Учебники / Otolaryngology - Basic Science and Clinical Review

Children with supraglottitis usually present between the ages of 2 and 6 years with a history of a rapidly progressive upper respiratory infection, with high fevers (102–103 F), severe odynophagia, restlessness, drooling, and a muffled voice.The patient will often be in the upright position, with the head held forward and the tongue protruding from the mouth. Marked inspiratory stridor, retractions, and tachypnea are common. Physical examination should be limited to an overall inspection and auscultation of the heart and lungs.The child should not be traumatized, particularly with a vigorous intraoral examination or by intravenous puncture.The only diagnostic test that might be appropriate is a lateral soft tissue x-ray of the neck to evaluate the epiglottic shadow (Fig. 18-2).

The child should be taken immediately to the operating room to undergo slow induction inhalation anesthesia while in a parent’s arms. Once a mask airway is obtained, intravenous line placement and blood cultures are obtained. Intraoral endotracheal intubation is performed by the most experienced physician, after which epiglottic cultures can be obtained. Blood and epiglottic cultures and sensitivity tests will usually confirm the diagnosis and guide antibiotic therapy. Laryngoscopes, rigid ventilating bronchoscopes, and tracheotomy equipment should be available immediately in the operating room. Patients treated in the intensive care unit with intravenous antibiotics typically respond within 48 hours and can be extubated.

GLOTTIC/SUBGLOTTIC

Laryngotracheobronchitis (Croup)

Acute laryngotracheobronchitis (LTB) is a common cause of stridor in children, usually occurring prior to age 2 years. LTB represents an acute viral illness usually caused by parainfluenza virus and presents with diffuse edema of the lower airway. The symptoms occur gradually over several days and may be associated with signs of an upper respiratory tract infection. Children demonstrate a “barking” cough with biphasic stridor due to subglottic edema. Few children develop airway obstruction severe enough to require endotracheal intubation. Most patients are less than 2 years old, although older children may be susceptible due to congenital narrowing of the subglottis (i.e., elliptical malformation).

Anteroposterior radiographs of the neck often reveal the narrowing of the subglottic tissues, termed the “steeple sign.” Although usually not required, FFL reveals soft tissue swelling just below the true vocal cords (TVCs). No significant leukocytosis is noted on complete blood count. Most cases can be treated expectantly on an outpatient basis. Only 10% of cases will require hospitalization for humidification, supplemental oxygen, fluids, racemic epinephrine, and corticosteroids, although the use of the latter is controversial. Airway support or pulmonary failure is considered uncommon.

Subglottic Stenosis

Subglottic stenosis (SGS) is the most common fixed anatomical airway obstruction.This is due to the narrow confines of this portion of the airway and the noncompliant circumferential cartilaginous support that is unique to the subglottis. The etiology is either from congenital narrowing or from soft tissue formation (acquired) after endotracheal intubation. No matter the etiology, the symptomatology in patients with SGS includes biphasic stridor, retractions, and a normal voice or cry. Respiratory distress and feeding difficulty may be present in severe cases. In milder cases, patients may be symptomatic only during bouts of upper respiratory infections. The diagnosis of SGS may be presumed from history, physical examination, flexible fiberoptic laryngoscopy, and AP radiographs of the neck, but surgical endoscopy is required to confirm the size of the airway. The stage of SGS is based on the calculated airway size reduction determined during surgical endoscopy, as previously described (Table 18-4).

Previously, cases of acquired SGS were thought to outnumber congenital SGS by 9:1, although congenital SGS may be more prevalent than once thought. Since the widespread use of endotracheal intubation in 1965, the number of cases of acquired SGS dramatically increased but has subsequently stabilized due to the improvements in intensive care. Damage from the endotracheal tube causes mucosal edema, ulceration, granulation tissue, and subsequent scar formation (Fig. 18-3). Occasionally, minor trauma may produce subglottic cysts, which usually respond to simple laser excision.Acquired SGS is usually treated with a tracheotomy for initial airway support, with subsequent laryngotracheal reconstruction performed after 1 year of age. Long-term stenting is used based on the degree of stenosis. Cricotracheal resection has been employed recently to improve the success rate of surgical repair in cases of grade III or IV stenosis.

