Kaposi Sarcoma
Kaposi sarcoma, a slowly progressive vascular neoplasm, was originally described in elderly Italian and Jewish men [see 2:XMalignant Cutaneous Tumors]. Subsequently, a more rapidly progressive form of the disorder was described in immunosup-pressed patients with lymphomas and in kidney transplant patients on immunosuppressive drugs. An aggressive form has been described in patients with AIDS [see Figure 15]. Classic Ka-posi sarcoma typically affects the lower extremities and only gradually progresses to other sites. In contrast, AIDS-related Ka-posi sarcoma can occur on any surface of the body, including mucous membranes. Human herpesvirus type 8 has been implicated in both classic and AIDS-related Kaposi sarcoma.50 Treatments include radiation therapy, cryotherapy, and intralesional injection with vinblastine; systemic chemotherapy can also be effective. In patients with AIDS, Kaposi sarcoma is best treated with antiretroviral regimens.
Oral Hairy Leukoplakia
Oral hairy leukoplakia, another condition that has been described in HIV-infected patients, consists of linear white papules on the lateral surfaces of the tongue that result in the so-called hairy appearance. Oral hairy leukoplakia can be distinguished from oral thrush in that the lesions cannot be rubbed off, as they can be in thrush.
Thanks to the development of effective antiretroviral therapy, the frequency of opportunistic infections in patients with HIV infection has diminished markedly.
Other immunodeficient states
Other inherited or acquired immunodeficiency states share a number of clinical features. Susceptibility to monilial infections or bacterial infections is increased in disorders such as chronic granulomatous disease and chemotherapy-induced neutrope-nia. Oral ulcers similarly occur in cyclic neutropenia and in chemotherapy-induced immunosuppression.
Some immunosuppressive drugs have characteristic cutaneous effects. Corticosteroids, when used long-term, cause vascular fragility, resulting in steroid purpura. They can also cause cutaneous atrophy, formation of striae, and acneiform eruptions. Cyclosporine is associated with hypertrichosis. Aphthous stomatitis is a characteristic effect of numerous immunosuppressive drugs, particularly agents that suppress bone marrow function. Chronic immunosuppression can lead to the development of lymphoma and nonmelanoma skin cancer. Avoidance of excessive exposure to sunlight may prevent development of the latter.
Infectious Diseases
Cutaneous manifestations can be major features of a number of systemic infections; for example, patients with overwhelming septicemia can develop disseminated intravascular coagulation (DIC), which results in cutaneous infarcts and hemorrhage into the skin. Key cutaneous features of selected systemic infections follow.
Infective endocarditis
The cutaneous manifestations of infective endocarditis include petechiae, splinter hemorrhages (linear red streaks under the nail), Osler nodes (tender purpuric nodules on the finger pads and toes), and Janeway lesions (nontender purpuric mac-ules of the palms and soles). Skin lesions are caused by either septic emboli or vasculitis. Treatment of the underlying infection results in resolution of the cutaneous manifestations [see 7:XVIII Infective Endocarditis].
Staphylococcal toxic-shock syndrome
Staphylococcal toxic-shock syndrome was first recognized in menstruating women who used superabsorbent tampons [see 7:I Infections Due to Gram-Positive Cocci]. It is caused by an exotoxin produced by certain strains of S. aureus.51 Staphylococcal infections in bone, soft tissue, and other sites have been implicated. Patients develop diffuse sunburnlike erythema, with swelling of the hands and feet, followed by desquamation of the palms and soles. Erythema of mucous membranes, fever, and hypotension also occur. Gastrointestinal symptoms, impaired renal function, elevated liver function values, thrombocytopenia, and myositis can develop.
Staphylococcal scalded skin syndrome
Staphylococcal scalded skin syndrome (SSSS) is caused by a circulating exfoliative toxin produced by S. aureus phage group 11. Generalized bulla formation with large areas of desquama-tion is characteristic of the disorder. Along with tenderness, erythema, and exfoliation of skin, patients have fever. The source of the staphylococcal infection is not always apparent; occasionally, the infection arises in a wound or in an occult abscess. Because the staphylococcal infection is usually remote from the affected skin, culture of the skin does not grow S. aureus.
SSSS must be differentiated from toxic epidermal necrolysis. Toxic epidermal necrolysis commonly affects adults and involves mucous membranes; SSSS usually affects children and spares mucous membranes. In addition, toxic epidermal necrol-ysis can last for several weeks and has a high mortality, whereas SSSS lasts a few days and usually has a good outcome. Histolog-ically, SSSS shows bulla formation in the upper epidermis, and the bulla cavity contains free-floating, normal-appearing, acan-tholytic cells. In toxic epidermal necrolysis, bulla formation occurs at the basal layer of the epidermis, and the epidermal cells are necrotic. Treatment with antibiotics effective against S. au-reus eliminates the underlying cause of SSSS.
