AI Quiz Skin and Hematology.docx

Skin and Hematology - **Primary lesions** - original appearance - **Secondary lesions** - appearance modified by normal progress over time or by such external agents as scratching (e.g., chicken pox) - Assess family/personal history, geographic origin, present abode, season, occupat...

Skin and Hematology - **Primary lesions** - original appearance - **Secondary lesions** - appearance modified by normal progress over time or by such external agents as scratching (e.g., chicken pox) - Assess family/personal history, geographic origin, present abode, season, occupation, leisure activity, any diseases, previous treatment, special history Terms for Skin Lesions (Table 25.1) Macroscopic Lesions - **Excoriation** - traumatic lesion breaking the epidermis and causing a raw linear defect (i.e., deep scratch); often self-induced. - **Lichenification** - thickened, rough skin (similar to lichen on a rock); usually the results of repeated rubbing. - **Macule, patch** - circumscribed, flat lesion distinguished from surrounding skin by color. Macules are 5 mm in diameter or less; patches are greater than 5 mm. - **Onycholysis** - Separation of nail plate from nail bed. - **Papule, Nodule** - Elevated dome-shaped or flat-topped lesion. Papules are 5 mm or less across; nodules are greater than 5 mm in size.  - **Plaque** - Elevated flat-topped lesion, usually greater than 5 mm across (may be caused by coalescent papules).\ **Pustule** - Discrete, pus-filled, raised lesion. - **Scale** - Dry, horny, plate-like excrescence; usually the result of imperfect cornification. - **Vesicle, Bulla, Blister** - Fluid-filled raised lesion 5 mm or less across (vesicle) or greater than 5 mm across (bulla). Blister is the common term for either lesion.  - **Wheal** - Itchy, transient, elevated lesion with variable blanching and erythema formed as the result of dermal edema Microscopic Lesions - **Acanthosis** - Diffuse epidermal hyperplasia - **Dyskeratosis** - Abnormal, premature keratinization within cells below the stratum granulosum. - **Erosion** - Discontinuity of the skin showing incomplete loss of the epidermis. - **Exocytosis** - Infiltration of the epidermis by inflammatory cells. - **Hydropic swelling (ballooning)** - Intracellular edema of keratinocytes, often seen in viral infections. - **Hypergranulosis** - ** **Hyperplasia of the stratum corneum, often associated due to intense rubbing - **Hyperkeratosis** - Thickening of the stratum corneum, often associated with a qualitative abnormality of the keratin. - **Lentiginous** - Linear pattern of melanocyte proliferation within the epidermal basal cell layer. - **Papillomatosis** - Surface elevation caused by hyperplasia and enlargement of contiguous dermal papillae.  - **Spongiosis** - Intercellular edema of the epidermis.   - **Ulceration** - Discontinuity of the skin marked by complete loss of the epidermis revealing dermis or subcutis. - **Vacuolization** - Formation of vacuoles within or adjacent to cells; often refers to basel cell-basement membrane zone area. **Tissue Repair** - Repair (healing) refers to the restoration of tissue architecture and functions after an injury. - Repair occurs by two processes: regeneration and scarring - **Regeneration** - tissues can replace the damaged components and essentially return to a normal cellular state - **Connective tissue deposition (scar formation)** - injured tissues are incapable of regeneration, or if the supporting structures of the tissue are too severely damaged to support regeneration of the tissue cells, repair occurs by the laying down of connective (fibrous) tissue. **Cell and Tissue Regeneration** - Regeneration of injured cells and tissues involved cell proliferation.  - Driven by growth factors and is critically dependent on the integrity of the extracellular matrix (ECM), and by the development of mature cells from tissue stem cells. - Tissues are classified as *labile, stable, and permanent,* according to the proliferative capacity of their cells. - Continuously dividing tissues (labile tissues) contain stem cells that differentiate to replenish lost cells and maintain tissue homeostasis. - Cell proliferation is controlled by the cell cycle and is stimulated by growth factors and interactions of cells with the ECM. Example: Liver Regeneration - classic example of repair by regeneration - Triggered by cytokines and growth factors produced in response to loss of liver mass and inflammation - Regeneration may occur by proliferation of surviving hepatocytes or repopulation from progenitor cells - Restoration of normal tissue structure can occur only if the residual tissue is structurally intact **Connective Tissue Deposition** - Tissues are repaired by replacement with connective tissue and scar formation if the injured tissue is not capable of proliferation or if the structural framework is damaged and cannot support regeneration. - Main components: angiogenesis, migration and proliferation of fibroblasts, collagen synthesis, and connective tissue remodeling - Repair starts with the formation of granulation tissue and culminates in the laying down of fibrous tissue - Multiple growth factors stimulate the proliferation of the cell types involved in repair. - TCG-β is a potent fibrogenic agent; ECM deposition depends on the balance between fibrogenic agents, metalloproteinases (MMPs) that digest ECM, and TIMPs - **Primary closure** - edges of incision are closely opposed (e.g., sutures, staple, or taping, to allow healing by injury intention - **Secondary closure** - incision left open and heals by secondary intention as new tissue infills from the base and sides of the wound (will scar) - **Delayed primary closure** - incision left open for several day and sometimes weeks, allowing treatment of infection/contamination, removal of nonviable tissue, and/or for resolution of swelling, before proceeding to primary closure or closure with a *flap/graft* **Defects in Healing** - **Venous leg ulcers** - develops mostly in elderly people as a result of chronic venous hypertension. These ulcers fail to heal because of poor delivery of oxygen to the site of the ulcer - **Arterial ulcers -** develop in those with atherosclerosis of peripheral arteries, especially with diabetes - Ischemia results in atrophy → necrosis; these lesions are painful - **Diabetic ulcers** - affects lower extremities (feet); tissue necrosis and failure to heal as a result of vascular disease causing ischemia, neuropathy, systemic metabolic abnormalities, and secondary infections - These lesions are characterized by ***epithelial ulceration and extensive granulation tissue*** in the dermis. - **Pressure sores -** skin ulceration and necrosis of underlying tissues caused by prolonged compression of tissues against a bone; the lesions caused by mechanical pressure and local ischemia. - **Hypertrophic scars** - accumulation of excessive amounts of collagen may give rise to a raised scar known as a hypertrophic scar; they ***grow rapidly*** and contain abundant myofibroblasts, but they *** tend to regress over several months***. - **Keloid** - scar tissue that grows beyond the boundaries of the original wound and ***does not regress***; keloid formation seems to be an individual predisposition, and common in black populations **Injury by Physical Agents** - **Mechanical Trauma** - type of injury depends on the shape of the colliding object, amount of energy discharged at impact, and the tissues or organs that bear the impact - Soft tissues react similarly to mechanical forces, patterns of injury can be divided (abrasions, contusions, lacerations, incised wounds, and puncture wounds) - **Thermal Injury -** injury depends on factors (depth of burns, percentage of body surface, internal injuries causes by inhalation of hot toxic fumes, promptness and efficacy of therapy, especially fluid and electrolyte management and prevention/control of wound infections) - **Superficial burns (1st degree burns)** - confined to the epidermis - **Partial - thickness burns (2nd degree burns)** - injury to dermis  - **Full - thickness burns (3rd degree burns)** - burns to the subcutaneous tissue - *White or charred, dry, and painless (due to destruction of nerve endings), whereas, depending on the depth, partial-thickness burns are pink or mottled with blisters and are **[painful]**; tissue reveals coagulative necrosis, adjacent to vital tissue that quickly accumulates inflammatory cells and marked exudation* - Burn Shock - Patho: capillary leak occurs within minutes and persists for 24 hours - Fluid lost in the area of the burn and internally collects in nearby soft tissues causing interstitial edema - Rate and volume of fluid lost directly related to severity of burn - Parkland formula - estimation of burn injury dictates fluid resuscitation **Shock, sepsis, and respiratory insufficiency are the greatest threats to life in burn patients. Particularly in burns of more than 20% of the body surface, there is a rapid (within hours) shift of body fluids into the interstitial compartments throughout the body due to the systemic inflammatory response syndrome, leading to shock** **Cardiovascular Dysfunction** - Often accompanied by significant drop in cardiac output that does not parallel gradual reduction in blood volume and is refractory to restoration of the circulating volume - Pathophysiologic mechanism is poorly understood but involvement of metabolic and immunologic factors is suggested **Respiratory Dysfunction** - Result of obstruction, interstitial alterations, and metabolic changes - Inhalation injury results in chemical denaturing of pulmonary tissue and edema - Acute respiratory distress syndrome (ARDS) usually seen within 6 days **Renal Dysfunction ** - Early renal failure develops within first 5 days post burn, due to low intravascular volume and presence of myoglobin (rhabdomyolysis; can cause kidney failure) - Late renal failure (\>5 days postburn) from sepsis, or use of nephrotoxic medications **Metabolic Changes** - Massive release of catecholamines: hypermetabolism manifests as tachycardia and increased oxygen consumption - Accelerated protein breakdown leads to muscle protein wasting **Cellular Changes** - Cell membrane transport defect related to alteration in the steady-state composition, characterized by high intracellular concentrations of sodium (sick cell syndrome) - Decrease in the efficiency of the sodium-potassium pump; diminished membrane potential (calcium channels disrupted) **Immune