key: cord-0046368-cuvfy4pj
authors: Baselga, Eulalia; Torrelo, Antonio
title: Inflammatory and Purpuric Eruptions
date: 2020-06-22
journal: Neonatal Dermatology
DOI: 10.1016/b978-1-4160-3432-2.50022-4
sha: 9fff65aad347ecc9b93ef6665188c0ca7e3ff7bc
doc_id: 46368
cord_uid: cuvfy4pj

nan

Infl ammatory and Purpuric Eruptions

This group of eruptions is composed of lesions of variable morphology and diverse etiology. However, all have erythema as a common feature, a refl ection of their infl ammatory nature. Several disorders appear to represent hypersensitivity reactions, but for most the etiologic agents are unknown. The differential diagnosis of purpura is extensive in neonates, and includes hematological disorders, infections, trauma, and iatrogenic disorders.

Annular erythema is a descriptive term that encompasses several entities of unknown etiology characterized by circinate polycyclic lesions that extend peripherally from a central focus. 1, 2 Because of subtle differences in clinical features, age of onset, duration of individual lesions, and total duration of the eruptions, a variety of descriptive terms have been coined for these disorders (Table 19-1) . For prognostic reasons, it is useful to subdivide annular erythemas into transient and persistent forms. 3 Transient forms include annular erythema of infancy and the less well-established entity erythema gyratum atrophicans transient neonatale. Persistent annular erythemas include erythema annulare centrifugum, familial annular erythema, and erythema gyratum perstans. Other annular erythemas known to be a manifestation of well-defi ned diseases (e.g. neonatal lupus) or with distinctive clinical or histologic features (e.g. erythema multiforme, erythema chronicum migrans, erythema marginatum rheumaticum, and erythema gyratum repens) are not considered under this heading.

Annular erythema of infancy is a benign disease of early infancy characterized by urticarial papules that enlarge peripherally, forming 2-3 cm rings or arcs with fi rm, raised, cord-like or urticarial borders. [4] [5] [6] Adjacent lesions become confl uent, forming arcuate and polycyclic lesions ( Fig. 19-1) . Neither vesiculation nor scaling is present at the border. The eruption is asymptomatic. Individual lesions resolve spontaneously without a trace within several days, but new lesions continue to appear in a cyclical fashion until complete resolution within the fi rst year of life. A few cases lasting for years have been described. [7] [8] [9] The cause of annular erythema is unknown, and there are no associated systemic fi ndings. Histologic studies reveal a superfi cial and deep, dense, perivascular infi ltrate of mononuclear cells and eosinophils. No fl ame fi gures are observed. The epidermis is normal or mildly spongiotic.

Laboratory studies are normal. Peripheral eosinophilia does not accompany tissue eosinophilia. Immunoglobulin levels, including IgE levels, are normal. The differential diagnosis should include other annular lesions of infancy (see the following discussion). No treatment is warranted because of the self-limited nature of the eruption.

Erythema gyratum atrophicans transiens neonatale is a less well-defi ned entity, 10 characterized clinically by annular plaques with an erythematous border and an atrophic center. The lesions appear in the newborn period and resolve within the fi rst year of life. Histologic fi ndings include epidermal atrophy and a mild perivascular mononuclear infi ltrate. Immunofl uorescence studies reveal granular deposits of IgG, C3, and C4 at the dermoepidermal junction and around capillaries. Erythema gyratum atrophicans transiens neonatale possibly represents a variant of neonatal lupus erythematosus. 11

Erythema annulare centrifugum is a more persistent type of annular erythema that usually affects adults, 12 but may also occur in children and rarely in newborns. 3, [13] [14] [15] [16] The lesions are clinically somewhat similar to those of annular erythema of infancy, but scaling or vesiculation is seen at the border. The scales lag behind the advancing border, which, in contrast to annular erythema of infancy, is not indurated. Individual lesions resolve spontaneously after a few weeks, but new plaques continue to develop for years, or may be a lifelong condition. There is no associated pruritus.

Erythema gyratum perstans falls within the spectrum of erythema annulare centrifugum. [16] [17] [18] Some authors defend the distinctness of erythema gyratum perstans and consider distinctive features of this disorder to be its early onset, a duration of more than 15 years, the presence of slight to severe pruritus, and especially the presence of vesiculation. 16 Erythema annulare centrifugum is thought to represent a hypersensitivity reaction to several trigger factors, including infectious agents (Candida, 19, 20 Epstein-Barr virus, 14 and Ascaris 21 ), drugs or foods, 22, 23 and neoplasia, especially in adults. Intradermal injection of candidin or trichophytin may reproduce the clinical lesions. 13 Histologic features consist of a dense, superfi cial, perivascular mononuclear infi ltrate. Parakeratosis or epidermal spongiosis may be present. No therapy has been successful in all cases. Treatment agents include oral nystatin, 20 oral amphotericin B, 19 topical antifungals, antihistamines, disodium cromoglycate, and interferon-α. 13 

Familial cases of annular erythema with autosomal dominant inheritance have been described. 25, 26 The onset is in early infancy. Scaling, vesiculation, and pruritus may be more common than in erythema annular centrifugum. Lesions resolve with residual hyperpigmentation. Chronicity is the rule. Geographic tongue may be associated. 26 

Differential diagnosis includes other eruptions with ringlike lesions, such as neonatal lupus, erythema multiforme, urticaria, urticarial lesions of pemphigoid, fungal infections, erythema chronicum migrans, and congenital Lyme disease. 7, 27, 28 Serum antibody determinations (antinuclear, SS-A, and SS-B) are recommended to exclude neonatal lupus. [29] [30] [31] [32] [33] [34] [35] [36] Neonatal lupus erythematosus (NLE) is a disease of newborns caused by maternally transmitted autoantibodies. The major manifestations are dermatologic and cardiac. Skin fi ndings are transient. Cardiac disease, which is responsible for the morbidity and mortality of NLE, begins in utero and affects the cardiac conduction system permanently. Other fi ndings include hepatic and hematologic abnormalities. Mothers of infants with neonatal lupus have anti-Ro/SS-A autoantibodies in 95% of cases. Anti-La/SS-B and anti-U1RNP autoantibodies have also been implicated in the pathogenesis of NLE in a minority of patients. 37, 38 

Fifty per cent of infants with NLE have skin lesions, and congenital heart block is present in about 10%. 29, 36 Lesions commonly develop at a few weeks of age but may be apparent at birth, which suggests that ultraviolet (UV) radiation is not essential for the development of skin lesions in NLE. 39 Clinically, skin lesions are analogous to those of subacute cutaneous lupus in its two variants: papulosquamous and annular. Papulosquamous lesions are more common and are characterized by erythematous, nonindurated scaly plaques ( Fig. 19-2 ). Sometimes the skin lesions have an atrophic appearance ( Fig. 19-3 ). Ulcerations may be present. 40 In contrast to discoid lupus, scarring and follicular plugging are absent. The annular variant, which occurs almost exclusively in Japan, consists of annular, more infl ammatory plaques. 41 Lupus profundus and generalized poikiloderma with erosions and patchy alopecia are rare manifestations. 42, 43 NLE lesions may be widespread but are most common on the face and scalp, predominantly affecting the periorbital and malar areas and often causing a 'raccoon eyes' appearance . The eruption is frequently precipitated or aggravated by sun exposure. Sun exposure is not strictly required, however, as the lesions may occur in sun-protected areas such as the diaper region, palms, and soles. 39, 44, 45 Skin lesions are transient and cease to appear around the age of 6 months, after the disappearance of maternal antibodies. Transient hypopigmentation and epidermal atrophy may result ( Fig. 19-5) . 36 Telangiectasia is a more permanent sequela. Telangiectasia also may be an initial sign of NLE, occurring without preceding identifi able infl ammatory lesions; features of cutis marmorata telangiectatica congenita have been observed. 35, 46 A case of NLE with a serological profi le consis-tent with drug-induced lupus has been described in a newborn whose mother was treated with α-interferon during pregnancy. 47

The most signifi cant manifestation is isolated complete congenital heart block. More than 90% of such cases are due to NLE. Most patients have third-degree block, but progression from a second-degree block has been reported. 48 Heart block can often be detected as early as 20 weeks of gestation.

Transient liver disease, manifesting as hepatomegaly (with a picture of cholestasis) or elevation of liver enzymes, 35, [49] [50] [51] and thrombocytopenia or other isolated cytopenias, may occur. 52 Petechiae and purpura have been described as presenting signs of NLE. 53 Less common fi ndings include thrombosis associated with anticardiolipin antibodies, hypocalcemia, spastic paraparesis, pneumonitis, and transient myasthenia gravis. [54] [55] [56] Central nervous system (CNS) involvement has been reported in 10 of 11 consecutive infants with NLE, in the form of ultrasound and CT scan abnormalities which did not result in clinical neurological manifestations. 57 Such CNS involvement in NLE is probably a transient phenomenon.

Between 30% and 50% of mothers of infants with NLE have a connective tissue disease, most commonly SLE or Sjögren syndrome. Most, however, are asymptomatic. The risk for developing overt connective tissue disease in these mothers is highly debated, with estimates ranging from 2% to more than 70%. 36, [58] [59] [60] [61] [62] [63] 

It is universally agreed that placentally transmitted maternal IgG autoantibodies are necessary for the pathogenesis of NLE, but not suffi cient. 64 The most commonly implicated autoantibodies have been anti-Ro/SS-A and anti-La/SS-B. More than 95% of NLE infants have anti-Ro antibody, and 60-80% have anti-La antibodies. A small subset of affected infants do not have detectable anti-Ro or anti-La antibodies, but instead have anti-U1RNP. 37, 38 Mothers with high titers of anti-Ro and anti-La antibodies are at greater risk of delivering an infant with NLE. Despite initial observations based on immunoblot or ELISA testing that anti-52 kDa Ro antibodies conferred a higher risk of NLE than anti-60 kDa Ro antibodies, more precise testing with line immunoassay has revealed that antibodies to 60 kDa Ro are signifi cantly more sensitive than antibodies to 52 kDa Ro and 48 kDa La. 65 Furthermore, comparing mothers of children with NLE with rash alone or with congenital heart block, there is no signifi cant difference in the prevalence of any of the three antibodies between the two groups. 65 However, signifi cantly more symptomatic mothers of children with congenital heart block have anti-La antibodies than do disease-matched mothers with unaffected children. 65 Moreover, the mean level of anti-La seems to be higher in mothers of infants with congenital heart block than in mothers of children with cutaneous NLE. 66 It is not clear why only less than 5% of mothers with anti-Ro and anti-La antibodies give birth to affected children and why mothers of affected infants are often asymptomatic despite having the same antibodies. Furthermore, fraternal twins are often discordant for NLE, and NLE does not occur in every pregnancy. Genetic factors may be important for the development of NLE in children with maternal lupus antibodies. A link has been suggested between NLE rash and the allele HLA-DRB1*03, as well as a -308A polymorphism in the TNF-α gene. 34 Alternatively, maternal and/or sibling microchimerism may play an additional role, as levels of microchimerism have been reported to correlate with NLE disease activity. 67

Serologic studies for autoantibodies in the mother and infant demonstrate anti-Ro, anti-La, and/or anti-U1RNP antibodies.

Anti-nDNA, anticardiolipin antibodies, antinuclear antibody, and rheumatoid factor may also be present. Anti-Sm antibody, highly specifi c for systemic lupus erythematosus, is not found in NLE. The maternal antibody titer is usually higher than the infant titer, which may even be negative if only immunodiffusion techniques are used. More sensitive methods, such as ELISA, immunoblotting, or line immunoassay, should be used in such instances. Skin biopsy, which is usually not necessary for diagnosis, shows changes characteristic of lupus erythematosus, that is, epidermal atrophy and vacuolization of the basal layer with a sparse lymphohistiocytic infi ltrate at the dermoepidermal junction and in a periappendageal distribution. In many instances, histopathological features in children with NLE rash are subtle. Direct immunofl uorescence is positive in 50% of cases, demonstrating granular deposits of IgG, C3, and IgM at the dermoepidermal junction. Histopathologic examination of the heart shows replacement of the atrioventricular node by fi brosis or fatty tissue. Endomyocardial fi broelastosis and patent ductus arteriosus may also be seen, 68, 69 as well as deposits of IgG and complement. 70

The differential diagnosis includes congenital rubella, cytomegalovirus infection, annular erythema of infancy, tinea corporis, and seborrheic dermatitis. Congenital syphilis should also be considered, but mucosal lesions are not a feature of NLE. False positive serologic tests for syphilis may occur in NLE. Telangiectasia and photosensitivity may suggest Bloom syndrome or Rothmund-Thomson syndrome. Serologic studies for autoantibodies in both infant and mother help to confi rm the diagnosis. Skin biopsy for histologic and direct immunofl uorescence studies is seldom necessary.

Neonates with suspected NLE should receive a complete physical examination, electrocardiogram, complete blood count with platelet count, and liver function tests (Box 19-1).

