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Acta Dermatovenerol Croat 2007;15(3):178-190 REVIEW

Differential Diagnosis of Neonatal and Infantile

Lena Kotrulja1, Slobodna Murat-Sušić2, Karmela Husar2

1University Department of and Venereology, Sestre milosrdnice University Hospital; 2University Department of Dermatology and Venereology, Zagreb University Hospital Center and School of Medicine, Zagreb, Croatia

Corresponding author: Summary Neonatal and infantile erythroderma is a diagnostic and Lena Kotrulja, MD, MS therapeutic challenge. Numerous underlying causes have been reported. Etiologic diagnosis of erythroderma is frequently difficult to University Department of Dermatology establish, and is usually delayed, due to the poor specificity of clinical and Venereology and histopathologic signs. Differential diagnosis of erythroderma is Sestre milosrdnice University Hospital a multi-step procedure that involves clinical assessment, knowledge of any relevant family history and certain laboratory investigations. Vinogradska 29 Immunodeficiency must be inspected in cases of severe erythroderma HR-10000 Zagreb with alopecia, , infectious complications, or evocative Croatia histologic findings. The prognosis is poor with a high mortality rate [email protected] in immunodeficiency disorders and severe chronic diseases such as Netherton’s syndrome.

Received: June 14, 2007 Key words: erythroderma, neonatal, infantile, generalized Accepted: July 11, 2007 exfoliative

Introduction Erythroderma is defined as an inflammatory Neonatal and infantile erythroderma is a diag- skin disorder affecting total or near total body sur- nostic and therapeutic challenge. Erythrodermic face with and/or moderate to extensive neonates and infants are frequently misdiagnosed scaling (1). It is a reaction pattern of the skin that with eczema and inappropriate topical steroid can complicate many underlying skin conditions at treatment can lead to Cushing syndrome. Delay any age. In neonatal period it can be the primary in the establishment of the correct diagnosis can manifestation of numerous conditions (2). How- be fatal. Differential diagnosis of erythroderma is a ever, some disorders in infants may initially be lo- multi-step procedure that involves clinical assess- calized and then eventually develop into extensive ment, knowledge of any relevant family history, erythroderma (1). Differential diagnosis includes and certain laboratory investigations (2). benign transient, inflammatory, infectious, meta- bolic and immune diseases, many of which have a hereditary basis. Some of these diseases are Laboratory investigations potentially life threatening, and erythroderma itself Differential diagnosis of erythroderma can can cause serious medical complications such as be facilitated by some laboratory tests (Table 1). electrolyte imbalance, hypoproteinemia, dehydra- Serum IgE levels are profoundly increased in tion, sepsis, and temperature instability (3). Netherton’s and Omenn’s syndromes, and mild-

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Kotrulja et al. Acta Dermatovenerol Croat Neonatal and infantile erythroderma 2007;15(3):178-190

