Dave M. Stocker, MD

• Division of Pediatric Emergency Medicine
• Carepoint, PC
• Denver, Colorado

Microscopically depression symptoms physical 40mg geodon order mastercard, the bloodfilled spaces are separated by cellular fibrous septa with scattered osteoclast-type giant cells and reactive bone walking depression definition purchase geodon master card. A gross specimen of an osteoid osteoma shows the central nidus anxiety during pregnancy purchase geodon 20mg, which is embedded in dense bone respiratory depression definition buy geodon overnight. A photomicrograph of the nidus reveals irregular trabeculae of woven bone surrounded by osteoblasts depression in adolescence discount geodon 40mg buy online, osteoclasts and fibrovascular marrow. Interestingly, the pain is often exacerbated by drinking alcohol and promptly relieved by aspirin or other anti-inflammatory drugs, possibly because of the high prostaglandin content and abundant nerve fibers within the tumor. Surgical excision or radioablation (electric probe inserted into the tumor) is curative. Solitary osteochondroma is one of the most common benign bone tumors and is more frequent in young males. Most osteochondromas are asymptomatic, and some may need surgical excision if cosmetically displeasing or if they press upon an artery or nerve. Osteoblastoma Is Usually Not Painful Osteoblastoma is an uncommon, benign neoplasm that is histologically similar to osteoid osteoma but larger (usually >2 cm) and with a tendency to progressive growth. It is not accompanied by the characteristic nocturnal pain of osteoid osteoma, although dull pain sometimes occurs. It stimulates less bone reaction and appears mostly as a purely radiolucent lesion, with only a thin shell of surrounding bone. Osteoblastoma occurs in people between the ages of 10 and 35 years, is more common in males and mainly affects the spine and long bones. The marrow cavity of the lesion is in continuity with that of the bone where it arose. The cartilage-capped, bony mass is surrounded by a surface fibrous membrane, which is the perichondrium. The bony stalk is composed of cortical lamellar bone, and the medullary cavity contains lamellar bone trabeculae and fatty marrow. Although not as common as solitary osteochondroma, the heritable variety is not rare, with an incidence of about 1 in 50,000. Osteochondroma Osteochondroma is a benign cartilaginous neoplasm consisting of a bony projection with a cartilaginous cap that arises on the surface of the bone. It occurs in bones formed by endochondral ossification and was viewed for many years as a developmental defect of the growth plate. A radiograph of an osteochondroma of the humerus shows a lesion that is directly contiguous with the marrow space. The cross-section of an osteochondroma shows the cap of calcified cartilage overlying poorly organized cancellous bone. Microscopically, the cartilaginous cap is covered by a fibrous membrane (perichondrium) and undergoes endochondral ossification. In severe cases of hereditary osteochondromatosis, dwarfism may result because of lateral displacement of the longitudinal growth plate by the osteochondroma. Metacarpals may be shortened, and fixed pronation or supination may develop if the lesions occur in the forearm and interfere with wrist function. Further difficulties may be caused by unequal leg length and disturbed joint function because of encroaching osteochondromas. When pain or pathologic fracture occurs, curettage and bone grafting are the treatment of choice. Enchondromatosis Is Marked by Multiple Cartilaginous Tumors Enchondromatosis, or Ollier disease, is characterized by development of multiple cartilaginous masses that lead to bony deformities. The condition is not strictly a disease of delayed maturation of bone; residual hyaline cartilage, anlage cartilage or cartilage from the growth plate does not undergo endochondral ossification and remains in the bones. As growth continues, the enchondromas settle in the diaphysis of adolescents and adults. There is a strong tendency for malignant transformation, mostly into chondrosarcoma. Therefore, a patient with enchondromatosis who has increasing pain or a lesion that is actively growing should be evaluated to rule out an underlying sarcoma. Solitary enchondroma and enchondromas of Ollier disease are histologically similar, but the latter tend to be more cellular and atypical. Maffucci syndrome is characterized by multiple enchondromas and cavernous or spindle cell hemangiomas of soft tissue. It usually manifests in early childhood and may lead to significant skeletal deformities. Chondrosarcoma develops in as many as half of all patients with Maffucci syndrome. Solitary Chondroma Is a Benign Intraosseus Tumor of Mature Hyaline Cartilage Although their neoplastic nature has been questioned, these benign tumors, also called enchondromas (because most are intramedullary), may occasionally show chromosomal abnormalities suggesting that they are in fact neoplasms. Rarely, they arise on the bone surface under the periosteum, in which case they are regarded as periosteal or juxtacortical chondromas. On gross examination, solitary enchondromas have the semitranslucent appearance of hyaline cartilage, often with a few calcified areas. An x-ray of an enchondroma demonstrates a well-demarcated, lytic lesion in the diaphysis of the proximal phalanx with internal calcification and associated pathologic fracture. Histologically, the tumor is composed of lobules of hypocellular hyaline cartilage without atypia. The mutant receptor may delay chondrocyte differentiation by activating Hedgehog signaling, which results in the formation of the multiple cartilaginous masses characteristic of the disease. Chondroblastoma Is a Benign Tumor of the Epiphyses of Long Bones Chondroblastoma is an uncommon, chondrogenic tumor with predilection for epiphyses of the proximal femur, tibia and humerus. It is more common in males than in females (2:1), and 90% of cases occur in young people between the ages of 5 and 25. On gross examination, the tumor is soft and compact with scattered gray or hemorrhagic areas. Well-developed hyaline cartilage as seen in enchondroma is not found in chondroblastoma. A radiograph of the hand shows bulbous swellings that represent nodular masses composed of hyaline cartilage, which is sometimes admixed with more primitive myxoid cartilage. A magnetic resonance image of the shoulder of a child shows a prominent lytic lesion of the head of the humerus that involves the epiphysis and extends across the epiphyseal plate. The histologic appearance of a chondroblastoma is defined by plump, round cells (chondroblasts) surrounded by a mineralized primitive chondroid matrix. In fact, these neoplasms may perforate the cortex, although they remain confined by the periosteum. If neglected, it may (rarely) attain a large size, destroy the epiphyseal area and invade the joint. Curettage is the treatment of choice, although in over 10% of cases, the tumor recurs. One population of mononuclear cells is believed to be of macrophagemonocyte origin and is likely nonneoplastic. Often, it has a multiloculated or "soap bubble" appearance, representing endosteal resorption of the bone. It usually occurs in the third and fourth decades, has a slight predilection for women and seems to be more common in Asia than in Western countries. Radiograph of the proximal tibia shows an eccentric lytic lesion with virtually no new bone formation (arrows). The tumor extends to the subchondral bone plate and breaks through cortex into the soft tissue. Photomicrograph shows osteoclast-type giant cells and plump, oval, mononuclear cells. The mononuclear ("stromal") cells are plump and oval, with large nuclei and scanty cytoplasm. Large osteoclastic giant cells, some with more than 100 nuclei, are scattered throughout the richly vascularized stroma. On low-power examination, the tumor often appears as a syncytium of nuclei with poor demarcation of cytoplasmic borders and random distribution of the giant cells. Osteosarcomas are associated with mutations in tumor suppressor genes; almost two thirds show mutations in the retinoblastoma (Rb) gene (see Chapter 5) and many have mutations in the p53 gene. There are also many other chromosomal and molecular abnormalities pertaining to apoptosis, replicative potential, insensitivity to growth inhibitory signals and cell cycle regulation that contribute in some part to the development of the tumor. Virtually all metastases have occurred after an initial surgical intervention and have the benign histology in appearance of the primary tumor. In contrast to patients with lung metastases from other malignant bone tumors, most of these patients enjoy an essentially normal life span, especially if the metastatic deposits are few and can be surgically removed. Thus, historical belief has been that local recurrence of the tumor reflects inadequate resection rather than biological aggressiveness and that