Skin lesions are transient. Treatment of skin disease consists of sun protection and the application of topical steroids. Pulsed dye laser therapy may be considered for residual telangiectasia. Congenital heart block is permanent. Half of newborns with complete congenital heart block require implantation of a pacemaker in the neonatal period. 32 mortality from complete congenital heart block in the neonatal period is 15%; another 10-20% die of pacemaker complications. 27, 32 Late-onset cardiomyopathy may develop in a few infants. [72] [73] [74] For mothers with anti-Ro or anti-La antibodies, the risk of delivering an infant with NLE is 1-20%, depending on whether they have asymptomatic or symptomatic SLE. 29, 32 The risk of recurrence of congenital heart block in subsequent pregnancies may be as high as 25%. 61 Such pregnancies should be closely monitored, with repeated fetal echocardiograms. 75 If signs of intrauterine congestive heart failure are detected dexamethasone or plasmapheresis, or both, have been given. 32, [76] [77] [78] [79] Although NLE is usually self-limited, SLE or other rheumatologic/autoimmune diseases may develop later in life in a small subset of patients. 62, 80, 81 The exact risk is unknown. [82] [83] [84] [85] Cutaneous drug reactions are extremely rare in the neonatal period because the ability to generate a drug-induced immune response appears to be lower in infants. [86] [87] [88] Furthermore, most drug reactions require time for sensitization, which may range from 1 to 4 weeks or more, as well as re-exposure to the causative drug. Finally, newborns and young infants are less exposed to drugs than adults. Cutaneous adverse reactions to drugs may be classifi ed according to the clinical characteristics of the eruption (Box 19-2). Whenever a suspect eruption is observed, a detailed history of medications should be obtained, including drugs administered to the mother, which may be present in breast milk. Morbilliform ( Fig. 19-6 ) or maculo-papular eruptions (Fig. 19-7) are the most frequent type of drug reaction in neonates, and antibiotics are commonly implicated ( Fig. 19-8) . Distinguishing a drug eruption from a viral exanthem is often diffi cult.

EMLA cream, a local anesthetic that may be used with great frequency in neonatal units, has been noted to produce a localized purpuric eruption. 89, 90 This type of reaction is seen preferentially in neonates, and subsequent applications of the cream do not always reproduce the purpuric lesions. Methemoglobinemia is another complication of EMLA use in this age group. 90 EMLA cream should therefore be used with caution in infants who are taking methemoglobin-inducing medications such as sulfonamides, acetaminophen, nitroglycerin, nitroprusside, and phenytoin, and particularly in those with a history of methemoglobinemia.

Vancomycin, an antibiotic frequently administered to premature newborn infants for Staphylococcus epidermidis nosocomial infections, may produce shock and rash in newborns (red-baby syndrome). [91] [92] [93] This reaction is characterized by the appearance of an intense, macular, erythematous eruption on the neck, face, and upper trunk shortly after the infusion is completed. It may be accompanied by hypotension and shock. The reaction resolves rapidly in a matter of hours. It is frequently associated with rapid infusion; however, lengthening the infusion to more than 1 hour does not completely eliminate the risk. 92 Newborns with AIDS have an increased susceptibility to drug reactions. 94, 95 Reactions to trimethroprim/sulfamethoxazole in patients with HIV infections can be severe and life-threatening. 96 Fixed drug reactions of the scrotum and penis, with erythema and edema resulting from hydroxyzine hydrochloride, have been described in early infancy. 97 However, hydroxyzine hydrochloride is administered infrequently in the neonatal period because of the risk of antimuscarinic effects, such as restlessness and excitation.

Serum sickness-like reaction is a type of drug reaction that occurs predominantly in children and has been reported in infants 5 months of age. 98 It is characterized by fever, an urticarial eruption, and arthralgias. Lymphadenopathy may be present. In contrast to true serum sickness, there are no immune complexes, vasculitis, or renal impairment. The most commonly implicated drug has been cefaclor. [98] [99] [100] This type of reaction may be seen in infants with an unknown or presumably viral etiology ( Fig. 19-9) Hypersensitivity syndrome reaction is a serious drug reaction characterized by fever, skin rash, lymphadenopathy, and internal organ involvement, especially of the liver. 101, 102 The most commonly implicated drugs are anticonvulsants, and therefore it is not rare in children. A fatal case in a 3-monthold infant has been reported, as well as a case in a premature infant. 103, 104 Toxic epidermal necrolysis (TEN) is extremely rare in newborns. Cases of TEN in newborns have been related to antibiotics and phenobarbital. 105 All cases described so far proved fatal.

Vegetant bromoderma is a reaction to bromides characterized by coalescing papules and pustules which form vegetant infl ammatory or pseudotumoral lesions. It usually affects the scalp, face, and legs. Most cases of vegetant bromoderma have been described in infants after the ingestion of syrups and solutions containing bromide, which has sedative and expectorant properties, or the spasmolytic agent scopolamine bromide. 106 The eruption ceases after withdrawal of bromide. The risk of systemic intoxication, known as bromism, makes it advisable to avoid bromide use in newborns and infants.

Other anectodal reports of toxicoderma in very young infants or newborns have been described, such as a papular eruption from G-CSF for collection of stem cells (Fig. 19-10) , 107 a lichenoid reaction to ursodeoxycholic acid for neonatal hepatitis, 108 and a maculopapular rash from diazoxide used for neonatal hyperglycemia (see Fig. 19 -7).

Urticaria (hives) occurs frequently in childhood but is uncommon in children younger than 6 months and even rarer in the neonatal period. 82, [109] [110] [111] [112] [113] [114] [115] [116] [117] Urticaria is usually sporadic; however, familial forms with autosomal dominant inheritance have been described for many of the physical urticarias, such as dermographism, heat urticaria, cold urticaria, and vibratory urticaria.

Urticaria can be divided into acute (lasting less than 6 weeks) and chronic (lasting more than 6 weeks) types. Nevertheless, this arbitrary division has prognostic and etiopathogenic signifi cance. In infants, chronic urticaria is very rare. 111, 118 Physical urticarias represent a special subgroup of urticaria in which wheals are elicited by different types of physical stimuli. 119 These include dermographism, cold, pressure, cholinergic, aquagenic, vibratory, and solar urticaria.

Urticaria is characterized by transient edematous pruritic wheals ( Fig. 19-11 ). By defi nition, individual lesions last less than 24 hours. Hives may occur on the skin and mucous membranes. Angioedema or giant urticaria is a closely related entity in which there is swelling of the deep subcutaneous tissues and diffuse swelling of the eyelids, genitalia, lips, and tongue. It may be seen alone, or more often in association with 'common' urticaria. Urticaria in children has certain characteristic features. The hives tend to coalesce, forming bizarre polycyclic, serpiginous, or annular shapes (fi gurative urticaria, Fig. 19-12 ; or annular urticaria, Fig. 19 -13), and may become hemorrhagic. 109, 112 Edema is often pronounced and painful. These features confer a dramatic appearance to the eruption. in children the itching may be absent. Urticaria may be more common and recurrent in atopic patients. 112, 115 

Acute urticaria may be accompanied by signs of anaphylactic shock. In cases of angioedema, abdominal pain, diarrhea, vomiting, respiratory compromise, and joint pain may occur. 82, 113 Urticaria develops as a result of an increased permeability of capillaries and small venules, which leads to leakage of fl uid into the extravascular space. Mast cell activation and subsequent mediator release are responsible for these changes. Histamine is the best-known mediator. Many triggers (secretagogues) initiate mast cell degranulation through receptors on mast cell membranes, either via an IgE-dependent mechanism or through complement activation (immunologic secretagogues) or by acting directly without the need for receptors (nonimmunologic secretagogues). The most common provocative agents in children are drugs, foods, and infections, which account for 40% of the cases of acute urticaria. 112, 115, 117 Antipyretics (primarily aspirin) and antibiotics (amoxicillin, macrolides, and oral cephalosporins) are the most frequently incriminated drugs. Food-related urticaria is associated with atopy. 112 Cow's milk allergy is one of the main causes of urticaria in infants, being present in 6-35% of cases of cow's milk intolerance. 116, 120, 121 

The diagnosis of urticaria is made on clinical grounds. Histopathologic examination of a skin biopsy specimen shows vascular dilation, edema, and a perivascular infl ammatory infi ltrate composed of lymphohistiocytic cells, polymorphonuclear cells, and more specifi cally eosinophils. Neutrophils may predominate.

Laboratory tests are not usually necessary for the evaluation of acute urticaria. IgE levels can be elevated in some patients. An exhaustive search for an underlying cause not elicited by history alone is not warranted. An erythrocyte sedimentation rate may suffi ce as a screening test in cases of chronic urticaria because it is usually elevated in diseases associated with chronic urticaria (e.g. collagen vascular diseases). In 10-15% of patients no cause is identifi ed. Intradermal skin tests to discover suspected allergens are not reliable.

Urticaria in infants is often misdiagnosed as erythema multiforme, acute hemorrhagic edema, annular erythema of infancy, or Kawasaki disease. In an infant with urticaria and dermographism the possibility of diffuse cutaneous mastocytosis without visible cutaneous lesions should also be considered. 122 NOMID/CINCA (see below) should be considered in young infant with urticaria. The predominance of neutrophils in skin biopsies of children with NOMID may help in the differential diagnosis, although it is not 100% specifi c. In case of doubt, genetic testic for NOMID is now available.

Despite its alarming symptoms, urticaria in early infancy is usually benign. Exceptions are chronic infantile neurological cutaneous and articular syndrome (CINCA) (see below) and the inherited physical urticarias, which may have a lifelong course. If medication is required, antihistamines such as diphenhydramine or hydroxyzine are the mainstay of therapy. However, newborns have an increased susceptibility to antimuscarinic side effects, such as central nervous system (CNS) excitation causing convulsions. Systemic corticosteroids should be reserved for cases of intractable urticaria.

Autosomal dominant variants have been described for many of the physical urticarias. Although rare, these familial cases begin early in life, even immediately after birth, and have a lifelong course, usually with increased severity. The exact pathogenic mechanism for many of the physical urticarias is unknown.

Familial cold urticaria (FCU) is an autosomal dominant disorder characterized by the development of burning wheals, and frequently pain and swelling of joints, stiffness, chills, and even fever after exposure to cold, especially in combination with damp and windy weather. [123] [124] [125] [126] The skin lesions appear on exposed areas and generalize afterwards. Leukocytosis may be present during the attacks. The reaction may be delayed for up to 6 hours after cold challenge. In contrast to acquired cold urticaria, the reaction cannot be elicited by an ice cube test: rather, the patient must be subjected to cold environmental temperatures or cold water immersion. On skin biopsy a neutrophilic infi ltrate predominates. The symptoms tend to improve with age. Responses to H 1 and H 2 blockers and ketotifen are poor. Stanozolol has been of limited benefi t. 127 FCU has also been described along with amyloidosis and deafness as Muckle-Wells syndrome (MWS). 128 It has been recently demonstrated that both FCU and MWS are due to mutations in the CIAS1 (cryopyrin) gene: in fact they are the same disorder and may share exactly the same genetic mutation. 129 FCU and MWS are also allelic diseases with CINCA syndrome (see below), which is also due to CIAS1 gene mutations. 130 Familial dermographism (autosomal dominant) has been described in a single large family. 131 In neonates dermographism can also be a manifestation of 'silent' diffuse cutaneous mastocytosis. 122, 132 Vibratory urticaria is an autosomal dominant physical urticaria in which wheals develop after repetitive vibratory stimulation or stretching. 133, 134 The need for repetitive trauma differentiates it from dermographism. Familial aquagenic urticaria and familial heat urticaria usually have onset in childhood. [135] [136] [137] CHRONIC INFANTILE NEUROLOGICAL CUTANEOUS AND ARTICULAR SYNDROME (CINCA) [138] [139] [140] [141] CINCA syndrome, also known as neonatal onset multisystemic infl ammatory disease (NOMID), is a chronic systemic infl ammatory disease of neonatal onset characterized by skin rash, arthropathy, and CNS manifestations. Cutaneous fi ndings are the presenting signs. The disease follows a chronic course with acute febrile exacerbations, lymph node enlargement, and hepatosplenomegaly. Two-thirds of patients are born prematurely.

A skin eruption is usually the fi rst manifestation of the disease and is present at birth or develops during the fi rst 6 months of life. It is characterized by generalized, evanescent, urticarial macules and papules that migrate over the course of a single day and wax and wane in intensity ( Fig. 19-14) . The rash is persistent, although recrudescence of the skin lesions is noted at fl are-ups. The lesions may be pruritic, especially after sun exposure, but are usually asymptomatic. 140, 141 Geographic tongue and oral ulcers have been noted in a single patient. 141

Symmetric or asymmetric arthropathy is another constant fi nding and is severe in half of patients. It is often absent in the fi rst few weeks of life, but usually develops during the fi rst year. 140, 142 The severity of the arthropathy correlates with an early onset of joint symptoms. The knees are most frequently affected, followed by the ankles and feet, elbows, wrists, and hands. Joint swelling and pain are more severe during febrile fl are-ups. On palpation, a bony consistency is characteristic as a result of epiphyseal and growth cartilage involvement and overgrowth of the patellae. Joint contractures and severe deformities result.

Neurologic signs and symptoms such as headache, vomiting, and seizures develop at a variable age. Intellectual impairment is also common. Both spasticity and hypotonia have been described. Eye involvement is an inconstant fi nding. Papilledema with or without optic nerve atrophy is the most common feature. Other ocular manifestations include uveitis, keratitis, conjunctivitis, and chorioretinitis. 143 These changes may lead to complete blindness in adulthood. Progressive sensorineural hearing loss and hoarseness are also common.

Affected children have a characteristic phenotype. There is progressive growth retardation and increased head circumference with frontal bossing. Fontanel closure is retarded. Icterus may be present in the neonatal period, especially in patients with severe arthropathy. 140

Mutations in the CIAS1 gene have been identifi ed in 60% of patients with CINCA syndrome. 144,145 CIAS1 encodes a protein called cryopyrin, which is involved in the regulation of apoptosis and the infl ammatory signaling pathway. 145 It is proposed that familial cold urticaria and CINCA represent extreme groups of the same disease, defi ned by the magnitude of phenotypic expression. 145 Considerable clinical overlapping exists between these disorders. 

Nonspecifi c fi ndings typical of a chronic infl ammatory process include microcytic anemia; leukocytosis with high neutrophil and eosinophil counts, elevated platelet counts, sedimentation rates, and acute-phase reactants; and polyclonal hyperglobulinemia G, A, or M. Rheumatoid factor and antinuclear antibodies are usually absent. Liver enzymes may be mildly elevated. CSF examination shows pleocytosis and high protein levels.