About 1% of “normal” children have a larynx two endotracheal tube sizes (1.0 mm) below predicted; in 0.06% of cases, the larynx is three tube sizes (1.5 mm)

TABLE 18-4 STAGES OF SUBGLOTTIC STENOSIS

(Data from Myer CM, O’Conner DM, Cotton RT. Proposed grading system for subglottic stenosis based on endotracheal tube sizes. Ann Otol Rhinol Laryngol 1994;103:319–323.)

Figure 18-3 Subglottic stenosis demonstrated on bronchoscopy after prolonged and multiple intubations.

smaller than normal.These children are at higher risk to develop damage from endotracheal tube intubation. Congenital SGS is typically cartilaginous in nature. Anomalies consist of a thickened cricoid, trapped first tracheal ring, elliptical or ovoid shape, and, rarely, soft tissue stenosis. Patients with congenital SGS typically present at several months of age, often during an upper respiratory infection. Most patients will require only observation and symptomatic treatment for episodes of croup. Less than 10% of children will require surgical treatment, which consists of laryngotracheal reconstruction with or without tracheotomy.

TrueVocal Cord Paralysis

TVC paralysis represents 10% of stridor in infants. Congenital disorders represent over 50% of all cases of paralysis. Neurological disorders, including ArnoldChiari malformations and Möbius’ syndrome, are relatively common causes of congenital paralysis in children and may exhibit bilateral paralysis. Other patients with neurological disorders may display paradoxical motion (vocal fold dyskinesia), which is inward motion of theTVCs during inspiration.A family history may discover familiar abductor paralysis.Acquired paralysis is secondary to birth trauma, intubation, and surgical trauma, including repairs of a congenital heart defect, tracheoesophageal fistula, and most commonly a patent ductus arteriosus. As compared with adults, bilateral TVC paralysis in children is relatively more common than unilateral paralysis, although the latter is still fortunately more common. Bilateral paralysis typically produces severe airway distress and stridor due to the location of the cords in the paramedian position, while the voice (cry) and feeding are often normal. The stridor is constant, worse with exertion, and high pitched.

After complete history and physical examination to rule out concomitant anomalies, the diagnosis is confirmed by flexible fiberoptic laryngoscopy in the awake child. It is highly recommended that complete videorecording capability be available to adequately evaluate the TVC motion. In search of the underlying etiology, the clinician must investigate the entire path of the recurrent laryngeal nerve, including the brainstem, neck, and chest. Consideration should be made for MRI or CT evaluation from the brain to the chest in cases where no etiology can be determined. Surgical endoscopy should be strongly considered to evaluate the remaining airway, rule out cricoarytenoid joint fixation, and perform electromyography (EMG) of the thyroarytenoid and posterior cricoarytenoid (PCA) muscles. Possible EMG patterns include polyphasic action potentials (reinnervation), fibrillation potentials (deinnervation), and no potentials (never innervated or long-standing paralysis). Spontaneous recovery of TVC paralysis is more likely in unilateral cases with evidence of polyphasic action potentials.

Tracheotomy is often required in children with bilateral TVC paralysis, and no therapy is required for most patients with unilateral paralysis. Surgical interventions for bilateral paralysis are aimed at opening the airway by either removing or lateralizing existing tissue. Definitive treatment includes arytenoidectomy (external via laryngofissure or endoscopic laser excision), endoscopic laser cordotomy, arytenoidopexy (lateralization), and PCA reinnervation. Many patients with unilateral paralysis require no therapy or can be decannulated by age 1 to 2 years if tracheotomy is present. Definitive treatment to improve the voice and prevent aspiration in patients with unilateral paralysis is attained by medialization of the TVC externally (thyroplasty), internally (injection), or by selective reinnervation.