distant metastases result from dislodgment of tumor fragments during surgery. Recurrence as pure sarcoma may occur spontaneously or after local radiation therapy. Microfractures and pathologic fractures are frequent, owing to thinning of the cortex. The tumor is treated with thorough curettage and bone grafting, although more aggressive management, including en bloc resection or even amputation, may be necessary. Local recurrence after simple curettage has been reported in one third to one half of cases, and 2%­5% metastasize to the lungs. In older people, they usually occur in the context of Paget disease or radiation exposure. For example, radium watch dial painters, who wetted their brushes by licking them, developed osteosarcoma many years later, owing to radium depositing in their bones. Today, osteosarcoma can develop in adults and children previously subjected to external therapeutic radiation for some other tumor such as lymphoma. Several preexisting benign bone lesions are associated with an increased risk of developing osteosarcoma, including fibrous dysplasia, osteomyelitis and bone infarcts. Although trauma may call attention to an existing osteosarcoma, there is no evidence that it ever causes the tumor. The proximal humerus is the second most common site; 75% of tumors arise adjacent to the knee or shoulder. Radiologic evidence of bone destruction and bone formation by osteosarcoma is characteristic, the latter representing neoplastic bone. Often, the periosteum produces an incomplete rim of reactive bone adjacent to the site where it is lifted from the cortical surface by the tumor. When this appears on a radiograph as a shell of bone intersecting the cortex at one end and open at the other end, it is referred to as Codman triangle. The gross appearance of osteosarcoma is highly variable, depending on the proportions of bone, cartilage, stroma and blood vessels. The cut surface may show any combination of hemorrhagic, cystic, soft and bony areas. The neoplastic tissue may invade and break through the cortex, spread into the marrow cavity, elevate or perforate the periosteum or grow into the epiphysis and even reach the joint space. The malignant cells have large hyperchromatic and pleomorphic nuclei, with a high nucleocytoplasmic ratio. The tumor cells stain prominently for alkaline phosphatase, osteocalcin and osteonectin. In areas of osteolysis, nonneoplastic osteoclasts are found at the advancing front of the tumor. It represents one fifth of all bone cancers and is most frequent in adolescents between 10 and 20 years old, affecting boys more often than girls (2:1). The distal femur contains a dense osteoblastic malignant tumor that extends through the cortex into the soft tissue and the epiphysis. A photomicrograph reveals pleomorphic malignant cells, tumor giant cells and mitoses (arrows). Less commonly, the tumor metastasizes to other bones (35%), the pleura (33%) and the heart (20%). Serum alkaline phosphatase is increased in half of patients and may decrease after amputation, only to increase again with recurrence or metastasis. Historically, osteosarcoma was treated exclusively by amputation or disarticulation of the involved limb, but the prognosis for 5-year survival did not exceed 20%. Today, standard therapy with preoperative chemotherapy and limb-sparing surgery gives 5-year disease-free rates from 60% to 80%. Juxtacortical osteosarcoma is a rare variant of osteosarcoma that occurs on the surface of the bone, especially the lower posterior metaphysis of the femur (70% of cases). Unlike classic osteosarcoma, most patients are older than 25 years, and the tumor is more common in women. Juxtacortical osteosarcoma spares the deep cortex and medulla of the bone and grows external to the shaft. Usually, Codman triangle is not evident radiologically, because the periosteum is not elevated. Most juxtacortical osteosarcomas are lowgrade lesions and do not require adjunctive chemotherapy. Other rare variants of osteosarcoma include telangiectatic and small cell osteosarcoma, which are high-grade tumors, and low-grade intramedullary osteosarcoma. Some patients have a history of multiple enchondromas, solitary osteochondroma or hereditary multiple osteochondromas. Chondrosarcoma is the second most common primary malignant bone tumor and is more common in men than in women (2:1). It is most frequently seen in the fourth to sixth decades (average age, 45 years). There probably is a different molecular mechanism resulting in tumor development between central chondrosarcoma and secondary peripheral chondrosarcoma (tumors arising in the cartilaginous cap of an osteochondroma; see below). Radiologically, poorly defined borders, a thickened shaft and perforation of the cortex characterize these tumors. Although central chondrosarcoma may penetrate the cortex, extension beyond the periosteum is uncommon.

An electron micrograph shows the characteristic filaments of the amyloid inclusions bipolar depression en espanol 20mg geodon with visa. C D Dermatomyositis Is an Immune-Mediated Microangiopathy Dermatomyositis differs from other myopathies in having a characteristic rash on the upper eyelids depression symptoms not showering order geodon australia, face depression cycle definition buy geodon cheap online, trunk and sometimes elsewhere depression and exercise purchase discount geodon line. It may occur alone or together with scleroderma depression lamp order geodon, mixed connective tissue disease or other autoimmune conditions. The rash clinically distinguishes dermatomyositis from the other inflammatory myopathies due to the same microangiopathy. These features suggest that muscle injury in dermatomyositis is mainly mediated by complement-fixing cytotoxic antibodies against skeletal muscle microvasculature. Complement deposition in capillary walls preceding inflammation or damage to muscle fibers is the most specific finding. The perifascicular atrophy is due to relative hypoperfusion of perifascicular zones. The inflammatory cells infiltrate predominantly the perimysium rather than the endomysium. The periphery of muscle fascicles shows most of the muscle fiber atrophy and damage, resulting in a pattern of injury characteristic of dermatomyositis, termed perifascicular atrophy. High-magnification image of perifascicular atrophy demonstrating the flattening and shrinkage of fibers at the periphery of the fascicle. Immunofluorescence (inset) reveals that the walls of many capillaries display C5b-9 (membrane attack complex), reflecting the altered microvasculature typical of dermatomyositis. In such instances, skeletal muscle may show neurogenic changes (see below) secondary to nerve damage. The disease typically begins in young adults, but first presentations may vary from childhood to old age. Most patients with myasthenia gravis have anti­Ach receptor antibodies and thymic hyperplasia. Surgical removal of the hyperplastic thymic tissue or the thymoma often causes the myasthenia gravis to remit. Ach receptors are present on the surface of some thymic cells in thymoma and thymic hyperplasia. However, electron microscopy shows that most muscle endplates are abnormal, even in muscles that are not weakened. Sarcolemmal secondary folds are simplified with breakdown, loss of the crests of the folds and widening of the clefts. Complement activation leads to shedding of the Ach receptor­rich terminal portions of the folds of the neuromuscular junction. The bivalent IgG antibodies also cross-link receptor proteins that remain in the postsynaptic membrane. This accelerates Ach receptor endocytosis so much that the muscle cannot replace them. The combination of reduced postsynaptic membrane area, decreased numbers of Ach receptors per unit area and widened synaptic space impairs signal transmission and causes muscle weakness and abnormal fatigability. Weakness of extraocular muscles is typically severe and causes ptosis and diplopia. In addition to thymectomy, corticosteroids, methotrexate and anticholinesterase drugs are used, alone or in combination. Plasmapheresis reduces anti­Ach receptor antibody titers, but any consequent clinical improvements are short-lived. Only primary hereditary abnormalities in metabolism of skeletal muscle resulting in abnormal muscular function are discussed here. In the severe form, Pompe disease, muscle shows massive accumulation of membrane-bound glycogen. There is very little regeneration, and apparently inactive satellite cells are present at the surfaces of muscle fibers that have been almost completely destroyed by the disease. Glycogen Storage Diseases Are Genetic Disorders with Variable Effects on Muscle Glycogen storage diseases (glycogenoses) are autosomal recessive, inherited, metabolic disorders characterized by an inability to degrade glycogen (see Chapter 6). Patients have severe hypotonia and areflexia and clinically resemble patients with Werdnig-Hoffmann disease (see below). Some have enlarged tongues and cardiomegaly