Skin lesions are signposts to an array of systemic conditions. This review covers some of the most distinctive associations.
Skin lesions are signposts to an array of systemic conditions. This review covers some of the most distinctive associations.
The skin can be a wonderful window into a world of visual diagnostic clues. The systemic processes reflected in the skin, or even just the fingernails and hair, can fill a multivolume textbook of dermatology. Thus, I will focus on conditions with skin signs that offer a central take-home message or clinical pearl, indicating other diagnostic criteria and treatment options. These examples highlight the importance of making an examination of the skin part of the diagnostic process.
The combination of fever and rash in a young patient can strike fear in the heart of a pediatrician. Most often, however, the child looks well and has a viral exanthem. The physician, quite correctly, does not even consider meningococcemia or other dreaded illnesses in the differential diagnosis. Exanthems tend to be nondescript, morbilliform, diffuse, and symmetric eruptions and are the classic "maculopapular" rash that is indistinguishable from a medication reaction. The rash itself is nonspecific and may be the external manifestation of any of many viruses. Some exanthems are quite distinctive, however, and bear particular mention.
Asymmetric periflexural exanthem, otherwise known by its tongue-challenging name of unilateral laterothoracic exanthem, is one such distinctive eruption.1 It is slightly more common in girls than in boys and tends to affect children in the first three years of life. Patients are generally well, but the rash may be preceded by symptoms of an upper respiratory infection. The asymptomatic eruption begins unilaterally, close to the axilla or thorax, then spreads centrifugally to the other side and then to most of the trunk. The rash itself is fairly nonspecific, consisting of discrete, tiny, erythematous papules that may coalesce into large confluent patches, sometimes with a circinate, annular, or reticulate pattern (Figure 1). After one or two weeks, the outbreak looks like scarlet fever or eczema so streptococcal infection and atopic dermatitis often become part of the differential diagnosis. The unique unilateralism of the eruption, established through the physical exam or by history, leads to the correct diagnosis. No single virus has been associated with the exanthem, and parents can be reassured that the rash will run a self-limited course, usually in three to six weeks. The main benefit of establishing the diagnosis is to limit unnecessary testing, treatment, and anxiety.
Gianotti-Crosti syndrome is another unique exanthem. It is characterized by multiple, nonpruritic, erythematous lichenoid (lichen planus-like) papules located exclusively on the face, neck, buttocks, and extremities (Figure 2).2 The exanthem is distinguished by an acral location with striking central sparing in an otherwise well 2- to 5-year-old, and diagnosis is based purely on the clinical picture. In Europe and Japan Gianotti-Crosti syndrome is closely linked to hepatitis B, and serology monitoring is often recommended. In the United States, serologies are not routinely obtained, though contact with hepatitis B virus or hepatosplenomegaly on exam should prompt a search for the virus. Gianotti-Crosti syndrome does not require treatment and generally resolves in from two to four weeks, though resolution can take as long as four months.
Fifth disease, or erythema infectiosum, is a distinctive exanthem caused by parvovirus B19. The child with this exanthem has bright red "slapped cheeks" and a reticulate, lacy erythematous eruption on the trunk and extremities. Fifth disease may be associated with cold symptoms and significant arthritis, but usually the child is well. Other presentations of parvovirus B19 are aplastic crisis, idiopathic thrombocytopenic purpura, nonimmune fetal hydrops, and Henoch-Schönlein purpura.3
Glove and socks syndrome, a variant of fifth disease, is an interesting and perhaps underreported disorder associated with parvovirus B19.4 The initial exanthem is characterized by a rapidly progressing, pruritic, or painful erythema and edema on the hands and feet, with a sharp line of demarcation at the wrists and ankles (Figure 3). The rash gradually evolves to a papular and petechial/purpuric eruption that maintains the gloves and socks distribution. About half of the cases are associated with a painful, pruritic, polymorphous exanthem that affects the hard and soft palates, buccal mucosa, and lips. Oral lesions are marked by swelling, vesicles, shallow ulcerations, or petechiae. Many of the reported cases have been part of a community- wide or family outbreak of erythema infectiosum, which greatly aids the diagnosis. Establishing the presence of parvovirus IgM antibodies facilitates a more definitive diagnosis. Rocky Mountain spotted fever must be considered in the differential if the child has been bitten by a tick or lives in an area where this condition is endemic.