and other ichthyoses. Fibroblast culture from bi- Table 1. Laboratory investigations in neonatal and opsy can help reach definitive diagnosis of several infantile erythroderma metabolic diseases (3). Non-bullous and bullous 1. Potassium hydroxide (KOH) stain for demon- ichthyosiform erythroderma are distinguishable stration of mycelia/spores and fungal culture on histology (4). In the graft-versus-host reaction, 2. Gram’s stain for bacteria and bacterial culture histology is valuable in severe cases, but in milder 3. Tzanck test cases only some of the findings may be present and the diagnosis can easily be missed. In - 4. Demonstration of Sarcoptes scabiei ing diseases, it is helpful to take biopsy from the 5. Microscopic analysis of hair shaft abnormali- border of the blister, including its roof, to facilitate ties assessment of the level of cleavage (2). 6. Complete hemogram It is helpful to divide the subject of neonatal 7. Skin biopsy for microscopic pathology erythroderma into several categories, roughly ac- 8. Serum and levels cording to pathogenesis (Table 2). 9. Sweat chloride levels 10. Lipid profile including lev- Table 2. Causes of neonatal and infantile eryth- els roderma 11. Evaluation of humoral and cellular immunity; Transient neonatal dermatoses IgA, IgG, IgM, IgE, complement component, T Erythema toxicum neonatorum and B lymphocytes 12. Biotinidase/holocarboxylase synthetase levels Cutaneous disorders 13. Plasma amino acid levels and urine organic acids Infantile seborrheic dermatitis ly increased in early atopic eczema. Appropriate Diffuse cutaneous mastocytosis smears for potassium hydroxide (KOH) stain, Gram stain, Tzanck test as well as cultures for fungal, bacterial, or viral diseases should be per- Netherton’s syndrome formed if infection is suspected. Chest radiograph Infections may be useful to evaluate thymic shadow, which Staphylococcal scalded skin syndrome (SSSS) may be absent in neonates with severe combined immunodeficiency (SCID) (3). Serum electrolyte Congenital and neonatal and albumin concentrations should be measured Congenital infection because children with erythroderma are at a risk of hypernatremic dehydration as well as enteral Toxic and drug reactions and transcutaneous protein losses. Complete Toxic epidermal necrolysis blood count should be supplemented by more de- tailed immunologic studies if Omenn’s syndrome Drug reactions or graft-versus-host disease is suspected (2). Metabolic disorders Serum amino and urine organic acids should be Acrodermatitis enteropathica determined if primary metabolic diseases such as Cystic fibrosis aminoaciduria or are suspected. Biotinidase level can be obtained if biotin deficien- Essential fatty acid deficiency cy is suspected (3). Amino acid disorders Disorders of biotin metabolism Histology Immune disorders As it is very important to establish the diag- Graft versus host disease (GVHD) nosis rapidly, it is advisable to take two or three Severe combined immunodeficiency (SCID) simultaneous skin biopsies from different sites. Omenn’s syndrome Histology and immunohistochemistry can dif- ferentiate Omenn’s from Netherton’s syndrome Hypogammaglobulinemia

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Transient neonatal dermatoses Erythema toxicum neonatorum (ETN) is the most common transient benign in healthy ne- onates. The incidence is controversial, and ranges from 30% to 70% in various surveys. The cause of ETN has not yet been established (5). The pres- ence of ETN correlates well with birth weight and gestational age. It is virtually never seen in pre- mature infants or those weighing less than 2500 g (6). Congenital lesions may occur, but the majority of cases have the onset between 24 and 48 hours of life. Lesions wax and wane, usually lasting for Figure 2. Atopic dermatitis, a more extensive dis- a week or less, but cases lasting beyond 2 weeks tribution with pronounced pruritus. of life have been reported. It is characterized by or pustules with surrounding erythema forming small erythematous macules with or without cen- erythematous plaques can occur and be more dif- tral or pustule, measuring 1 to 3 mm in di- ficult to diagnose (Fig. 1b). Peripheral eosinophilia ameter, which may appear first on the face and has also been associated in about 15% of cases spread to the trunk and proximal extremities, but (6). Skin biopsy is rarely needed. The diagnosis of may appear anywhere on the body except for the ETN can usually be made by clinical appearance palms and soles (Fig. 1a) (5,6). Although the char- alone, but scraping of the pustule will reveal eosin- acteristic lesions of ETN are usually discrete and ophils with a few scattered neutrophils. No therapy scattered, extensive cases with confluent , is needed, for ETN resolves spontaneously (5,6).

Miliaria The term miliaria is used to describe a group of transient eccrine disorders. Miliaria is common in summer months and is also noted in infants housed in incubators (5). There are three forms of miliaria due to occlusion of sweat ducts at vari- ous levels, resulting in leakage of sweat in the epi- dermis or papillary dermis. Only miliaria rubra can progress to erythroderma, mostly in hot and humid conditions (5,6). Miliaria rubra occurs between the 11th and 15th day of life and it usually affects sites of friction or occlusion such as the neck and face, but also occurs on the trunk. Lesions are erythem- Figure 1. (a) Erythema and pustules in erythema atous, non-follicular papules or papulovesicles of toxicum neonatorum; (b) erythema toxicum neo- 1-3 mm in size (6). natorum with numerous pustules. Cutaneous disorders Atopic dermatitis Atopic dermatitis (AD) presents within the first 6 months of life in 60% of children. Severe gener- alized AD is unusual in neonates, but because AD is such a common problem, it is the most common cause of acquired or non-congenital erythroderma in infants (Fig. 2) (3). From the clinical point of view, in the first months of life AD is characterized by exudative lesions. There is considerable over- lap between the manifestation of infantile sebor- rheic dermatitis and AD, and some authors believe that infantile seborrheic dermatitis is a variant of AD (2,7). About 30% of cases of AD starting in the