and die of cardiac failure, usually within their first 2 years. Later-onset forms of the disease entail milder, but relentlessly progressive, myopathy. Glycogen accumulates in other organs, but clinical expression of the disorder is usually limited to muscle. Acid maltase is a lysosomal enzyme that is expressed in all cells and participates in glycogen degradation. Because the debranching enzyme is absent, phosphorylase can hydrolyze 1,4-glycosidic linkages of the terminal glucose chains of glycogen, but not beyond branch points. Muscle symptoms vary, and the most severe and consistent involvement is related to liver dysfunction in children. An electron micrograph demonstrates an abnormal mass of glycogen particles just beneath the sarcolemma. The glycogen is not surrounded by a membrane, in contrast to the lysosomal glycogen storage of acid maltase deficiency. Without this enzyme, skeletal muscle glycogen cannot be cleaved at 1,4-glycosidic chains to produce glucose for energy production during physical exertion. Patients also cannot produce lactate during ischemic exercise, which is the basis for a metabolic test for the condition. Electron microscopy will often demonstrate accumulation of non­membrane-bound glycogen. In muscle, this enzyme has four identical subunits (M4), while in erythrocytes, it has two different (M and L) subunits, each encoded separately. In red blood cells, the remaining active enzyme is composed of four normal L subunits. Lipid Myopathies Are Caused by Defective Fat Metabolism A muscle biopsy from a patient with exercise intolerance or muscle weakness may sometimes show excess neutral lipids. This occurs in several metabolic disorders of lipid metabolism, more than a dozen of which are known. In brief, lipid myopathies may involve deficiencies in (1) fatty acid transport into mitochondria (carnitine deficiency syndromes, carnitine palmityl transferase deficiency), (2) several enzymes that mediate -oxidation of fatty acids, (3) respiratory chain enzymes and (4) triglyceride use. However, prolonged, vigorous exercise can lead to widespread myofiber necrosis and release of soluble muscle proteins like creatine kinase and myoglobin into the blood. Muscle biopsy should be performed several weeks after an episode of symptoms to allow regeneration of the muscle. Muscle carnitine deficiency is an autosomal recessive condition, with progressive proximal muscle weakness and atrophy, often with signs of denervation and peripheral neuropathy. This threshold varies in different organs and is related to cellular energy requirements. Oil red-orcein stain (inset) demonstrates that the cytoplasmic vacuoles contain neutral lipid. These are called ragged red fibers because these deposits have an irregular contour at the fiber periphery. Such defects cause myofiber atrophy and accumulation of sarcoplasmic lipid and glycogen owing to impaired mitochondrial energy utilization. Increased ragged red fibers and cytochrome oxidase­ negative fibers may also occur in elderly patients with unexplained muscle weakness ("mitochondrial cytopathy of old age"), presumably because numbers of mutant mitochondria increase with age. Ragged red fibers, cytochrome oxidase­ negative fibers and intramitochondrial paracrystalline inclusions may suggest a mitochondrial disorder but are not specific, as similar changes occur in some muscular dystrophies, in inclusion body myositis and after certain drugs. Conversely, the absence of such changes does not exclude a mitochondrial disorder. Carnitine Palmitoyltransferase Deficiency Patients with carnitine palmitoyltransferase deficiency cannot metabolize long-chain fatty acids, owing to an inability to transport these lipids into mitochondria, where they undergo -oxidation. After heavy exercise, these patients have muscular pain, which may progress to myoglobinuria. Biopsies are microscopically normal; the diagnosis requires biochemical assay for carnitine palmitoyltransferase activity. The nervous system, skeletal muscle, heart, kidney and other organs can be affected in different combinations as part of a multisystem disease. Other organs, such as the heart (arrhythmias), are often affected as part of a multisystem disorder. Despite the presence of these congenital mutations, symptoms typically appear in adulthood. It is a common, autosomal recessive condition, seen in 1%­2% of all muscle biopsies. A ragged red fiber shows prominent proliferation of reddish, granular mitochondria, located chiefly in a subsarcolemmal region. A ragged red fiber displays lack of histochemical staining for cytochrome oxidase (central pale fiber). An electron micrograph reveals mitochondria with ultrastructural abnormalities, including paracrystalline inclusions. Familial Periodic Paralysis Reflects Impaired Electrolyte Flux Familial periodic paralysis encompasses several autosomal dominant disorders in which episodic muscular weakness or even complete paralysis is followed by rapid recovery. These reflect abnormalities in sodium and potassium fluxes into and out of muscle cells. During an attack, muscle fiber surfaces do not propagate action potentials, although calcium entry into the muscle fiber causes contraction. Muscle biopsies during an attack show no detectable abnormalities of recent onset. These vacuoles are dilated or remodeled sarcoplasmic reticulum and transverse tubules. Patients present with bilateral ptosis and weakness of eye muscles as in Kearns-Sayre syndrome. Some patients develop rhabdomyolysis with apparently mild exercise and probably have some form of metabolic myopathy. A spectrum of muscle dysfunction, from pain (myalgia) to rhabdomyolysis, is also well known during treatment with statin cholesterol-lowering agents. Alcoholism is occasionally associated with either acute or chronic rhabdomyolysis. Pathologically, rhabdomyolysis is an active, noninflammatory myopathy, with scattered muscle fiber necrosis and varying degrees of degeneration and regeneration. Macrophages, but no other inflammatory cells, are present in and around muscle fibers. The pathology of denervation reflects lesions of lower motor neurons and/or axons. Muscle biopsy detects lower motor neuron lesions, but patterns of denervation do not identify the cause of the lesion. The morphology may indicate whether denervation is recent or chronic but does not distinguish between, for example, amyotrophic lateral sclerosis, a disorder of motor neurons, and neuropathy due to diabetes mellitus. Lesions of upper motor neurons, as in multiple sclerosis or stroke, lead to paralysis and atrophy but leave lower motor neurons intact. Pathologic changes thus reflect nonspecific diffuse atrophy rather than denervation atrophy. When a skeletal muscle fiber becomes separated from contact with its lower motor neuron, it invariably atrophies, owing to progressive loss of myofibrils. If a fiber is not reinnervated, atrophy progresses to complete loss of myofibrils, with nuclei condensing into aggregates. In the end stage, muscle fibers disappear and are replaced chiefly by adipose tissue. Spinal Muscular Atrophy Reflects Progressive Degeneration of Anterior Horn Cells this disease is, strictly speaking, not a primary muscle disorder but is usually included in discussions of skeletal muscle pathology since it represents a major consideration in the differential diagnosis of childhood or infantile weakness. This change occurs during or shortly after denervation or reinnervation and indicates that the process is active. The lesion consists of central pallor of the muscle fiber, which is surrounded by a condensed zone, in turn surrounded by a normal zone of sarcoplasm. New sprouting nerve endings make synaptic contact with the muscle fiber at the site of the previous motor endplate. As in the myotubular phase of embryogenesis, nicotinic Ach receptors (extrajunctional receptors) cover muscle fibers soon after denervation. This denervated state induces sprouting of new nerve endings from adjacent surviving nerves. With reinnervation, extrajunctional receptors again disappear from the sarcolemma, except at the point of synaptic contact. In a chronic denervating condition, reinnervation of each surviving motor unit gradually enlarges. As a specific type of lower motor neuron takes over innervation of a given field of fibers, fiber groups of one type are seen adjacent to groups of another type. Patients with striking fiber­type grouping often have symptoms of muscle cramping in addition to progressive muscular weakness. After a single episode of denervation, such as in poliomyelitis, reinnervation often leads to remarkable recovery of strength. Years later, one sees conspicuous-type grouping, with scattered pyknotic nuclear clumps. If denervation continues after development of fiber-type grouping, large motor units become atrophic. In such cases, reinnervation may favor one type of lower motor neuron over another. Then, muscle degeneration causes a modest increase in serum creatine kinase levels.

