Syndromes and Genetics

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Syndromes and Genetics

Pediatric Otolaryngology
Author Credentials 

Luke Schloegel, MD
Assistant Chief 
Department of Head and Neck Surgery
Kaiser Permanente 
Oakland, California
Luke.J.Schloegel@kp.org


Brianne Barnett Roby, MD
Children’s of Minnesota
University of Minnesota Department of Otolaryngology-Head and Neck Surgery
Assistant Professor
St. Paul, MN
barne284@umn.edu

Module Summary

The role of genetics in the evaluation and management of otolaryngologic problems is increasing. From cancer treatment to pediatric hearing loss, the otolaryngologist is expected to understand inheritance patterns, genetic testing and the impact of genetics on patient care. Genetic disorders are the basis of the syndromes that significantly affect the head and neck. Furthermore, a keen understanding of common craniofacial syndromes is necessary as many of these syndromes are a routine part of our practice. Genetics is a rapidly advancing field with commercial testing also being marketed directly to patients. Therefore, it is now more important to help patients and families navigate the complexities of how genetics can affect their care. 

Module Learning Objectives 
  1. Review the basics of medical genetics.
  2. Perform a comprehensive exam of a patient with a genetic diagnosis and/or syndrome.
  3. Describe genetic testing and the clinical significance of genetic diseases affecting the head and neck.
  4. Construct a differential diagnosis of syndromes that affect craniofacial development.
  5. Describe common syndromes that significantly affect the head and neck.
  6. Explain the different syndromes that cause pediatric hearing loss.

Embryology

Learning Objectives 
  1. Use embryology, growth and development of the head and neck to facilitate understanding of syndromic disorders.
  2. Understand the embryologic development of the branchial apparatus of the head and neck, including branchial arches, pouches, and grooves.
References 
  1. Chun-Hui A, Walton C.  Phylogenetic aspects and embryology.  In: Bluestone CD, Simons JP, Healy, editors. Bluestone and Stool’s Pediatric Otolaryngology. 5th ed. Connecticut; 2014. p. 13-25.
  2. Langman’s Medical Embryology 11th ed - Ch. 9 (Skeletal System): pp. 127-134; Ch. 16 (Head & Neck): pp. 265-287.
  3. Langman’s Medical Embryology 12th ed - Ch 10. (Axial Skeleton): pp. 133-141; Ch. 17 (Head & Neck): pp. 260-282.

Anatomy

Learning Objectives 
  1. Describe the anatomy of the facial skeleton.
  2. Understand the anatomy of the aerodigestive tract.
  3. Describe the structures of the inner, middle, and external ears.
References 
  1. Jahan-Parwar B. Facial Bone Anatomy. eMedicine 2013. Editor Meyers, A.
  2. Leem T, Milam B, and Sokoya M. Head and Neck Anatomy and Embryology with Radiology Correlates. ENT Secrets Ch 9, pg 55-64. Ed. Scholes and Ramakrishnan.
  3. Francis HW. Anatomy of the temporal bone, external ear, and middle ear. In: Flint PW, Haughey BH, Lund VJ, Niparko JK, Robbins KT, Thomas JR. Lesperance MM, editors. Cummings Otolaryngology, 6th ed. Philadelphia (PA): Saunders; 2015. p.1977-86.

Pathogenesis

Learning Objectives 
  1. Describe the genetic basis of disease.
  2. Identify the difference between genetic and non-genetic craniofacial syndromes.
  3. Understand the association of clinical findings in craniofacial syndromes.
References 
  1. Alford RL, Darilek SA.  Basic Medical Genetics for the Otolaryngologist.  Adv Otorhinolaryngol. 2011; 70:10-17.
  2. Rozen S and Salyer K. Craniofacial Syndromes. Plastic Surgery Secrets Plus Ch 36 pg 238-243. Ed Weinzweig.
  3. Tewfik T. Manifestations of Craniofacial Syndromes. eMedicine 2017. Editor Meyers, A. 