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because it probably refers to a heterogeneous group of disorders (10). It has become clear, over the past decade, that Leiner’s disease is an “um- brella phenotype” rather than a specific entity, and often applied to babies in whom the known causes of erythroderma have been excluded (2). Infants with erythroderma, failure to thrive and chronic need thorough investigations, searching for the underlying cause of their disor- der. In Leiner phenotype, many of the diseases need to be considered, especially immunodefi- ciencies, Netherton’s syndrome and Omenn’s Figure 3. Infantile seborrheic dermatitis with in- syndrome (3). volvement of the head, face, body folds and nap- kin area. Psoriasis Congenital psoriasis, meaning psoriasis pres- first months of life involve primarily the scalp with ent at birth or appearing during the neonatal period, lesions resembling seborrheic dermatitis (2). is exceptional. Only 15 cases of congenital eryth- Classic infantile AD involves the scalp, cheeks rodermic psoriasis have been reported (11,12). and extensor surfaces of the extremities, and does Positive family history for psoriasis and human not appear until the infant is 2 to 3 months of age. leukocyte antigen (HLA) B17 is found in more than Itching in children with AD is usually not apparent half of the patients and their relatives (12). Con- until 2 to 3 months of age (2,7). Typically, the dia- genital and neonatal erythrodermic psoriasis are per region is spared even in cases of widespread among the most serious and difficult forms of pso- AD, as a result of the moist, occlusive environment riasis to treat. Clinical diagnosis is usually difficult, caused by the diaper. AD may occasionally be and many differential diagnoses should be consid- complicated by a rare form of food hypersensitiv- ered, mainly congenital non-bullous ichthyosiform ity known as eosinophilic gastroenteritis, mostly to erythroderma (11). Most cases later develop clas- cow’s milk protein, with excessive loss of protein sic erythematosquamous lesions (13). through the gastrointestinal tract (8). Less than 1% of all cases of psoriasis occur in When the distribution is generalized and the infants under 1 year of age (3). Infantile psoriasis onset early, the diagnosis can be more difficult. may have similar clinical presentation as both seb- In contrast to infants with severe metabolic or im- orrheic and atopic dermatitis. Facial involvement mune disease, infants with AD usually grow and may be more common in the infant, and the scalp, thrive normally, assuming the disease is recog- palms and soles may have diffuse erythema and nized and treated promptly (3). scales. Psoriasis in infants often involves the diaper area because it develops in areas of injured skin Seborrheic dermatitis (Koebner phenomenon), e.g., after prior irritant or Infantile seborrheic dermatitis typically pres- candida diaper dermatitis (Fig. 4) (14). Cases of ents during the first month of life. The character- istic feature of infantile seborrheic dermatitis is in- flammation, yellowish scaling on the scalp (cradle cap) with frequent involvement of the skinfolds of the neck, axillae, and groin (Fig. 3). The lesions are sometimes more infiltrated and resemble pso- riasis. Progression to erythroderma is rare (9). A syndrome characterized by erythema, in- filtration and desquamation in the seborrheic lo- calization with rapid progression to erythroderma, accompanied by recurrent local and systemic infections, severe diarrhea and failure to thrive was called Leiner’s disease. It was considered to be caused by complement C5 deficiency or dys- Figure 4. : psoriasiform confluent function (8). The term is no longer appropriate generalized lesions started in the napkin area.

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Treatment is directed at alleviation of symp- toms; H1- and H2-receptor antagonists, disodium cromoglycate and ketotifen (a stabilizer of mast cell membranes) are helpful. Particular foods and medicines can liberate histamine and should be restricted. Children with a history of anaphylaxis should be equipped with injectable adrenaline in the form of an Epi-Pen. Special care should be taken when these patients are to undergo anes- thesia (8).