Dynamic regulation of transcriptional states by chromatin and transcription factors bipolar depression 45 40 mg geodon purchase with visa. Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis anxiety xanax dosage buy genuine geodon online, growth depression definition american psychiatric association buy geodon 40mg mastercard, and bone maturation anxiety in the bible cheap geodon 40mg overnight delivery. The role of corepressors in transcriptional regulation by nuclear hormone receptors anxiety when trying to sleep discount geodon 20 mg buy online. Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge. Thyroid hormone signaling in vivo requires a balance between coactivators and corepressors. Hormone-responsive enhancer-activity maps reveal predictive motifs, indirect repression, and targeting of closed chromatin. Transactivation functions of the N-terminal domains of nuclear hormone receptors: protein folding and coactivator interactions. Multi-modulation of nuclear receptor coactivators through posttranslational modifications. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Nongenomic thyroid hormone signaling occurs through a plasma membranelocalized receptor. Mendelian endocrine disorders are caused by variants found rarely in the population, usually from a relatively small number of genes, and each variant has a large individual effect on disease risk so that in any one individual, most of the disease risk is explained by variants in a single gene. Genetic information is most likely to be of direct clinical use in patients with suspected mendelian syndromes. The Role of Genetics in Endocri ology the sequencing of the human genome has~ hered in an era of genomic medicine. The catalog of protein-coding genes in humans is essentially complete, and the number of associations between genes and specific diseases is growing rapidly. The ability to interpret this variation is less advanced but is improving, as databases of variants and their clinical associations increase in both size and accuracy. Available sequencing data are growing exponentially, and the volume of information places increasing the demand for methods to distinguish pathologic variants from benign ones. Perhaps even more important, it is critical that clinicians understand the limits of such information. We then focus on endocrine disorders, providing an overview of the genetics of endocrine diseases, with illustrative examples from both mendelian disorders (caused by mutations in single genes) and polygenie disorders (in which variation in many genes influences disease risk). Finally, we examine scenarios for clinical uses of genetic information in endocrinology and provide recommendations. Chapter 3 Genetics of Endocrinology 43 Most diseases, including endocrine disorders, are heritable, meaning that genetic variation contributes to disease risk in a population. The detailed discussions of the genetics of these and other disorders can be found throughout this textbook; this chapter provides illustrative examples that illuminate key concepts and refers the reader to the appropriate chapters for additional detail. Heritability: An Estimate of the Importance of Genetic Factors to Disease Causation Relatives resemble each other in many ways. Heritability quantifies, as a proportion, how much of this familial resemblance is due to genetic factors. A trait that has no genetic influence would have a heritability of 0%; a trait that is completely determined by inherited factors would have a heritability of 100%. Most clinically important traits have heritabilities ranging from 20% to 80% (Table 3. Appreciating the heritability of a trait is important when interpreting the contribution of genetic risk factors in disease: genetic factors are less influential for traits with low heritability and are likely to have more predictive or explanatory power for traits with high heritability. In the past, the gold standard for heritability estimation was the comparison of monozygotic and dizygotic twin concordance rates for diseases/traits. Such studies relied on the rationale that an excess of disease correlation between genetically identical individuals (monozygotic twin pairs) compared with those who share only 50% of their genes (dizygotic twin pairs) pointed to the role of genetic factors. However, the validity of comparing twin concordance rates across different families relied on the assumption that the effect of environment was the same for the twin pairs, regardless of whether they were monozygotic or dizygotic twins. More recent methods for heritability estimation can overcome some of these limitations by leveraging subtle fluctuations in genetic similarities between sibling pairs. The heritability estimate from any study must be interpreted in the context of the population in which it is being measured, including the historical period, and variability in environmental factors such as socioeconomic status and nutrition. These factors likely explain the wide range of heritability estimates for type 2 diabetes, ranging from 40% in Finland7 to 80% in Japan. In 1940, this region was divided between Finland and the former Soviet Union with little contact between the two sections over the next 60 years. Finnish Karelians have a sixfold increased rate of type 1 diabetes compared with Russian Karelians. The difference in diabetes rate is likely due to environmental factors, because both Karelian populations recently originated from a common ancestry and therefore likely have similar genetic risk factors for type 1 diabetes. But it was not until 1865 that the Austrian abbot Gregor Mendel, after decades of careful experimentation in pea plants, posited and provided evidence for the modern genetic concept of genes (as coined by the botanist Wilhelm Johannsen in 1909). It was recognized in the early 20th century that certain human phenotypes, including diseases, were inherited according to the same rules that Mendel had described; these diseases are called mendelian. The first description of the molecular basis of a mendelian disease was made for sickle cell anemia, which involved a mutation in a single gene. By tracing the transmission of these polymorphisms in families, it became possible to identify genes causing mendelian human disorders (those caused by altered function in a single gene and that consequently show distinctive patterns of inheritance in families). Biometricians had appreciated in the early 1900s that most continuous and commonly varying traits. Fisher4 provided a general framework explaining continually varying traits as the consequence of polygenic inheritance-that is, polygenic phenotypes are a result of combined, small, and additive effects of variation in many genes simultaneously. Despite this recognition, only a few genetic variants were convincingly connected with polygenic diseases/traits over the next 80 years. When comparing two versions of a human genome, either within the same person or between two different people, about 1/1000 of these bases vary. These nonsense variants typically dramatically impair or eliminate the function of the protein. For example, noncoding variants can alter the level, timing, or location of gene expression, without changing the sequence of the encoded protein. Common and rare genetic variation in 10 individuals, carrying 20 distinct copies of the human genome. The amount of variation shown here is typical for a 5-kb stretch of genome and is centered on a strong recombination hotspot. Although these six polymorphisms could theoretically occur in 26 possible patterns, only 3 patterns are observed (indicated by pink, orange, and green). Similarly, the six common polymorphisms on the right side are strongly correlated and reside on only two haplotypes (indicated by blue and purple). The haplotypes occur because there has not been much genetic recombination between the sites. By contrast, there is little correlation between the two groups of polymorphisms because a hotspot of genetic recombination lies between them. In addition to the common polymorphisms, lower-frequency polymorphisms occur in the human