Radiologic studies of the affected joints show irregularly enlarged, bizarre, spiculated epiphyses with a grossly coarsened trabecular appearance. 140, 142 There is periosteal new bone formation, and growth cartilage abnormalities are frequent. With time, there is bowing deformity of long bones and shortening of diaphyseal length. CT scans of the head have demonstrated hydrocephalus and cerebral atrophy.

Histopathologic examination of the skin reveals interstitial and perivascular neutrophilia. 141, 142 Neutrophilic eccrine hidradenitis has been described. 141 Biopsies of lymph nodes, liver, and synovium show nonspecifi c signs of chronic infl ammation.

NOMID must be differentiated from systemic onset juvenile arthritis. The main differences are its neonatal onset, persistent rash, the short duration of bouts of fever, absence of morning stiffness, and central nervous system involvement. The arthropathy is more deforming, and the radiographic fi ndings of enlarged and disorganized epiphyses are distinctive. In addition, the response to NSAIDs is poor. Urticaria should also be considered and the predominance of eosinophils in skin biopsy may be a relative clue.

The disease follows a chronic course with acute febrile exacerbations. Occasionally it causes death in the fi rst or second decade. Nonsteroidal anti-infl ammatory drugs may be effective for pain relief but do not alter the course of the disease. Prednisone has been palliative in doses ranging from 0.5 to 2.0 mg/kg/day. 142 Chlorambucil and penicillamine have been tried, with limited success. 146, 147 Thalidomide has shown benefi cial effects in a single patient. 148 Other choices include methotrexate, the recombinant human IL-1 receptor antagonist anakinra, [149] [150] [151] [152] and the anti-TNF-α agent etanercept. 153

Erythema multiforme (EM) is an acute, self-limited disorder of skin and mucous membranes. [154] [155] [156] It has been considered a spectrum of disorders, designated EM minor, consisting of skin involvement only or of both the skin and the mouth, and as EM major (Stevens-Johnson syndrome; SJS), which involves at least two mucous membranes with variable cutaneous lesions. Some authors include toxic epidermal necrolysis within this spectrum as a severe form of SJS. Recent evidence suggests that EM and SJS have distinct clinical features and different precipitating factors, so perhaps the terms EM major and EM minor are best avoided. 157, 158 EM is a common disease in children 155 but extremely unusual in the neonatal period. 94, 155, [159] [160] [161] [162] Toxic epidermal necrolysis is discussed in Chapter 10.

The prototypic lesion of EM is a 1-3 cm erythematous, edematous papule that develops a dusky vesicular, purpuric, or necrotic center. A raised edematous ring of pallor surrounded by an erythematous outer ring is often present. These concentric color changes produce the typical target, or iris, lesion. In many cases only two zones are seen, with a single ring around the central papule (atypical target lesions). The lesions are distributed symmetrically and acrally on the extensor surface of the extremities. They may extend to the trunk, fl exural surfaces, palms, and soles. In children, lesions on the face and ears are common, but are rare on the scalp 163 (Fig. 19-15 ).

In SJS, the lesions are more centrally located, predominating on the trunk. The targets are atypical and are usually fl at. Individual lesions tend to coalesce in large patches. Areas of epidermal detachment may occur, but usually affect less than 10% of the body surface area. Mucosal lesions occur frequently in EM and are requisite for a diagnosis of SJS. Mucous membrane involvement is characterized by erythema or blisters that rapidly evolve to confl uent erosions with pseudomembrane formation. The oral mucosa and conjunctiva are most commonly involved, but genital, anal, pharyngeal, and upper respiratory tract involvement may be seen. The number of mucous membranes involved has been considered one of the main distinguishing features of EM and SJS.

Mild, nonspecifi c, prodromal symptoms of cough, rhinitis, and low-grade fever are occasionally present in EM. Fever, arthralgias, and prostration are common in SJS.

EM has been considered a hypersensitivity phenomenon to multiple precipitating factors such as infectious agents or drugs. Three etiologic factors have been well documented: herpes simplex for erythema multiforme, and Mycoplasma infections and drugs for SJS. Herpes simplex (HSV-1 or HSV-2) is considered to be responsible for more than 80% of EM in children, even if clinical infection is inapparent. 164 HSVassociated EM follows the lesions of herpes by 1-3 weeks and is often recurrent. However, not every episode of recurrent herpes is followed by EM. HSV-specifi c DNA has been detected by polymerase chain reaction and in situ hybridization in lesional skin from a large number of children with EM, whether 'idiopathic' or clearly HSV related. 164 Erythema Multiforme   FIG. 19-15 Target lesions of erythema multiforme in a newborn.

Cow's milk intolerance has been described as a cause of erythema multiforme in a neonate. 159 Drugs are the most common cause of SJS. Sulfonamides, phenylbutazone, diphenylhydantoin, and penicillin derivatives are most frequently implicated. 163 Vaccinations were the only known possible causative agents in a newborn and two infants with erythema multiforme. 162, 165 

In cases of extensive involvement an elevated sedimentation rate, leukocytosis, and mild elevation of transaminases may be seen. Electrolyte imbalance and hypoproteinemia may be encountered in SJS. Eosinophilia may be seen in drug-related cases.

Histopathologic examination of early lesions reveals a lymphocytic band-like infi ltrate at the dermoepidermal junction, with exocytosis and individual necrotic keratinocytes in close proximity to lymphocytes ('satellite cell necrosis'). There is vacuolization of the basal layer with focal cleft formation at the dermoepidermal junction. The upper dermis is edematous. Over time, more extensive confl uent necrosis of the epidermis supervenes, resulting in subepidermal blister formation. In EM a lichenoid infi ltrate predominates, whereas in SJS epidermal necrosis predominates.

In typical cases EM or SJS is rarely confused with other entities. Urticarial vasculitis may be considered in some cases. Kawasaki disease may produce target-like lesions; however, associated fi ndings should allow differentiation. Serum sickness-like reactions often associated with the use of Cefaclor or other antibiotics, or even without any known etiology, can also produce targetoid lesions (see Fig. 19-9 ).

Erythema multiforme is usually self-limited. Individual lesions heal in 1-2 weeks, with residual hyperpigmentation. Conservative supportive care is the preferred form of treatment. Possible underlying causes should be sought. Treatment of underlying infection and discontinuation of nonessential drugs are indicated. Corticosteroids are unnecessary and may even worsen a concurrent infection. 166, 167 In HSV-associated EM, early intervention or even prophylactic treatment with oral aciclovir may be benefi cial. 168 SJS has a less favorable prognosis, with a mortality rate of 5-15% if left untreated. The use of corticosteroids in SJS is more controversial. 166, 167, 169, 170 No controlled study has proved their effi cacy, and in some studies patients treated with corticosteroids have had a worse prognosis. 171 Corticosteroids may predispose to secondary infection while suppressing the signs of sepsis. Supportive care is extremely important.

Sweet syndrome, or acute febrile neutrophilic dermatosis, is a benign disease characterized by tender, raised erythematous plaques, fever, peripheral leukocytosis, histologic fi ndings of a dense dermal infi ltrate of polymorphonuclear leukocytes, and a rapid response to systemic corticosteroids. [172] [173] [174] [175] [176] Only a few pediatric cases have been reported, [177] [178] [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] the youngest being 5 weeks of age. 180 Two brothers with Sweet syndrome starting at 2 weeks of life have been reported. 188

The lesions of Sweet syndrome have an acute, explosive onset and are characterized by indurated, tender, erythematous plaques or nodules that vary in size from 0.5 to 4 cm ( Fig.  19-16 ). Tiny pustules may appear at a later stage. The borders may be raised, mammillated, or even vesicular. Some of the lesions may show central clearing, forming annular or gyrate plaques ( Fig. 19-17) . The lesions are usually multiple and distributed over the face and extremities or, more rarely, the trunk. Without treatment, they tend to heal spontaneously within a few months. In some patients, especially children, the lesions heal with areas of secondary cutis laxa, also known as Marshall syndrome. 179, 189, 191 

A high, spiking fever is characteristic but may be absent in up to 50% of patients. 176 Arthralgias or asymmetric arthritis may be associated, and conjunctivitis or iridocyclitis may be seen in one-third of patients. 176 Renal involvement manifesting as proteinuria or hematuria, as well as lung involvement with infi ltrates visible on chest radiographs, has also been described. Central nervous system involvement may occur in rare instances and manifest as headaches, convulsions, or disturbance of consciousness. Cerebrospinal fl uid pleocytosis with lymphocyte predominance is usually found in such cases. 192

The pathogenesis is unknown. Many of the patients reported have had a preceding respiratory tract infection or elevated antistreptolysin O titers. 176 Ten per cent of the cases have been seen in the setting of a variety of hematologic malignancies, particularly acute myeloid and myelomonocytic leukemias. 193 Sweet syndrome has also been associated with solid tumors, infl ammatory bowel disease, connective tissue diseases, and chronic granulomatous disease, or it may occur as an adverse reaction to drugs, [194] [195] [196] particularly granulocyte colonystimulating factor 197 or after vaccination. 198 Because of these associations and the rapid response to systemic corticosteroids, Sweet syndrome is thought to represent a hypersensitivity reaction to infectious agents or tumoral antigens.

An elevated erythrocyte sedimentation rate and peripheral leukocytosis are frequent accompanying abnormalities. Eosinophilia, microcytic anemia, mild elevation of liver enzymes, and urinalysis abnormalities may be present occasionally. Antineutrophil cytoplasmic antibodies have been detected in some cases. 176 α 1 -Antitrypsin defi ciency has been documented in one case of Marshall syndrome. 191 The histopathologic fi ndings are diagnostic. 173 There is a dense perivascular infi ltrate composed almost entirely of neutrophils. The dermis appears edematous, and subepidermal blisters may form. Spongiosis, exocytosis, and intraepidermal vesiculation may be seen. There is endothelial swelling and nuclear dust, but true vasculitis is characteristically absent.

The lesions of Sweet syndrome may initially resemble those of EM or acute hemorrhagic edema. Lesions on the lower extremities may resemble those of erythema nodosum, but lesions more characteristic of Sweet syndrome are usually present in other locations.

Sweet syndrome is a benign disease but may be a marker of malignancy. If left untreated it resolves spontaneously over weeks to months. Recurrences are common. Marshall syndrome may have a poorer prognosis, with the development of elastolysis in the lungs or cardiovascular involvement.

Oral corticosteroids are the treatment of choice and usually elicit a prompt response. 199 Potassium iodide administration has been successful in a few cases, 200 as have colchicine, 201 dapsone, 202 clofazimine, 189 and intravenous immunoglobulin. 184 

Kawasaki disease is an acute systemic vasculitis involving small and medium-sized muscular arteries, especially the coronary arteries, of young children. In the past, many cases were called infantile polyarteritis nodosa. The disease is characterized by fever lasting at least 5 days, nonpurulent conjunctivitis, a polymorphous exanthem, erythema and swelling of the hands and feet, infl ammatory changes of the lips and oral cavity, and acute nonpurulent cervical adenopathy. [203] [204] [205] [206] Coronary artery aneurysms or ectasia develop in 15-25% of untreated children and may lead to ischemic heart disease or sudden death.

Kawasaki disease occurs predominantly in children under 5 and has a peak incidence between 9 and 11 months. [207] [208] [209] It is infrequent before 6 months of age, although it has been reported in patients less than 2 weeks of age [210] [211] [212] Boys are affected 1.5 times as often as girls. Kawasaki disease is an endemic disease with epidemic and geographic clustering. There is seasonal predominance in late winter and spring, although this may differ in different countries. 213, 214 It is most common in Japan, with an annual incidence of 112 cases per 100 000 children under 5, and is steadily increasing. 215, 216 Familial cases in household contacts have been described. 217 The recurrence rate is 3%, with some patients having two or more recurrences. 205, 218 The skin is involved in 99% of patients. The fi rst sign often consists of diffuse erythema and painful induration of the hands and feet. Between 1 and 3 weeks after disease onset the eruption characteristically begins to desquamate beneath the distal nail plates, and peeling may extend to involve the entire palm and sole. Horizontal depressions in the nail plates (Beau's lines) usually result.

A polymorphous exanthem on the trunk and proximal extremities usually appears within 5 days of onset of fever ( Fig. 19-18 ). It is a nonspecifi c, diffuse maculopapular or Kawasaki Disease   FIG. 19-18 Morbiliform eruption in an infant with Kawasaki disease. morbilliform eruption, but may be urticarial, scarlatiniform, targetoid, or even pustular. Bullous or vesicular eruptions have not been described. The rash is usually in the perineum, which is a distinctive feature at this early stage, and it desquamates within 48 hours, preceding fi nger-tip and toe-tip desquamation 219 (Fig. 19-19) . Plaque-type, guttate, and pustular psoriasis have been described, either during the acute or the convalescent phase of the disease, which supports a superantigenmediated etiology. [220] [221] [222] [223] Changes in the lips and oral mucosa include erythema, swelling and fi ssuring of the lips, strawberry tongue, and erythema of the oropharynx. Oral ulcerations and pharyngeal exudates are not seen.

Intermittent acrocyanosis has been observed in infants younger than 6 months of age, 209 as well as peripheral gangrene. 224 Infl ammatory changes with necrosis at the site of a previous BCG inoculation have been reported. [225] [226] [227] [228] Extracutaneous Findings 205, 206, 218, 229 Prolonged fever for at least 5 days is the cardinal and initial feature of the disease. It begins abruptly and is high, with peak temperatures generally >39°C (102°F) and in many cases >40°C (104°F), with several spikes each day (remittent fever). In the absence of appropriate therapy, fever persists for a mean of 11 days, but it may continue for 3-4 weeks and, rarely, even longer.