Necrotizing fasciitis
Necrotizing fasciitis is caused by a mixed anaerobic infection of an ulcer or a surgical or traumatic wound. The affected skin is erythematous, warm, and tender and develops hemorrhagic bullae that rupture to form rapidly enlarging areas of gangrene that extend down to the fascia. Surgical debridement is essential for this life-threatening infection.52
Meningococcemia
Acute meningococcemia can occur either in epidemics or in isolated cases [see 7:III Infections Due to Neisseria]. Fever, headache, and a hemorrhagic rash develop. If untreated, patients develop DIC, with extensive hemorrhage, hypotension, and ultimately death. The causative organism, Neisseria meningitidis, is usually identified in cerebrospinal fluid but can also be identified by smear or cultures of skin lesions or by blood cultures.
Figure 16 Several weeks after primary infection with Lyme disease, hematogenous dissemination of spirochetes results in multiple patches of erythema chronicum migrans.
Treatment with antibiotics and supportive care are essential aspects of therapy.
Scarlet fever
Scarlet fever begins with pharyngitis caused by group A Streptococcus [see 7:IInfections Due to Gram-Positive Cocci]. A generalized rash develops 1 to 2 days after onset of the pharyngitis. The rash is characterized by pinpoint erythematous papules that may be easier to palpate than to see. Other characteristic lesions include a white strawberry tongue and linear petechial macules occurring in body folds (Pastia lines). As the rash fades, desqua-mation of the palms and soles appears. Treatment with penicillin results in rapid resolution of all symptoms.
VIBRIO infection
Vibrio vulnificus infection arises from minor trauma sustained while swimming in lakes or the ocean or while cleaning seafood. Cellulitis occurs, with lymphangitis and bacteremia. In patients with hepatic cirrhosis, infection can occur after eating raw oysters. These patients develop hemorrhagic bullae, with leukope-nia and DIC.53 Treatment with antibiotics is necessary; management of complications may require intensive supportive care.
Lyme disease
Lyme disease is caused by the spirochete Borrelia burgdorferi and is transmitted primarily by the tick Ixodes scapularis [see 7:XVII Infections Due to Rickettsia, Ehrlichia, and Coxiella]. The characteristic skin lesion, erythema chronicum migrans, begins as an erythematous macule or papule at the site of the tick bite. Over days and weeks, the erythematous lesion expands to form a red ring, often with central clearing. If left untreated, lesions last weeks or months. Hematogenous dissemination of spiro-chetes occurs after several weeks, resulting in multiple annular patches of erythema chronicum migrans [see Figure 16]. Systemic complications include an acute arthritis involving one or a few large joints a few weeks after the onset of symptoms. A chronic erosive arthritis develops in approximately 10% of patients. Neurologic symptoms, including Bell palsy, can occur, as can cardiac complications, including heart failure and cardiac conduction abnormalities.
Lyme disease can be prevented by the removal of ticks within 18 hours of attachment. Once symptoms have developed, oral antibiotics are effective at destroying B. burgdorferi. A vaccine containing a genetically engineered protein from the surface of the bacteria was found to prevent infection in most vaccinated people54; however, for a number of reasons, including lack of demand, the vaccine has been discontinued.55
Rocky mountain spotted fever
Rocky Mountain spotted fever (RMSF) is a tick-borne illness caused by Rickettsia rickettsii [see 7:XV11 1nfections Due to Rick-ettsia, Ehrlichia, and Coxiella]. It is characterized by the sudden onset of fevers, chills, and headache. Approximately 4 days later, a characteristic erythematous rash develops on the wrists and ankles and becomes purpuric. The rash then spreads centrally to involve the extremities, trunk, and face.
Because the mortality of RMSF is high, patients should be treated immediately with intravenous chloramphenicol or tetra-cycline if RMSF is suspected. Diagnosis can then be established by skin biopsy: immunofluorescence with antibodies against R. rickettsii shows the organism in the walls of cutaneous blood vessels. Serologic tests, such as the Weil-Felix reaction, can confirm the diagnosis after the acute phase of the illness.
Neurologic Diseases
Basal cell nevus syndrome
The basal cell nevus syndrome is an autosomal dominant disorder attributed to mutational inactivation of the PTCH gene56 in which patients develop basal cell carcinomas at an early age [see 2:XMalignant Cutaneous Tumors]. Multiple skeletal abnormalities are associated with the syndrome, and affected individuals may also develop jaw cysts. Lamellar calcification of the falx cerebri occurs, as well as other neurologic abnormalities, including medulloblastomas.
Epidermal nevus syndrome
The epidermal nevus syndrome is characterized by systemic manifestations, such as seizures, mental retardation, blindness, and skeletal abnormalities in association with large epidermal nevi. The nevi consist of long pigmented streaks that are linear or whirled and involve large areas of the body [see Figure 17].
Incontinentia pigmenti
Incontinentia pigmenti is an inherited syndrome that affects the skin and nervous system. Mutations in the NEMO gene, an essential component of the nuclear factor-KB signaling cascade, account for 85% of cases.57 The inheritance pattern is X-linked dominant and is lethal in male fetuses. The first skin manifestations begin within weeks after birth, occasionally occurring in utero, and consist of linear patterns of vesiculobullous lesions. Within weeks, these lesions evolve into verrucous papules and, eventually, into pigmented whirls. Apart from neurologic symptoms, patients may have ocular abnormalities, scarring alopecia, and skeletal malformations.