Ichthyosis Hereditary ichthyoses are a large and heteroge- neous group of disorders, which have in common Figure 5. Diffuse cutaneous mastocytosis. The rough, dry and scaly skin. Of the different types of entire skin is erythematous, heavily infiltrated and ichthyosis, congenital non-bullous ichthyosiform thickened, Darier’s sign is positive with urtication erythroderma (CIE)/lamellar ichthyosis (LI) and and bullae formation. bullous ichthyosiform erythroderma (bullous CIE) manifest at birth with variable degrees of erythro- derma. CIE is characterized by fine white-gray- infantile psoriasis may prove to be mild and oc- ish scales and erythroderma, and LI manifests as casionally even clear completely as the child gets generalized ichthyosis with large, dark, plate-like older. The prognosis of generalized erythrodermic scales and an underlying mild or minimal erythe- or pustular psoriasis in infancy is more guarded, ma. At present, LI and CIE may be considered two and treatment usually requires systemic retinoid polar ends of the clinical spectrum, caused by sev- therapy as well as supportive care (3). eral different genes and including many interme- diate phenotypes (17,18). About 90% of patients Diffuse cutaneous mastocytosis present at birth as “collodion babies” with a glis- It is a rare variant of mastocytosis that gener- tening membrane which envelopes the neonate ally presents in the neonatal period. The entire and produces ectropion, and nasal ob- skin is heavily infiltrated with mast cells; the skin is struction (Fig. 6). thickened, lichenified and erythematous, and may Bullous CIE, also referred to as epidermo- have leathery appearance (8). Mild pressure or lytic hyperkeratosis (EH), presents with general- trauma to the skin induces mast cell release with ized erythema and superficial that are urtication (Darier’s sign) that can progress to bulla frequently mistaken for staphylococcal scalded formation (Fig. 5). In the first months of life, the skin syndrome (SSSS) or epidermolysis bullosa. condition can be dangerous and life threatening due to electrolyte and fluid loss (15). Bullous mani- festations in mastocytosis occur only in the first two or three years of life. Blister formation may mimic staphylococcal scalded skin syndrome (16). To distinguish mastocytosis from vesicular and bul- lous neonatal disorders, Darier’s sign and Tzanck smear should be performed. Systemic symptoms such as flushing attacks, respiratory difficulty and diarrhea are common. Rarely, infants may have extracutaneous mast cell infiltration (gastrointes- tinal tract, bones, liver, spleen and lymph nodes). Systemic mastocytosis and mast cell are extremely rare in childhood. Mastocytosis tends to remit spontaneously, especially when it occurs in infancy or early childhood. Skin biopsy is diagnos- Figure 6. Collodion baby with a generalized glis- tic with a dense, band-like infiltrate of mast cells tening, taut membrane stretched over the entire in the upper dermis, which can be confirmed with skin, constricting band encircling the digit on the Giemsa stain (3). right hand.

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These children later develop typical ichthyosiform to improve in later childhood. Ichthyosis linearis hyperkeratosis. It is transmitted as an autosomal circumflexa, with its migrating, erythematous dominant trait with mutations in the genes encod- patches and fringe of double-edged scales, de- ing keratin 1 and 10, however, spontaneous muta- velop after the age of 2 years (21). During the first tions may account for approximately one-half of year of life, patients with NS undergo a period of cases (2,18). life threatening infections, hypernatremic dehydra- Interestingly, some parents to the children with tion, diarrhea and failure to thrive, with mortality of bullous CIE have had limited disease expression 30%-40% during this period (2). Apart from raised in the form of linear epidermal nevi with similar total IgE and multiple positive specific IgE reac- histology to EH. It has been proven that mosaic tions, there are no consistent immunologic abnor- keratin 10 mutations give rise to an epidermo- malities in NS (19,21). lytic epidermal , whereas the presence of Genetic linkage has been established to the the mutation in all cells gives rise to bullous CIE. mutation of SPINK-5 gene locus on chromosome The mutation can involve other organs includ- 5q31-32 encoding the serum protease inhibitor ing gonads. In patients with linear epidermolytic LEKTI (lymphoepithelial Kazal type inhibitor). It is epidermal nevus, gonadal mosaicism may be re- absent or abnormally expressed on immunohisto- sponsible for transmission of the abnormality to chemistry staining in the stratum granulosum of the offspring, leading to diffuse skin involvement patients with NS in comparison with normal skin in the child. Therefore, it is important to do histo- (1,22). NS can be distinguished from neonatal logic examination in all cases of linear epidermal graft-versus-host disease and Omenn’s syndrome nevus to look for EH. Patients with epidermolytic by psoriasiform acanthosis, thickening of the base- epidermal nevus should be informed on the pos- ment membrane, prominent dermal blood vessels, sible risk of transmission of bullous CIE to the next and dermal infiltrate in which lymphocytes and generation (18-20). macrophages are represented equally (22).

