Recent Advances in Otolaryngology—Head & Neck Surgery (Volume 5) Anil K Lalwani, Markus HF Pfister
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Precision Medicine in OtolaryngologyChapter 1

Markus HF Pfister,
Nikolaus Blin
 
INTRODUCTION
Precision medicine proposes the customization of healthcare tailoring medical treatment to the individual characteristics of each patient. Diagnostic testing is used to classify individuals into subpopulations that differ in their susceptibility to a particular disease, in the prognosis of diseases they may develop, or in their response to a specific treatment. In addition, prevention or therapeutic approaches can be individualized based on the individual genetic information.
The area of the otolaryngology and head and neck surgery is especially demanded by today's communication society with the individualized diagnosis and treatment of hearing loss (HL) (congenital as well as age-related HL or syndromic HL), of tumors in the head and neck area, and of rare diseases such as hemorrhagic telangiectasia. The focus of this chapter is on aspects of precision medicine that already have an impact on the field of Otolaryngology and Head and Neck Surgery.
 
STATE OF THE ART OF MOLECULAR DIAGNOSTICS
The current medical evaluation of hereditary diseases involves a myriad of clinical and laboratory tests, many of them being costly, time-consuming, and stressful for the patient. Deoxyribonucleic acid (DNA) diagnostics for monogenic diseases have emerged and evolved over the last decades. At this moment, genetic tests are available for most frequent genetic diseases. The benefit of these tests for the patients is very large. They aid in determining prognosis (i.e. whether the condition will deteriorate), and provide the best intervention and recurrence risk to future children and other family members. As such they allow patients and clinicians to take appropriate measures in a timely manner. In addition, genetic diagnostics are being used to predict the occurrence of disease, both in adults for diseases with late onset and prenatally. Genetic testing is fundamentally different from other clinical tests in several aspects, and important ethical issues are involved.
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It is beyond any doubt that genetic testing has taken a very important place in modern society, and it is to be expected that the demand for genetic testing will grow substantially. For some diseases, the current situation for DNA diagnostics is relatively favorable. For genetically homogeneous diseases (i.e. diseases caused by a single gene such as cystic fibrosis), it is clear which gene needs to be analyzed. Analysis of a single gene by current technology is feasible and affordable. Prices may range from <100 euros for small genes to several thousand euros for several large genes. However, for genetically heterogeneous diseases, where the same disease can be caused by many different genes, significant problems still arise.
Probably the most extreme example of a genetically heterogeneous disease is the hereditary HL. Hearing loss in children is in most cases caused by mutations in a single gene. Among these genetic cases, 70–80% are nonsyndromic, with HL being the only clinical abnormality. Most cases have an autosomal recessive inheritance. At this moment, already 70 different genes responsible for nonsyndromic HL have been identified. The rate of discovery of HL genes has been relatively constant over the last 10 years. The total number of responsible genes is unknown, but > 100 different genes can be expected.
From the clinical side, there are almost no criteria to distinguish between genes. A large majority of early childhood HL shows profound hearing impairment, and little further clinical classification can be made. Newborns with HL are partly being picked up shortly after birth by neonatal hearing screening programs, but diagnostics have to be further improved and implemented. This is very important in terms of early intervention and rehabilitation. Hearing is critical to early development and if mutations and polymorphisms linked to HL could be detected at birth then learning and development would be facilitated in the formative early months and years of life. Genetic testing of a single gene, GJB2, explaining some 5–25% of cases, is nearly always part of the follow-up protocol, as it provides very valuable information in terms of early intervention and rehabilitation in case of a positive result. However, for a majority of cases no molecular cause can be identified. This creates a very frustrating situation for clinicians and parents. In order to be fully informative, molecular diagnostics directed to HL (as would be the case for other diseases with allelic heterogeneity) involve mutation scanning of entire coding regions including exon boundaries of all known genes. Clinical genetics centers that are carrying out genetic testing for HL are experiencing increased demand for more and better genetic testing by parents, audiologists, pediatricians, and other professionals involved in neonatal hearing screening, who are witnessing the successful identification of many HL genes.
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New methods that allow for high throughput and affordable mutation scanning are now implemented and lead to improved diagnostic results.1 The new diagnostic approaches provide answers in a much higher percentage of cases, creating a benefit for patients with severe HL. One particular example is Usher syndrome.
The genotypically and phenotypically heterozygous Usher syndrome is one of the most challenging diseases known. It is the secondmost common syndromic hearing impairment with an additional loss of vision and vestibular problems. Depending on the Usher syndrome type (I, I, III), patients suffer from a loss of the both most important senses known, the sight and hearing. Patients show a progressive visual loss due to retinitis pigmentosa and a congenital sensorineural HL, which is moderate in type II and profound in type I. Typically, type I patients show also an absent vestibular response during caloric testing. In addition to the two classic clinical types, a third type featuring progressive HL has been described.2 This type is rare and has so far been found almost exclusively in Finland. Genetically, there are seven known loci for type I (USH1B-H), three for type II (USH2 A), and one for type III (USH3 A).2,3 The general speculation is that a defect in the cytoskeleton structure might be one reason for Usher syndrome. It has thus been speculated that the cilia of cochlear and vestibular hair cells could be the primary target structure in the inner ear, and that the nasal ciliary cells might also be defective, resulting in an olfactory loss. Due to the progressive visual loss, it is crucial to diagnose patients as early as possible in order to rehabilitate the hearing.
In type I patients, Cochlear implant surgery is the only option early in life to fully rehabilitate the hearing status. The genotype offers early additional information in subtyping the syndrome and allows an earlier integration in an implant program in order to use the visual input for rehabilitation.4
In types II and III patients, the situation is much more complex because a multitude of devices are possible including surgicalimplanted hearing devices. The progression of hearing in combination with the genotype allows a prediction of the phenotype. This knowledge is used regarding the choice of the hearing device, e.g. conventional hearing aids versus implantable hearing aids versus middle ear implants (Figs. 1.1A and B).44
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Figs. 1.1A and B: Part (A) represents moderate hearing impairment that can be progressive in type 3 Usher syndrome or stable in type 2 Usher syndrome. Possible implantable devices are represented by device c oder d showing a middle ear implant. Part (B) represents severe to profound hearing impairment. In this case, a cochlear implant fits best if implantation requirements are fulfilled device e.
 