Bilateral nonexudative conjunctival injection, involving mainly the bulbar conjunctivae, begins shortly after disease onset and may already be resolved at time of fi rst consultation. Anterior uveitis is frequently noted on slit-lamp examination but is rarely symptomatic.

Cervical lymphadenopathy is the least common diagnostic sign, with a prevalence of approximately 65%. It is usually unilateral, and confi ned to the anterior cervical triangle. The lymph nodes are often fi rm, nonfl uctuant, and only slightly tender.

Cardiac conditions are the main cause of long-term morbidity and mortality. The pericardium, myocardium, endocardium, and coronary arteries may all be involved. Myocarditis may manifest in the acute phase, and arrhythmias due to ischemia, congestive heart failure, and valvular involvement, usually mitral, may occur. Occasionally there may low cardiac output syndrome or shock. Cardiac auscultation of the infant or child with Kawasaki disease in the acute phase often reveals a hyperdynamic precordium, tachycardia, a gallop rhythm, and an innocent fl ow murmur. A pansystolic regurgitant murmur may be heard in children with signifi cant mitral regurgitation. Electrocardiography may show arrhythmia, prolonged PR interval, or nonspecifi c ST and T-wave changes. Pericardial effusion may be detected by an echocardiogram in 30% of patients. Without treatment, coronary artery aneurysms develop in 20% and are most commonly detected 10 days to 4 weeks after onset. Risk factors for the development of coronary aneurysms include age younger than 1 year, male gender, fever for more than 2 weeks, recurrent fever, and delayed treatment. Aneurysms may also develop in systemic medium-sized arteries and result in peripheral gangrene. 224 Polyarticular arthritis and arthralgias may occur in the fi rst weeks of the illness. It affects small as well as large joints. Irritability is usually prominent. Lethargy and other signs of aseptic meningitis may be present. Abdominal symptoms such as vomiting, diarrhea, and pain are common. In rare instances acute abdominal pain, mimicking a surgical abdomen, may herald the onset of the disease. Mild hepatitis occurs frequently, as does acute distension of the gallbladder (hydrops).

Transient unilateral peripheral facial nerve palsy occurs rarely. Respiratory symptoms due to pulmonary nodules, infi ltrates, or pleural effusion may also be observed. [230] [231] [232] Rare fi ndings include testicular swelling, hemophagocytic syndrome, 233 and transient high-frequency sensorineural hearing loss (20-35 dB). 234 [235] [236] [237] Epidemiologic and clinical data suggest that Kawasaki disease has features of infectious disease in an immunologically susceptible host and of an immune-mediated vasculitis. Many etiologic agents, ranging from bacteria such as Propionibacterium, Staphylococcus, Streptocuccus, Chlamydia and Yersinia to viruses such as Epstein-Barr, parvovirus, adenoviruses, retroviruses, and a novel human coronavirus, have been linked to Kawasaki disease in different geographic outbreaks, but none has been consistently demonstrated. 235 Much of the continuing debate in the literature concerns whether Kawasaki disease is caused by a superantigen or a conventional antigen. 235, 237 Evidence of a superantigen-mediated disease process includes the identifi cation of superantigen-producing organisms, isolation of bacterial superantigens, or fi nding the hallmark of superantigen activation in affected children, such as selective expansion of Vβ2 and Vβ8 T-cell receptor families. However, the immune response in Kawasaki disease is oligoclonal (antigen driven, i.e. similar to a response to a conventional antigen) rather than polyclonal (as found typically in superantigen-driven responses), and immunoglobulin A (IgA) plasma cells play a central role. 235, 237 Regardless of the cause, evidence points to a generalized immune activation with production of various proinfl ammatory cytokines and endothelial cell activation which lead to coronary artery alteration. [238] [239] [240] [241] The most studied cytokine has been TNF-α, which is usually elevated in children with Kawasaki disease. Enzymes, including matrix metalloproteinases that are capable of damaging arterial wall integrity, may also be important in the development of aneurysmal dilatation. Various chemotactins that attract neutrophils and monocytes to coronary arteries may also play an important role. 242 Host genetic determinants play a role in both susceptibility and coronary artery outcome in Kawasaki disease. 243 The FIG. 19-19 Early perineal desquamative eruption of Kawasaki disease.

incidence rate in siblings is 10 times the population incidence. 217, 244, 245 The risk of occurrence in twins is higher than in ordinary siblings. Parents who had Kawasaki disease in childhood are more likely to have affected children, and children with recurrent disease. 246

In the acute phase, laboratory studies show leukocytosis (>15 000/mm 3 ) with a left shift, normochromic normocytic anemia, increased sedimentation rate and other acute-phase reactants, depressed albumin, and elevated IgM and IgE levels. The degree of elevation of ESR and C-reactive protein may show discrepancy, and both should be measured. Furthermore, elevation of ESR can be caused by IVIG therapy and therefore can not be the sole determinant of the degree of infl ammatory activity. 218 Plasma lipids are altered in the acute stage, with depressed plasma cholesterol and HDL. 247, 248 There may be mild elevation of transaminases and polyclonal hypergammaglobulinemia. In the subacute stage, in the second and third weeks of illness, there is a marked and almost universal thrombocytosis, which returns to normal in 4-8 weeks. Thrombocytopenia is rarely seen in the acute stage and may be a sign of disseminated intravascular coagulation. Antineutrophil cytoplasmic antibodies may be detectable as a nonspecifi c epiphenomenon. There may be sterile pyuria with mild proteinuria. Cerebrospinal fl uid shows a mononuclear pleocytosis with normal protein and glucose levels. Skin biopsy fi ndings are not specifi c. There is edema in the papillary dermis, with a mild perivascular mononuclear cell infi ltrate. Vasculitis of medium and large arteries is observed.

There is no single diagnostic test for Kawasaki disease and therefore clinical criteria have been established to guide treatment decisions (Box 19-3) . The classic diagnosis has been based on the presence of 5 days of fever and four of the fi ve principal clinical features. Clinical features usually appear sequentially and are not all present at a single point in time, therefore watchful waiting is sometimes necessary before a diagnosis can be made. To avoid holding treatment until more than four clinical criteria are met, and the recognition that many patients with 'incomplete' Kawasaki still develop coronary artery disease, one may diagnose and treat Kawasaki on day 4 of illness in the presence of four principal criteria. 230, 249 Also, the diagnosis can be made in patients with fever for 5 days and fewer than four principal features when coronary artery disease is detected by two-dimensional echocardiography (2DE) or coronary angiography. Kawasaki disease should be considered in the differential diagnosis of a young child, specially under 1 year of age, with unexplained fever for 5 days that is associated with any of the principal clinical features of this disease, or even in the presence of other clinical and laboratory fi ndings that are not classic criteria but which are commonly encountered in this disease (Box 19-3). 218 For example, an elevated CRP or ESR and elevated platelet count after 7 days of illness are uncommon in viral infections but are universally seen in children with Kawasaki disease. Echocardiography may be useful in evaluating 'incomplete Kawasaki disease' and should be considered in any infant under 6 months with fever of more than 7 days' duration, laboratory evidence of systemic infl ammation, and no other explanation for the febrile illness. 218 Although aneurysms rarely form before day 10 of illness there may be signs of coronary arteritis, decreased contractibility, mitral regurgitation, and pericardial effusion. With all these considerations a new algorithm has been proposed to help in deciding which patient with incomplete Kawasaki disease should undergo echocardiography or receive IVIG treatment (Fig. 19-20) . 218 

The morbidity and mortality of Kawasaki disease depend primarily on coronary artery lesions. [250] [251] [252] [253] [254] Coronary artery aneurysms or ectasia develop in 15-25% of untreated children and may lead to ischemic heart disease or sudden death. With early treatment the risk is reduced to around 5-12%. 215, 216 Small aneurysms resolve completely within the fi rst 2 years after disease onset in 30-60% of these patients. 255 However, coronary aneurysms, especially if giant (>8 mm), may persist and be complicated by thrombotic occlusion or the development of stenosis at the outlet of the aneurysm. Stenotic lesions as well as early coronary atherosclerosis may develop gradually over several years, so long-term follow-up is warranted. 252, 253, 256, 257 Several scoring systems have been developed to predict risk for coronary artery aneurisms. 258 The Harada score is one that is used in Japan. 259 Sometimes Kawasaki disease may be 'atypical,' presenting at onset with clinical features that are not generally seen, such as acute abdominal pain, renal impairment, meningeal irritation, pneumonia, or retropharyngeal abscess.

Many diseases mimic Kawasaki disease, including viral infections, streptococcal infection, juvenile rheumatoid arthritis, erythema multiforme, staphylococcal scalded skin syndrome, toxic shock syndrome, drug hypersensitivity reactions, Rocky Mountain spotted fever, leptospirosis, mercury hypersensitivity reaction (acrodynia), and bacterial cervical adenitis. Low white blood cell count, lymphocytosis and low platelet count may be useful in suggesting a viral infection instead of Kawasaki disease. Because the major sequelae of Kawasaki disease are related to coronary artery systems, cardiac imaging is critical in the evaluation of all patients with suspected Kawasaki disease, and serial echocardiograms are recommended. Echocardiography should focus on coronary artery visualization and measurement, but also on left ventricle contractibility, valve function, the presence of pericardial effusion, and measurement of the aortic root. 260 An initial examination should be performed as soon as the diagnosis is suspected and is useful as a baseline for follow-up. Thereafter, for uncomplicated cases it should be repeated at 2 weeks and at 6-8 weeks after disease onset. 218 For those who develop coronary artery aneurysms or other cardiac abnormalities more frequent evaluation is recommended. Other noninvasive imaging modalities, such as MRI, MRA, and ultrafast CT, as well as cardiac stress testing, are being evaluated in the management of Kawasaki disease. Until the aneurysm resolves a stress test may be needed to guide recommendations for physical activity and the need for angiography.

Treatment in the acute phase of the disease is directed to reducing infl ammation in the coronary artery wall and preventing coronary thrombosis, whereas long-term therapy in individuals who develop coronary aneurysms is aimed at preventing myocardial ischemia or infarction. Intravenous γglobulin (IVIG) combined with high-dose aspirin is the treatment of choice in the acute phase of the disease. 229 Aspirin alone does not appear to reduce the frequency of the development of coronary abnormalities, but together with IVIG it has an additive anti-infl ammatory effect. In the acute stage aspirin is given in doses of 80-100 mg/kg divided into four. The duration of high-dose aspirin varies in different centers. In many institutions the dose is reduced after the child has been afebrile for 48-72 hours. Others continue until day 14 of illness and >48-72 hours after fever cessation. Following this acute phase low-dose aspirin (3-5 mg/kg) is given as an antiplatelet agent until there is no evidence of coronary changes at 6-8 weeks from disease onset. For patients who develop coronary abnormalities, low-dose aspirin is continued until regression of coronary artery aneurysms, but some clinicians continue indefi nitely. Ibuprofen should be avoided in children taking aspirin for its antiplatelet effect because it antagonizes platelet inhibition.

IVIG has been shown to reduce the incidence of coronary artery aneurisms from 20% to 3-4%. [261] [262] [263] [264] A single dose of 2 mg/kg has been shown to be superior than lower doses for 4 consecutive days. 261,262 IVIG should be started early, within 10 days of disease onset and preferably within 7 days. Treatment before day 5 does not appear to prevent cardiac sequelae and may be associated with an increased need for IVIG retreatment. 265, 266 Treatment after day 10 should be considered if there are still signs of ongoing infl ammation (elevated ESR or CRP) or persistent fever. 267 Not all patients respond to a single dose of IVIG and may have persistent or recrudescent fever 36 hours after completion of the initial treatment, and require a second dose. It has been observed that those children who received IVIG very early in the illness are more prone to require a second infusion. Vaccination with live or other vaccines should be deferred for at least 11 months after high-dose IVIG treatment, both to ensure correct immunization and to avoid fl ares of Kawasaki disease. 268 The usefulness of steroids in combination with IVIG in the initial therapy of Kawasaki disease is not well established. Steroids shorten the duration of fever and lower ESR and CRP, but do not seem to infl uence the coronary outcome. 269, 270 Steroids have also been used for IVIG treatment failures, but their role in preventing or reversing coronary anomalies is uncertain. It has been recommended to restrict their use in children who have persistent fever after two infusions of IVIG. 218 The most common regimen is intravenous pulse methylprednisolone, 30 mg/kg for 1-3 days.

Because of its inhibition of TNF-α messenger RNA transcription, pentoxifylline may have a theoretical benefi t in the initial treatment of Kawasaki disease, although there are only small clinical trials reported. 271 The role of TNF-α antagonists such as infl iximab; abciximab, a platelet glycoprotein IIb/IIa receptor inhibitor; plasma exchange; and cytotoxic agents for patients with refractory Kawasaki disease, remains uncertain. 218, 272 

Acute hemorrhagic edema (AHE), purpura en cockade, or Finkelstein disease, is an acute, benign leukocytoclastic vasculitis of limited skin involvement occurring in children under 2 years of age. [273] [274] [275] [276] [277] [278] [279] [280] AHE has been considered an infantile variant of Henoch-Schönlein purpura; however, because of clinical and prognostic differences it is sometimes regarded as a separate entity.

The disease is characterized by the abrupt onset of fever; tender edema of the face, eyelids, ears, scrotum, and acral extremities; and ecchymotic purpura on the face and extremities. The trunk is usually spared. Individual lesions often have a darker center and expand centrifugally, giving them a cockade or target-like confi guration. Lesions range in size from 0.5 to 4.0 cm and may become confl uent, forming polycyclic, annular plaques ( Fig. 19-21 ). Necrotic 279, 281 and bullous lesions may be seen. 279, 282 Petechiae in the mucous membranes have also been described. 283 

Except for fever, there are no associated manifestations. In many patients there is a preceding upper respiratory tract infection. The dramatic cutaneous fi ndings contrast with the general wellbeing of the patient.