Basic Science

Learning Objectives 
  1. Draw a familial pedigree for recognition of genetic susceptibilities and inheritance patterns.
  2. Understand variations in traditional inheritance patterns.
  3. List the molecular basis of selected craniofacial syndromes.
References 
  1. Chun-Hui A, Walton C. Genetics, syndromology, and craniofacial anomalies. In: Bluestone CD, Simons JP, Healy, editors. Bluestone and Stool’s Pediatric Otolaryngology. 5th ed. Connecticut; 2014. p. 27-58.

Incidence

Learning Objectives 
  1. Recount the incidence and prevalence for genetic conditions commonly seen in pediatric otolaryngology.
  2. Understand the incidence of craniofacial syndromes.
  3. Describe the incidence of pediatric hearing loss related to syndromes and genetic abnormalities.
References 
  1. Friedmann DR, Lalwani AK. Genetic basis of conditions commonly seen in ORAL practice.  Adv Otorhinolaryngol. 2011; 70:1-9.
  2. Murray, J and Marazita M. Clefting, Dental, and Craniofacial Syndromes. Emery and Rimoin’s Principles and Practices of Medical Genetics 6th edition, 2013. Editor Rimoin D, Pyeritz R, and Korf B.
  3. Koffler T, Ushakov K, Avraham KB. Genetics of hearing loss – syndromic. Otolaryngol Clin N Am. 2015; 48(6):1041-61.

Genetics

Learning Objectives 
  1. Understand the mechanisms of genetic mutation and patterns of inheritance.
  2. Describe the genetic basis of cystic fibrosis, hereditary hemorrhagic telangiectasia, and primary ciliary dyskinesia.
  3. Identify the role of genetic counselor in patient management.
References 
  1. Alford RL, Darilek SA. Basic Medical Genetics for the Otolaryngologist. Adv Otorhinolaryngol. 2011; 70:10-17.
  2. Sosnay PR, Raraigh KS, Gibson, RL. Molecular Genetics of Cystic Fibrosis Transmembrane Conductance Regulator: Genotype and phenotype. Pediatr Clin N Am. 2016; 63:585-598.
  3. Faughnan ME, Palda VA, Garcia-Tsao GG, et al. International guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. J Med Genet. 2011; 48:73-87.
  4. Kurkowiak M, Zietkiewicz E, Witt M. Recent advances in primary ciliary dyskinesia genetics. J Med Genet. 2015; 52: 1-9.
  5. Duncan RD, Prucka S, Wiatrak BJ, et al. Pediatric otolaryngologists’ use of genetic testing.  Arch Otolaryngol Head Neck Surg.  2007; 133(3): 231-6.

Patient Evaluation

Learning Objectives 
  1. Take a comprehensive history and perform a complete physical examination for a child with a genetic or syndromic problem.
  2. Understand the airway abnormalities that can affect patients with craniofacial abnormalities.
  3. Discuss the importance of multi-disciplinary evaluation of patients with craniofacial syndromes.
References 
  1. Bohm, LA, Sidman JD, Roby B. Early Airway Intervention for Craniofacial Anomalies. Facial Plastic Surg Clin North Am. 2016 Nov; 24(4):427-436.
  2. Swibel Rosenthal, LH, Caballero N, and Drake, A. Otolaryngology Manifestations of Craniofacial Syndromes. Otolaryngologic Clinics of North America. 45(3):557-577 2012.
  3. Capone RB, Butts SC, Jones LR, et al.  Starting a cleft team: a primer.  Facial Plast Surg Clin North Am.  2014 Nov; 22(4):587-91.

Measurement of Functional Status

Learning Objectives 
  1. Understand the current options for genetic testing in hearing loss.
  2. Discuss universal hearing screening and audiologic testing in pediatric patients with hearing loss.
  3. Stay up to date on genetic testing options for specific syndromes.
  4. Discuss the different feeding, growth, and neurologic issues associated with craniofacial and airway syndromes.
References 
  1. Sloan-Heggen CM, Bierer AO, Shearer AE, et al.  Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss.  Hum Genetics.  2016; 135:441-450.
  2. Cohen M, Phillips JA 3rd.  Genetic approach to evaluation of hearing loss. Otolaryngol Clin North Am. 2012; 45:25-39.
  3. Singleton AJ, Waltzman SB. Audiometric evaluation of children with hearing loss. Otolaryngol Clin N Am. 2015; 48(6):891-901.
  4. Genetic Testing Registry 
  5. Swibel Rosenthal, LH, Caballero N, and Drake, A. Otolaryngology Manifestations of Craniofacial Syndromes. Otolaryngologic Clinics of North America. 2012 Jun; 45(3):557-577.