Hand-foot-and-mouth disease is another unique viral illness. It is usually caused by coxsackievirus A16, but may result from infection with other coxsackieviruses or enterovirus 71. The illness generally features a prodrome of nonspecific symptoms such as fever, malaise, anorexia, and sore mouth, followed by development of vesicles and ulcerations on an erythematous base on the buccal mucosa, tongue, uvula, or tonsils. Small, oval vesicopustules with an erythematous rim develop one to two days later on the buttocks, palms, and soles. The skin surface lines can be seen in the lesions (Figure 4). The entire spectrum of findings is easily recognized, especially during community-wide outbreaks of hand-foot-and-mouth disease during the summer months.
Although generally a mild, self-limited infection, the severity of hand-foot-and-mouth disease varies significantly with the infecting virus. During Taiwan's 1998 epidemic, a large number of cases of aseptic meningitis, encephalitis, and poliomyelitis-like syndrome and 78 cases of fatal pulmonary edema were seen.5 A comparison of the effects of different infecting agents in this epidemic showed that most children among 177 patients with enterovirus 71 infection and 64 patients with coxsackievirus A 16 infection presented with either hand, foot, and mouth syndrome or herpangina. An acute infectious disease, herpangina is caused by either group A or B coxsackievirus or by echoviruses. Four patients in the coxsackievirus group had aseptic meningitis and none died. By contrast, among the children with enterovirus 71, there were 14 deaths, 12 from pulmonary edema and two from encephalitis, as well as significant complications. Of particular note, the virus was cultured three times as often from the throat as from the rectum in this study, which suggests that saliva and respiratory droplets are significant avenues for spreading the disease.
Fevers that are higher than 39° C or last longer than three days, vomiting, or signs of altered consciousness are distinguishing features of enterovirus 71 infection and should prompt special concern. Diligent handwashing, usually recommended to prevent spread of an enterovirus, is inadequate with enterovirus 71 infection; respiratory isolation also is required.
Skin signs offer important diagnostic clues to ecthyma gangrenosum, a serious bacterial infection, and Kawasaki disease, an acute multisystem inflammatory disease that should be diagnosed early to minimize cardiac complications.
Ecthyma gangrenosum, a potentially fatal disease, is caused by Pseudomonas aeruginosa, usually associated with immunocompromise because of chemotherapy, HIV, organ transplantation, or a genetic immunodeficiency syndrome.6 The initial lesion is a hemorrhagic vesicle with a rim or erythema. The vesicle ruptures, leaving a punched- out, discrete ulceration with a black, necrotic base (Figure 5). Deep nodules and bullae are seen less frequently. Initially, the child may not be clinically septic, and a small early lesion must be diagnosed correctly to avert a disastrous outcome from bacteremic pseudomonal infection. The typical clinical morphology of the skin lesions in an immunocompromised host establishes the diagnosis, which is confirmed with a gram stain of fluid below the eschar showing gram-negative rods. Blood and tissue cultures verify the diagnosis, but the child must be admitted to the hospital and receive intravenous antibiotics while results are being awaited.
Kawasaki disease is believed to be a superantigen reaction to an infection, perhaps from toxin-producing staphylococcal or streptococcal bacteria. No conclusive diagnostic laboratory test is available so diagnosis and treatment must be based on clinical observation. The skin and mucous membranes provide valuable clinical clues since major criteria for a diagnosis of Kawasaki disease include conjunctival injection, erythema, fissuring and crusting of the lips and oral mucosa, and erythema, edema, and induration of the extremities.7 Desquamation of the hands and feet occurs later in the illness and is not usually a helpful initial diagnostic sign. The rash is polymorphous, variably described as scarlatiniform, erythema multiforme-like, urticarial, morbilliform, or erythrodermic. Perineal or "diaper area" erythema and desquamation (Figure 6) are early and frequent findings, occurring in up to 60% to 70% of affected children.8 This underrecognized and underdescribed finding may be instrumental in establishing the diagnosis.