Response** - Burns suppress immune system making infections possible - Cytokines act directly on burn wound; activate agents that release oxidants, arachidonic acid metabolites and proteases; further local and systemic inflammation; multisystem organ failure - As a result of vascular changes, fluid and fibrinogen leave the dilated, permeable vessels; leads to burn shock +-----------------+-----------------+-----------------+-----------------+ | **BURNS** | **1st Degree** | **2nd Degree** | **3rd Degree** | | | | | | | | **(SUPERFICIAL) | **(PARTIAL | **(FULL | | | ** | THICKNESS)** | THICKNESS)** | +=================+=================+=================+=================+ | Area | ***ONLY | ***Epidermis to | ***Epidermis, | | | superficial | the level of | dermis, and | | | tissue*** | the dermis*** | underlying | | | destruction of | | subcutaneous | | | outermost | | tissue*** | | | layers of the | | | | | epidermis | | | +-----------------+-----------------+-----------------+-----------------+ | Signs/symptoms | Local | Moist, | Appear white, | | | discomfort, | thin-walled | cherry red, or | | | erythema, | blisters with | black, with | | | headache, | pain | deep blisters; | | | chills, N/V | | ***painless*** | | | | Mottled | areas | | | | appearance: | | | | | large areas of | | | | | waxy-white | | | | | tissue | | | | | surrounded by | | | | | light pink or | | | | | red tissue, | | | | | blisters flat | | | | | and dry | | +-----------------+-----------------+-----------------+-----------------+ | Healing | Typically | Injuries heal | Wound has dry, | | | self-limiting | 3-4 weeks; | hard, leathery | | | healing in 3-6 | absence of | texture | | | days | infection  | | +-----------------+-----------------+-----------------+-----------------+ | Treatment | In infants and | Hair typically | Often | | | elderly may | reappears in | necessitate | | | require IV | 7-10 days in | escharotomies | | | resuscitation | less severe | or fasciotomies | | | to treat | burns | to restore | | | dehydration  | | distal | | | | | circulation | +-----------------+-----------------+-----------------+-----------------+ - Injury by ionizing radiation Hyperthermia - **Heat cramps** - result from loss of electrolytes via sweating. Cramping of voluntary muscles, usually in association with vigorous exercise, is the hallmark.  - **Heat exhaustion** - onset is sudden, with prostration and collapse, and results from a failure of the cardiovascular system to compensate for hypovolemia caused by dehydration. Resolves if the rehydration occurs. - **Heat stroke** - is associated with high ambient temperatures, high humidity, and exertion. Older adults, individuals undergoing intense physical stress, and persons with cardiovascular disease are at particularly high risk for heat stroke. - Thermoregulation mechanisms fail, sweating ceases, and the core body temperature rises to more than 40C, leading to multiorgan dysfunction that can be rapidly fatal. - Accompanied by marked generalized vasodilation, with peripheral pooling of blood and a decreased effective circulating blood volume. - Hyperkalemia, tachycardia, arrhythmias, and other systemic effects are common. Particularly important, however, are sustained contractions of skeletal muscle that can exacerbate the hyperthermia and lead to muscle necrosis (rhabdomyolysis) - Melanocytic Nevus - Common benign neoplasms are caused in most cases by acquired activating mutations in components of the RAS signaling pathway. - Acquired mutations that lead to constitutive activation of RAS or the serine/threonine kinase BRAF - Tan to brown, uniformly pigmented, small (usually less than 6 mm across), relatively flat macules or elevated papules with well-defined, rounded borders. - **Junctional nevi** - early lesion, small, ***flat***, symmetric, and uniform; aggregates or nests of round cells that grow along the dermoepidermal junction - **Compound nevi** - junctional nevi form into compound nevi; grows in the underlying dermis as nests or cords of cells - Dysplastic Nevi  - Can be direct precursors of melanoma and when multiple in number are a marker of an increased risk for melanoma - May be isolated - risk of malignant transformation is very low - Acquire activating mutations in the *NRAS* and *BRAF* genes - Inherited loss-of-function mutations in *CDKN2A* - RAS or BRAF activation and increased CDK4 activity contribute to the development of dysplastic nevi - Larger than most acquired nevi (often greater than 5 mm across) - May appear as flat macules, slightly raised plaques with a "pebbly" surface, or target-like lesions with a darker raised center and irregular flat periphery - Diagnostic architectural feature: coalescent intraepidermal nests - Cytologic feature: cytologic atypia - Clinical significance potential marker or precursor of melanoma - Can occur on the sun exposed and protected body surfaces - Melanoma - Common neoplasm that can be cured if it is detected and treated when it is in its earliest stages. - Melanoma arises in the skin; other sites of origin include the oral and anogenital mucosal surfaces (i.e., oropharynx, gastrointestinal and genitourinary tracts), the esophagus, the meninges, and the uvea of the eye - 10-15% of affected patients, the risk of melanoma is inherited as an autosomal dominant trait with variable penetrance - Most deadly of all skin cancers and is strongly linked to acquired mutations caused by exposure to UV radiation in sunlight. - Normally seen on left side, i.e., driving - Toenail - aggressive - Familial cases are associated with germline mutations affecting genes that regulate cell cycle progression (disrupt cell cycle control genes and activate pro-growth signaling pathways), whereas others are associated with germline mutations affecting telomerase expression - Remaining patients: melanoma is sporadic and strongly related to a single predisposing environmental factor: UV radiation exposure from sunlight - Variations in color, appearing in shades of black, brown, red, dark blue, and gray - May have zones of white or flesh-colored hypopigmentation sometimes due to focal regression of the tumor - The borders of melanomas are irregular and often notched - Clinical features: The most important warning signs, sometimes called the ABCDEs of melanoma, are (1) asymmetry; (2) irregular borders; and (3) variegated color; (4) increasing diameter; and (5) evolution or change over time, especially if rapid. - 6 mm or greater is CONCERNING - Examples - tanning bed exposure, sunburn, and peeling - Pathways important in melanoma. Growth factors activate signaling circuits involving receptor tyrosine kinases, RAS, and two key downstream pathways that include serine/threonine kinase BRAF and the phospholipid kinase P13K. - The most frequent "driver" mutations in melanoma affect cell cycle control, pro-growth pathways, and telomerase. - Typically has a superficial spreading-radial growth phase and then shifts to a vertical growth phase during which the tumor cells invade downward into the deep dermis as an expansile mass. Vertical growth phase is often heralded by the appearance of a nodule and correlates with the emergence of a tumor subclone with metastatic potential.  **Benign Epithelial Tumors** Seborrheic Keratosis - Occur most frequently in middle-aged or older individuals - Arise spontaneously and are particularly numerous on the trunk, although the extremities, head, and neck may also be involved. - In people of color, multiple small seborrheic keratoses on the face are termed *dermatosis papulosa nigra*, a condition that is present in up to 35% of African-American adults - Activating mutations in fibroblast growth factor receptor-3 (FGFR3), a receptor tyrosine kinase, are found in many sporadic seborrheic keratoses and are thought to drive the growth of the tumor. - The growths resemble flattened or raised [warts] but have no viral origins and may exhibit a variety of colors, from pink or yellow to brown and black, and are often described as having a "pasted-on" appearance. - Inspection with a hand lens typically reveals small, round, pore-like ostia impacted with keratin, a feature helpful in differentiating these pigmented lesions from melanoma.  **Premalignant and Malignant Epidermal Tumors** Actinic Keratosis - Usually occurs in sun-damaged skin and exhibits hyperkeratosis - May show progressively worsening dysplastic changes that culminate in cutaneous squamous cell carcinoma - Usually less than 1 cm in diameter - Typicaly, tan-brown, red, or skin-colored and have a rough, sandpaper-like consistency - Some lesions produce so much keratin that a "cutaneous horn" develops - Sun-exposed sites (face, arms, dorsum, of hands) are most frequently affected - They may regress or remain stable throughout life, but enough transform to malignancy that local eradication (gentle curettage, freezing, or topical application of chemotherapeutics agents) is warranted. Squamous Cell Carcinoma - Second most common tumor arising on sun-exposed in older people, only by basal cell carcinoma - Higher in men - Lesions are nodular and ulcerated - Invasive squamous cell carcinomas are usually discovered while they are small and resectable. - Less than 5% of these tumors metastasize to regional nodes; these lesions are generally deeply invasive and involve the subcutis - Most important cause of cutaneous squamous cell carcinoma is DNA damage induced by exposure to UV light - Incidence is proportional to the degree of lifetime sun exposure - P53 dysfunction is an early event in the development of tumors induced by sunlight Basal Cell Carcinoma - Locally aggressive cutaneous tumor that is associated with mutations that activate the ***Hedgehog*** signaling pathway  - Most common invasive cancer in humans; slow-growing tumors that rarely metastasize - Vast majority are recognised at an early stage and cured by local excision - Occurs at sun-exposed sites in lightly pigmented elderly adults - Usually present as ***pearly papules*** containing prominent dilated subepidermal blood vessels (**telangiectasias)** - Advanced lesions may ulcerate, and extensive local invasion of bone or facial sinuses may occur after many years of neglect or in unusually aggressive tumors **Acute Inflammatory Dermatoses** Urticaria (hives) - Common disorder of the skin that is usually caused by localized mast cell degranulation and is uniformly associated with dermal microvascular hyperpermeability - Produces pruritic edematous plaques called *wheals* - Urticaria most often occurs between ages 20-40, but all ages are susceptible - Lesions develop and fade within hours (usually less than 24 hours), and episodes may last for days or persist for months - Sites of for urticarial eruptions include any area exposed to pressure, such as the trunk, distal extremities, and ears - Commonly the result of antigen-induced release of vasoactive mediators from mast cells - *Mast cell--dependent, immunoglobulin E (IgE)--dependent*. - Urticaria of this type follows exposure to many different antigens (pollens, foods, drugs, insect venom) and is an example of a localized immediate hypersensitivity (type I) reaction triggered by the binding of antigen to IgE antibodies that are attached to mast cells through Fc receptors  - *Mast cell--dependent, IgE-independent* - *This subset results from substances that directly incite the degranulation of mast cells, such as opiates, certain antibiotics, and radiographic contrast media.