Imaging

Learning Objectives 
  1. Understand the imaging modalities best at assessing anatomy for pediatric syndromic hearing loss.
  2. Discuss imaging modalities to assess craniofacial anomalies, including prenatal ultrasound, CT with 3-dimensional reconstruction, and MRI.
References 
  1. DeMarcantonio M, Choo DI. Radiographic evaluation of children with hearing loss. Otolaryngol Clin N Am. 2015; 48(6):913-32.
  2. Robson CD and Juliano A. Head and Neck Imaging. Pediatric Radiology: The Requisites 4th edition, Chap 10, 353-404.

Treatment

Learning Objectives 

Describe how genetic-based therapies may be utilized in cystic fibrosis and congenital hearing loss.

References 
  1. Egan ME. Genetics of Cystic Fibrosis. Clinical Implications. Clin Chest Med. 2016 Mar;37(1):9-16.
  2. Chien WW, Monzack EL, McDougald DS, et al.  Gene therapy for sensorineural hearing loss.  Ear Hear. 2015;36:1-7
  3. Chien WW.  A CRISPR Way to Restore Hearing.  N Engl J Med. 2018; 378(13):1255-1256.

Medical Therapies

Learning Objectives 

Relate emerging medical therapies for sensorineural hearing loss.

References 
  1. Kelly KM, Lalwani AK. On the Distant Horizon – Medical Therapy for Sensorineural Hearing Loss. Otolaryngol Clin N Am. 2015; 48:1149-1165.

Surgical Therapies

Learning Objectives 
  1. Determine if an underlying genetic diagnosis can predict functional outcomes in cochlear implantation.
  2. Discuss surgical treatment of craniofacial syndromes.
References 
  1. Park JH, Kim AR, Han JH, et al.  Outcome of Cochlear Implantation in Prelingually Deafened Children According to Molecular Genetic Etiology.  Ear Hear. 2017; 38:316-324.
  2. Crockett DJ and Goudy SL. Cleft lip and palate. Facial Plast Surg Clin North Am. 2014 Nov; 22(4):573-86.

Case Studies

  1. 4 year old male presents with frequent and prolonged epistaxis.  Present since about 1 year of age.  He has a history of nasal cauterization in the office.  An extensive coagulopathy workup was normal.  Regular application of ointment has yielded no improvement.  Allergy testing was negative.  The patient’s father has also had nosebleeds his whole life, and his younger brother is also having frequent nosebleeds.  Would you offer patient genetic testing?  Would genetic testing change your management?  In healthy children with HHT, would you recommend surveillance for AVMs?
  2. An 8 year old boy presented after failing a school hearing screen.  He also recently started speech therapy at school for articulation problems.  A diagnostic audiogram was obtained that showed bilateral mild to profound sensorineural hearing loss.  No hx of sudden change in hearing, no tinnitus, no vertigo.  He does not report ear symptoms.  No perinatal risk factors for hearing loss, no familial history of hearing loss.  Which diagnostic test is highest yield to identify an etiology of his hearing loss?  The patient was found to have an autosomal dominant mutation associated with progressive hearing loss.  What does this result mean for this patient? And his family?
  3. A 3 month old female presents after finding bilateral neck cysts consistent with branchial cleft cysts. Parents can’t remember if she passes her newborn hearing screen, but an audiogram performed in clinic shows bilateral sensorineural hearing loss. What syndrome would this be consistent with? What other testing should be performed?
     

Review

Review Questions 
  1. What are the branchial arches and the structures that they form?
  2. What are the most common craniofacial syndromes?
  3. What syndromes are most likely to affect the aerodigestive tract?
  4. Please relate how a genetic diagnosis as an etiology for hearing loss can directly impact patient care?
  5. What are some ways to find out which genetic tests are available for certain disease conditions?
Resources 

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  1. Annual Meeting Webcast (AMW):