Hypomelanosis of 1to
Hypomelanosis of Ito, also called incontinentia pigmenti achromians, consists of whirls of hypopigmentation that are associated with neurologic symptoms in 50% of patients. Skin lesions are present at birth or develop in early childhood. In addition to seizures and mental retardation, skeletal and ocular abnormalities occur.
Neurofibromatosis
Neurofibromatosis is a common autosomal dominant disorder involving the skin and nervous system [see 2:XI Benign Cutaneous Tumors]. Skin lesions include cutaneous neurofibromas, which are soft, skin-colored nodules that are often pedunculated [see Figure 18]. Cafe au lait macules are flat, evenly pigmented patches up to several centimeters in diameter. Six or more cafe au lait macules greater than 1.5 cm in diameter are found in most patients with neurofibromatosis type 1 (also called von Reckling-hausen disease). Plexiform neuromas are larger, deeper tumors that are associated with hypertrophy of bony and soft tissues. In a small proportion of tumors, neurofibrosarcomas will arise. On skin biopsy, cafe au lait macules are found to contain macrome-lanosomes—giant granules of pigment in melanocytes and ker-atinocytes. Axillary and inguinal freckling also appear as pig-mented macules that resemble small cafe au lait spots in inter-triginous sites. Lisch nodules—pigmented iris hamartomas—are also found in most patients with neurofibromatosis.
Several variants of neurofibromatosis exist, including segmen-tal neurofibromatosis, in which patients develop a segmental distribution of cafe au lait spots and cutaneous neurofibromas, and neurofibromatosis type 2, which consists of acoustic neuromas, schwannomas, and meningiomas without Lisch nodules and with fewer cafe au lait macules than appear in type 1. Patients with neurofibromatosis type 2 may have some cutaneous neurofibromas as well. Neurofibromatosis types 1 and 2 are caused by different genetic defects. Neurofibromatosis type 1 is caused by mutations in the NF1 gene for neurofibromin on chromosome 17.58 Neurofibromatosis type 2 has been attributed to inactivating mutations in the NF2 tumor suppressor gene whose product, merlin, plays a number of roles in tumorigenesis.59
Sneddon syndrome
Sneddon syndrome is a disease of the skin and nervous system caused by occlusion of small to medium-sized arteries in persons younger than 45 years. The skin lesions resemble livedo reticularis and have been called livedo racemosa. Transient is-chemic attacks or strokes are common. Definitive diagnosis is made by demonstrating characteristic vascular changes on skin biopsy of patients with associated neurologic findings.
Tuberous sclerosis
Tuberous sclerosis is an autosomal dominant disease that affects the skin and nervous system. Mutations that inactivate the TSC1 or TSC2 tumor suppressor genes affect the respective gene products, hamartin and tuberin, leading to tuberous sclerosis.60 Affected patients can develop seizures, mental retardation, and brain lesions called tubers, which can be seen on CT scans. Adenoma sebaceum, the most characteristic cutaneous manifestation of tuberous sclerosis, consists of skin-colored papules of the face [see Figure 19a]. Other skin lesions are hypopigmented macules referred to as ash-leaf macules [see Figure 19b], smaller hy-popigmented lesions called confetti macules, periungual and subungual fibromas (skin-colored nodules that arise around the fingers and toenails) [see Figure 19c], and the shagreen patch (a skin-colored plaque made of thick dermal connective tissue).
Renal Diseases
Fabry disease
Fabry disease is caused by an abnormality of a-galactosidase
Figure 17 The epidermal nevus syndrome is characterized by linear or whirled streaks of pigmentation that involve large areas of the body.
A, resulting in deposition of glycosphingolipids in body tissues. The disorder is inherited as an X-linked recessive trait. A variety of different mutations in the gene for a-galactosidase A have been found in unrelated families with Fabry disease.61 Affected males often complain of severe pain in the extremities, with burning of the palms and soles. Episodes of pain are transient, but patients complain of persistent paresthesias in the hands and feet.
Skin lesions consist of angiokeratomas, which are pinpoint red or purple papules that resemble cherry hemangiomas [see Figure 20]. Angiokeratomas are most commonly found in the periumbilical area but can also occur on the palms, soles, trunk, extremities, and mucous membranes. In adults, glycosphin-golipids become deposited in blood vessels and organs, affecting the heart, heart valves, coronary arteries, and kidneys. Replacement therapy with recombinant human a-galactosidase A can improve cutaneous, gastrointestinal, neurologic, and psychiatric symptoms; it has been shown to be safe and can eliminate substrate storage of glycosphingolipids, but questions remain regarding optimal dosing.62
Figure 18 Axillary freckling, cafe au lait spots, and neurofibromas are evident in a patient with neurofibromatosis type 1.