Systemic lupus erythematosus (SLE) typically affects many organ systems. Diagnosis requires a thorough review of systems and a physical examination. Diagnostic criteria for SLE related to the skin and mucous membranes include malar rash, discoid rash, photosensitivity, and oral ulcers. The skin may provide valuable clues since 80% to 95% of children with SLE have a cutaneous eruption. The most common skin finding is discoid (coin-shaped) lesions, usually in areas exposed to the sun, such as the face and scalp. Discoid lesions are erythematous, sharply demarcated, round plaques characterized by adherent scale, follicular plugging, telangiectasia, and scarring. These lesions may appear in the classic "butterfly" distribution over the nose and cheeks (Figure 7). The rash on the cheeks may also be urticarial or dermatitic, with no tendency to scar. Other skin findings such as alopecia, petechiae, nail fold telangiectasia, Raynaud's phenomenon, ice-pick digital infarcts, chilblains, livedo reticularis, oral aphthous ulcers, urticaria, or urticarial vasculitis are seen in SLE but are not major diagnostic criteria.
Minocycline, the antibiotic most often prescribed for acne, has been recognized as a cause of drug- induced SLE since 1991.9 The incidence may be as high as five per 10,000 prescriptions with a strong female predominance. Symptoms include arthralgias, myalgias, nonerosive arthritis of small and large joints, fever, and positive antinuclear antibodies (ANA). Autoimmune hepatitis may be an associated finding. Symptoms usually develop after the patient has been taking minocycline for six to 24 months, and once the medication is discontinued, symptoms spontaneously resolve and the ANA titer drops.
Although classic SLE is not seen in children younger than 1 year, mothers may passively transfer IgG lupus autoantibodies transplacentally to their newborns, leading to the syndrome of neonatal lupus.10 The initial manifestation is either congenital heart block or a rash, and only about 10% of infants have both. The rash may be seen at birth, but is more likely to appear several days to weeks postnatally. Ultraviolet light may be an initiating or exacerbating factor. The rash resembles subacute cutaneous lupus erythematosus of adulthood and consists of superficial annular or polycyclic plaques with scaling (Figure 8). It frequently affects the face and scalp with a predilection for the upper eyelids ("raccoon eyes") but may be generalized. Spontaneous resolution is the rule, usually by 6 to 8 months of age as maternal antibodies are cleared, but residual telangiectasia or hyperpigmentation has been reported. The diagnosis may be confirmed by skin biopsy or by detection of anti-Ro or anti-La antibodies in the infant's or mother's serum.
Rarely, the UlRNP antibody is found in Ro/La negative individuals. Many mothers are asymptomatic at delivery, but later develop SLE, Sjögren syndrome, or undifferentiated autoimmune syndrome. Thus, the diagnosis carries more significance for the mother than for the baby. Infants with neonatal lupus are at increased risk for SLE, however, usually after adolescence. Recurrence risk for a subsequent pregnancy may be as high as 25% for some neonatal lupus manifestations.
More than any other autoimmune connective tissue disease, dermatomyositis is defined by its distinctive cutaneous features.11 The rash may be the initial manifestation, predating the proximal muscle weakness, or, rarely, may be the only manifestation of the disease. Periorbital purplish erythema, edema, and telangiectasia develop in 50% to 90% of affected children, the so-called heliotrope sign. This photosensitive rash may affect the nose and cheeks, prompting confusion with SLE. Scaly, purple-red, sharply demarcated, often atrophic plaques known as Gottron's papules appear on the skin over the extensor interphalangeal joints of the fingers. Similar plaques on the elbows, knees, and ankles may be confused with psoriasis. Lesions on the scalp, psoriasis-like or seborrhea-like scaling, atrophy, and alopecia, are common and often overlooked (Figure 9).12 Ulcerations and poikiloderma (atrophy, telangiectasia, hypopigmentation, and hyperpigmentation) are late, chronic skin findings. Calcinosis tends to occur on sites exposed to trauma such as the knees, elbows, and buttocks and is highly correlated with the chronicity and severity of the disease. Rapid initiation of aggressive therapy eliminates this most vexing complication, which highlights the need for an early diagnosis.
Lesions associated with inflammatory bowel disease may be due to direct or metastatic extension of the underlying disease (particularly Crohn disease), a manifestation of an associated nutritional disorder, or a nonspecific inflammatory reaction pattern, usually pyoderma gangrenosum or erythema nodosum.