Recurrent Respiratory Papillomatosis

The most common tumor of the larynx, squamous papilloma, accounts for more than 80% of laryngeal growths. Recurrent respiratory papillomatosis (RRP) represents a benign tumor that recurs frequently after surgical excision and can cause complete airway obstruction. Six thousand children are affected per year in the United States, usually presenting prior to the age of 7 years, often before 2 years of age.Two broad classifications exist in patients with RRP. Juvenile, or aggressivetype, RRP has an unrelenting course of recurrent disease that may take many years to resolve and typically occurs in younger patients. Although spontaneous regression can occur around puberty, lifelong disease

can be present, sometimes complicated by distal airway papillomas. Adult, or benign-type, RRP tends to have much fewer recurrences after surgical therapy, does not involve the distal airways, and tends to occur postpuberty. Because multiple surgical excisions are required during the prolonged course of many patients with this disease, over $100 million is spent annually in the United States for the management of RRP.The human papilloma virus (primarily subtypes 6 and 11) is the causative organism. An association with vaginal papillomas has been made, although the practice of elective cesarean sections has not been shown to be completely protective for the newborn.

Patients with RRP present with a hoarse or muffled voice (or cry), and some patients may be aphonic.Airway distress may be present if the papillomas obstruct the larynx. Diagnosis is made either by FFL or at the time of DLB in the operating room. Biopsy is often recommended to confirm the papilloma subtype and to rule out malignant degeneration, although the latter is a rare phenomenon. CO2 laser laryngoscopic excision is the standard therapy. Several adjuvant therapies have been developed in light of the generally high recurrence rate, with surgery alone for those patients with “aggressivetype” disease. Interferon- -2a has been the most widely studied adjuvant therapy, followed by indole-3-carbinol, acyclovir, ribavirin, methotrexate, retinoic acid, and most recently photodynamic therapy. All have shown initial promise, but further study is being done to confirm the role of these adjuvant therapies in the treatment of RRP. Recently another antiviral, cidofovir, has shown clinical promise in lessening the extent of disease and even eradicating papillomas.

Hemangioma

Hemangiomas are the most common tumor of the head and neck in children and represent a benign neoplastic collection of endothelial cells that undergo an initial rapid growth phase during the first few years of life. Subsequently, the tumor undergoes spontaneous regression with fibrofatty tissue deposition.The classic growth pattern and characteristic appearance are adequate for the diagnosis.A biopsy of the lesion is not recommended. Most hemangiomas in children are innocuous pink or red macules that cause no dysfunction. It is estimated that 10% of the Caucasian population and as much as 22% of preterm infants will develop hemangiomas. There is a 3:1 female preponderance as well as a predilection for Caucasians.

When the lesions are cutaneous, the diagnosis is easily made. Skin lesions can vary from small red macules to massive tumors that distort normal features

Figure 18-4 Subglottic narrowing due to a subglottic hemangioma. Note the erythematous soft tissue stenosis and narrowing of the airway.

and cause compression of the visual axis or aerodigestive tract. Multifocal local and systemic disease that requires active therapy occurs in less than 5% of all cases. Stridor can be caused by subglottic hemangiomas, which is associated with cutaneous hemangiomas in 50% of children (Fig. 18-4). These children present with airway symptoms similar to patients with subglottic stenosis. A severe and potentially life-threatening complication that may occur in a hemangioma-like lesion (hemangioendothelioma) is Kasabach-Merritt syndrome. This is a consumptive coagulopathy that occurs within these large vascular tumors.

Treatment depends on the severity of the lesions. Careful observation in patients with small macular lesions is still recommended. At the first sign of rapid growth either medical or laser therapy should be instituted. Some patients present with massive tumors or airway lesions already present. Medical therapy has traditionally consisted of high dose (2–4 mg/kg/day) corticosteroids given for weeks to months based on the response to therapy. Complete response to corticosteroid therapy is reported in only about one third of cases. Recently, interferon- -2a was reported to induce complete responses in up to 60% of patients. Due to the possibility of neurological complications (fine motor and gait dysfunction), particularly in patients under 1 year of age, dosages should be gradually increased up to a goal of 3 million units/m2.The duration of interferon therapy in massive hemangiomas can be for up to

16 months. Laser therapy, such as with the yttrium- aluminum-garnet (YAG) laser, flash lamp pumped dye, and copper vapor lasers, have been used successfully to treat superficial hemangiomas, but they are limited by the depth of penetration of the laser. Therefore, early recognition and treatment are vitally important for laser therapy to be successful. Recently, intralesionalYAG laser therapy has been proposed in massive tumors.This treatment holds promise, but further studies are required.