SKULL BASE TUMORS/HEAD AND NECK TUMORS
 
Paraganglioma
Paragangliomas (PGL, OMIM 16,800) represent a group of generally benign tumors developing from extra-adrenal paraganglionic tissue. The majority of these tumors arise from the head and neck region with the carotid body being the most common site of origin. The incidence of paragangliomas is estimated to be between 1:100,000 and 1: 1,000,000.5 Although paragangliomas usually occur sporadically, inheritance is observed in 10–50% of cases.6
Paragangliomas (Hereditary paraganglioma–pheochromocytoma) are genetically heterogeneous. To date at least four loci within one gene family are known to be involved in their development, namely PGL1 (11q23), PGL2 (11q13), PGL3 (1q21), and PGL4 (1p36).5
The most frequently affected and, therefore, most important locus is PGL1, which was first demonstrated to co-segregate with the disease in a large Dutch family.7
Up to day, numerous mutations in the SDHD gene predispose an individual to hereditary paraganglioma–pheochromocytoma type 1; mutations in the SDHAF2 gene predispose to type 2; mutations in the SDHC gene predispose to type 3; and mutations in the SDHB gene predispose to type 4.
Hereditary paraganglioma–pheochromocytoma is inherited in an autosomal dominant pattern. An additional mutation that deletes the normal copy of the causative gene is needed to cause the condition. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only in tumor cells.
The risk of developing hereditary paraganglioma–pheochromocytoma types 1 and 2 is passed on only if the mutated copy of the gene is inherited from the father. The mechanism of this pattern of inheritance is unknown. The risk of developing types 3 and 4 can be inherited from the mother or the father.
Based on high throughput molecular testing, evaluation of relatives at risk as well as genetic counseling is possible and diagnostic as well as therapy can be tailored (see Chapter 9).8
 
Hereditary Hearing Loss and Hereditary Hemorrhagic Telangiectasia9
Several published studies suggest that infection with oncogenic human papillomavirus (HPV) constitutes is a significant risk factor for the development of head and neck carcinomas. Prevalence of HPV positivity in oropharyngeal squamous cell carcinoma has increased significantly from 16.3% between 1984 and 1989 to 72.7% between 2000 and 2004 in the United States. The same trend can be seen in Europe. At least half of oropharyngeal carcinomas contain high-risk HPV. The significance in laryngeal carcinoma is less clear.
Human papillomavirus is today a proven genetic risk factor, particularly for oropharyngeal carcinoma. An HPV detection in tumor tissue of the oropharynx is now also associated with a better prognosis. Human papillomavirus-positive oropharyngeal carcinoma patients have a reduced risk of death (28% less) as well as a reduced risk of recurrence. Some evidence indicates that outcome benefits associated with HPV positivity are greater when patients are treated with radiotherapy, than when treated by other methods.10,11-136
 
Hereditary Hemorrhagic Telangiectasia or Rendu-Osler-Weber
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder of the blood vessels, which affects approximately 1 in 5,000 people including males and females from all racial and ethnic groups. The disorder is also sometimes referred to as Osler-Weber-Rendu, named after several doctors who studied HHT about 100 years ago. In 1896, Dr Rendu first described HHT as a hereditary disorder involving nosebleeds and characteristic red spots that were distinctly different from hemophilia. Before Dr Rendu's work, doctors did not understand that individuals with what we now call HHT have abnormalities of their blood vessels, not a clotting problem in the blood itself. Dr Weber and Dr Osler reported on additional features of HHT in the early 1900s (Fig. 1.2).
Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder affecting >1.4 million people worldwide. The main manifestations are epistaxis, telangiectasias in the oral and nasal aperture, and arteriovenous malformations in the internal organs, especially in the lungs, the brain, and the gastrointestinal tract. Vascular malformations of the heart and the blood supplying coronary arteries are also described. Two important genes have been identified whose mutations lead to the formation of HHT: endoglin (ENG-HHT1) and activin receptor-like kinase 1 (ACVRL1-HHT 2). Changes in another gene, SMAD-related protein 4 (SMAD4), cause a combined syndrome of juvenile polyps of the gastrointestinal tract and HHT. At least two other unidentified genes also appear to cause HHT in a smaller number of individuals. There are hundreds of different mutations in each of the three known genes that can cause HHT. Having a mutation in an HHT-associated gene causes some blood vessels to form improperly leading to symptoms of HHT.
A detection of a mutation in these genes leads to earlier diagnosis, the possibility of risk evaluation, and allows early interventional therapy of vascular shunts in the brain, the lung, the liver, or elsewhere.14
 
SUMMARY
This chapter highlights developments in the field of otolaryngology. These developments will be significantly expanded in the upcoming years. Based on the refinement of high throughput diagnostic procedures and the integration of phenotype data/retrospective outcome data with genotype data, new diagnostic as well as treatment approaches will be seen. This will ultimately lead to an interdisciplinary, comprehensive and thus more precise approach in the treatment of patients worldwide.7
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Fig. 1.2: Typical features of Morbus Osler with autosomal dominant inheritance.
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