Pyoderma gangrenosum, which may be associated with many underlying conditions (Table 1), begins as a small pustule that evolves into an enlarging necrotic ulcer with a yellow-white, purulent, boggy, soupy base and irregular, dusky, violaceous, undermined borders (Figure 10).13 The painful ulcer may be preceded by trauma, a phenomenon known as pathergy. Thus, debridement of these ulcers should be minimized. The clinical appearance is enough to make an accurate diagnosis. Biopsy offers nonspecific findings but may be considered to rule out other entities in the differential diagnosis such as deep tissue infections (mycobacterialor fungal) or vasculitis. Treatment is geared toward correcting any identifiable underlying cause. Systemic therapy with corticosteroids, dapsone, minocycline, cyclosporine, or other immunosuppressive agents is usually needed to control pyoderma gangrenosum.
Erythema nodosum occurs in 4% of patients with ulcerative colitis and 6.8% of patients with Crohn disease.14 It also is associated with several other diseases and medications (Table 2) so it is not a specific finding of inflammatory bowel disease. The classic lesions of erythema nodosum are bilateral, warm, erythematous, tender pretibial nodules (Figure 11) that during several weeks evolve into a yellow-purple, bruise-like color. The lesions can appear on any part of the legs or on the rest of the body, may be asymmetric, and may be associated with fever, chills, malaise, and arthralgias. Making a clinical diagnosis is generally not difficult, but a biopsy that includes a generous portion of subcutaneous fat may be helpful. Treatment, as in pyoderma gangrenosum, is directed at finding and correcting an underlying cause. Bedrest and nonsteroidal anti-inflammatory agents are usually the first lines of therapy, followed by saturated solution of potassium iodide, five drops twice a day, which are slowly increased to 10 drops. Systemic corticosteroids may be considered if an underlying infection, particularly tuberculosis, has been ruled out.
Cutaneous Crohn disease is rare and presents a challenging dilemma in the 20% of patients whose skin manifestations precede a diagnosis of their bowel disease.15 Perianal and perineal lesions are most common and usually are associated with colorectal Crohn disease. Erythema, swelling, and a dusky cyanotic discoloration herald the more advanced lesions, which consist of infiltrative plaques, erosions, ulcers, draining sinuses, fistulae, and scarring (Figure 12). Edematous, polypoid, tag-like projections are characteristic of perianal Crohn disease and may be mistaken for a skin tag, condyloma acuminatum, or condyloma latum. Exam findings may be similar to those in sexual abuse. A skin biopsy showing a granulomatous infiltrate, corroborated with appropriate bowel work-up, confirms the diagnosis of Crohn disease. Oral lesions include cobblestoning, nodules, aphthous ulcers, angular cheilitis, diffuse swelling, pyostomatitis vegetans, and gingival hyperplasia.
Recurrent aphthous stomatitis ("canker sore") affects about 20% of the population and usually is not associated with any underlying disease.16 Lesions consist of one to several discrete, shallow, painful ulcers on the mucosa of the labia and cheeks. Once again, systemic associations include SLE and Crohn disease. Behçet's syndrome, nutritional deficiencies, medications, and cyclic neutropenia are also rare causes of aphthous ulcers. Since recurrent aphthous stomatitis is so common in the general population while these associated diseases are so uncommon, work-up should be limited to a complete blood count, erythrocyte sedimentation rate, ferritin, B12, and folate, or simply be directed toward any positives on a review of symptoms.
The periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a newly recognized, relatively common condition that may stymie physicians and parents for years before a diagnosis is reached. Beginning at about 3 years of age, affected children have regular, recurrent bouts of fevers that last from three to six days and are characterized by a brisk rise above 39° C. The interval between bouts is three to six weeks, and the periodicity is so regular that families may plan vacations to coincide with the period between episodes when the child is totally well. Despite the fevers, an infectious focus is notably absent and laboratory studies are unrevealing. About two thirds of children with PFAPA syndrome have aphthous stomatitis, and ulcers heal in five to 10 days. Cervical adenopathy appears and regresses rapidly.
In a recent compilation of 122 cases of PFAPA, outcome was universally good and symptoms basically resolved in a mean of 4.5 years.17, 18 The main differential diagnosis includes familial Mediterranean fever, hyper-IgD syndrome, systemic juvenile-onset rheumatoid arthritis, cyclic neutropenia, and Hibernian fever. Only symptomatic treatment is needed and antibiotics are not helpful, though episodes are milder in some patients when they take antibiotics at the onset of high fever. Aspirin, acyclovir, and colchicine are ineffective. Brief courses of prednisone at doses of 1 to 2 mg/kg/d resolve the fever dramatically, but sometimes also shorten the interval between fevers. Aphthous stomatitis is the last symptom of PFAPA to respond to steroids. A handful of patients have had no further episodes after treatment with cimetidine 150 mg twice a day for six months, and symptoms completely resolved in seven of 11 patients who had a tonsillectomy. The surgery cannot be recommended as standard therapy for this benign, self-limited condition, however. Most families are content with obtaining a diagnosis and reassurance.