* - *Mast cell--independent, IgE-independent*. - These forms of urticaria are triggered by local factors that increase vascular permeability. One form is initiated by exposure to chemicals or drugs, such as aspirin, that inhibit cyclooxygenase and arachidonic acid production. The precise mechanism of aspirin-induced urticaria is unknown. A second form is hereditary angioneurotic edema (Chapter 6), caused by an inherited deficiency of C1 inhibitor that results in excessive activation of the early components of the complement system and production of vasoactive mediators. Acute Eczematous Dermatitis - Eczematous dermatitis typically results from T-cell mediated inflammatory reactions (type IV hypersensitivity) - 5 categories: 1. Allergic contact dermatitis - Results from external application of an antigen ***(e.g. poison ivy)*** or a reaction to an internal circulating antigen (ingested food or drug) - Typically results from t-cell mediated inflammatory reactions (type IV hypersensitivity) - Rhus dermatitis (poison ivy, oak, sumac) is the most common type of allergic contact dermatitis - Symptoms begin within 48 hours of contact; red, papulovesicular, crusted lesions in a sometime-linear pattern that can develop reactive **acanthosis** and **hyperkeratosis** and take on the appearance of raised scaling plaques - If the allergen remains on the skin, it can spread to non exposed areas. Exposure to blister fluid does not spread poison ivy lesions 2. Atopic dermatitis - Patho: Genetic defects in the epidermal barrier protein filaggrin have been cited as a major cause - The stratum corneum layers with this mutation (loss-of-function of filaggrin) have lower levels of natural moisturizing factor and are also deficient in extracellular lipids including ceramides. - Clinical manifestations: - Atopy: genetic component - Most common in children; usually improves with age - Lesions pruritic, oozing, crusting, coalescent papule; thickening of the skin or lichenification occurs  - Atopic triad - asthma, allergies (allergic rhinitis/hay fever), conjunctivitis 3. Drug-related eczematous dermatitis 4. Photo Eczematous dermatitis 5. Primary irritant dermatitis Erythema Multiforme - Hypersensitivity reaction to certain infections and drugs - Individuals of any age and is associated with the following conditions: - 1\. Infections such as herpes simplex, mycoplasmal infections, histoplasmosis, coccidioidomycosis, typhoid, and leprosy - 2\. Exposure to certain drugs (sulfonamides, penicillin, barbiturates, salicylates, hydantoins, and antimalarials) - 3\. Cancer (carcinomas and lymphomas) - 4\. Collagen vascular diseases (lupus erythematosus, dermatomyositis, and polyarteritis nodosa) - Characterized by keratinocyte injury mediated by skin-homing CD8+ cytotoxic T lymphocytes  - CD8+ cytotoxic T-cells and more prominent in the central portion of the lesions, while CD4+ helper T-cells and Langerhans cells are more prevalent in the peripheral portions - The epidermal antigens that are recognized by the infiltrating T-cells in erythema multiforme remain unknown - Diverse array of lesions (hence the term multiforme), including macules, papules, vesicles, bullar, and characteristic targetoid (target-like) lesions - Stevens-Johnson syndrome, which is often seen in children - Lesions involve not only on the skin but also the lips and oral mucosa, conjunctiva, urethra, genital, and perianal areas. Secondary infection of involved areas due to loss of skin integrity may results in life-threatening sepsis - Toxic epidermal necrolysis is characterized by diffuse ***necrosis and sloughing*** of cutaneous and mucosal epithelial surfaces. The widespread epidermal damage produces a clinical picture similar to patients with extensive burns  **Chronic Inflammatory Dermatoses** Psoriasis - Chronic, inflammatory, autoimmune disorder that develops in response to environment and genetic factors, including particular HLA gene variants. Sensitized CD4+ T-cells lead to infiltration into the skin and overexpression of multiple cytokines, including tumor necrosis factor-ɑ (TNF) and various interleukins - Induces keratinocyte proliferation, resulting in the characteristic lesions - Most frequently affects elbow, knees, scalp, lumbosacral areas, intergluteal cleft, and glans penis - The typical lesion is well-demarcated, pink to salmon-colored plaque covered by loosely adherent silver-white scale - Auspitz sign - proximity of vessels within the dermal papillae to the overlying parakeratotic scale accounts for the characteristic clinical phenomenon of multiple, minute, bleeding points when the scale is lifted from the plaque - Inherited condition with immune system involvement - Lesions on knees, elbow, lower back, scalp, nails; exacerbation and remission - Psoriasis is one cause of total body erythema and scaling known as erythroderma. Nail changes occur in 30% of cases of psoriasis and consist of yellow-brown discoloration (often likened to an oil slick), with pitting, dimpling, separation of the nail plate from the underlying bed (onycholysis), thickening, and crumbling. **Types of Psoriasis** 1. **Plaque Psoriasis** (80% of cases): - Characterized by sharply demarcated, red, scaly patches of skin with a silvery sheen. 2. **Scalp Psoriasis** (45-56% of cases): - Involves raised red or silver scaly plaques on the scalp, which are often itchy. 3. **Nail Psoriasis** (50% of cases): - Affects fingernails and/or toenails, causing dimpling that resembles a golf ball. 4. **Guttate Psoriasis** (10% of cases): - Presents as small scaly lesions scattered across the arms, legs, and torso. 5. **Inverse Psoriasis** (\>10% of cases): - Develops in skin folds (e.g., armpits, belly button, genital areas) and involves red, smooth lesions. 6. **Erythrodermic Psoriasis** (2% of cases): - Severe form causing lobster-like redness from head to toe, with peeling and scaling; potentially dangerous. 7. **Pustular Psoriasis** (Rare): - Dangerous form characterized by widespread areas (including hands, feet, and torso) covered with pus-filled bumps. **Disorders of Epidermal Appendages** Acne Vulgaris - Middle to late teenage years, acne vulgaris affects males and females, with males tending to have more severe disease - Acne is seen in all races but is usually milder in people of Asian descent  - May be induced or exacerbated by:  - Drugs: corticosteroid, adrenocorticotropic hormone, testosterone, gonadotropins, contraceptives, trimethadione, iodides, and bromides - Occupational exposures: cutting oils, chlorinated hydrocarbons, and coal tars - Conditions that favor occlusion of sebaceous glands, such as heavy clothing, cosmetics, and tropical climates - Hormonal changes! - ***Open comedones*** are small follicular papules containing a central black keratin plug. This color is the result of oxidation of melanin pigment (not dirt). - BLACK HEAD - ***Closed comedones*** are follicular papules without a visible central plug. Because the keratin plug is trapped beneath the epidermal surface, these lesions are potential sources of follicle rupture and inflammation. - WHITE HEAD - Pathogenesis of acne is incompletely understood and is likely multifactorial  - 1\. Keratinization of the lower portion of the follicular infundibulum and development of a keratin plug that blocks outflow of sebum to the skin surface - 2\. Hypertrophy of sebaceous glands during puberty under the influence of androgens - 3\. Lipase-synthesizing bacteria (*Propionibacterium acnes)* colonizing the upper and mid portion of the hair follicle, converting lipids within sebum to proinflammatory fatty acids - 4\. Secondary inflammation of the involved follicle Rosacea - Common disease of middle age and beyond - Four stage are recognized: - 1\. Flushing episodes (pre-rosacea) - 2\. Persistent erythema and telangiectasia - 3\. Pustules and papules - 4\. Rhinophyma (permanent thickening of the nasal skin by confluent erythematous papules and prominent follicles) - High cutaneous levels of the antimicrobial *peptide cathelicidin*, an important mediate of the cutaneous innate immune response - Rosacea is characterized by a nonspecific perifollicular infiltrate composed of lymphocytes surrounded by dermal edema and telangiectasia - In the pustular phase, neutrophils may colonize the follicles, and follicle rupture may occur and cause a granulomatous dermal response - The development of rhinophyma is associated with hypertrophy of sebaceous glands and follicular plugging by keratotic debris **Panniculitis** - Is an inflammatory reaction in the subcutaneous adipose tissue that may preferentially affect (1) the lobules of fat or (2) the connective tissue that separates fat into lobules - Panniculitis often involves the lower legs - Erythema nodosum is the most common form and usually has a subacute presentation - A second somewhat distinctive form is erythema induratum Erythema Nodosum - Presents poorly defined, exquisitely tender, erythematous plaques and nodules that may be more readily palpated than seen - Often associated with infections (β-hemolytic streptococcal infection, tuberculosis, and less common, coccidioidomycosis, histoplasmosis, and leprosy), drug administration (sulfonamides and oral contraceptives), sarcoidosis, inflammatory bowel disease, and certain malignant neoplasms - Fever and malaise may be present - Pathogenesis is a mystery - Thought to be caused by a delayed hypersensitivity reaction to microbial or drug-related antigens - Over the course of weeks, lesions usually flatten and become bruise-life, leaving no residual clinical scars, while new lesions develop Molluscrum Contagiosum - common , self-limited viral disease of the skin caused by a poxvirus - Infection spread by direct contact, particularly amount children and young adults - Multiple lesions may occur on the skin and mucous membranes, with a predilection for the trunk and anogenital area - Individual lesions are firm, often pruritic, pink to skin-colored umbilicated papules - A curd-like material can be expressed from the central umbilication Impetigo - Common superficial bacterial infection of skin - Highly contagious and is frequently seen in otherwise healthy children as well as occasionally in adults in poor health - 2 forms exist: *Impetigo contagiosa and Impetigo bullosa* - Differ from each other simply by the size of the pustules - Both most commonly caused by S. aureus - Patho: bacteria in the epidermis evoke an innate immune response that causes epidermal injury, leading to local serous exudate and formation of a scale crust (scab) - Related to bacterial production of a toxin that specifically cleaves desmoglein 1, the protein responsible for cell-to-cell adhesion within the uppermost epidermal layers - Clinical manifestations: formation of vesicles, pustules, and yellow/honey-colored crusts - Innate immune response Superficial Fungal Infections - *Trichophyton Rubrum* causes tinea - Infection (tinea) named after location: - Tinea **cap**itis (scalp) - usually occurs in children and is only rarely seen in infants and adults.  - dermatophytosis of the scalp characterized by  - asymptomatic, patchy skin lesions associated with mild erythema, crust formation, scaling, and frequent hair loss. - Tinea **fac**iei (face) - Tinea corporis (trunk) - Common superficial fungal infection of skin that affects persons of all ages, but particularly children.  - Predisposing factors include excessive heat and humidity - Exposure to *infected animals*, and chronic dermatophytosis of the feet or nails. - Most common type of tinea corporis is an expanding, round, slightly erythematous plaque with an elevated scaling border - Tinea **man**us (hand) - *Tinea cruris (groin)* - *Occurs most frequently in the inguinal areas of obese men during warm weather* - *Heat, friction, and maceration all predispose to its development.* - *Infection usually first appears on the upper inner thighs as moist, red patches with raised scaly borders.* - Tinea **ped**is (athete's foot) - Affects 30% to 40% of the population at some time in their lives - Diffuse erythema and scaling, often initially localized to the web spaces.  - Most of the inflammatory reaction, however, appears to be the result of bacterial superinfection and is not directly related to the primary dermatophytosis.  - Spread to (or primary infection of the nails) is referred to as *onychomycosis.* This produces discoloration, thickening, and deformity of the nail plate. - Onychomycosis (nails) - Tinea barbae (beard) - is a dermatophyte infection of the beard area that affects adult men - it is relatively uncommon. - Tinea vesicolor - Usually occurs on the upper trunk and is highly distinctive in appearance - Caused by *Malassezia furfur* (a yeast, not a dermatophyte) - The lesions consist of groups of macules of varied size and color with a fine peripheral scale. - Pathophysiology: dermatophytes invade, infect, and persist in the stratum corneum. Rarely penetrate below the surface of the epidermis - Clinical manifestations: clinical signs vary depending on the location of the infection; may manifest as erythematous or plaques with peripheral scaling and central clearing  **Varicella-Zoster Virus (VZV) infections** - Acute infection with VZV causes chickenpox, and reactivation of latent VZV causes shingles (also called herpes zoster).  - Mild in children but more severe in adults and in immunocompromised people. - VZV evades immune responses and establishes a latent infection in sensory ganglia. In contrast to HSV, VZV is transmitted in epidemic fashion by respiratory aerosols, disseminates hematogenously, and causes widespread vesicular skin lesions.  - Latent VZV infection is seen in neurons and/or satellite cells around neurons in the dorsal root ganglia. Reactivation and clinical recurrences causing shingles are uncommon but may occur many years after the primary infection.  - Localized recurrence of VZV is most frequent and painful in dermatomes innervated by the trigeminal ganglia, where the virus is most likely to be latent.  - Physical manifestations: - Chickenpox rash occurs approximately 2 weeks after respiratory infection.  - Lesions appear in multiple waves centrifugally from the torso to the head and extremities. Each lesion progresses rapidly from a macule to a vesicle, which resembles a dewdrop on a rose petal. - After a few days, most chicken pox vesicles rupture, crust over, and heal by regeneration, leaving no scars.  - Bacterial superinfection of vesicles that are ruptured by trauma may lead to destruction of the basal epidermal layer and residual scarring. - Shingles: causes vesicular lesions, are often associated with intense itching, burning, or sharp pain because of concomitant radiculoneuritis.  - This pain is especially severe when the trigeminal nerves are involved; rarely, the geniculate nucleus is involved, causing facial paralysis (Ramsay Hunt syndrome).  - Due to infections in doral roots lesions follow dermatomes and present unilaterally.  - If it is seen in the eye = MEDICAL EMERGENCY **Lyme Disease** - **Patho: ** Tick bite that carries spirochete *Borrelia burgdorferi* from deer and mice - Much of the pathology associated with the infection is thought to be secondary to the immune response against the bacteria and the inflammation that accompanies it. - ***Clinical Manifestations:*** - Affects skin, nervous, heart, and musculoskeletal system.  - Stage I:  single or multiple erythematous papules that itch, burn, or sting; flulike symptoms  (Bull\'s eye rash) - Stage II:  meningitis, cranial nerve palsies, and peripheral neuropathy; stage III:  oligoarticular arthritis  **Scabies** - **Patho:** - *Sarcoptes scabiei* is a mite - Begins with eggs laid in the stratum corneum, hatch into larvae within 3-4 days - Contracted after close contact with an infested individual - **Clinical Manifestations:** - Small erythematous papules with overlying dry scale or crust; linear burrows - Severe, constant itching **Tick Borne Illness** Rocky Mountain Spotted Fever - **Patho:** Caused by tick that carries *Rickettsia rickettsii*; most states have reported cases.  The rickettsiae then enter the bloodstream and multiply in body tissues. - **Clinical Manifestations:** Initial bite appears as papule or macule with or without a central punctate area - Within 4 to 8 days HA, fever, N/V, and muscle aches appear; macular, maculopapular rash on wrist/ankle  - Ehrlichiosis and anaplasmosis have similar presentations. The rash is nonspecific and can be macular, maculopapular, or petechial. **Vitiligo (Leukoderma)** - **Patho:** Pigment disappears from a patch of skin; sudden onset - Exact cause is unknown.   - Pathogenic theories include autoimmune involvement, viral causes, decreased melanocyte survival, genetic defects in the structure of the melanocyte, and neurochemical destruction of the melanocyte. ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOMA +-----------------+-----------------+-----------------+-----------------+ | DIAGNOSIS | CELL OF ORIGIN | GENOTYPE | SALIENT | | | | | CLINICAL | | | | | FEATURES | +=================+=================+=================+=================+ | B-cell acute | Bone marrow | Diverse | Predominantly | | lymphoblastic | precursor B | chromosomal | children; | | leukemia/lympho | cell | translocations; | symptoms | | ma | | t(12;21) | relating to | | | | involved RUNX1 | marrow | | | | ad ETV6 present | replacement and | | | | in 25% | pancytopenia; | | | | | aggressive 85% | | | | | manifest in | | | | | childhood | +-----------------+-----------------+-----------------+-----------------+ | T-cell acute | Precursor T | Diverse | Predominantly | | lymphoblastic | cell (often of | chromosomal | adolescent | | leukemia/lympho | thymic origin) | translocations | males; thymic | | ma | | (50%-70%) | masses and | | | | | variable bone | | | | Most T-ALLs | marrow | | | | have mutations | involvement; | | | | in *NOTCH1*, a | aggressive | | | | gene that is | | | | | essential for | | | | | T-cell | | | | | development | | | | | (50%-70%) | | +-----------------+-----------------+-----------------+-----------------+ - Acute lymphoblastic leukemia/lymphomas (ALLs) are neoplasms composed of immature B (pre-B) or T (pre-T) cells, which are referred to as *lymphoblasts.* - ***ALL is most common cancer of children*** - Approximately 2500 new cases are diagnosed each year in the United States, most occurring in individuals younger than 15 years of age. ALL is almost three times more common in Caucasians than in African-Americans and is slightly more frequent in boys than in girls. Hispanics have the highest incidence of any ethnic group.  - B-ALL peaks in incidence at about the age of 3, perhaps because the number of normal bone marrow pre-B cells (the cell of origin) is greatest very early in life.  - The peak incidence of T-ALL is in adolescence, the age when the thymus reaches maximum size. B-ALL and T-ALL also occur less frequently in adults of all ages - - PATHOGENESIS OF ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOMAS - Many of the chromosomal aberrations seen in ALL dysregulate the expression and function of transcription factors required for normal B- and T-cell development. - By disturbing the expression and function of "master" regulatory factors, these mutations promote maturation arrest and increased self-renewal, a stem cell-like phenotype. - Aberrations that promote cell growth, such as mutations that increase tyrosine kinase activity and RAS signaling, are commonly present. - Approximately 90% of ALLs have numerical or structural chromosomal changes. Most common is hyperploidy (\>50 chromosomes), but ***hypoploidy*** and a variety of balanced chromosomal translocations also are seen.  +-----------------------------------+-----------------------------------+ | - B - ALL | - T - ALL | +===================================+===================================+ | - \- ***Bone pain*** resulting | - \- Mediastinal *thymic* | | form marrow expansion and | masses occur in 50% to 70% of | | infiltration of the | T-ALLs | | subperiosteum | | | | - \- Complications related to | | - - \- Testicular enlargement | compression of large vessels | | | and airways in the | | | mediastinum | +-----------------------------------+-----------------------------------+ - [**Favorable** prognostic markers] include: - *2 - 10 years old* - Low white cell count - Hyperdiploidy - Trisomy of chromosomes 4, 7, and 10 - The presence of a T(12;21) - [Several factors are associated with a worse prognosis:] - Age younger than 2 years, largely because of the strong association of infantile ALL with translocations involved the ***MLL gene*** - Presentation in adolescence or adulthood - Peripheral blood blast counts greater than 100,000 which probably reflects a high tumor burden. - ALL must be distinguished from AML, a neoplasm of immature myeloid cells that can cause identical signs and symptoms. - Although most chromosomal aberrations in ALL alter the function of transcription factors, the t(9;22) instead creates a fusion gene that encodes a constitutively active BCR-ABL tyrosine kinase. In B-ALL, the BCR-ABL protein has stronger tyrosine kinase activity than the form of BCR-ABL that is found in chronic myeloid leukemia. CLINICAL MANIFESTATIONS OF ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) - Prognosis and treatment: intensive treatment necessary to extend life - 85% 5-year survival rate in children: 30%-50% in adults - Certain forms of ALL more responsive to therapy +-----------------+-----------------+-----------------+-----------------+ | Typical Signs | Leukopenia | Anemia | Thrombocytopeni | | and Symptoms | | | a | +=================+=================+=================+=================+ | - Malaise and | - Lymphadenop | - Pallor | - Platelet | | weakness | athy | | count below | | | | - Fatigue  | 20,000 | | - Unexplained | - Joint | | cells/μl | | fever, | swelling | - Malaise | | | night | and pain | | - Petechiae | | sweats | | - Shortness | | | | - Weight loss | of breath | - Easy | | - Abrupt, | | | bruising | | recurrent | - Anorexia | - Decreased | | | infections | | activity | - Bleeding | | | - Hepatomegal | tolerance | gums | | - Enlarged, | y | | | | nontender | | | - Occult | | lymph nodes | - splenomegal | | hematuria | | (lymphadeno | y | | | | pathy) | | | - Retinal | | with | | | hemorrhages | | lymphoma | | | | | and some | | | - - Neutrop | | leukemias | | | enia: | | | | | absolute | | - Very high | | | neutrophil | | total WBC | | | count \< | | count or | | | 500 | | presence of | | | cells/μl | | abnormal | | | | | cell types | | | | | | | | | | - ***Children | | | | | may refuse | | | | | to walk*** | | | | | | | | | | - ***Abdomina | | | | | l | | | | | pain*** | | | | | | | | | | - 3% may | | | | | present | | | | | with CNS | | | | | signs | | | | +-----------------+-----------------+-----------------+-----------------+ BURKITT LYMPHOMA - There are 3 categories - African (endemic) Burkitt lymphoma - Sporadic (nonedemic) Burkitt lymphoma - A subset of aggressive lymphomas occurring in individuals infected with HIV - Burkitt lymphomas occurring in these 3 settings are histologically identical but have distinct clinical, genotypic, and virologic characteristics - **Pathogenesis**: - All forms of Burkitt lymphomas are associated with ***translocations of MYC gene on chromosome 8*** that lead to increased MYC protein levels. - ***Burkitt lymphoma is among the fastest growing human tumors*** - Essentially ***all endemic Burkitt lymphomas are latently infected with [EBV]***, which also is present in about 25% of HIV-associated tumors and 15% to 20% of sporadic cases. - **Clinical Features:** - Both endemic and sporadic Burkitt lymphomas are found mainly in ***children or young adults*** - Burkitt lymphoma accounts for about 30% of childhood NHLs in the United States - Most children and young adults can be cured. The outcome is more guarded in older adults. - Most tumors manifest at extranodal sites - ***Endemic Burkitt lymphoma*** often presents as a ***mass involving the mandible*** and shows an unusual predilection for involvement of ***abdominal viscera***, particularly the ***kidneys, ovaries, and adrenal glands*** - ***Sporadic Burkitt lymphoma*** most often appears as a mass involving the ***ileocecum*** and endemic cases.  - Burkitt lymphoma is very aggressive but responds well to intensive chemotherapy. MULTIPLE MYELOMA -------------------------------------------- ----------------------------------------------------- ---------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------ **Multiple myeloma/solitary plasmacytoma** Post-germinal center bone marrow homing plasma cell Diverse rearrangements involved ***IGH*; 13q deletions** Myeloma: older adults with lytic bone lesions, pathologic fractures, hypercalcemia, and renal failure; moderately aggressive -------------------------------------------- ----------------------------------------------------- ---------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------ - Incidence is ***higher in men and people of African descent*** - Chiefly a disease of older adults, with a peak age of incidence of 65 to 70 years. - **Usually presents as destructive plasma cell tumors (plasmacytomas) involving the axial skeleton** - **Factors produced by neoplastic plasma cells mediate bone destruction, the major pathologic feature of multiple myeloma.** - One important factor appears to be myeloma-derived ***MIP1ɑ (also known as CCL3)***, a chemokine that augments ***osteoclast formation*** through several different mechanisms. - Excessive production of light chain antibody fragments by the malignant plasma cells accumulate in ***blood and urine***. These are known as ***[Bence Jones proteins]*** which are excreted in the kidney and contribute to a form of renal disease called **myeloma kidney**. - **Clinical features:** - Stem from:  - 1\. The effects of plasma cell growth in tissues, particularly the bones  - 2\. The production of excessive Igs, which often have abnormal physicochemical properties - 3.The suppression of normal humoral immunity - Clinicopathological diagnosis of multiple myeloma relies on identification of clonal plasma cells in the marrow and the presence of ***[CRAB criteria (hyperCalcemia, Renal dysfunction, Anemia, and Bone lesions)]*** - ***Hypercalcemia*** can give rise to neurologic manifestations, such as confusion, weakness, lethargy, constipation, and polyuria, and contributes to renal dysfunction. Decreased production of normal Igs sets the stage for recurrent bacterial infections. - Renal insufficiency, which trails infections as a cause of death. The pathogenesis of renal failure, which occurs in up to 50% of patients, is multifactorial. However, the single most important factor seems to be ***Bence Jones proteinuria***, as the excreted light chains are toxic to renal tubular epithelial cells. Certain light chains (particularly those of 𝜆6 and 𝜆3 families) are prone to cause amyloidosis of the AL type, which can exacerbate renal dysfunction and deposit in other tissues as well.  - ***Bone pain is usually the first symptom***. Bone destruction results in hypercalcemia. Pathological fractures, especially in the spine, are common. X-rays may show a characteristic "honeycomb" appearance. - The ones commonly affected (in descending order of frequency) are the vertebral column, ribs, skull, pelvis, femur, clavicle, and scapula. Lesions begin in the medullary cavity, erode cancellous bone, and progressively destroys the bony cortex, often leading to pathological fractures; these are most common in the vertebral column but may occur in any affected bone. - **The bone lesions appear radiographically as** ***[punched-out defects]*, usually 1- 4 cm in diameter** and consist of soft, gelatinous, red tumor masses.** ** - Prognosis is variable - Median survival is 4-7 years, and cures have yet to be achieved. - Patients with multiple bony lesions, if untreated, rarely survive for more than 6-12 months, whereas patients with "smoldering myeloma" may be asymptomatic for many years. - ***Translocations involving cyclin D1 are associated with a good outcome, whereas deletions of 13q, deletions of  17p, and the t(4;14) are all associated with a more aggressive course. *** ***[\ DIFFERENCES BETWEEN HODGKIN AND NON-HODGKIN LYMPHOMAS ]*** +-----------------------------------+-----------------------------------+ | - **HODGKIN LYMPHOMA** | - **NON - HODGKIN LYMPHOMA** | +===================================+===================================+ | - More often localized to a | - More ***[frequent involvement | | ***[single axial group of | of multiple peripheral | | nodes]*** | nodes]*** | | (cervical, mediastinal, | | | para-aortic) | | +-----------------------------------+-----------------------------------+ | - ***[Orderly | - Noncontiqous spread | | spread]*** by | | | contiguity | | +-----------------------------------+-----------------------------------+ | - Mesenteric nodes and Waldeyer | - Waldeyer ring and mesenteric | | ring rarely involved  | nodes commonly involved | +-----------------------------------+-----------------------------------+ | - Extranodal presentation rare | - Extranodal presentation | | | common | +-----------------------------------+-----------------------------------+ HODGKIN LYMPHOMA - Hodgkin lymphoma accounts for 0.7% of all new cancers in the United States; there are about 8,000 cases each year. - The average age at diagnosis is 32 years. It is one of the most common cancers of young adults and adolescents, but also occurs in the aged. - Hodgkin lymphoma arises in a single node or chain of nodes and spreads first to anatomically contiguous lymphoid tissues. - Morphologically, the distinctive feature of hodgkin lymphoma is the presence of neoplastic giant cells called ***[Reed-Sternerg Cells]**.* - Reed-Sternberg Cells - These cells release factors that induce the accumulation of reactive lymphocytes, macrophages, and granulocytes, which typically make up greater than 90% of the tumor cellularity. Molecular studies have shown that the neoplastic Reed-Sternberg cells are derived from germinal center or post-germinal center B cells.  - **Pathogenesis** - Originate from B cells in germinal centers of lymph nodes. - ***[Epstein-Barr virus]*** frequently found in the genome of transformed Reed-Sternberg cells; may be an important pathogenesis of HD.  - ***[Reed-Sternburg cells of classic Hodgkin lymphoma fail to express most B-cell-specific genes, inglucing the Ig genes. ]*** - Activation of the transcription factor NF-kB is a common event in classic Hodgkin lymphoma and turns on genes that are believed to promote the growth and survival of Reed-Sternberg cells - ***PD-1 ligand gene amplification*** in Hodgkin lymphoma (leading to evasion of host immunity) - The WHO classification recognized five subtypes of Hodgkin lymphoma: - 1\. Nodular sclerosis - 2\. Mixed cellularity  - 3\. Lymphocyte - rich - 4\. Lymphocyte depletion - 5\. Nodular lymphocyte predominance - Clinical Features: - Early stages: often asymptomatic - Painless lymphadenopathy;possibly with fever, night sweats, pruritus, weight loss, and malaise - Lymph node enlargement above diaphragm, [cervical] nodes most common site - ***[Supraclavicula]***r, axillary, and mediastinal as well.  - Nodes below diaphragm less common primary site - Inguinal nodes most common subdiaphragmatic site - Disease spreads from site of origin to other lymph nodes/lymphatic tissue, including spleen and bone marrow. +-----------------------+-----------------------+-----------------------+ | - **Subtype** | - **Morphology and | - **Typical | | | Immunophenotype** | Clinical | | | | Features** | +=======================+=======================+=======================+ | - Nodular Sclerosis | - Frequent lacunar | - Most common | | | cells and | subtype; usually | | | occasional | stage I or II | | | diagnostic RS | disease; frequent | | | cells | mediastinal | | | | involvement; | | | - | equal occurrence | | | | in males and | | | - ***RS cells | females, most | | | CD15+, CD30+***; | patients' young | | | usually | adults | | | ***[EBV-]{.underl | | | | ine}*** | | +-----------------------+-----------------------+-----------------------+ | - Mixed cellularity | - Frequent | - More than 50% | | | mononuclear and | present as stage | | | diagnostic RS | III or IV | | | cells | disease; | | | | occurrence | | | - | greater in males | | | | than females; | | | - Background | biphasic | | | infiltrate rick | incidence, | | | in T lymphocytes, | peaking in young | | | eosinophils, | adults and again | | | macrophages, | in adults older | | | plasma cells | than 55 | | | | | | | - | | | | | | | | - ***RS cells | | | | CD15+, CD30+***; | | | | 70% | | | | ***[EBV+]{.underl | | | | ine}*** | | +-----------------------+-----------------------+-----------------------+ MYELODYSPLASTIC SYNDROME (MDS) - **Group of cloak stem cell disorders characterized by maturation defects that are associated with *[ineffective hematopoiesis]* and a high risk of transformation to AML.** - Bone marrow is partly or wholly replaced by the clonal progeny of a neoplastic multipotent stem cell that retains the capacity to differentiate but does so in an ineffective and disordered fashion.  - MDS may be either primary (idiopathic) or secondary to previous genotoxic drug or radiation therapy (t-MDS). - t-MDS usually appears from 2-8 years after the genotoxic exposures. - All forms of MDS can transform to AML, but transformation occurs with highest frequency and most rapidly in t-MDS.  - Pathogenesis & Clinical Features: MDS is associated with driver mutations that partially overlap with those seen in AML, which is unsurprising given that MDS often evolves to AML. The affected proteins can be lumped into 3 major functional categories, as follows: - ***Epigenetic factors*** - Frequent mutations are seen involving many of the same epigenetic factors that are mutated in AML, including factors that regulate DNA methylation, histone modifications, and chromatin looping - ***RNA splicing factors*** - A subset of tumors has mutations involving components of the 3′ end of the RNA splicing machinery. Precisely how these mutations contribute to the development of MDS has yet to be determined. - ***Transcriptions factors *** - These mutations affect transcription factors that are required for normal myelopoiesis and may contribute to the deranged differentiation that characterizes MDS.  - **[Most of the mutations are loss-of-function mutations in genes such as *RUNX1.*]** - roughly 10% of MDS cases have loss-of-function mutations in TP53, which as in AML correlate with the presence of a complex karyotype and particularly poor clinical outcomes. Both primary MDS and t-MDS are associated with similar recurrent chromosomal abnormalities, including monosomies 5 and 7; deletions of 5q, 7q, and 20q; and trisomy 8 - Predominantly a disease of older adults; the mean age of onset is 70 years. - When symptomatic, it presents with weakness, infections, and hemorrhages, all due to pancytopenia. - Median survival in primary MDS varies from less than 6 months to greater than 5 years. - Patients frequently succumb to the complications of thrombocytopenia (bleeding) and neutropenia (infection)  CHRONIC MYELOID LEUKEMIA (CML) - CML is primarily a disease of adults but also occurs in children to adolescents. The peak incidence is in the fifth and sixth decades of life.  - ***[Distinguished from other myeloproliferative neoplasms by the presence of a chimeric BCR/ABL gene derived from portions of BCR gene on chromosome 22 and the ABL gene on chromosome 9. (Philadelphia chromosome)]*** - Translocation of ***chromosomes 9 and 22*** causes two genes to be juxtaposed and ***creates a new fusion gene: bcr/abl*** - Protein product of bcr/abl spurs cells proliferation and ***reduces apoptotic cell death.*** - Induce signaling through the same pro-growth and pro-survival pathways that are turned on by hematopoietic growth factors, including the RAS and JAK/STAT pathways. For unknown reasons, BCR-ABL preferentially drives the proliferation of granulocytic and megakaryocytic progenitors and also causes the abnormal release of immature granulocytic forms from the marrow into the blood. - Clinical features of CML: - The onset is insidious. Mild-to-moderate anemia and ***[hypermetabolism]*** due to increased cell turnover ***leads to fatigability, weakness, weight loss, and anorexia.*** - Sometimes the 1st symptom is a ***[dragging sensation]*** in the abdomen caused by ***splenomegaly*** or the acute onset of ***[left upper quadrant (LUQ) pain due to splenic infarction]***.  - WIthout any treatment, the median survival is about 3 years. - After a variable period averaging 3 years, about 50% of patients enter an "accelerated phase\": marked by increasing anemia and thrombocytopenia, sometimes accompanied by a rise in the number of basophils in the blood. - Within 6 - 12 months, the ***accelerated phase terminates*** in a picture resembling acute leukemia **[(*blast crisis*)]**.  - In 70% of crises, the blasts are of ***[myeloid origin (myeloid blast crisis)]***, whereas in most of the remainder the blasts are o***[f pre-B cell origin (lymphoid blast crisis).]***  POLYCYTHEMIA VS. POLYCYTHEMIA VERA (PCV) - Absolute polycythemia is *primary* when it results from an intrinsic abnormality of hematopoietic precursors and secondary when it stems from the response of red cell progenitors to elevated levels of erythropoietin. - PCV is characterized by increased marrow production of red cells, granulocytes, and platelets (panmyelosis), but it is the increase in red cells (polycythemia) that is responsible for most of the clinical symptoms. - ***[Transformed progenitor cells have markedly decreased requirements for erythropoietin and other hematopoietic growth factors due to activating mutations in the tyrosine kinase JAK2.]*** - Abnormally high number of circulating red cells, usually with a corresponding increase in the hemoglobin level. - It may be relative (when there is hemoconcentration due to decreased plasma volume) or absolute (when there is an increase in the total red cell mass) - ***Relative polycythemia results from dehydration***. - Clinical features: most symptoms related to the increased red cell mass and hematocrit. - Patients are plethoric and cyanotic due to stagnation and deoxygenation of blood in peripheral vessels. - HA, dizziness, HTN, and gastrointestinal symptoms are common. - **[Intense pruritus and peptic ulceration]** may occur, both possibly resulting from the release of histamine from basophils. - ***[High cell turnover]*** gives rise to ***hyperuricemia***; symptomatic gout is seen in 5-10% of cases. - ***[Abnormal blood flow and platelet function]* that accompany PCV lead to an *increased risk of both major bleeding and thrombotic episodes*** - Hemoglobin concentration is typically greater than 16 g/dL, and the hematocrit is often 55% or more. - PCV: The white cell count ranges from 12,000 to 50,000 cells/mm\^3, and the platelet count is often greater than 500,000 platelets/mm\^3 - PCV often progresses to a ***[spent phase]*** characterized by ***extensive marrow fibrosis that displaces hematopoietic cells.*** This is accompanied by increased extramedullary hematopoiesis in the spleen and liver, often leading to prominent organomegaly. - About 25% of patients first come to attention due to deep venous thrombosis, myocardial infarction, or stroke. Thromboses sometimes also occur in the hepatic veins (producing Budd-Chiari syndrome) and the portal and mesenteric veins (leading to bowel infarction). It must be remembered that thrombotic complications may precede the appearance of the typical hematologic findings. Minor hemorrhages (epistaxis, bleeding gums) are common, and life-threatening hemorrhages occur in 5% to 10% of cases. LANGERHANS CELL HISTIOCYTOSIS - *Histiocytosis* is an "umbrella" designation for a variety of proliferative disorders of dendritic cells or macrophages. - Pathogenesis: The majority of cases have driver mutations in cancer-associated genes. The most common mutation is an activating ***valine-to-glutamate*** substitution at residue 600 in BRAF, which is present in 55%-60% of cases. - Less common mutations have also been deleted in TP53, RAS, and the receptor tyrosine kinase MET. - Because Langerhans cells are part of the innate immune system, these tumors (as well as other clonal histiocytosis) can be considered unusual myeloid neoplasms. - Regardless of the clinical picture, the proliferating Langerhans cells have abundant, often vacuolated cytoplasm and vesicular nuclei containing linear grooves or folds ([Fig. 13.39A](https://jigsaw.vitalsource.com/books/9780323531139/epub/OPS/xhtml/chp00013_s3.xhtml?favre=brett)). The presence of *Birbeck granules* in the cytoplasm is characteristic. Birbeck granules are pentalaminar tubules, often with a dilated terminal end producing a tennis racket--like appearance ([Fig. 13.39B](https://jigsaw.vitalsource.com/books/9780323531139/epub/OPS/xhtml/chp00013_s3.xhtml?favre=brett)), which contain the protein langerin. In addition, the tumor cells also typically express HLA-DR, S-100, and CD1a. - Clinical features: Langerhans cells histiocytosis presents as several clinicopathologic entities: - ***Multifocal multisystem Langerhans cells histiocytosis (Letterer-Siwe disease)*** occurs most frequently before 2 years of age but occasionally affects adults. - ***Unifocal and multifocal unisystem Langerhans cell histiocytosis (eosinophilic granuloma)*** is characterized by *proliferations of Langerhans cells* admixed with variable numbers of eosinophils, lymphocytes, plasma cells, and neutrophils. - *Eosinophils* are usually, but not always, a p***rominent component of the infiltrate.