TRACHEAL

Tracheomalacia/Tracheal Stenosis

Obstruction of the trachea by either functional collapse (malacia) or a fixed narrowing (stenosis) is generally considered a rare cause of significant airway compromise in children.Tracheomalacia may be primary or secondary to external compression. Primary tracheomalacia may be related to cartilaginous weakness that has been hypothesized to be a factor in the pathogenesis of laryngomalacia. The narrowing may be generalized or segmental. External compression is most commonly caused by anomalous vascular structures, or more rarely by mediastinal tumors or bronchogenic cysts. Common vascular anomalies include aberrant innominate artery, left pulmonary artery, left subclavian artery, and aortic arch and cardiac anomalies. Stenosis represents a congenital narrowing of the trachea either by scar tissue or due to complete tracheal rings. The narrowing may be segmental, funnel-like, or generalized in nature.

Stridor is primarily expiratory and may be associated with a deep seal-like cough. Patients may experience cyanosis, apneic spells, or recurrent lower respiratory infections. The diagnosis is confirmed by surgical endoscopy, with radiographic imaging (MRI or CT) reserved for patients with external tracheobronchial compression. Primary tracheomalacia usually resolves spontaneously during the first year of life. Patients with severe primary tracheomalacia require continuous positive airway pressure via nasal catheter or tracheotomy. Surgical intervention is typically required in patients with vascular compression or tracheal stenosis. Repair of the former consists of either aortopexy (innominate artery compression) or complex cardiac reconstruction. Segmental or funnel-type tracheal stenosis, fortunately, is the most common and requires a tracheoplasty using either cartilage interposition grafts or pericardial patches. In addition, resection with primary anastomosis has been successfully used for short-segment tracheal stenosis. Tracheal homograft transplant has also been advanced in Europe as a successful treatment, particularly in long-segment stenosis.

Figure 18-5 Lateral chest radiograph of a 2-year-old child with an upper esophageal foreign body (coin).Note the secondary narrowing of the trachea due to edema of the tracheoesophageal membrane.

Foreign Bodies

Inhaled or ingested foreign objects are a relatively common cause of airway obstruction and can be associated with significant mortality and morbidity. Public awareness and prevention education, rapid-response paramedic teams, and the introduction of the Heimlich maneuver have all decreased the mortality of children with foreign bodies in the United States from 650 deaths in 1968 to 261 deaths in 1990. Although a variety of foreign objects have been aspirated or ingested, esophageal coins are most commonly found. Airway obstruction occurs due to secondary swelling of the posterior tracheal wall (Fig. 18-5). Due to either the immediate demise of the patient or the rapid expulsion of the object, laryngopharyngeal foreign bodies rarely present to the clinician.Tracheobronchial foreign bodies primarily consist of vegetative matter, primarily peanuts, followed by a variety of inanimate objects (e.g., beads, toys).

Esophageal foreign bodies may be asymptomatic for long periods of time, until airway distress, dysphagia, and drooling develop. Pulmonary objects often produce a period of violent paroxysms of coughing, choking, and occasionally a color change. This acute episode may go unnoticed and is followed by an asymptomatic stage that may last for weeks to months. The final stage is that of intrathoracic complications, such as airway obstruction,

infection, or tracheal erosion. Chest radiographs, with inspiratory and expiratory views, will often demonstrate a unilateral infiltrate or air trapping. Because the right mainstem bronchus take-off is at less of an angle to the trachea, most foreign bodies tend to lodge in the right bronchus intermedius or segmental bronchi. A high index of clinical suspicion should be maintained for airway foreign bodies in any child with atypical, unilateral, or suspicious respiratory symptoms, so as to initiate prompt treatment and avoid possibly devastating complications.