genome. Five rare single-nucleotide polymorphisms are shown, with the variant nucleotide marked in red and the reference nucleotide not shown. Indels in protein-coding sequences are called frameshift mutations, as long as the number of bases inserted or deleted is not a multiple of three. In addition, the population frequency of a variant, whether it is common or rare, can also provide information about its likely impact on phenotype. The relative balance between common and rare genetic variation is strongly influenced by evolution and human demographic history. Modern humans likely originated from a small population residing in Africa that had been evolving over millions of years. Within the past 50,000 years, members of this ancestral population migrated "out of Africa," settled the globe, and only recently, over the past 5000 to 10,000 years, multiplied exponentially. Individuals also inherit thousands of genetic variants unique to themselves and their relatives. These rare genetic variants arose more recently from spontaneous mutation in the past 10 millennia, after the migration of many humans out of Africa, and are typically observed infrequently (<0. Factors Influencing the Biologic Impact of Genetic Variants in a Particular Gene As discussed previously, the impact of a genetic variant on gene function will depend on the type of variant and its location with respect to the gene. However, even a single, specific variant may have different effects in different individuals. The effect of any given genetic variant (genotype) on the phenotype can be modified by variants in other genes (gene-gene interactions) or by environmental factors (gene-environment interactions) or by random chance. It is usually not possible to measure or quantify these factors in any one person, but their combined effect can be quantified on a population level as penetrance, the proportion of individuals carrying a genetic variant who exhibit the phenotype. The penetrance of a genetic variant is highly context dependent with respect to phenotypic definition. Temporal context is also an important consideration, as disease incidence often increases with age. A common observation in members of a family carrying the same disease-causing genetic variant is that not all members of the family are equally affected. This range of phenotypic expression resulting from a particular genotype is referred to as variable expressivity and, as with penetrance, arises from the range of impacts of specific variants, as well as modifying influences of genetic background (gene-gene interactions), environment (geneenvironment interactions), and random chance. Mosaicism, whereby cells within a single individual have different genotypes, is another mechanism that leads to variable expressivity. Most mutations known to influence disease are germline mutations-inherited from the sperm or egg and present in every cell-but some diseases can be caused by somatic mutations that occur after fertilization and are present in only some cells, leading to mosaicism. In these cases, which tissues or organs carry the mutation will influence the clinical outcome. The most familiar class of disease caused in large part by somatic mutations is neoplasia, including endocrine tumor syndromes such as Conn syndrome and Cushing disease. The mechanism of variable expressivity likely maps to the zygotic stage in which the mutation arose: a mutation earlier in embryogenesis is present in more tissue lineages. Conversely, blood cells can contain somatic variation that is absent in other tissues or the germline. A striking example of the effect of epigenetics is imprinting, the expression of a genetic variant in a parent-of-origin specific manner. Variants that greatly increase the risk of a disease that is deleterious from a reproductive standpoint are less likely to be passed on to offspring and will be rare in the population (unless they have a compensatory benefit like malaria resistance in carriers of sickle cell disease). If a disease is at least mildly evolutionarily deleterious, then most common variants associated with that disease will only modestly increase disease risk. This is because those common variants, if they had strongly increased disease risk, would have then been subject to strong negative evolutionary selection and never would have risen in frequency to become common in the first place. By contrast, it is more plausible for rare/recent variants to exert strong effects on phenotype and greatly increase disease risk. Finally, the number of genes that contribute to disease in a single individual (mendelian or polygenic disease) will be related to the strength of effect of any one variant on disease risk. By definition, variants that cause mendelian disorders have strong effects, whereas variants contributing to risk of polygenic diseases will typically have more modest effects. Thus, most variants with strong effects on disease will be rare, especially for those diseases that are clearly deleterious from an evolutionary standpoint (lethal before reproductive age). By contrast, common polygenic diseases and traits will have a much more substantial contribution from common genetic variants, although these considerations do not rule out an important role for rarer variants in polygenic phenotypes. As we will see later in this chapter, these patterns of genetic variation have important implications for identifying genetic variants that underlie disease and for interpreting the impact of genetic variation on disease. The demographic history of modern human populations explains the presence of common and rare genetic variants in the human genome (see Table 3. Common variants are mostly ancient and typically have relatively modest clinical effects, whereas rare variants tend to have arisen more recently and can exert larger clinical effects (Table 3. Genetics of Endocrine Diseases As described earlier, heritable diseases and traits, including endocrine phenotypes, span a range of genetic architectures ranging from single-gene mendelian disorders to common, polygenic diseases and traits. Although we distinguish between these two extremes of genetic architecture, it is important to appreciate that many disorders lie between these two extremes: rare variants of moderate effect can affect the common form of the disease, and genetic and nongenetic modifiers can strongly influence the outcome of mendelian disorders. Furthermore, many polygenic endocrine disorders also have rare mendelian forms (see Table 3. The genes for a wide range of mendelian endocrine diseases have been mapped, revealing great mechanistic insight. Although mendelian diseases have offered valuable insights into pathophysiology, not all insights gained from mendelian forms of disease translate directly to the common forms of disease. For example, mendelian obesity caused by recessive inactivating mutations in the leptin receptor could be well treated by exogenous leptin, but this clinical insight did not apply to most obese individuals who actually demonstrate elevated leptin levels and do not respond to exogenous therapy with leptin (see Chapter 40). And, of course, the variants that have strong effects on quite rare genetic syndromes do not explain much, if any, of the risk of the common forms of disease. Thus, genetics of both mendelian forms and common polygenic forms will have important and often complementary impacts on our understanding of disease and on patient care. The sections that follow discuss representative examples of mendelian and polygenic endocrine disorders that illustrate important concepts in gene discovery, understanding of the impact of genetic variation on disease, and implications for clinical care and insights into new biology. We discuss several classes of mendelian diseases and highlight three polygenic endocrine diseases/traits: (1) type 2 diabetes, (2) stature, and (3) serum lipids. In each section, we discuss what is known about the underlying genetic contributors, the impact of genetics on our understanding of disease biology, and the translation into clinical care in the short and long term.