Acute Hemorrhagic Edema   FIG. 19-21 Acute hemorrhagic edema.

The cause of AHE is unknown. It is thought to represent an immune complex-mediated disease precipitated by a preceding infection, particularly an upper respiratory tract infection, drug intake, or immunization. Staphylococci and Streptococcus spp. and viruses (adenoviruses, rotavirus) have been implicated most commonly.

Leukocytosis (both lymphocytic and granulocytic), thrombocytosis, eosinophilia, and an elevated ESR may be present. Urinalysis, tests for occult blood in the stool, immunoglobulin, and complement levels are usually normal or negative. Circulating immunocomplexes may occasionally be found. 282 Histopathologic examination of skin biopsy specimens demonstrates a small vessel leukocytoclastic vasculitis. Direct immunofl uorescence shows deposition of C3 and fi brinogen in the vessel wall. IgM, IgG, IgA, and IgE deposition has also been noted in up to one-third of cases. 282, [284] [285] [286] 

The differential diagnosis includes Henoch-Schönlein purpura, child abuse, meningococcemia and other infectious purpuras, erythema multiforme, Kawasaki disease, and Sweet syndrome. 273, 283 Distinction from Henoch-Schönlein purpura may be impossible 280 (Table 19 -2). Perivascular deposits of IgA are not useful for differentiation because they may be present in both entities.

The prognosis is excellent. The eruption resolves spontaneously without sequelae in 1-3 weeks. Treatment with corticosteroids is not necessary and may lead to complications and worsen the prognosis. 284 Exacerbations may be observed during the clinical evolution, with new crops of lesions and fever, 281,285 but true recurrences weeks or months after the fi rst episode are rare. 280, 283 There has been a single report of a fatal ileoileal intussusception in an infant with cutaneous lesions otherwise typical for AHE. 281 [287] [288] [289] [290] [291] [292] [293] [294] [295] The porphyrias are a group of diseases characterized by abnormalities of porphyrin-heme metabolism. Each type results from defi cient activity of one of the enzymes of the heme biosynthetic pathway, which leads to an accumulation of heme precursors within plasma, red blood cells, urine, and feces. 295 The genes for these enzymes have been characterized. 287, 289, 295 Porphyrias are mainly inherited in an autosomal dominant manner with incomplete penetrance, but autosomal recessive and more complex patterns of inheritance are also possible. Porphyrias are classifi ed as hepatic or erythropoietic, according to the organ site in which the underlying defect of heme synthesis is predominantly expressed (see Table 19 -3). Cutaneous manifestations in porphyrias may be classifi ed as acute photosensitivity with burning pain, edema, and erythema shortly after sun exposure, or delayed photosensitivity manifesting as skin fragility, subepidermal blisters, milia, disorders of pigmentation, and sclerodermoid signs. Hepatic porphyrias usually manifest acute neurovisceral attacks and delayed photosensitivity, and rarely present before puberty except from the homozygous variants. Elevated porphyrins may be detected in the stool or urine. Erythropoietic porphyrias are characterized by acute cutaneous photosensitivity from early childhood. The more delayed photosensitivity, although less characteristic of this type of porphyria, may be also present. 293 Erythrocyte and plasma porphyrin levels are elevated in erythropoietic porphyrias.

Photosensitivity in porphyrias is maximum for ultraviolet wavelengths between 400 and 410 nm ('Soret band'), the spectrum of maximum absorption of porphyrins.

The pathophysiologic mechanisms involved in the cutaneous manifestations of the porphyrias are multiple and involve the creation of reactive oxygen specimens. [296] [297] [298] Childhood porphyrias are relative uncommon and their exact incidence is unknown. Only those porphyrias manifesting early in infancy are reviewed here.

Congenital erythropoietic porphyria (CEP), also called Günther disease, is a rare autosomal recessive disorder caused by deficient activity of uroporphyrinogen III (UROGEN III) synthase which leads to nonenzymatic conversion of hydroxymethylbilane to uroporphyrinogen I, a nonphysiologic substrate that is converted to coproporphyrinogen I; these porphyrinogen I isomers are then oxidized to uroporphyrin I (URO-I) and coproporphyrin I (COPRO-I), which are phototoxic compounds. Elevated levels of URO-I and COPRO-I in erythrocytes result in massive hemolysis, and the released porphyrins accumulate in peripheral blood, skin, bone, and teeth and are excreted in large amounts in the urine and feces. 292, 299, 300 CEP presents with severe photosensitivity from birth or early infancy with formation of vesicles and bullae on areas exposed to sun, phototherapy devices, or even ambient lighting. 301 There is also marked skin fragility. As a result of the phototoxic injury and the increased skin fragility, there are severe mutilations, mainly of the fi ngers, hands, and face, particularly the nose and ears, but also in sun-protected areas. Hypertrichosis of the face and extremities, scarring alopecia of the scalp and eyebrows, and pigmentary changes (hyperpig- 

Histologic examination of skin biopsy specimens from blisters reveals subepidermal cleavage (within the lamina lucida) and minimal infl ammatory infi ltrate. Perivascular accumulation of PAS-positive, diastase-resistant, homogeneous hyaline material (porphyrins) may be seen, which is best viewed with fl uorescence microscopy. See Table 19 -3 for porphyrin excretion profi le. Measurement of URO III synthase activity is available. Prenatal diagnosis from amniotic fl uid is possible by either measurement of uroproporphyrin I or direct gene mutation analysis. [307] [308] [309] [310] 

Other photosensitivity diseases presenting early in life (Box 19-4) or diseases manifesting with blisters, such as epidermolysis bullosa and bullous pemphigoid, should be considered. Determination of porphyrins is diagnostic and allows differentiation from other porphyrias presenting early in life with photosensitivity.

The clinical severity of CEP is highly variable, ranging from hydrops fetalis, hepatosplenomegaly, and severe anemia in utero to adult-onset disease with only cutaneous manifestations. 311 In most cases, however, patients survive well into adulthood, albeit with severe mutilations or major disfi gurement. mentation and hypopigmentation) are also common. Over time, severe facial mutilation results, with destruction of nasal and auricular cartilages, ectropion, and eclabium, as well as shortening and contraction of the fi ngers. Milder phenotypes may have onset later in childhood. 302

The accumulation of porphyrins in deciduous and permanent teeth produces red discoloration (erythrodontia) and reddish fl uorescence on Wood's light examination, which is pathognomonic. The urine is also reddish, which causes pink discoloration of the diapers that fl uoresces -an early bed-side diagnostic sign. Porphyrins accumulate in the amniotic fl uid and brownish amniotic fl uid may be observed. Severe hemolytic anemia and secondary splenomegaly occur. Anemia may be so severe as to lead to hydrops fetalis and death in utero. Patients with late-onset disease may not develop hemolytic anemia but only thrombocytopenia and myelodysplasia. Ocular changes include ectropion, photophobia, and keratoconjunctivitis. 303 Other manifestations include osteodystrophy with increased bone fragility, and porphyrin-rich gallstones.

The gene for UROGEN III synthase is localized on chromosome 10. Several mutations have been identifi ed, 304 Protection from sun exposure is essential. Chemical sunscreens do not achieve good protection against Soret band radiation, so protective clothing and physical sunblocks are necessary. Long-wavelength, UV-absorbing fi lms are encouraged on car windows and windows at home. Children with the severe phenotypes and severe hemolysis benefi t from repeated erythrocyte transfusions and hydroxyurea to suppress erythropoiesis. Hematocrits should be maintained above 32%, with appropriate iron chelation. The effi cacy or repeated erythrocyte transfusion may decrease at puberty. Subsequent splenectomy is often needed to control hemolytic anemia. 313, 314 Activated charcoal, [315] [316] [317] [318] and β-carotene 319, 320 have been used, with inconsistent results. Bone marrow transplantation or stem cells from cord blood offer the possibility of correcting enzyme activity. [321] [322] [323] [324] [325] Replacement gene therapy has been accomplished in vitro. 326, 327 Erythropoietic Protoporphyria 287, 298, 328 Erythropoietic protoporphyria (EPP) is the most common form of cutaneous porphyria apart from porphyria cutanea tarda (PCT). EPP is caused by defi cient activity of ferrochelatase, leading to the accumulation of protoporphyrin in erythrocytes, plasma, and feces. Clinical symptoms typically begin in infancy or early childhood, with a peak incidence between 2 and 4 years of age. EPP is usually inherited as an autosomal dominant condition, but most individuals who are heterozygous for the inherited mutations are asymptomatic, because of halfnormal ferrochelatase activity 329 For protoporphyrin to accu-mulate suffi ciently to cause photosensitivity, a reduction of enzymatic activity to below a critical threshold of about 35% of normal is required. Some families may have autosomal recessive inheritance. [329] [330] [331] 

Clinical manifestations are those of an acute phototoxic reaction, which triggers an episode of crying within minutes of sunlight exposure due to burning pain or stinging sensations on exposed areas (the face and the dorsal aspect of hands). Some patients are photosensitive to fl uorescent lighting. 328 Erythema, edema, and urticarial lesions occur, but vesicles and bullae are rare (Fig. 19-22) . Fine petechiae may occur on sunexposed areas after prolonged exposure. Some patients have only subjective symptoms. 328 With chronic exposure there is characteristic thickening and wrinkling of the knuckle pads, furrowing around the mouth (pseudorhagades), and shallow elliptical scars on the nose, cheeks, and forehead. Hemolytic anemia is absent, but in some patients a mild hypochromic, microcytic anemia may occur. Protoporphyrinrich gallstones may develop in childhood. Fatal liver failure resulting from the progressive accumulation of protoporphyrin in hepatocytes is a possible outcome in about 2.5% of patients, altering the prognosis for an otherwise clinically benign disorder. Recessive inheritance may predispose to severe liver disease. 329 families. 329, 333 In most symptomatic patients inheritance of a second mutation is needed in order to reduce the enzymatic activity to a critical threshold where clinical symptoms are caused. Autosomal recessive inheritance has been demonstrated in 3% of patients with EPP. 329

Histopathologic examination of skin biopsy specimens of sunexposed areas shows marked concentric deposits of a hyaline material around dermal blood vessels. This material is PAS positive and diastase resistant. Patients with EPP should undergo frequent liver function tests, and those with persistent abnormalities should have a liver biopsy. Children with high erythrocyte protoporphyrins should have periodic determination of blood, urinary, and fecal porphyrins because increased excretion of copropophyrins, high erythrocyte protoporphyrins and reduced excretion of faecal protoporhyrins can predict liver failure. 334

The diagnosis of EPP is established by detecting elevated levels of protoporphyrin in erythrocytes, plasma, and feces. In addition, fecal and erythrocyte coproporphyrins may be increased. A rapid microfl uorometric assay for free erythrocyte protoporphyrins and examination of a blood smear for fl uorescent erythrocytes may also be used as screening tests. 335 The differential diagnosis includes other types of porphyria, but causes of immediate photosensitivity such as PMLE or solar urticaria do not occur in infants.

The mainstay of treatment for erythropoietic protoporphyria is sun avoidance and the use of physical sunscreens. 336, 337 Topical dihydroxyacetone may be helpful in some patients by producing brown pigment. 287 Oral administration of βcarotene (30-90 mg/day for children) has been shown in uncontrolled studies to increase tolerance to sun exposure because it quenches the formation of free radicals. 334, 338, 339 Narrowband ultraviolet B phototherapy has been proposed, as this wavelength does not cause photosensitivity. 340 Desensitization with PUVA therapy has also been used. Oral iron, intravenous hematin, transfusion therapy, and a highcarbohydrate diet have been used to prevent protoporphyrin accumulation in the liver by reducing protoporphyrin production, but their effi cacy is unproven. 334 Cholestyramine or activated charcoal have been used to interrupt the enterohepatic circulation of protoporphirins. 341 Avoidance of alcohol and drugs that interfere with hepatic excretory function is also essential. Liver transplantation has been performed in a few patients with liver failure, although the enzymatic defect is not thereby corrected and hence the long-term outcome is poor. [342] [343] [344] [345] Modifi cation of the lighting in the operating room is necessary to avoid photoxicity to exposed organs.

Hepatoerythropoietic porphyria (HEP) is an extremely rare disorder caused by a marked defi ciency of uroporphyrinogen decarboxylase due to a homozygous state. [346] [347] [348] [349] Clinical manifestations begin in infancy, or more commonly in early childhood, and resemble both porphyria cutanea tarda and Günter disease. The disease usually presents with darkening of the urine and delayed-type cutaneous photosensitivity, with vesicles, skin fragility, milia, and scarring. With time, hypertrichosis, sclerodermoid changes, and mutilation similar to the manifestations of Günter disease become apparent. Anemia, hepatosplenomegaly, and abnormalities of liver function of varying degrees may also occur, but are less common than in congenital erythropoietic porphyria. The porphyrin excr etion pattern resembles that of porphyria cutanea tarda (PCT), with elevated urinary uroporphyrins and 7-carboxylated porphyrins, and a smaller elevation of coproporphyrins, 6-and 5-carboxylated porphyrins. Increased isocoproporphyrins in feces are characteristic. Unlike in PCT, erythrocyte proto is increased.