The treatment of aerodigestive foreign bodies involves prompt endoscopic evaluation and removal of the object. For nontraditional objects, the surgeon should obtain a duplicate object and practice the extraction technique. Endoscopic forceps offer state-of-the-art visualization and extraction capabilities. Fogerty catheters are often helpful to either manipulate the foreign body to a more proximal location or stabilize the object for endoscopic removal. Vegetative matter is especially difficult to remove because of the soft and immunoreactive nature of the fragments. Bronchoalveolar lavage is often required to assist in clearing the debris from the airway. Other adjuvant therapies include antibiotics, mucolytics, bronchodilators, and chest physiotherapy. Although rare, the protocol for laryngeal foreign bodies should be similar to that for the careful and gentle approach to patients with epiglottitis. The otolaryngologist, with full airway support equipment available, should perform laryngeal foreign body extraction.

SUGGESTED READINGS

Albert D, Leighton S. Stridor and airway management. In: Bailey BJ, ed. Otolaryngology–Head and Neck Surgery. 2nd ed. Philadelphia: Lippincott-Raven; 1998

Cotton RT, Reilly JS. Stridor and airway obstruction. In: Bluestone CD, Stool SE, Kenna MA, eds. Pediatric Otolaryngology. 3rd ed. Philadelphia:WB Saunders; 1996

Greinwald JH, Smith RJH. Laryngeal disorders. In: Oski FA, DeAngelis CD, Feigin RD, McMillan JA, Warshaw JB, eds. Principles and Practice of Pediatrics. Philadelphia: Lippincott; 1999

Lesperance MM, Zalzal GH. Assessment and management of laryngotracheal stenosis. Pediatr Clin N Am 1996;43: 1413–1427

Pransky SM, Albright JT, Magit AE. Long-term follow-up of pediatric recurrent respiratory papillomatosis managed with intralesional cidofovir. Laryngoscope 2003;113:1583–1587

Roger G, Denoyelle F,Triglia JM, Garabedian EN. Severe laryngomalacia: surgical indications and results in 115 patients. Laryngoscope 1995;105:1111–1117

SELF-TEST QUESTIONS

For each question select the correct answer from the lettered alternatives that follow.To check your answers, see Answers to Self-Tests on page 716.

1.Which of the following statements is correct?

A.Stertor is a high-pitched musical noise.

B.Rhonchi are high-pitched noises caused by reverberation of oropharyngeal tisues.

C.Rales are a popping noise heard in the peripheral lung fields.

D.Stridor, wheezing, and rales all refer to the same pathological airway noises

2.Which of the following types of radiographic evaluations may be used to evaluate patients with airway noise?

A.Barium swallow study

B.CT

C.MRI

D.Ultrasound

E.All of the above

3.Which of the following is not a part of the CHARGE association?

A.Choanal atresia

B.Colobomas of the eyes

C.Cardiac defects

D.Hyalinization of the glottic tissue

E.Ear malformations

HUMAN MEDICAL GENETICS

TUMORS OF THE HEAD AND NECK

FEATURES OF HEREDITARY NEOPLASMS

(MUTATIONS IN PATIENT’S GERM LINE)

MEDULLARY THYROID CARCINOMA AND

PARATHYROID TUMORS

FAMILIAL PAPILLARY CARCINOMA OF THE THYROID

HEAD AND NECK SQUAMOUS CELL CARCINOMA

NASOPHARYNGEAL CARCINOMA

LYMPHOMA

RHABDOMYOSARCOMA

HEREDITARY PARANGANGLIOMA

NEUROFIBROMATOSIS TYPE 2, CENTRAL-TYPE

NEUROFIBROMATOSIS, BILATERAL ACOUSTIC

SCHWANNOMAS, AND ACOUSTIC

NEUROFIBROMATOSIS

COAGULOPATHIES

VON WILLEBRAND’S DISEASE

HEMOPHILIA A (CLASSIC HEMOPHILIA,

FACTOR VIII DEFICIENCY)