*** It typically arises within the medullary cavities of bones, most commonly the calvaria, ribs, and femur.  - The combination of ***calvarial bone defects, diabetes insipidus, and exophthalmos*** is referred to as the ***[Hand-Schüller-Christian triad.]*** - Many patients experience spontaneous regression; others can be treated successfully with chemotherapy. - ***Pulmonary Langerhans cell histiocytosis*** represents a special category of disease, most often seen in ***adult smokers***, which may regress spontaneously upon cessation of smoking.  SPLENOMEGALY - Enlargement can cause a syndrome known as *hypersplenism*, which is characterized by ***anemia, leukopenia, and/or thrombocytopenia.*** - The probable cause of the cytopenias is increased ***sequestration of formed elements*** and the consequent enhanced phagocytosis by the splenic macrophages. - **Nonspecific Acute Splenitis**: enlargement of the spleen occurs in any blood-borne infection. - Chronic venous outflow obstruction causes a form of splenic enlargement referred to as *congestive splenomegaly.* - **Cirrhosis of the liver is the main cause of massive congestive splenomegaly.** - Systemic, or central, venous congestion is encountered in cardiac decompensation involving the right side of the heart, as can occur in tricuspid or pulmonic valvular disease, chronic cor pulmonale, or following left-sided heart failure. - Splenic rupture is usually precipitated by blunt trauma. - "Spontaneous ruptures" *never involve normal spleens* but stem from some physical insult to a spleen made by an underlying condition. The most common predisposing conditions are infectious mononucleosis, malaria, typhoid, fever, and lymphoid neoplasms, which may cause the spleen to enlarge rapidly, producing a thin, tense capsule that is susceptible to rupture. - Chronically enlarged spleens are unlikely to rupture because of the toughening effect of extensive reactive fibrosis.  RED BLOOD CELL AND BLEEDING DISORDERS - **Anemia is defined as a reduction of total circulating red cell mass below normal limits.** - Reduces the oxygen-carrying capacity of the blood, leading to tissue hypoxia. - Usually diagnosed based on a reduction in the *hematocrit* (the ratio of packed red cells to total blood volume) and the *hemoglobin* concentration of the blood to levels that are below the normal range.  - These values correlate with the red cell mass except when there are changes in plasma volume caused by fluid retention or dehydration. - Morphologic characteristics that provide etiologic clues include: - Red cell size (normocytic, microcytic, or macrocytic) - Degree of hemoglobinization, reflected in the color of red cells (normochromic or hypochromic) shape. - Microcytic hypochromic anemias are caused by ***[disorders of hemoglobin synthesis]***, and macrocytic anemias often stem from abnormalities that impair the maturation of erythroid precursors in the bone marrow. - Normochromic, normocytic anemias have diverse etiologies; in some of these anemias, characteristic abnormalities of red cell shape provide an important clue as to the cause.   - *Mean cell volume*: the average volume of a red cell expressed in femtoliters (fL). - *Mean cell hemoglobin*: the average content (mass) of hemoglobin per red cell, expressed in picograms (pg). - *Mean cell hemoglobin concentration:* the average concentration of hemoglobin in a given *volume* of packed red cells, expressed in grams per deciliter (g/dL) - *Red cell distribution width*: the coefficient of *variation of red cell volume.* - Severe anemia leads to manifestations related to the diminished hemoglobin and oxygen content of the blood.  - *Appear pale* and often report *weakness, malaise, easy fatigability, and dyspnea on mild exertion.* - Hypoxia can cause fatty change in the liver, myocardium, and kidney. ACUTE BLOOD LOSS - **The effects of acute blood loss are mainly due to the loss of intravascular volume, which if massive can lead to cardiovascular collapse, shock, and death.** - The clinical features depend on the rate of hemorrhage and whether the blooding is external or internal.  - If the patient survives, the blood volume is rapidly restored by movement of water from the interstitial fluid compartment to the intravascular compartment.  - This fluid shift produces hemodilution and lowers the hematocrit. - The ***[resulting reduction in tissue oxygenation triggers increased secretion of erythropoietin from the kidney,]*** which stimulates the **[proliferation of committed erythroid progenitors (colony-forming unit-erythroid \[CFU-E\]) in the marrow.]** - It takes about 5 days for the progeny of these CFU-Es to mature and appear as newly released red cells (reticulocytes) in the peripheral blood. The iron in hemoglobin is recaptured if red cells extravasate into tissues, hampering the restoration of normal red cell counts.  - ***Significant bleeding results in predictable changes* in the blood involving not only *red cells, but also white cells and platelets.*** - As marrow production increases, there is a striking increase in the reticulocyte count (reticulocytosis), which reaches 10% to 15% after 7 days. - Early recovery from blood loss also is often accompanied by thrombocytosis, which results from an increase in platelet production. - Anemia and lowered tissue oxygen tension trigger the production of erythropoietin, which stimulates erythroid differentiation and leads to the appearance of **increased numbers of erythroid precursors (normoblasts)** in the marrow. Compensatory increases in erythropoiesis result in a **prominent reticulocytosis** in the peripheral blood. The phagocytosis of red cells leads to the accumulation of the iron-containing pigment **hemosiderin,** particularly in the spleen, liver, and bone marrow. Such iron accumulation is referred to as **hemosiderosis**. If the anemia is severe, **extramedullary hematopoiesis** can appear in the liver, spleen, and lymph nodes. With chronic hemolysis, elevated biliary excretion of bilirubin promotes the formation of **pigment gallstones** (cholelithiasis). HEREDITARY SPHEROCYTOSIS - **HS is caused by diverse mutations that lead to an insufficiency of membrane skeletal components.** - **An autosomal dominant inheritance pattern is seen in about 75% of cases.** - This life span of affected red cells is decreased on average to 10 to 20 days from the normal 120 days. - The pathogenic mutations ***[most commonly affect ankyrin, band 3, spectrin, or band 4.2, the proteins]*** involved in one of the two tethering interactions - Most mutations cause ***[frameshifts or introduce premature stop codons]***, such that the mutated allele fails to produce any protein. - The resulting deficiency of the affected protein reduces the assembly of the skeleton as a whole, destabilizing the overlying plasma membrane. - Young HS red cells are normal in shape, but the destabilized lipid bilayer sheds membrane fragments as red cells age in the circulation. - **Inherited disorder caused by intrinsic defects in the red cell membrane skeleton that render red cells spheroid, less deformable, and vulnerable to splenic sequestration and destruction. ** - The loss of membrane relative to cytoplasm "forces" the cells to assume the smallest possible diameter for a given volume, namely, a sphere.  - Spherocytosis is distinctive but not pathognomonic, as spherocytes are also seen in other disorders associated with red cell membrane loss, such as in autoimmune hemolytic anemia.  - Other features are common to all hemolytic anemias. These include reticulocytosis, marrow erythroid hyperplasia, hemosiderosis, and mild jaundice. **Choletlitiasis (pigment stones)** occurs in 40% to 50% of affected adults. Moderate **splenomegaly** is characteristic (500 to 1000 g); in few other hemolytic anemias is the spleen enlarged as much or as consistently. Splenomegaly results from congestion of the cords of Billroth and increased numbers of phagocytes. - The generally stable clinical course is sometimes punctuated by *aplastic crises*, usually triggered by an acute parvovirus infection Parvovirus infects and kills red cell progenitors, causing all red cell production to cease until an immune response clears the virus, generally in 1 to 2 weeks. Because of the reduced life span of HS red cells, cessation of erythropoiesis for even short periods leads to sudden worsening of the anemia. Transfusions may be necessary to support the patient during the acute phase of the infection.  - *Hemolytic crises* are produced by intercurrent events leading to increased splenic destruction of red cells (e.g., infectious mononucleosis and its attendant increase in spleen size); these are clinically less significant than aplastic crises. Gallstones, found in many patients, may also produce symptoms. Splenectomy treats the anemia and its complications, but brings with it an increased risk of sepsis because the spleen acts as an important filter for blood-borne bacteria. RED CELL ENZYME DEFECTS: GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY - Abnormalities in ***[glutathione metabolism (glycolytic pathway]***) resulting from ***deficient or impaired enzyme function*** reducing the ability of red cells to protect themselves against ***oxidative injuries and leads to hemolysis.*** - Recessive X-linked trait, placing males at much higher risk for symptomatic disease - Most common defects: G6PD B, G6PD^--^ and G6PD Mediterranean - **Episodic hemolysis that is characteristic of G6PD deficiency is caused by exposures that generate *oxidant stress.