Treatment is directed to sun protection. Hypertrichosis in hepatoerythropoietic porphyria has been treated successfully with high-intensity pulses of noncoherent light. 350

Other porphyrias with onset of symptoms in infancy or early childhood include homozygous variants of aminolevulinate dehydratase (ALAD) defi ciency, homozygous coproporphyria (harderoporphyria), homozygous variegate porphyria, and homozygous acute intermittent porphyria. 351 ALAD defi ciency porphyria is rare (fewer than 10 patients reported) and usually manifests later in childhood or adulthood, but neonatal onset has been reported. 352 Clinical manifestations from birth are recurrent attacks of pain, vomiting, hyponatremia, and symptoms of polyneuropathy affecting motor functions, including respiration. Raised levels of 5aminolevulinic acid and coproporphyrin in urine are found. Very low erythrocyte aminolevulinate dehydratase activity is diagnostic. Liver transplantation in patients with neonatal onset has little effect. 353 In harderoporphyria, neonatal jaundice, hemolytic anemia, and hepatosplenomegaly dominate the clinical picture. [354] [355] [356] [357] Blisters may occur during phototherapy for neonatal jaundice. Diagnosis depends on detecting very low coproporphyrinogen oxidase activity, elevated coproporphyrin in urine, markedly Homozygous variegate porphyria may present shortly after birth with marked photosensitivity or, more commonly, with erosions, blisters, and milia following minor trauma in sunexposed areas. [358] [359] [360] Acute attacks are absent, but mental and growth retardation, seizures, nystagmus, and clinodactyly have been described.

Homozygous variant of acute intermittent porphyria may present early in life with ataxia, mental retardation, convulsions, cataracts, and hepatosplenomegaly, but acute attacks typical of acute intermittent porphyria do not occur in these children. [361] [362] [363] [364] There are no cutaneous manifestations. Markedly increased porphobilinogen and ALAD in urine are found and are responsible for the orange urine. [365] [366] [367] [368] Transient increases in porphyrin levels have been described in neonates with hemolytic disease of the newborn and in a neonate with severe liver failure due to tyrosinemia type 1. 368 These infants develop erythema, violaceous discoloration, purpura, erosions, and blisters in areas exposed to phototherapy, with sharp demarcation at photoprotected sites. Sensitivity to sunlight may occur.

Elevated levels of plasma/urine porphyrins (mainly coproporphyrin) and/or erythrocyte protoporphyrin are found, which normalize spontaneously during the fi rst few months. The cause of transient porphyrinemia is unclear but is probably due to cholestasis. Other factors likely to be involved include blood transfusions and drug use.

Purpura in the neonate is almost always an emergency and should prompt an immediate search for an underlying disorder. Apart from trauma, purpura in the newborn may be due to coagulation defects, platelet abnormalities, or infections (see . Extramedullary erythropoiesis also causes purpuric lesions by a different mechanism.

In the evaluation of a neonate with purpura it is important to obtain a maternal and familial history of bleeding diathesis and thromboembolic phenomena, drug intake, and symptoms of infectious diseases. A general physical examination and workup for sepsis is warranted. Laboratory studies should include hemoglobin and hematocrit values, platelet count, white blood count, coagulation studies, and TORCH serologies.

Persistence of the erythropoietic activity of fetal dermal mesenchyme into the newborn period produces a characteristic purpuric eruption for which the term blueberry muffi n baby was coined. The eruption, fi rst observed in newborns with congenital rubella (Fig. 19-23) , may be the result of other intrauterine infections (Fig. 19-24 ) and hematologic dyscrasias. [369] [370] [371] A blueberry muffi n-like eruption may also represent metastatic infi ltration of the dermis by congenital malignancies, without true extramedullary erythropoiesis (Fig. 19-25 ).

The cutaneous lesions of blueberry muffi n babies consist of dark blue or magenta, nonblanchable, round to oval papules ranging in size from 1 to 7 mm and have a generalized distribution, with emphasis on the head, neck, and trunk ( Fig. 19-26 ). The papules are fi rm to palpation, with an infi ltrative quality that distinguishes them from petechiae and purpura, which often coexist in the same patient. These lesions evolve into dark purple to brown macules and involute spontaneously within 2-6 weeks. 273 Blueberry muffi n lesions caused by infi ltrative processes are usually larger, more nodular, less hemorrhagic, fewer in number, and fi rmer to palpation.

Accompanying abnormalities vary with the underlying cause.

In the prevaccination era rubella was the most common cause of dermal erythropoiesis, but now congenital cytomegalovirus (CMV) infection is the major cause. 369, 370 Dermal erythropoiesis has been associated with other intrauterine infections, such as Coxsackie B2 369 and parvovirus B19, 372 as well as hematologic dyscrasias such as Rh incompatibility (Fig. 19-24) , 373, 374 maternofetal ABO incompatibility, 369 spherocytosis, 375 and the twin transfusion syndrome 210, 216 (Box 19-6) . In rare instances it may occur in otherwise healthy newborns. 369, 376 

Histopathologic examination demonstrates poorly circumscribed collections of nucleated and nonnucleated red blood cells, predominantly confi ned to the reticular dermis and extending to the subcutaneous tissue. [369] [370] [371] Occasionally a few myeloid precursors may be interspersed.

Laboratory fi ndings depend on the underlying cause. In the evaluation of a blueberry muffi n baby the following tests are indicated: peripheral blood count, hemoglobin level, TORCH serologies, viral cultures, and a Coombs' test. Skin biopsy is not always necessary for diagnosis, but may be helpful if an infi ltrative process is suspected.

The differential diagnosis includes other causes of neonatal purpura, such as coagulation defects, platelet abnormalities, and infections. 273 Neoplastic diseases that produce infi ltrative metastases in the neonatal period, such as neuroblastomas, [377] [378] [379] rhabdomyosarcomas, 380 

The lesions of true dermal erythropoiesis fade and resolve spontaneously 3-6 weeks after birth. Treatment is directed at the underlying condition.

Neonatal purpura fulminans is a rare condition characterized by massive and progressive hemorrhagic necrosis of the skin accompanied by thrombosis of the cutaneous vasculature in the neonatal period. [386] [387] [388] [389] [390] [391] Occasionally larger vessels and other organs are involved. The primary pathologic event is widespread thrombosis, which is responsible for a hematologic picture of disseminated intravascular coagulation (DIC). In neonates, purpura fulminans is usually the result of inherited thrombophilic disorders that are attributable to protein C deficiency, protein S defi ciency, or resistance to activated protein C due to factor V mutations.

Neonatal purpura fulminans manifests 2-12 hours after birth. In rare instances, delayed onset of up to 6-10 months of age has been described. 392 Cutaneous lesions consist of extensive ecchymoses in a diffuse and often symmetric distribution that rapidly evolve into hemorrhagic bullae and purple-black necrotic skin lesions, which ultimately form a thick eschar ( Fig. 19-27 ). The initial ecchymotic areas are sharply defi ned from the surrounding skin and usually have a red, advancing infl ammatory rim. They are most common at sites of trauma or pressure, the buttocks, extremities, trunk, and scalp. Mucous membranes may rarely be involved. 393 If treatment is instituted in the fi rst 1-3 hours, before necrosis ensues, the initial lesions may be reversible. 390

Other organs may be affected by the microvascular thrombosis, most commonly the CNS and eye, but also the kidney and gastrointestinal tract. Cavernous sinus involvement, which may occur in utero, can result in hydrocephalus, seizures, intracerebral hemorrhage, and mental retardation. 388, 394, 395 Microphthalmia, cataracts, and blindness due to vitreous or retinal hemorrhage may be seen. 388, 389 Deep venous thrombosis and pulmonary embolism have also been described. 394 

Purpura fulminans in the neonatal period is almost always caused by inherited thrombophilic states such as homozygous protein C and S defi ciency or resistance to activated protein C. Severe bacterial infection associated with DIC can also induce purpura fulminans in the neonate, although it is more common in infancy or early childhood. 396, 397 Proteins C and S are vitamin K-dependent glycoproteins with antithrombotic properties. 398, 399 Protein C defi ciency is an autosomal dominant disease with incomplete penetrance. 399 Homozygous or compound heterozygous patients have a severe clinical phenotype and usually present with neonatal purpura fulminans, although they may be asymptomatic or present later in life with recurrent thrombosis. 400, 401 Protein S defi ciency is also transmitted as an autosomal dominant trait with incomplete penetrance. 399 Homozygous patients may develop neonatal purpura fulminans, although the risk is lower than in patients with homozygous protein C defi ciency. 387, 402 Neonatal purpura fulminans may also be caused by activated protein C resistance due to a mutation in the factor V gene. 393, 403 Resistance to activated protein C may coexist with protein S and protein C defi ciencies, becoming an additional genetic risk factor for purpura fulminans or thromboembolic complications, and explaining in part the incomplete clinical penetrance of inherited thrombophilic disorders. 404 

Blood coagulation studies demonstrate evidence of DIC, including prolonged prothrombin and partial thromboplastin times, increased fi brin split products, reduced fi brinogen, and reduced platelets. Microangiopathic hemolytic anemia may occur.

Biopsy of the early skin lesions demonstrates occlusion of dermal blood vessels by microthrombi. Hemorrhage and dermal necrosis are present in the more advanced stages. Necrosis of the overlying epidermis with subepidermal hemorrhagic bullae occurs in later phases. Secondary fi brinoid necrosis of dermal vessel walls may be present in the necrotic areas, but primary vasculitis is absent. 390, 405 A defi nitive diagnosis of protein C and S defi ciency is established by measurements of protein C and S levels. 399 Protein C defi ciencies can be identifi ed by immunoenzymatic assays measuring the actual concentration of the protein in plasma, and two functional assays measuring the enzymatic activity and the anticoagulant activity. These tests distinguish two types of protein C defi ciency. In type I, which is the most common, reduced synthesis of the normal protein leads to a low plasma concentration in all three assays. In type II, a qualitative defi ciency, levels are normal but functional assays are abnormal. For protein S defi ciency, functional and immunoenzymatic assays are available, and both the free form and the inactive form that circulates bound to C4b-binding protein have to be measured. 399 Type I defi ciency is characterized by low total and free protein S, type II by normal free protein S and low activity, and type III by low free protein levels with normal total levels.

Interpreting the results of the assays may be diffi cult because protein C and S levels are physiologically reduced in the neonatal period, and may be undetectable in sick newborns with liver disease, respiratory distress syndrome, DIC, or sepsis. 389, 390, 396, 397, 406 A complete sepsis workup is therefore recommended in any case of neonatal purpura fulminans. Serial determination of protein levels in patients and other family members is necessary to exclude a transient defi ciency and confi rm true congenital defi ciency.

The cutaneous lesions of purpura fulminans are very characteristic and rarely mistaken for any other condition. Other causes of purpuric eruptions in the newborn may be considered (see .

Without treatment, neonatal purpura fulminans is often fatal. If the diagnosis is suspected, therapy should be initiated immediately without waiting for the results of protein C and S measurements. Prompt treatment may completely reverse early skin lesions. Initial therapy consists of the administration of fresh frozen plasma (10-15 mL/kg/12 h) or prothrombin complex concentrate, sources of protein C, protein S, and activated protein C. 389,390 A protein C concentrate has been developed that has the advantage of avoiding blood volume overload and does not carry the risk of transmission of viral   FIG. 19-27 Neonatal purpura fulminans due to protein C defi ciency. ment therapy to avoid coumarin-induced skin necrosis. Experience with long-term treatment using protein C infusions is limited. There are few case reports of a successful liver transplant for homozygous protein C defi ciency. 409, 410 

This benign, transient purpura in transfused neonates who undergo phototherapy is characterized by raspberry-colored, nonblanching lesions at exposed sites, sparing sites that are protected from lights (e.g. leads and temperature probes). 206, 208 The eruption develops after 1-4 days of phototherapy and clears spontaneously after discontinuation of light therapy. Histologically there is extravasation of red blood cells in the dermis without epidermal damage. The pathogenesis of this disease is unknown, although transient porphyrinemia has been detected in some patients. 367, 411 The purpuric nature of the eruption and the absence of 'sunburn cells' differentiate this eruption from 'sunburn' caused by exposure to UVA from fl uorescent lamps. 412 Congenital erythropoietic porphyria and transient elevated porphyrin levels in neonates with hemolytic disease may also cause photosensitivity. 411 Drug-induced phototoxicity in neonates who have received photosensitizing chemicals such as fl uorescein dye, furosemide or methyleneblue must be considered. [413] [414] [415] [416] diseases. 407, 408 Protein S concentrate is not yet available for clinical use. Replacement therapy should be continued until all lesions have healed, usually after 4-8 weeks. Long-term treatment involves careful administration of oral anticoagulants, starting at very low doses and with protective replace-

The annular erythemas

Persistent' annular erythema of infancy

An annular erythema of infancy

Annular erythema of infancy

Annular erythema of infancy

Congenital annular erythema persisting in a 15-year-old girl

Persistent annular erythema of infancy

Erythema annulare centrifugum: report of a case with neonatal onset

Erythema gyratum atrophicans transiens neonatale

Erythema gyratum atrophicans transiens neonatale: a variant of cutaneous neonatal lupus erythematosus

Reactive erythemas: erythema annulare centrifugum and erythema gyratum repens

Erytheme annulaire centrifuge de Darier à debut neonatal avec 15 ans de suivi. Effi cacité de l'interféron et role de cytokines

Erythema annulare centrifugum coincident with Epstein-Barr virus infection in an infant

Erythema annulare centrifugum (Darier) in a newborn infant

Erythema gyratum perstans (Colcott Fox): a case report, with discussion on relations with erythema centrifugum annulare (Darier) and dermatitis herpetiformis

Érythème annulaire centrifuge type Colcott-Fox (erythema gyratum perstans)

Erythema gyratum repens

Erythema annulare centrifugum and intestinal Candida albicans infection -coincidence or connection?

Erythema annulare centrifugum due to candida albicans

Erythema annulare centrifugum associated with ascariasis

Erythema annulare centrifugum due to hydroxychloroquine sulfate and chloroquine sulfate

Erythema annulare centrifugum. A case due to hypersensitivity to blue cheese penicillium

Further amplifi cation of the concept of dermatophytid. I. Erythema annulare centrifugum as a dermatophytid

Annular erythema in identical twins

Familial annular erythema. An apparently new dominant mutation

Pityrosporum infection in an infant with lesions resembling erythema annulare centrifugum

Neonatal skin lesions due to a spirochetal infection: a case of congenital Lyme borreliosis?