VENOUS THROMBOSIS DUE TO FACTOR V

LEIDEN DEFICIENCY

INCREASED ANESTHESIA AND OPERATIVE RISK

MALIGNANT HYPERTHERMIA SUSCEPTIBILITY

SICKLE CELL ANEMIA

INHERITED SYNDROMES ASSOCIATED WITH SINUSITIS

CYSTIC FIBROSIS

KARTAGENER’S SYNDROME (DEXTROCARDIA,

BRONCHIECTASIS AND SINUSITIS, IMMOTILE

CILIA SYNDROME)

METABOLIC SYNDROMES INVOLVING THE

HEAD AND NECK

MUCOPOLYSACCHARIDOSIS TYPE I

MUCOPOLYSACCHARIDOSIS TYPE II

(HUNTER SYNDROME)

CHROMOSOMAL SYNDROMES

DOWN SYNDROME, TRISOMY 21

TURNER SYNDROME, X CHROMOSOME

DEFICIENCY (XO)

CRANIOFACIAL DYSMORPHISM SYNDROMES

CLEFT LIP AND CLEFT PALATE SYNDROMES

22Q11 DELETION SYNDROMES

STICKLER’S SYNDROME

CRANIOFACIAL SYNOSTOSIS

TREACHER COLLINS SYNDROME,

MANDIBULOFACIAL DYSOSTOSIS

OSTEOPETROSIS (ALBERS-SCHÖNBERG DISEASE)

HEREDITARY HEARING IMPAIRMENT

BRACHIO-OTO-RENAL SYNDROME

PENDRED SYNDROME

ALPORT SYNDROME

JERVELL AND LANGE-NIELSEN SYNDROME

NORRIE DISEASE

USHER SYNDROME

Genetics is playing an increasingly critical role in the practice of clinical medicine. This is due in part to the importance that knowledge of genetics has in the treatment of genetic diseases, but also in part to the fact that such knowledge provides an understanding of the fundamental biological process of most diseases. Some common disorders are due to the interaction of multiple genes and environmental factors, and genetic variations may have either a protective or a pathological role in the expression of a disease. For example, although presbycusis and noise-induced hearing loss could be dismissed as the result of accumulated age and environmental trauma, animal studies have shown that genetic background is an important determinant of the final outcome. Today’s otolaryngologist must understand the science of medical genetics because this knowledge can lead to more effective disease diagnosis, treatment, and prevention. Hearing loss, neoplastic disease, metabolic disease, coagulopathies, and congenital malformations of the head and neck are the disorders in otolaryngology most likely to involve genetic variations, and in these instances knowledge of genetics and molecular biology may be fundamental for making a differential diagnosis and selecting a management protocol.

HUMAN MEDICAL GENETICS

Genetic information is passed from one generation to the next as coded information in the human genome. Deoxyribonucleic acid (DNA) sequences form genes that are expressed through ribonucleic acid (RNA) into proteins. The human genome includes all DNA in the 46 chromosomes: 22 pairs of autosomes and the sex chromosomes XY in males and XX in females. An estimated 30,000 to 35,000 genes are present on the human genome, but they account for only 2% of its length (see Chapter 15). It is currently accepted that more than one protein can derive from one gene through the mechanism of alternative splicing. Scattered within and between genes are vast stretches of DNA whose function is less well understood.

Genes are distributed unevenly between chromosomes and within each chromosome. Chromosomes 17, 19, and 22 are particularly gene dense as compared with other chromosomes, such as 4, 8, 13, 18, and Y. Within each chromosome, gene density is highest in areas rich in the DNA bases cytosine and guanine. Gene locus refers to the position of the gene in a chromosome. An alphanumeric code describes the locus of a gene on each nuclear chromosome. The first number (or letter) designates the chromosome: autosomes 1 through 22, sex chromosomes X or Y. The next part of a gene locus is a letter: q for the long arm of a chromosome, p for the short arm. The final part of the locus code is a number that often contains a decimal point.This refers to a Giemsa-stained band on the arm of the designated chromosome. Several genes that are involved in energy metabolism are located not on chromosomes located within the nucleus but rather on a mitochondrial chromosome; these are designated mitochondrial DNA (mtDNA).