*** - G6PD reduced nicotinamide adenine dinucleotide phosphate (NADP) to NADPH while oxidizing glucose-6-phosphate ([Fig. 14.5](https://jigsaw.vitalsource.com/books/9780323531139/epub/OPS/xhtml/chp00014.xhtml?favre=brett)). NADPH then provides reducing equivalents needed for conversion of oxidized glutathione to reduced glutathione, which protects against oxidant injury by participating as a cofactor in reactions that neutralize compounds such as H2O2 - G6PD-- is present in about 10% of American blacks; G6PD Mediterranean, as the name implies, is prevalent in the Middle East. The high frequency of these variants in each population is believed to stem from a protective effect against *Plasmodium falciparum* malaria. G6PD variants associated with hemolysis result in misfolding of the protein, making it more susceptible to proteolytic degradation.  - Compared with the most common normal variant, G6PD B, the half-life of G6PD-- is moderately reduced, whereas that of G6PD Mediterranean is more markedly abnormal. Because mature red cells do not synthesize new proteins, as red cells age G6PD-- and G6PD Mediterranean enzyme activities quickly fall to levels that are inadequate to protect against oxidant stress. Thus, older red cells are much more prone to hemolysis than younger ones. SICKLE CELL DISEASE - Common hereditary hemoglobinopathy is caused by a ***[point mutation in β-globin]*** that promotes the ***polymerization of deoxygenated hemoglobin***, ***leading to red cell distortion***, hemolytic anemia, microvascular obstruction, and ischemic tissue damage. - Sickle cell disease is caused by a missense mutation in the β-globin gene that leads to the ***[replacement of a charged glutamate residue with a hydrophobic valine residue. ]*** - The abnormal physicochemical properties of the resulting ***sickle hemoglobin (HbS***) are responsible for the disease. - ***Hemoglobin (Hb) is a tetrameric protein composed of two pairs of globin chains, each with its own heme group. Normal [adult] red cells contain mainly [HbA (α2β2)], along with small amounts of [HbA2 (α2δ2)] and fetal hemoglobin (HbF; α2γ2). *** - About 8% to 10% of African Americans in the United States are heterozygous for HbS, a largely **asymptomatic condition known as *sickle cell trait.* ** - The offspring of two heterozygotes has a 1 in 4 chance of being homozygous for the sickle mutation, a state that produces symptomatic sickle cell disease.  - In *affected* individuals, almost ***all the hemoglobin in the red cell is HbS (α2βs2).*** - The high prevalence of sickle cell trait in certain African populations stems from its *protective effects against falciparum malaria*. - Two scenarios to explain these falciparum malaria protection: - Metabolically active intracellular parasites consume oxygen and decrease intracellular pH, both of which promote sickling of AS red cells. These distorted, stiff cells may be cleared more rapidly by splenic and hepatic phagocytes, keeping parasite loads low. - Sickling also impairs the formation of membrane knobs containing a protein made by the parasite called *PfEMP-1.* These membrane knobs are implicated in adhesion of infected red cells to endothelium, which is believed to have an important pathogenic role in the most severe form of the disease, cerebral malaria. - Pathogenesis: ***Chronic hemolysis, microvascular occlusions, and tissue damage*---all stem from the tendency of HbS molecules to stack into polymers when deoxygenated** - Several variables affect the rate and degree of sickling: - *Interaction of HbS with the other types of hemoglobin.* - *Mean cell hemoglobin concentration* (MCHC)- intracellular dehydration, which increases the MCHC, facilitates sickling. - *Intracellular pH.* A **[decrease in pH reduces the oxygen affinity of hemoglobin, increasing the fraction of deoxygenated HbS at any given oxygen tension and augmenting the tendency for sickling.]** - *Transit time of red cells through microvascular beds* - In heterozygotes with sickle cell trait, about 40% of the hemoglobin is HbS and the rest is HbA, which interferes with HbS polymerization. As a result, red cells in heterozygous individuals only sickle if exposed to prolonged, relatively severe hypoxia. HbF inhibits the polymerization of HbS even more than HbA; hence, infants with sickle cell disease do not become symptomatic until they reach 5 or 6 months of age, when the level of HbF normally falls. However, in some individuals HbF expression remains relatively high, a condition known as *hereditary persistence of fetal hemoglobin;* in these individuals, sickle cell disease is much less severe.   - HbSC cells tend to lose salt and water and become dehydrated, an effect that increases the intracellular concentration of HbS. These factors increase the tendency for HbS to polymerize, and as a result compound HbSC heterozygotes have a symptomatic sickling disorder termed *HbSC disease* that is somewhat milder than sickle cell disease. - Clinical Features: - Moderately severe hemolytic anemia (hematocrit 18% to 30%) associated with reticulocytosis, hyperbilirubinemia, and the presence of irreversibly sickled cells.  - ***[Vaso-occlusive crises]*** - **[*Acute chest syndrome*  ]** - **[*Priapism* ]** - Stroke and retinopathy leading to loss of visual acuity and even blindness - Increased susceptibility to infection with encapsulated organisms is due in large part to altered splenic function - ***[Howell-Jolly bodies]*** (small nuclear remnants) also are ***present in red cells due to asplenia***. The bone marrow is hyperplastic as a result of a compensatory erythroid hyperplasia.  - ***Marked expansion of the marrow leads to bone resorption*** and secondary new bone formation, producing ***[prominent cheekbones]*** and changes in the ***skull that resemble a ["crew cut"] on x-ray. *** - The increased breakdown of hemoglobin may cause ***[hyperbilirubinemia]*** and formation of pigment ***[gallstones.]*** - Vaso-occlusive crisis-Although infection, dehydration, and acidosis (all of which favor sickling) may act as triggers, in most instances no predisposing cause is identified. The most commonly involved sites are the bones, lungs, liver, brain, spleen, and penis. - In children, painful bone crises are extremely common and often difficult to distinguish from acute osteomyelitis. These frequently manifest as the *hand-foot syndrome* or dactylitis of the bones of the hands and feet. (parvovirus infections) -  Pulmonary inflammation may cause blood flow to become sluggish and "spleen like," leading to sickling and vaso-occlusion. This compromises pulmonary function, creating a potentially fatal cycle of worsening pulmonary and systemic hypoxemia, sickling, and vaso-occlusion. - *Vaso-occlusive crises,* also called *pain crises,* are episodes of hypoxic injury and infarction that cause severe pain in the affected region. - *Acute chest syndrome* is particularly dangerous involving the lungs that typically presents with fever, cough, chest pain, and pulmonary infiltrates.  - *Priapism* affects up to 45% of males after puberty and may lead to hypoxic damage and erectile dysfunction.  - Defects of uncertain etiology in the alternative complement pathway also impair the opsonization of bacteria. *Pneumococcus pneumoniae* and *Hemophilus influenzae* septicemia and meningitis are common, particularly in children, but can be reduced by vaccination and prophylactic antibiotics. - Much of the pathology of sickle cell disease is related to vascular occlusion caused by sickling within microvascular beds. Transit times in most normal microvascular beds are too short for significant aggregation of deoxygenated HbS to occur, and as a result sickling is confined to microvascular beds with slow transit times. Blood flow is sluggish in the normal spleen and bone marrow, which are prominently affected in sickle cell disease, and also in vascular beds that are inflamed. The movement of blood through inflamed tissues is slowed because of the adhesion of leukocytes to activated endothelial cells and the transudation of fluid through leaky vessels. As a result, inflamed vascular beds are prone to sickling and occlusion. A-THALESSEMIA - **Caused by inherited deletions that result in reduced or absent synthesis of α-globin chains.**  - Normal individuals have four α-globin genes, and the severity of α-thalassemia depends on how many α-globin genes are affected.  - Anemia stems both from inadequate hemoglobin synthesis and the presence of excess, unpaired β, γ, and δ globin chains. - **Genetic basis of alpha thalassemia:\ Two alpha genes (α2 and α1) are located on each chromosome 16 (red and yellow chromosomes are inherited from different parents).**  **Silent Carrier State.** - Silent carrier state is associated with the deletion of a single α-globin gene, which causes a barely detectable reduction in α-globin chain synthesis. These individuals are completely asymptomatic but have slight microcytosis. **α-Thalassemia Trait. (minor)** - α-Thalassemia trait is caused by the deletion of two α-globin genes from a single chromosome (α/α −/−) or the deletion of one α-globin gene from each of the two chromosomes (α/− α/−). The former genotype is more common in Asian populations, the latter in regions of Africa. Both genotypes produce similar deficiencies of α-globin, but they have different implications for the children of affected individuals, who are at risk of clinically significant α-thalassemia (HbH disease or hydrops fetalis) only when at least one parent has the −/− haplotype. As a result, symptomatic α-thalassemia is relatively common in Asian populations and rare in African populations. The clinical picture in α-thalassemia trait is identical to that described for β-thalassemia minor, that is, small red cells (microcytosis), minimal or no anemia, and no abnormal physical signs. HbA2 levels are normal or low. **Hemoglobin H (HbH) Disease.** - HbH disease is caused by deletion of three α-globin genes. It is most common in Asian populations. With only one normal α-globin gene, the synthesis of α chains is markedly reduced, and tetramers of β-globin, called HbH, form. HbH has an extremely high affinity for oxygen and therefore is not useful for oxygen delivery, leading to tissue hypoxia disproportionate to the level of hemoglobin. Additionally, HbH is prone to oxidation, which causes it to precipitate and form intracellular inclusions that promote red cell sequestration and phagocytosis in the spleen. The result is a moderately severe anemia resembling β-thalassemia intermedia. **Hydrops Fetalis.** - Hydrops fetalis, the most severe form of α-thalassemia, is caused by deletion of all four α-globin genes. In the fetus, excess γ-globin chains form tetramers (hemoglobin Barts) that have such a high affinity for oxygen that they deliver little to tissues. Signs of fetal distress