The combined analysis (immunolocalization and immunoblot) of the dystrophin protein is diagnostic of this group of dystrophies (dystrophinopathies) depression natural cures cheap 20 mg geodon amex. The number of muscle fibers then progressively decreases kindliche depression definition generic geodon 40 mg free shipping, to be replaced by fibrofatty connective tissue anxiety high blood pressure purchase geodon on line amex. Early in the disease great depression definition dictionary discount geodon 20 mg overnight delivery, necrotic fibers and regenerating fibers tend to occur in small groups anxiety xanax not working 80mg geodon purchase overnight delivery, together with scattered, large, hyalinized dark fibers. Macrophages invade necrotic fibers and reflect a scavenging function rather than an inflammatory process. About 30% of patients have small rearrangements or point mutations and are evaluated by muscle biopsy, which shows little or no detectable dystrophin by immunoblot or immunohistochemistry. If there is an affected family member, prenatal diagnosis using chorionic villi may be useful. Boys with Duchenne muscular dystrophy have markedly increased serum creatine kinase levels from birth and morphologically abnormal muscle, even in utero. Clinical weakness is not detectable during the first year but is usually evident by 3 or 4 years of age, mainly around pelvic and shoulder girdles (proximal muscle weakness). A section of vastus lateralis muscle shows necrotic muscle fibers, some of them invaded by macrophages (arrow). Calcium influx across the defective surface membrane overwhelms mechanisms that maintain a low resting Ca2+ concentration and triggers excessive contraction. The pathologic changes in skeletal muscle (illustration of modified Gomori trichrome stain). These represent overcontracted segments of sarcoplasm situated between degenerated segments. Other fibers are packed with macrophages (myophagocytosis), which remove degenerated sarcoplasm. These fibers have enlarged, vesicular nuclei with prominent nucleoli and represent regenerating fibers. Developing endomysial fibrosis is represented by the deposition of collagen around individual muscle fibers. Pathologically, these diseases resemble other muscular dystrophies, with variable fibrosis and fatty infiltration of muscle. Some affected proteins also cause certain limb-girdle muscular dystrophies, albeit with different mutations. Other extraskeletal manifestations include gastrointestinal dysfunction (from degeneration of smooth muscle) and intellectual impairment. While the clinical presentation of patients with Becker muscular dystrophy is typically milder and of later onset, affected individuals often have exercise intolerance with muscle cramping, occasional rhabdomyolysis and myoglobinuria. Defects in many proteins have been implicated, but these patients show similar clinical features that include pelvic and shoulder girdle weakness. As a result, proper diagnosis requires detailed clinical histories, plus immunohistochemical, immunoblotting and genetic tests. Nucleotide Repeat Syndromes May Cause Muscular Dystrophies Several human genetic diseases are caused by abnormal numbers of intragenic oligonucleotide repeats. Myotonic dystrophy and oculopharyngeal muscular dystrophy are trinucleotide repeat syndromes with very different muscle pathologies. Myotonic Dystrophy Is the Most Common Adult Muscular Dystrophy Myotonic dystrophy is an autosomal dominant disease characterized by slowed muscle relaxation (myotonia), progressive muscle weakness and wasting. Its prevalence is about 14 per 100,000, although minimally affected individuals are hard to diagnose, so this estimate may be low. Congenital Muscular Dystrophies Present in the Perinatal Period these diseases are characterized by hypotonia, weakness and contractures (Table 31-2). Patients develop slowly progressive eyelid ptosis and dysphagia and weakness of other muscle groups including the face and limbs. The autosomal dominant form is prevalent among French Canadians in Quebec and Bukhara Jews (formerly from central Asia), now living in Israel. Biopsies show intranuclear inclusions, rimmed vacuoles and filamentous inclusions similar to those in inclusion body myositis (see below). Normally, there are fewer than 30 copies of this repeat, but in minimally affected myotonic dystrophy patients, there may be 50 or more copies. The greater the number of repeats (sometimes as many as 4000), the more severe the disorder. Necrosis and regeneration, although occasionally present, are not prominent (as they are in Duchenne muscular dystrophy). Muscles in congenital myotonic dystrophy show myofiber atrophy, frequent central nuclei and failure of fiber differentiation. These features closely resemble those of the X-linked recessive type of myotubular myopathy (see below). Life expectancy is usually normal, and extraskeletal involvement includes bundle branch block, hearing loss and retinal vasculopathy. Chronic inflammation is prominent, resembling an inflammatory myopathy such as polymyositis (see below), but does not correlate with the disease course. A detailed clinical history is essential to making the proper diagnosis; otherwise, a patient with muscle weakness and a lymphocytic inflammatory infiltrate could easily be misdiagnosed as suffering from polymyositis. Extraskeletal features sometimes present in myotonic dystrophy include frontal balding, gonadal atrophy, cataracts, personality degeneration and endocrine abnormalities. A few patients exhibit involvement of smooth muscle, with disorders of the gastrointestinal tract, gallbladder and uterus. Many of these children have a difficult perinatal period because of pulmonary complications of weak respiration. Many of the muscle diseases already described are "congenital" in the sense that they are due to mutations present at birth. Many muscle fibers contain a single central nucleus, and most of the affected muscle fibers are abnormally small. These fibers resemble the late myotubular stage of fetal development of skeletal muscle. These people become ambulatory and live a normal life span, although sometimes with secondary skeletal complications of hypotonia such as severe scoliosis. Muscle from these patients rarely reveals distinctive structurally abnormal myofibers. All show congenital hypotonia, decreased deep tendon reflexes, decreased muscle bulk and delayed motor milestones. In all three conditions, abnormal muscle morphology is usually limited to type I fibers, with type I fiber predominance in some disorders and type I hypotrophy in others. There is no active myofiber necrosis or fibrosis, and patients have normal serum creatine kinase. The disease has been traced to a mutation on the long arm of chromosome 19 (19q13. By electron microscopy, mitochondria and other membranous organelles are lost in the central cores, with or without myofibril disorganization. Central core anomalies may resemble the target fibers seen in active denervating conditions (see below), although target fibers typically have dark rims around the areas of pallor and there is no evidence of denervation in central core disease. An electron micrograph of the same biopsy shows that the structures are rod shaped and are derived from the Z disk (47,500×). Central core disease and malignant hyperthermia may coexist in some patients, so patients with central core disease may be at risk for malignant hyperthermia. However, patients with malignant hyperthermia often have no abnormal histologic changes. Malignant hyperthermia is suspected by family history and confirmed by an in vitro caffeine-halothane contraction test. The tangled, thread-like appearance of the inclusions led to the original name, "nemaline" myopathy. The latter tend to manifest in adolescence and show modestly increased serum creatine kinase. They progress slowly and, like rod myopathy, resemble the limb-girdle dystrophies (see above). Some patients exhibit a striking involvement of facial and extraocular musculature. The gene responsible, dynamin 2, is involved in endocytosis, membrane trafficking and centrosome and actin assembly. Myotubular myopathy is an X-linked disorder caused by myotubularin gene mutations. Myotubularin is a phosphatase expressed in most tissues and involved in phosphatidylinositol signaling. Clinically, myotubular myopathy is characterized by marked neonatal hypotonia and respiratory failure at birth. Pathologically, like central nuclear myopathy, there are centrally placed nuclei within both fiber types. This apparent immature state suggests a possible defect in the nerve supply to the muscle fiber because the lower motor neuron normally promotes subsequent maturation of the fiber. However, lower motor neurons in these patients, including motor endplates, are not demonstrably abnormal. Later-onset forms of myotubular myopathy are characterized morphologically by more mature muscle fibers, in which fibers are larger, have