Individuals inherit 50% of their chromosomal makeup from their father and 50% from their mother. Every gene is paired, one copy of the pair being paternal and the other maternal in origin. The two genes of the gene pair are not necessarily identical; subtle differences may be present. Each copy of a gene is known as an allele. Certain alleles are associated with a change in gene function that is reflected by a specific physical characteristic or phenotypic appearance. Disease-causing alleles arise from mutations. Mutant genes can occur in the germ line (hereditary) or can arise de novo from changes in DNA sequences (sporadic). Different mutations in the same gene can act as alleles and cause different manifestations of disease (e.g., familial medullary carcinoma and multiple endocrine neoplasias). Current data indicate that mutations known to cause diseases have been identified in nearly 1000 genes.

Genetic disorders are broadly classified into four major groups:

•Chromosome disorders, in which entire chromosomes or large segments of them are altered. These changes are often visible by karyotyping, and may be inherited in a Mendelian fashion or

may represent isolated genetic mutations. Examples of chromosome disorders include Down syndrome and Turner syndrome.

•Monogenic disorders, also known as Mendelian disorders, because they involve alterations in single nuclear genes and follow Mendel’s laws of inheritance. Examples include nonsyndromic sensorineural hearing loss and cystic fibrosis.

•Multifactorial disorders, which are due to a combination of multiple genetic as well as environmental causes.Well-known examples include birth defects such as cleft lip and palate, as well as some adult disorders such as heart disease, diabetes, and cancer.

•Mitochondrial disorders, which are single-gene disorders caused by alterations in the mitochondrial chromosome. Each mitochondrion contains two to 10 mitochondrial chromosomes. Human mtDNA encodes 13 messenger RNA (mRNA) molecules, as well as 2 ribosomal RNAs (rRNAs) and 22 organelle-specific transfer RNAs (tRNAs), which are required for assembling a functional proteinsynthesizing system. MtDNA, along with its variations, is inherited solely from the mother because ova are rich in mitochondria and sperm are not.Therefore, it follows a maternal pattern of inheritance, which is different from the pattern of inheritance of nuclear genes (Fig. 19-1). Examples

include familial susceptibility to aminoglycoside ototoxicity and presbycusis.

Mendelian disorders traditionally have received the greatest amount of attention since the establishment of the interaction between alleles and phenotypic appearance by Gregor Mendel in the 19th century. Alleles that express in only a single gene (i.e., heterozygous) are dominant inheritance. Recessive alleles are only expressed if present doubly (homozygous).These patterns of allelic inheritance are referred to as autosomal dominant and autosomal recessive, respectively. Autosomal dominant inheritance is characterized by transmission of the disease phenotype generation after generation, with an equal number of affected males and females and a recurrence risk of 50%.Autosomal recessive inheritance is characterized by “skipped” generations (the disease is seen in multiple siblings, but usually no earlier generations are affected), no sex predilection, and a recurrence risk of 25%. Consanguinity is usually present in recessive disease because related individuals are more likely to share the disease gene.

Fewer genes exist on the Y chromosome than on the X chromosome; therefore, sex chromosome alleles usually are not paired. X-linked patterns of inheritance usually are recessive.This implies that a female, by virtue of two X chromosomes, is a carrier. Fifty percent of a carrier female’s sons are affected, and 50% of her daughters are

Figure 19-1 A family tree depicting the inheritance of deafness for three generations of a family carrying a mutation in their mitochondrial DNA. Note that both male (squares) and female (circles) family members are affected but that the pattern of inheritance is

strictly maternal. This is because only the fertilized ovum contains most of the heritable mitochondrial DNA, and the contribution of mitochondrial DNA to the fertilized zygote from the spermatazoa is negligible.

carriers. All male progeny of affected males are normal, and all female progeny of affected males are carriers.