Neonatal lupus erythematosus

Neonatal lupus: clinical features, therapy, and pathogenesis

Neonatal lupus erythematosus: clinical fi ndings and pathogenesis

Neonatal lupus erythematosus

Neonatal lupus erythematosus. A clinical, serological and immunogenetic study with review of the literature

Neonatal lupus: basic research and clinical perspectives

The clinical spectrum of anti-Ro-positive cutaneous neonatal lupus erythematosus

Cutaneous manifestations of neonatal lupus without heart block: Characteristics of mothers and children enrolled in a national registry

U1RNP positive neonatal lupus erythematosus: association with anti-La antibodies?

The neonatal lupus syndrome associated with U1RNP (nRNP) antibodies

Congenital lupus erythematosus: case report and review of the literature

Neonatal lupus erythematosus

Neonatal lupus erythematosus: a review of the racial differences and similarities in clinical, serological and immunogenetic features of Japanese versus Caucasian patients

Lupus erythematosus profundus associated with neonatal lupus erythematosus

Neonatal lupus erythematosus: an unusual congenital presentation with cutaneous atrophy, erosions, alopecia, and pancytopenia

Ultraviolet light exposure is not a requirement for the development of cutaneous neonatal lupus

Neonatal lupus erythematosus presenting as papules on the feet

Cutaneous telangiectases in neonatal lupus erythematosus

Neonatal lupus and IUGR following alphainterferon therapy during pregnancy

Postnatal progression from second-to thirddegree heart block in neonatal lupus syndrome

Hepatobiliary disease in neonatal lupus: prevalence and clinical characteristics in cases enrolled in a national registry

Incidence and spectrum of neonatal lupus erythematosus: a prospective study of infants born to mothers with anti-Ro autoantibodies

Neonatal lupus erythematosus mimicking Langerhans' cell histiocytosis

Neonatal lupus manifests as isolated neutropenia and mildly abnormal liver functions

Thrombocytopenia in the neonatal lupus syndrome

Neonatal lupus erythematosus with persistent telangiectasia and spastic paraparesis

Neonatal lupus erythematosus simulating transient myasthenia gravis at presentation

Neonatal thrombosis with anticardiolipin antibody in baby and mother

Central nervous system involvement in neonatal lupus erythematosus

The health of mothers of children with cutaneous neonatal lupus erythematosus differs from that of mothers of children with congenital heart block

Long-term outcome of mothers of children with isolated heart block in Finland

Isolated congenital complete heart block: longterm outcome of mothers, maternal antibody specifi city and immunogenetic background

Maternal and fetal outcome in neonatal lupus erythematosus

Neonatal lupus: long-term outcomes of mothers and children and recurrence rate

Long-term outcome of mothers of children with complete congenital heart block

Anti-Ro/SSA antibodies and congenital heart block: necessary but not suffi cient

Anti-52 kDa Ro, anti-60 kDa Ro, and anti-La antibody profi les in neonatal lupus

Autoantibody response to the Ro/La particle may predict outcome in neonatal lupus erythematosus

Maternal and sibling microchimerism in twins and triplets discordant for neonatal lupus syndrome-congenital heart block

Anti-SSA/Ro antibodies and the heart: more than complete congenital heart block? A review of electrocardiographic and myocardial abnormalities and of treatment options

Endocardial fi broelastosis associated with maternal anti-Ro and anti-La antibodies in the absence of atrioventricular block

Cardiac immunoglobulin deposition in congenital heart block associated with maternal anti-Ro autoantibodies

Is isolated congenital heart block associated to neonatal lupus requiring pacemaker a distinct cardiac syndrome?

Outcome of pregnancies in patients with anti-SSA/ Ro antibodies: a study of 165

with special focus on electrocardiographic variations in the children and comparison with a control group

Delayed dilated cardiomyopathy as a manifestation of neonatal lupus: case reports, autoantibody analysis, and management

Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela

Congenital complete heart block in the fetus: hemodynamic features, antenatal treatment, and outcome in six cases

Comparison of treatment with fl uorinated glucocorticoids to the natural history of autoantibodyassociated congenital heart block: retrospective review of the research registry for neonatal lupus

Successful preventive treatment of congenital heart block during pregnancy in a woman with systemic lupus erythematosus and anti-Sjögren's syndrome A/Ro antibody

Intrauterine therapy for presumptive fetal myocarditis with acquired heart block due to systemic lupus erythematosus. Experience in a mother with a predominance of SS-B (La) antibodies

Neonatal lupus erythematosus: dissolution of atrioventricular block after administration of corticosteroid to the pregnant mother

Long-term followup of children with neonatal lupus and their unaffected siblings

Neonatal lupus: review of proposed pathogenesis and clinical data from the US-based Research Registry for Neonatal Lupus

Hypersensitivity reactions in neonates and infants

Cutaneous drug reactions: pathogenesis and clinical classifi cation

Réactions cutanées aux médicaments chez l'enfant

Drug eruptions in children

Serious dermatologic reactions in children

Adverse drug reactions in general pediatric outpatients

Clinical pattern of cutaneous drug eruption among children and adolescents in north India

Petechial eruption after the application of EMLA cream

Use of EMLA cream in a department of neonatology

Vancomycin-associated shock and rash in newborn infants

Adverse reactions to vancomycin used as prophylaxis for CSF shunt procedures

Clinical pharmacology and effi cacy of vancomycin in pediatric patients

Erythema multiforme major in a 2-month-old child with human immunodefi ciency virus (HIV) infection

Cutaneous manifestations of pediatric HIV infection

Life-threatening reaction to trimethoprim/ sulfamethoxazole in pediatric human immunodefi ciency virus infection

Fixed drug eruption of the scrotum due to hydroxyzine hydrochloride (Atarax)

Adverse skin and joint reactions associated with oral antibiotics in children: The role of cefaclor in serum sickness-like reactions

Cefaclorassociated serum sickness-like disease: eight cases and review of the literature

Serum sickness-like reactions from cefaclor in children

Drug-induced hypersensitivity syndrome in pediatric patients

Antiepileptic hypersensitivity syndrome in children

Druginduced hypersensitivity syndrome in a premature infant

Fatal anticonvulsant hypersensitivity syndrome in an infant

Toxic epidermal necrolysis in a premature infant of 27 weeks' gestational age

Vegetant bromoderma in an infant

A cutaneous eruption from G-CSF in a healthy donor

Drug reaction to ursodeoxycholic acid: lichenoid drug eruption in an infant using ursodeoxycholic acid for neonatal hepatitis

Acute annular urticaria in infants and children

Prognosis of acute urticaria in children

The etiology of different forms of urticaria in childhood

Acute urticaria in infancy and early childhood: a prospective study

Urticaria: reassessed

Urticaria in children

Urticaria in infants: a study of forty patients

Urticaria in children. Retrospective evaluation and follow-up

Neonatal urticaria due to prostaglandin E1

Les urticaires chroniques de l'enfant

Cow's milk allergy in infancy

L'urticaire alimentaire de l'enfant. Revue de 51 observations

Diffuse dermographic mastocytosis without visible skin lesions

The spectrum of acquired and familial cold-induced urticaria/urticaria-like syndromes

Familial cold urticaria

Familial cold urticaria. A generalized reaction involving leukocytosis

Familial cold urticaria. Clinical fi ndings

Familial cold urticaria. Investigation of a family and response to stanozolol

Muckle-Wells syndrome: clinical and histological skin fi ndings compatible with cold air urticaria in a large kindred

New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes

Inherited autoinfl ammatory recurrent fevers

Familial dermographism

Atypical diffuse cutaneous mastocytosis

Dermo-distortive urticaria: an autosomal dominant dermatologic disorder

Vibratory angioedema: a hereditary type of physical hypersensitivity

Familial aquagenic urticaria and Bernard-Soulier syndrome

Familial aquagenic urticaria

Familial localized heat urticaria of delayed type

Neonatal-onset multisystem infl ammatory disorder: the emerging role of pyrin genes in autoinfl ammatory diseases

The expanding spectrum of systemic autoinfl ammatory disorders and their rheumatic manifestations

A recently recognised chronic infl ammatory disease of early onset characterised by the triad of rash, central nervous system involvement and arthropathy

Neonatal onset multisystem infl ammatory disease

NOMID -a neonatal syndrome of multisystem infl ammation

Chronic infantile neurological cutaneous and articular/neonatal onset multisystem infl ammatory disease syndrome: ocular manifestations in a recently recognized chronic infl ammatory disease of childhood

Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes

Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cellmediated autoinfl ammatory disorders CINCA/NOMID, MWS, and FCU

Chronic infantile neurological cutaneous articular syndrome in a patient from Japan

Neonatal onset multisystem infl ammatory disease

The clinical course of a child with CINCA/NOMID syndrome improved during and after treatment with thalidomide

Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra

Neonatal-onset multisystem infl ammatory disease (NOMID) due to a novel S331R mutation of the CIAS1 gene and response to interleukin-1 receptor antagonist treatment

Interleukin-1 blockade by anakinra improves clinical symptoms in patients with neonatal-onset multisystem infl ammatory disease

Anakinra therapy for CINCA syndrome with a novel mutation in exon 4 of the CIAS1 gene

Etanercept induces improvement of arthropathy in chronic infantile neurological cutaneous articular (CINCA) syndrome

Erythema multiforme minor in children

Erythema multiforme in childhood and early infancy

Erythema multiforme: a review of its characteristics, diagnostic criteria, and management

Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme

Clinical classifi cation of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme

Erythema multiforme as a single manifestation of cow's milk intolerance

Neonatal erythema multiforme major

Erythema multiforme in a 9-day-old neonate

Erythema multiforme in a neonate

Erythema multiforme in children: unusual clinical features with seasonal occurrence

Herpes simplex virus in childhood erythema multiforme

Erythema multiforme minor following vaccination with paediatric vaccines

Controversy: are systemic steroids indicated in the treatment of erythema multiforme?

Use of steroids for erythema multiforme in children

A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme

Stevens-Johnson syndrome developing in a girl with systemic lupus erythematosus on high-dose corticosteroid therapy

Corticosteroid treatment of erythema multiforme major (Stevens-Johnson syndrome) in children

Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids

Sweet's syndrome revisited: a review of disease concepts

Neutrophilic dermatoses

Sweet's syndrome

Sweet's syndrome (acute febrile neutrophilic dermatosis)

Sweet's syndrome: a clinicopathologic review of twenty-nine cases

Sweet syndrome in a neonate with aseptic meningitis

Multiple erythematous tender papules and nodules in an 11-month-old boy. Sweet syndrome (SS) (acute febrile neutrophilic dermatosis)

The Sweet syndrome in children

Sweet's syndrome in an infant -report of a rare case

Sweet syndrome as the presenting manifestation of chronic granulomatous disease in an infant

Sweet's syndrome as an initial manifestation of pediatric human immunodefi ciency virus infection

Acute febrile neutrophilic dermatosis in childhood (Sweet's syndrome)

Pediatric Sweet syndrome and immunodefi ciency successfully treated with intravenous immunoglobulin

Acute febrile neutrophilic dermatosis in children

Sweet's syndrome in infancy

Persistent Sweet's syndrome occurring in a child with a primary immunodefi ciency

Familial Sweet's syndrome in 2 brothers, both seen in the fi rst 2 weeks of life

Acute febrile neutrophilic dermatosis (Sweet's syndrome). Four case reports

Sweet's syndrome with arthritis in an 8-month-old boy

Sweet's syndrome leading to acquired cutis laxa (Marshall's syndrome) in an infant with alpha 1-antitrypsin defi ciency

Sweet's syndrome with neurologic manifestation: case report and literature review

Sweet's syndrome and cancer

Trimethoprimsulfamethoxazole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet's syndrome

Sweet syndrome associated with furosemide

Drug-induced Sweet's syndrome in acne caused by different tetracyclines: case report and review of the literature

Sweet's syndrome associated with granulocyte colony-stimulating factor

Acute febrile neutrophilic dermatosis (Sweet's syndrome) after infl uenza vaccination

Sweet's syndrome: a review of current treatment options

Sweet's syndrome: a report on the use of potassium iodide

Colchicine in the treatment of acute febrile neutrophilic dermatosis (Sweet's syndrome)

Acute febrile neutrophilic dermatosis (Sweet's syndrome). Response to dapsone

A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan

Kawasaki syndrome

Kawasaki disease

Kawasaki disease: recent advances

Kawasaki disease in infants less than one year of age

Clinical spectrum of Kawasaki disease in infants younger than 6 months of age

Classical Kawasaki disease in a neonate

Lethal vasculitis of coronary arteries in a neonate and two infants: possible neonatal variant of the MLNS/IPN complex?

Myocarditis and coronary dilatation in the 1st week of life: neonatal incomplete Kawasaki disease?

Kawasaki disease: what is the epidemiology telling us about the etiology?

Kawasaki syndrome in the United States 1976 to 1980

Incidence survey of Kawasaki disease in 1997 and 1998 in Japan

Results of the nationwide epidemiologic survey of Kawasaki disease in 1995 and 1996 in Japan

Kawasaki disease in families

Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young

The perineal eruption of Kawasaki syndrome

Psoriatic eruption in Kawasaki disease

Development of psoriatic lesions during acute and convalescent phases of Kawasaki disease

Guttate psoriasis following Kawasaki disease

Annular pustules in Kawasaki disease: a further case indicating the association with psoriasis?

Peripheral gangrene associated with Kawasaki disease

Kawasaki disease characterized by erythema and induration at the Bacillus Calmette-Guérin and purifi ed protein derivate inoculation sites

Skin complications of Bacillus Calmette-Guérin immunization

BCG reactivation: a useful diagnostic tool even for incomplete Kawasaki disease

Infl ammation at a previous inoculation site: an unusual presentation of Kawasaki disease

Diagnosis and therapy of Kawasaki disease in children

Kawasaki disease: more patients are being diagnosed who do not meet American Heart Association criteria

Infl ammatory pulmonary nodules in Kawasaki disease

Acute respiratory distress syndrome in a child with Kawasaki disease

Hemophagocytic syndrome after Kawasaki disease

Sensorineural hearing loss and Kawasaki disease: A prospective study

Pathogenesis and treatment of Kawasaki's disease

Kawasaki disease: infection, immunity and genetics

Kawasaki disease: what is the epidemiology telling us about the etiology?

