E.H., Goldmuntz, E. 2002. Chromosomal and cardiovascular anomalies associated with congenital laryngeal webs. International Journal of Pediatric Otorhinolaryngology. 66(1):23-27.

12. Miyamoto, R.C., Cotton, R.T., Rope, A.F., Hopkin, R.J., Cohen, A.P., Shott, S.R., Rutter, M.J. 2004. Association of anterior glottic webs with velocardiofacial syndrome (chromosome 22q11.2 deletion). Otolaryngology Head and Neck Surgery. 130:415-417.

13. Morgan, D., Bailey, M., Phelps, P., Bellman, S., Grace, A., Wyse, R. 1991. Ear-Nose-Throat Abnormalities in the CHARGE association. Archives of Otolaryngology Head and Neck Surgery. 119: 49-54.

14. Olney, A.H., Kolodziej, P. 1998. Pallister-Hall syndrome. ENT: Ear, Nose & Throat Journal. 77(5):370-372.

15. Ondrey, F., Griffith, A., Van Waes, C., Rudy, S., Peters, K., McCullagh, L., and Biesecker, L.G. 2000. Asymptomatic laryngeal malformations are common in patients with Pallister-Hall Syndrome. American Journal of Medical Genetics. 94:64-67.

16. Riutort, K.T., Feinglass, N.G., Brull, S.J. 2009. Anesthetic implications of Pallister-Hall Syndrome in patients with a bifid epiglottis. J Roman de Anestezie Terapie Intensiva. 16(1):71-74.

17. Roger, G., Morisseau-Durand, M.P., Van Den Abbeele, T., Nicollas, R., Triglia, J.M., Narcy, P., Abadie, V., Manac’h, Y., Garabedian, E.N. 1999. The CHARGE association: the role of tracheotomy. Archives of Otolaryngology Head and Neck Surgery. 125:33-38.

18. Stevens, C.A., Ledbetter, J.C. 2005. Clinical Report: significance of bifid epiglottis. American Hournal of Medical Genetics. 134A:447-449.

19. Sturgis, E.M., Howell, L.L. 1995. Bifid epiglottis syndrome. International Journal of Pediatric Otorhinolaryngology. 33(2):149-157.

20. Vantrappena, G., Rommela, N., Swillin, A., Cremers, C.W., Fryns, J.P., Devriendt, K. 2003. Velo-cardio-facial syndrome: guidelines for diagnosis, treatment, and follow-up of ENT manifestations. Acta Otorhinolaryngol Belgium. 57(2):101-106.