Genetic diseases usually show variable expressivity beyond simple Mendelian inheritance. An affected individual may exhibit few, some, or all of the manifestations of an allele. Occasionally, an individual with a particular gene abnormality will not exhibit the disease phenotype at all,even though the person can transmit the disease gene to the next generation, and the gene is said to have reduced penetrance.Variable expression of a genetic disease may be caused by genetic or environmental factors. Among the genetic factors, modifier genes, allelic heterogeneity, and genomic imprinting are common. Other genes can influence the expression of a disease-causing gene and are termed modifier genes.Allelic heterogeneity refers to the effect that different types of mutations within the same gene (i.e., different alleles) can have on the phenotypic expression. An example of allelic heterogeneity is sensorineural hearing loss due to MYO7A gene defects: separate mutations in this gene are responsible for autosomal recessive nonsyndromic congenital deafness, autosomal dominant nonsyndromic progressive deafness, and syndromic deafness with blindness (Usher syndrome type 1B). Genetic imprinting is another form of phenotypic variation.An imprintable allele will be transmitted in a Mendelian mode, but expression will be determined by the sex of the transmitting parent. Paternal imprinting is used to imply that there will be no phenotypic expression if the disease allele is transmitted from the father; his offspring, however, will be nonmanifesting carriers. Other sources of modification of the effect of a gene are alternative splicing, uniparental disomy (both members of an allele pair derive from one parent), and “epigenetic” phenomena such as methylation and histone modification. Additionally, the expression of a gene may depend on an environmental factor; for example, a tumor from a proto-oncogene after carcinogen exposure and susceptibility to aminoglycoside ototoxicity due to an mtDNA mutation.

The most comprehensive reference source for genetic diseases for clinicians, Mendelian Inheritance in Man, edited by Victor A. McKusick, was reviewed for the creation of this chapter and is available in published book form in medical libraries and online at http://www.ncbi.nlm.nih.gov/Omim/, aWeb site supported by the National Institutes of Health.

TUMORS OF THE HEAD AND NECK

Cells develop, differentiate, grow, and die in response to a complex system of biochemical signals. Neoplastic cells usually contain mutations that free them from the

normal constraints thereby allowing them to proliferate uncontrollably. Although virtually all neoplasms are genetic, the overwhelming majority of mutations in tumors are found only in a patient’s neoplastic cells and are not inherited. Mutations in somatic cells are caused by intrinsic errors in DNA replication or repair, or are induced by carcinogen exposure. However, 1% of all cancers arise in patients with germ line mutations that predispose them to cancer, but even in this situation additional somatic cell mutations are required for a tumor to develop. These patients have a hereditary cancer syndrome.

Three classes of genes are involved in both sporadic and hereditary neoplasia: (1) those that normally inhibit cell proliferation (tumor suppressor genes), (2) those that activate cell proliferation (oncogenes), and (3) those that participate in DNA repair.

•Tumor suppressor genes stop tumor growth. Loss-of-function mutations that deactivate or downregulate tumor suppressor genes are associated with neoplasia. These mutations are usually recessive; both normal gene copies must be lost for disease to develop. The gene for p53 is an example of a tumor suppressor gene.

•Oncogenes initiate and promote neoplastic cell growth. Mutations that activate or amplify oncogenes are associated with tumors. Most oncogenes originate from proto-oncogenes, which are genes involved in the basic regulation processes of cell growth. When a mutation occurs in a protooncogene, it can become an oncogene. RET is an example of a dominant oncogene whose deregulated expression drives cell transformation. Multiple mutations are seen in most malignancies. Inactivation of tumor suppressor genes coupled with activation of oncogenes produces malignant neoplasia.

•Inherited defects in DNA repair during DNA replication can lead to a high frequency of somatic mutations. Familial breast cancer is an example of a somatic mutation affecting DNA repair in cell regulatory pathways.

FEATURES OF HEREDITARY NEOPLASMS

(MUTATIONS IN PATIENT’S GERM LINE)

Hereditary tumors tend to have a different clinical picture than sporadic tumors of the same histology. Familial tumors typically exhibit some or all of the following clinical characteristics:

•Bilateral or multifocal sites

•Presentation at a relatively young age