Development of coronary artery lesions in Kawasaki disease patients in relation to plasma interferon-gamma and interleukin-4 levels in the acute phase

Circulating soluble CD23 levels in Kawasaki disease with coronary artery lesions

High levels of circulating interleukin-4 and interleukin-10 in Kawasaki disease

Immunopathology and cytokine detection in the skin lesions of patients with Kawasaki disease

Circulating soluble L-selectin levels in Kawasaki disease with coronary artery lesions

Genetic variations in the receptor-ligand pair CCR5 and CCL3L1 are important determinants of susceptibility to Kawasaki disease

Kawasaki disease in siblings

Familial occurrence of Kawasaki syndrome in North America

Clinical features of patients with Kawasaki disease whose parents had the same disease

Serum cholesterol levels during and after Kawasaki disease

Altered lipid profi le after Kawasaki syndrome

Diagnosing Kawasaki syndrome: the need for a new clinical tool

Diagnosis, treatment and outcome of Kawasaki disease in an Australian tertiary setting: a review of three years experience

National survey of coronary artery bypass grafting for coronary stenosis caused by Kawasaki disease in Japan

Mortality among persons with a history of Kawasaki disease in Japan: can paediatricians safely discontinue follow-up of children with a history of the disease but without cardiac sequelae?

Mortality among persons with a history of Kawasaki disease in Japan: the fi fth look

Longterm outcomes in patients with giant aneurysms secondary to Kawasaki disease

Long-term consequences of Kawasaki disease. A 10-to 21-year follow-up study of 594 patients

Report from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young

Mortality among persons with a history of Kawasaki disease in Japan: existence of cardiac sequelae elevated the mortality

Use of laboratory data to identify risk factors of giant coronary aneurysms due to Kawasaki disease

Intravenous gammaglobulin treatment in Kawasaki disease

Coronary artery dimensions may be misclassifi ed as normal in Kawasaki disease

Prevalence of coronary artery abnormalities in

Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose

The prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the effi cacy of aspirin and immunoglobulin treatment

The treatment of Kawasaki syndrome with intravenous gamma globulin

High-dose intravenous gammaglobulin for Kawasaki disease

Evaluation of the effi cacy of treatment of Kawasaki disease before day 5 of illness

Early intravenous gamma-globulin treatment for Kawasaki disease: The nationwide surveys in Japan

Late intravenous gamma globulin treatment in infants and children with Kawasaki disease and coronary artery abnormalities

Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research

Corticosteroids in the initial treatment of Kawasaki disease: Report of a randomized trial

Effect of corticosteroids in addition to intravenous gamma globulin therapy on serum cytokine levels in the acute phase of Kawasaki disease in children

Pentoxifylline and intravenous gamma globulin combination therapy for acute Kawasaki disease

Infl iximab treatment for refractory Kawasaki syndrome

Purpura in infants and children

Report of eight infants with acute infantile hemorrhagic edema and review of the literature

Seidlmayer's syndrome: postinfectious cockade purpura of early childhood

Neonatal acute hemorrhagic edema of childhood: case report and review of the English-language literature

Acute hemorrhagic edema of childhood present at birth

Acute hemorrhagic edema of childhood (AHE)

Infantile acute hemorrhagic edema: a variant of leukocytoclastic vasculitis

Infantile acute hemorrhagic edema of the skin: study of ten cases

Oedème aigu hémorragique du nourrisson avec complication léthale digestive

Acute hemorrhagic edema of infancy (AHEI) -a variant of Henoch-Schonlein purpura or a distinct clinical entity?

Acute hemorrhagic edema of childhood: an unusual variant of leukocytoclastic vasculitis

Henoch-Schonlein purpura in infants

Cedeme aigu hémorragique du nourrisson. Données immunologiques et ultrastructurales

Infantile acute hemorrhagic edema of the skin

Childhood porphyrias

Erythropoietic and hepatic porphyrias

Porphyrias in children

Porphyria update

The cutaneous porphyrias

Porphyria in childhood

The cutaneous porphyrias: a review. British Photodermatology Group

Update on enzyme and molecular defects in porphyria

Pathogenesis of photosensitivity in the cutaneous porphyrias

Molecular and cellular mechanisms of porphyrin photosensitization

Clinical features of the porphyrias

The porphyrias

Congenital erythropoietic porphyria

Congenital erythropoietic porphyria: clinical, biochemical, and enzymatic profi le of a severely affected infant

Two brothers with mild congenital erythropoietic porphyria due to a novel genotype

Congenital porphyria with necrotizing scleritis in a 9-year-old child

A systematic analysis of the mutations of the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria

Congenital erythropoietic porphyria: advances in pathogenesis and treatment

Molecular basis of congenital erythropoietic porphyria: mutations in the human uroporphyrinogen III synthase gene

Brown amniotic fl uid in congenital erythropoietic porphyria

The prenatal presentation of congenital erythropoietic porphyria: report of two siblings with elevated maternal serum alpha-fetoprotein

Congenital erythropoietic porphyria: prenatal diagnosis and autopsy fi ndings in two sibling fetuses

Prenatal diagnosis in congenital erythropoietic porphyria by metabolic measurement and DNA mutation analysis

Late onset erythropoietic porphyria

Congenital erythropoietic porphyria: dilemmas in present day management

Hydroxyurea in congenital erythropoietic porphyria

Complete suppression of the symptoms of congenital erythropoietic porphyria by long-term treatment with high-level transfusions

Porphyrins in urine, plasma, erythrocytes, bile and faeces in a case of congenital erythropoietic porphyria (Gunther's disease) treated with blood transfusion and iron chelation: lack of benefi t from oral charcoal

Lack of effect of oral charcoal in congenital erythropoietic porphyria

The effect of oral activated charcoal on the course of congenital erythropoietic porphyria

Therapeutic effi cacy of oral charcoal in congenital erythropoietic porphyria

Porphyrie erythropoietique congenitale de Gunther et carotenoides. Essai therapeutique de 4 ans

Treatment of photosensitivity in congenital erythropoietic porphyria (CEP) with beta-carotene

Congenital erythropoietic porphyria successfully treated by allogeneic bone marrow transplantation

Correction of congenital erythropoietic porphyria by bone marrow transplantation

Treatment of congenital erythropoietic porphyria in children by allogeneic stem cell transplantation: a case report and review of the literature

Treatment of severe congenital erythropoietic porphyria by bone marrow transplantation

Successful match-unrelated donor bone marrow transplantation for congenital erythropoietic porphyria (Gunther disease)

Lentivirus-mediated gene transfer of uroporphyrinogen III synthase fully corrects the porphyric phenotype in human cells

Congenital erythropoietic porphyria: prolonged high-level expression and correction of the heme biosynthetic defect by retroviralmediated gene transfer into porphyric and erythroid cells

Erythropoietic protoporphyria. 10 years experience

Autosomal recessive erythropoietic protoporphyria in the United Kingdom: prevalence and relationship to liver disease

Ferrochelatase activities in patients with erythropoietic protoporphyria and their families

Genetic heterogeneity in erythropoietic protoporphyria: a study of the enzymatic defect in nine affected families

Recessive inheritance of erythropoietic protoporphyria with liver failure

Erythropoietic protoporphyria: identifi cation of novel mutations in the ferrochelatase gene and comparison of biochemical markers versus molecular analysis as diagnostic strategies

Diagnosis and management of the erythropoietic porphyrias

Rapid quantitative assay for erythrocyte porphyrins

The treatment of erythropoietic protoporphyria

Therapeutic options for erythropoietic protoporphyria

Beta carotene treatment and erythrocytic protoporphyrin levels

Erythropoietic protoporphyria: treatment with antioxidants and potential cure with gene therapy

Erythropoietic protoporphyria treated with narrowband (TL-01) UVB phototherapy

Liver failure in protoporphyria: long-term treatment with oral charcoal

Liver transplantation for erythropoietic protoporphyria: report of a case with medium-term follow-up

Liver transplantation for erythropoietic protoporphyria liver disease

Long-term follow-up after liver transplantation for erythropoietic protoporphyria

Roles and pitfalls of transplantation in human porphyria

Hepatoerythropoietic porphyria: a new uroporphyrinogen decarboxylase defect or homozygous porphyria cutanea tarda?

Hepatoerythropoietic porphyria: a variant of childhood-onset porphyria cutanea tarda. Porphyrin profi les and enzymatic studies of two cases in a family

Porphyrie hepato-erythroctaire, une nouvelle forme de porphyrie

Hepatoerythropoietic porphyria: clinical, biochemical, and enzymatic studies in a three-generation family lineage

Successful and safe treatment of hypertrichosis by high-intensity pulses of noncoherent light in a patient with hepatoerythropoietic porphyria

Hepatic porphyrias in children

Aminolaevulinate dehydratase porphyria in infancy. A clinical and biochemical study

Liver transplantation in a boy with acute porphyria due to aminolaevulinate dehydratase defi ciency

Structural basis of hereditary coproporphyria

Characterization of mutations in the CPO gene in British patients demonstrates absence of genotypephenotype correlation and identifi es relationship between hereditary coproporphyria and harderoporphyria

A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria

Harderoporphyria: a variant hereditary coproporphyria

Homozygous variegate porphyria: a compound heterozygote with novel mutations in the protoporphyrinogen oxidase gene

Homozygous variegate porphyria: 20 year follow-up and characterization of molecular defect

Molecular characterization of homozygous variegate porphyria

A retrospective study of a patient with homozygous form of acute intermittent porphyria

Identifi cation of the mutations in the parents of a patient with a putative compound heterozygosity for acute intermittent porphyria

Homozygous acute intermittent porphyria: compound heterozygosity for adjacent base transitions in the same codon of the porphobilinogen deaminase gene

Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias

Skin signs of systemic disease: an update

Neonatal bullous eruption as a result of transient porphyrinemia in a premature infant with hemolytic disease of the newborn

Purpuric phototherapy-induced eruption in transfused neonates: relation to transient porphyrinemia

Cutaneous porphyria in a neonate with tyrosinaemia type 1

Dermal hematopoiesis in neonates: report of fi ve cases

Dermal erythropoiesis in neonatal infants: a manifestation of intrauterine viral disease

Dermal erythropoiesis in congenital rubella. Description of an infected newborn who had purpura associated with marked extramedullary erythropoiesis in the skin and elsewhere

Anemia, blueberry-muffi n rash, and hepatomegaly in a newborn infant

Dermal erythropoiesis in Rh hemolytic disease of the newborn

Neonatal dermal erythropoiesis associated with severe rhesus immunization: amelioration by highdose intravenous immunoglobulin

Dermal erythropoiesis in a neonate

Blueberry muffi n syndrome: cutaneous erythropoiesis and possible intrauterine viral infection

Blanching subcutaneous nodules in neonatal neuroblastoma

Blueberry muffi n baby: neonatal neuroblastoma with subcutaneous metastases

Cutaneous metastases in neuroblastoma

Congenital alveolar rhabdomyosarcoma presenting as a blueberry muffi n baby

Transient blueberry muffi n appearance of a newborn with congenital monoblastic leukemia

Acute myelomonocytic leukemia with skin localizations

Analysis and review of the world literature with report of an additional case

Blueberry muffi n baby': hematopoiese extramedullaire neonatale? Leucemie monoblastique congenitale involutive? Ou histiocytose congenitale involutive?

Histiocytoses langerhansiennes congenitales cutanees. A propos de 7 cas

Purpura fulminans. A cutaneous manifestation of severe protein C defi ciency

Homozygous protein S defi ciency in an infant with purpura fulminans

Neonatal purpura fulminans: a genetic disorder related to the absence of protein C in blood

Report of the Working Party on Homozygous Protein C Defi ciency of the Subcommittee on Protein C and Protein S, International Committee on Thrombosis and Haemostasis

Neonatal purpura fulminans due to homozygous protein C or protein S defi ciencies

Purpura fulminans in a newborn baby

Homozygous protein C defi ciency with delayed onset of symptoms at 7 to 10 months

Neonatal purpura fulminans in association with factor V R506Q mutation

Homozygous protein C defi ciency manifested by massive venous thrombosis in the newborn

Severe homozygous protein C defi ciency

Severe acquired neonatal purpura fulminans

Causes of purpura fulminans

Protein C pathway in infants and children

Protein C and protein S defi ciencies

Late-onset homozygous protein C defi ciency

Asymptomatic homozygous protein C defi ciency

Homozygous protein S defi ciency due to a one base pair deletion that leads to a stop codon in exon III of the protein S gene

The discovery of activated protein C resistance

Blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseases

Dermatopathology of skin necrosis associated with purpura fulminans

Neonatal purpura fulminans and transient protein C defi ciency

Homozygous protein C defi ciency -management with protein C concentrate

Replacement therapy with a monoclonal antibody purifi ed protein C concentrate in newborns with severe congenital protein C defi ciency

En bloc heterotopic auxiliary liver and bilateral renal transplant in a patient with homozygous protein C defi ciency

Successful treatment of homozygous protein C defi ciency by hepatic transplantation

Transient erythroporphyria of infancy

Ultraviolet light burn: a cutaneous complication of visible light phototherapy of neonatal jaundice

Methylene-blue-induced hyperbilirubinemia and phototoxicity in a neonate

Methylene blue-induced phototoxicity: an unrecognized complication

Fluorescein phototoxicity in a premature infant

Phototoxic blisters from high frusemide dosage