more numerous myofibrils and display single central nuclei that appear more mature. Genes responsible for rod myopathy include nebulin (most common), skeletal muscle -actin, - and -tropomyosin and slow troponin T. Aggregates of these inclusions often occur in subsarcolemmal regions, near nuclei. Rods are described in several neuromuscular diseases, including denervation atrophy, muscular dystrophy and inflammatory myopathies. Experimental tenotomy (cutting a tendon) induces formation of rods in the muscle when the nerve supply remains intact. Dermatomyositis afflicts children and adults, but polymyositis almost always begins after 20 years of age. These myopathies are thought to have an autoimmune origin (see Chapter 11) because (1) they often occur in association with other autoimmune and connective tissues diseases, (2) the pathology suggests autoimmune cellular injury, (3) serum autoantibodies are detected and (4) polymyositis and dermatomyositis (but not inclusion body myositis) respond to immunosuppressive therapy. No specific target autoantigens in muscle or blood vessels have been identified, but antinuclear and anticytoplasmic antibodies against several different antigens exist in all. The inflammatory myopathies are characterized by (1) the presence of inflammatory cells, (2) necrosis and phagocytosis of muscle fibers, (3) a mixture of regenerating and atrophic fibers and (4) fibrosis. Later-onset (childhood and adult) forms tend to be associated with some muscle degeneration, increased serum creatine kinase levels and a slowly or nonprogressive course. Patients have problems with simple activities that require use of proximal muscles, including lifting objects, climbing steps or combing hair. Dysphagia and difficulty in holding up the head reflect involvement of pharyngeal and neck-flexor muscles. Some patients with inclusion body myositis have distal muscle weakness of the limbs that equals or exceeds that of proximal muscles. Interstitial lung disease may also compromise respiratory function in 10% of polymyositis and dermatomyositis patients. Inclusion Body Myositis Is Characterized by b-Amyloid Deposits Inclusion body myositis typically occurs in older patients (>50 years) and is the most common inflammatory myopathy of the elderly. It resembles polymyositis pathologically, showing single-fiber necrosis and regeneration, with predominantly endomysial cytotoxic T cells. Other proteins associated with Alzheimer disease are also present including phosphorylated tau, -synuclein, ubiquitin and presenilins (see Chapter 32). Parkin, which accumulates in hereditary Parkinson disease, and the prion precursor protein have also been localized to the inclusions. The pathogenic role of these inclusions is unclear as similar neurodegenerative disease-associated protein accumulation has been observed in other rare myopathies (X-linked Emery-Dreifuss muscular dystrophy and myofibrillar myopathies) as well as in chronic denervation. Unique features of inclusion body myositis include Congo red­positive inclusions, the characteristic cytoplasmic (or rarely nuclear) filaments in muscle fibers and an inflammatory infiltrate, though the latter may be slight. An autosomal recessive hereditary form of the disease shows similar features but may present in late adolescence or adulthood. The pathogenetic role of autoantibodies against nuclear antigens and cytoplasmic ribonucleoproteins in muscle injury is unknown. Viral infections may precede polymyositis, but virus cultures of muscle are negative. Region of healing inflammatory myopathy demonstrates intact fibers (I) and necrotic fibers (N). Modified Gomori trichrome stain (cryostat section) shows granular basophilic rimming of vacuoles. The inclusion has weak congophilia, but the color signal is strong because it has been enhanced by fluorescence excitation. As neurons degenerate, surviving neurons sprout more nerve endings and reinnervate some of the denervated fibers. This process results in fewer, but larger, motor units and the appearance of clusters of fibers of one type adjacent to clusters of the other type, a pattern called "type grouping. This field would appear normal except for a few atrophic fibers if it were stained with hematoxylin and eosin. With more advanced (severe, chronic) denervation, entire lower motor neurons or numerous axonal processes degenerate, causing small groups of angular atrophic fibers (grouped atrophy) to appear as illustrated in the photomicrograph. In this frozen section of the biceps muscle subjected to the nonspecific esterase reaction, a few irregularly scattered, angular, atrophic fibers (arrows) are excessively dark stained. There are also fascicles of normal muscle fibers and almost invariably clusters of hypertrophied type I fibers. In addition to the absent survival motor neuron gene, a second gene (neuronal apoptosis inhibitory protein gene) has also been implicated in the pathogenesis of Werdnig-Hoffmann disease. These patients had often been designated as having limb-girdle muscular dystrophy, but the electromyographic pattern of denervation helps to make the diagnosis.

Other prognostic factors include depth of tumor invasion anxiety symptoms in women generic 40 mg geodon visa, perineural invasion and lymphovascular tumor emboli anxiety 31 weeks pregnant geodon 20mg buy on-line. Negative resection margins are important in local and regional control of the tumor mood disorder with psychotic features code geodon 80mg order free shipping. They may arise anywhere in this region but are most common on the buccal mucosa depression and anger geodon 40mg fast delivery, gingiva and larynx mood disorder research discount 20mg geodon with mastercard. These include mucoepidermoid carcinomas, adenoid cystic carcinomas and polymorphous low-grade adenocarcinomas (see below). Some tumors that are more common malignancies of major salivary glands occur uncommonly in minor salivary glands. Microscopically, there is prominent surface keratinization ("church-spire" keratosis) composed of bland-appearing uniform squamous cells without dysplasia, and broad or bulbous rete pegs with a pushing margin into the submucosa. Some of these, particularly those expressed in the skin and mucous membranes, are systemic; others reflect localized disease. Acquired macroglossia may be due to amyloidosis, acromegaly, or infiltration or lymphatic obstruction by tumors. Some forms of glossitis reflect vitamin deficiencies of, for example, vitamin B12, riboflavin, niacin (B3) and pyridoxine (B6). This cystic lesion is associated with the minor salivary glands and is probably caused by trauma that permits escape of mucus. Many communities fluoridated their drinking water, leading to huge reductions in dental caries in those children whose teeth were formed while they drank fluoride-containing water. When the process reaches the dentinoenamel junction, it spreads laterally and also penetrates the dentin along the dentinal tubules. A substantial cavity then forms in the dentin, producing a flask-shaped lesion with a narrow orifice. Only when the vascular pulp of the tooth is invaded, does an inflammatory reaction (pulpitis) appear, accompanied for the first time by pain. Unless the surfaces are cleaned thoroughly and frequently, bacterial colonies coalesce into a soft mass known as dental plaque. Carious lesions occur because acids produced from food residues by microorganisms on tooth surfaces leach the minerals in teeth. The culprits include streptococci, lactobacilli and actinomycetes in the oral flora. Indirect evidence points strongly to Streptococcus mutans as the primary etiologic agent that initiates caries. It also contains bacteriostatic factors such as lysozyme, lactoferrin, lactoperoxidases and secretory immunoglobulins. Xerostomia (chronically dry mouth due to lack of saliva), which may be iatrogenic, for example, due to surgery or radiation therapy, results in rampant caries. Roughage in raw and unrefined foods necessitates heavy mastication, which cleanses the teeth. By contrast, soft and refined foods tend to stick to the teeth and also require less chewing. A periodontal ligament of collagen fibers holds teeth in position in the socket (alveolus) of the jawbone. Periodontal diseases are acute and chronic disorders of the soft tissues around the teeth, which eventually erode the supporting bone. Chronic periodontal disease typically occurs in adults with poor oral hygiene but may develop even in people with apparently impeccable habits who have strong family histories of periodontal disease. It causes more loss of teeth in adults than does any other disease, including caries. Periodontal disease occurs when bacteria accumulate under the gingiva in the periodontal pocket. This newly formed dentin is opposite the area of tooth destruction and was produced by the stimulated odontoblasts. Adult periodontitis is mostly associated with Bacteroides gingivalis, Bacteroides intermedius, Actinomyces