Observers have debated about whether the cause of PFAPA is infectious or immunologic, though most evidence points toward an infection, perhaps with a concomitant dysregulation of cytokines. It is interesting to note that one form of familial recurrent fevers recently was linked to an inherited abnormality of the tumor necrosis factor receptor,19 and it is possible that similar abnormalities of cytokines, their receptors, or their inhibitors may underlie some of the recurrent fever syndromes.
The medical literature uses the term "hemangioma" loosely, and many syndromes, such as Sturge- Weber, are inappropriately linked to hemangiomas when they actually are associated with vascular malformations. More precise classification of vascular lesions has eliminated much of this confusion. When "hemangioma" is correctly applied only to the common, benign, self-limited vascular tumors affecting 10% of infants, surprisingly few of them are associated with underlying conditions.20 Even the well-recognized Kasabach-Merritt syndrome, long thought to represent the association of a large hemangioma with consumptive coagulopathy, is now known to be related to other vascular tumors such as kaposiform hemangioendotheliomas or tufted angiomas.
An underlying problem should be suspected in conjunction with a hemangioma in some notable instances, however. For example, diffuse neonatal hemangiomatosis is the association of multiple cutaneous hemangiomas with visceral hemangiomas, especially of the liver (Figure 13).21 The brain, lungs, and gastrointestinal tract may be affected in this rare but serious syndrome. Left untreated, this condition is fatal in about 75% of patients, usually from high-output cardiac failure. A multispecialty approach that encompasses dermatology, gastroenterology, cardiology, and pediatric intensive care is essential for managing this critical condition. The more common entity, benign cutaneous hemangiomatosis, affects just the skin and the course is harmless and self-limited. Close medical follow-up and ultrasound imaging is indicated in all children with many hemangiomas, however.
Large hemangiomas in a "beard" distribution over extensive areas of the cheek and neck have about a 60% chance of developing into symptomatic airway obstruction.22 Respiratory failure and death may ensue. Careful monitoring with auscultatory exam and direct visualization is necessary, and magnetic resonance or computed tomography imaging should be considered. Early aggressive treatment with systemic steroids or a-interferon is indicated, but tracheostomy may also be needed.
The PHACES syndrome (posterior fossa malformations, hemangiomas of the cervicofacial region, arterial anomalies, cardiac anomalies, eye anomalies, and sternal or abdominal clefting or ectopia cordis) is one of the syndromes that truly is associated with a hemangioma rather than a vascular malformation.23 About 88% of cases are in girls with large facial hemangiomas (Figure 14) that have a strong tendency to ulcerate and destroy the soft tissues of the lip and ears.
Dandy-Walker malformation, characterized by a hypoplastic or absent cerebellar vermis and a posterior fossa cyst continuous with the fourth ventricle, is the most common central nervous system anomaly, but cerebellar atrophy and arachnoid cysts with cerebellar hypoplasia have also been reported. In infants with large facial hemangiomas, neurodevelopment and head circumference should be followed closely, and imaging studies of the brain should be strongly considered, especially if ultrasound can be performed through an open fontanel. Airway obstruction may occur, as is seen in the beard area hemangiomas, and surveillance is necessary. A careful cardiac exam and blood pressure monitoring is needed to assess for coarctation of the aorta or associated structural cardiac anomalies.
Midline hemangiomas of the lumbosacral spine may be markers of occult spinal dysraphism and anomalies of the anorectal and urogenital regions.24 Imaging is indicated for hemangiomas with this distribution.
This article barely scratches the surface of the extremely broad topic of skin signs of systemic diseases in children. I hope that the illustrations it offers highlight the importance of a thorough understanding and examination of the skin. Using skin examination and biopsy, dermatologists and pediatric dermatologists may be of great assistance to pediatricians in the diagnosis of several systemic illnesses. Pediatricians are invaluable in the management of these sometimes critically ill and very challenging children. A team approach to diagnosis and treatment yields the optimum outcome.
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Howard Pride. When a rash is more than a rash: Skin signs of systemic disease.