sp. Untreated, it progresses to chronic periodontitis, in which the chronic inflammation weakens and destroys the periodontium, causing loosening and eventual loss of teeth. Agranulocytosis may lead to necrotizing ulcers anywhere in the oral and pharyngeal mucosa, but especially in the gingiva. Infectious mononucleosis often causes gingivitis and stomatitis, with exudation and ulceration. In acute monocytic leukemia, 80% of patients have gingivitis, gingival hyperplasia, petechiae and hemorrhage. Necrosis and ulceration of the gingiva lead to severe superimposed infection, which may cause loss of teeth and alveolar bone. Mild scurvy (vitamin C deficiency; see Chapter 8) affects the marginal and interdental gingiva, which become swollen and bright red and bleed and ulcerate readily. A common histologic pattern is characterized by islands of odontogenic epithelium with a central stellate reticulumlike area, surrounded by basal cells with a "picket fence" appearance, due to subnuclear vacuoles. Most common are radicular (apical, periodontal) cysts, involving tooth apices, usually after infection of the dental pulp. Dentigerous cysts are associated with the crowns of impacted, embedded or unerupted teeth, most often involving mandibular and maxillary third molars. They form after the crown has completely developed; fluid accumulates between the crown and overlying enamel epithelium. Ameloblastomas are tumors of odontogenic epithelia and are the most common clinically significant odontogenic tumors. They are slow growing and locally invasive, generally following a benign clinical course, even as they can be locally destructive. Most arise in the mandibular ramus or molar area, maxilla or floor of the nasal cavity. The tumors grow slowly as central lesions of bone, showing a characteristic "soap bubble" radiographic appearance. Ameloblastomas resemble the enamel organ in its various stages of differentiation, and a single tumor may show several histologic patterns. Some may metastasize and yet remain histologically benign (metastasizing ameloblastoma). Ameloblastic carcinomas are frankly malignant, with atypia, necrosis, nuclear pleomorphism and abundant mitoses. Beyond the nares, the median septum divides the nasal cavity into two symmetric chambers, the nasal fossae. Each nasal fossa has an olfactory region, consisting of the superior nasal concha and the opposed part of the septum, and a respiratory region, which is the rest of the cavity. Laterally, the inferior, middle and superior nasal conchae (turbinates) overhang the corresponding nasal passages or meatus. The paranasal sinuses are paired air spaces that communicate with the nasal cavity. The respiratory portion of the nasal cavity is covered by ciliated, columnar epithelium with interspersed goblet cells. Infections can spread to maxillary, ethmoid, frontal and sphenoid sinuses, causing intraorbital and intracranial disease. The vein of Vesalius, medial to the foramen ovale, puts the cavernous sinus at risk. Arrows indicate the direction of spread from the teeth to the maxillary sinus and through the inferior orbital fissure to the orbit. A deeper route is along the lateral pterygoid lamina up to the base of the skull, where, medial to the foramen ovale, a small aperture admits the vein of Vesalius. Through this small vein, the pterygoid plexus communicates with the cavernous sinus. Its causes range from the common cold to unusual infections such as diphtheria, anthrax or glanders (see Chapter 9). The virus replicates in epithelial cells, and degenerating epithelial cells are shed. The mucosa is edematous and engorged, infiltrated by neutrophils and mononuclear cells. Abundant mucus secretion and increased vascular permeability lead to rhinorrhea (free discharge of a thin watery mucus). Secondary infection caused by normal nasal and pharyngeal flora may follow viral rhinitis by a few days. The abundant serous discharge then becomes mucopurulent, after which the surface epithelium is shed. Rhinophyma is a protuberant bulbous mass on the nose caused by marked hyperplasia of sebaceous glands and chronic inflammation of the skin in acne rosacea. Nosebleed (epistaxis) is most often due to trauma but has many causes, including hypertension, diverse hematologic abnormalities, inflammatory conditions and nasal mucosal tumors. Epistaxis often originates in a triangular area of the anterior nasal septum called "Little area," where the epidermis is thin and the anterior ethmoid, greater palatine, sphenopalatine and superior labial arteries anastomose to form the Kiesselbach plexus. Ulcers and perforations, which may be caused by various diseases or by trauma to the septum, occur here (Table 29-1). Thus triggered, mast cells release cytoplasmic granules that contain diverse chemical mediators and enzymes. It is followed by a prolonged inflammatory reaction as the various mediators exert their effects, causing the signs and symptoms of allergic rhinitis. Typically characterized by erythema over the bridge of the nose and cheeks, as well as pustules and papules. The late phase of mast cell­mediated reactions is associated with persistent mucosal edema and manifests clinically as nasal obstruction. In this condition, the nasal mucosa is thickened by persistent hyperemia, mucous gland hyperplasia and infiltration with lymphocytes and plasma cells. Inflammatory Polyps Are Nonneoplastic Swellings these polyps arise in the nose and sinuses, mostly from the lateral nasal wall or ethmoid recess. Multiple etiologies are responsible, including allergy, cystic fibrosis, infections, diabetes mellitus and aspirin intolerance. These polyps are lined by respiratory epithelium and have mucous glands within a loose mucoid stroma, containing plasma cells, lymphocytes and eosinophils. Infection followed chronic obstruction of the orifice caused by adenocarcinoma of the nasal mucosa. Sinusitis Is Inflammation of the Mucous Membranes It usually reflects bacterial infections of the paranasal sinuses. If a sinus ostium is blocked, secretions or exudate accumulate behind the obstruction. Maxillary sinusitis may also be caused by odontogenic infections: bacteria from the roots of the first and second molars penetrate the thin bony plate that separates them from the floor of the maxillary sinus. Incomplete resolution of infection or recurrent acute sinusitis may lead to chronic sinusitis, in which the purulent exudate almost always includes anaerobic bacteria. Overlying skin is often markedly edematous, and subcutaneous cellulitis or a subcutaneous abscess also may develop. Osteomyelitis also may spread rapidly between the outer and inner tables of the skull. Septic thrombophlebitis: Sinus infections that penetrate the bone may spread to frontal and diploe venous systems. Resulting septic thrombophlebitis may involve the cavernous venous sinus through the superior ophthalmic veins and is a potentially life-threatening condition. Intracranial infections: Sinusitis may also spread infection to the cranial cavity. Lesions include epidural, subdural and cerebral abscesses and purulent leptomeningitis. Spread may be via lymphatics and veins and need not involve extensive destruction of bone. Syphilis May Destroy the Nasal Bridge Primary chancres in the nose are rare, but mucosal lesions of secondary syphilis are common in the nose and nasopharynx. In tertiary syphilis, inflammation may involve large portions of the nasal mucosa, underlying cartilage and bone. Perichondrial or periosteal gummas may destroy nasal cartilage and bone, causing the nasal bridge to collapse and producing "saddle nose. If infected, a mucocele may cause a sinus to fill with mucopurulent exudate, called a pyocele. Mucoceles occur most often in the anterior compartments ("cells") of frontal and ethmoid sinuses. Mucoceles of anterior ethmoid or frontal sinuses may be large enough to displace the contents of the orbit and occasionally, erode into the central nervous system. Osteomyelitis: Suppurative infection of nasal sinus walls may spread through Volkmann canals to the periosteum, producing periostitis and subperiosteal abscess. If these Leprosy Is Spread through Nasal Secretions Mycobacterium leprae multiplies best at lower temperatures and so prefers cooler body sites, like the nares and anterior nasal mucosa. Tuberculoid and intermediate forms of leprosy account for most cases (see Chapter 9). The skin around the nares and anterior nasal mucosa shows nodules, ulceration or perforations. Nasal involvement is important as leprosy is spread via nasal secretions teeming with bacilli. Fungus balls, or aspergillomas, occur in immunologically normal patients, usually with chronic sinusitis and poor drainage. In this setting, fungi proliferate to form a dense mass of hyphae that causes nasal obstruction. In the rare rhinocerebral aspergillosis, the organisms penetrate venous sinuses and spread to the meninges and brain.

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