Netherton’s syndrome Infections Netherton’s syndrome (NS) is a rare autosomal Many perinatal or early neonatal infectious dis- recessive genodermatosis that is classified as an eases are associated with skin eruption present at ichthyosiform syndrome. Infants affected with this birth or in the early neonatal period. disorder show a triad of generalized exfoliative dermatitis, sparse hair with trichorrhexis invagi- Staphylococcal scalded skin syndrome nata (“bamboo hair”), and atopic features (Fig. 7). (SSSS) The main differential diagnosis is Omenn’s syn- drome, but in practice a frequent misdiagnosis is SSSS is a potentially life-threatening toxin- generalized atopic dermatitis (2,10). Ichthyosiform mediated manifestation of localized infection with erythroderma in NS is worst in infancy and tends certain toxigenic strains of Staphylococcus aureus (mostly group II phage, types 71 and 55). Exfolia- tive toxins (ET-A and ET-B) that have been char- acterized as serine proteases cause the symp- toms. SSSS is predominantly a disease of infancy and early childhood, with most cases seen before the age of 5 years due to renal immaturity and decreased toxin clearance, and the lack of immu- nity to toxins in these age groups. Congenital and neonatal cases of SSSS following chorioamnion- itis have been described (2,13,24). In generalized forms of SSSS, toxin diffuses from an infected fo- cus (conjunctiva, umbilicus, nose, urine) and, in the absence of specific antitoxin antibody, spreads by hematogenous route to produce its widespread effects by cleaving a specific amino acid of des- Figure 7. Netherton’s syndrome: generalized des- moglein 1 (8). SSSS is an acantholytic intraepi- quamative erythroderma and alopecia in an infant dermal blistering process in which cleft appears in with failure to thrive complicated by sepsis. the granular layer just beneath the stratum corne-

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Figure 9. Neonatal candidiasis: generalized ery- thema with scattered pustules and erythematous papules. Congenital and neonatal candidiasis It is assumed that in congenital candidiasis the fetus has been infected in utero during the last days of pregnancy. Congenital candidiasis typi- cally presents either at birth or within 48 hours of life with , vesicles, pustules, papules, and scaling (3,25). It spreads rapidly and often involves the umbilicus, palms and soles (Fig. 9) (1). can also cause a diffuse Figure 8. Staphylococcal scaled skin syndrome burn-like erythema within the first 2 weeks of life in (SSSS): accentuated erythema in the circumoral, premature infants. The risk of extracutaneous dis- neck and scrotal region with positive Nikolsky’s ease and the prognosis depend on the gestational sign (flaccid blisters and erosions) in a high febrile age and weight of the infant. In infants less than child. 1500 g with either congenital or acquired general- ized cutaneous candidiasis, there is a significant um (2,8). Unlike other , in children risk of disseminated disease, including involve- with SSSS the onset is acute, accompanied by fe- ment of the lung, meninges, and urinary tract. An ver, systemic toxicity, and positive Nikolsky sign. infant with a possible systemic candidiasis must The erythema generalizes rapidly and progresses be thoroughly evaluated as systemic infection to sloughing and erosions (Fig. 8). Although there presents a life threatening condition. After the is often periorificial accentuation, the staphylo- blood, spinal fluid, and urine have been cultured, coccal toxin requires keratinizing epithelium and it is recommended to introduce systemic antifun- therefore spares mucous membrane surfaces (3). gal agents (3,8,26). Differential diagnosis includes Histopathology of the lesion distinguishes it from intrauterine herpes simplex virus infection, erythe- toxic epidermal necrolysis. ma toxicum neonatorum, pustular miliaria rubra, and neonatal pustular melanosis (3). Staphyloderma pustulosa In the neonatal form of cutaneous candidiasis, Rarely a widespread form of staphylococcal the lesions usually start in the oral cavity or the pustulosis can acutely and rapidly develop in an napkin area and develop three to seven days after otherwise healthy infant, resembling generalized birth. Topical therapy with an antifungal cream is candidiasis. Hundreds of 1-mm superficial pus- usually sufficient because dissemination does not tules within erythematous patches desquamate, develop in an immunocompetent infant (3,25). leaving widespread areas of erythema and scales. Cultures grow Staphylococcus aureus and the Congenital herpes simplex infection disease clears rapidly with appropriate antibiotics Intrauterine variant of herpes simplex infection (1,8). can present at birth with either isolated or diffuse

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erythema, and scaling or crusted erosions on an diagnosis of TEN, whereas evidence of preceding erythematous base. It may be difficult to recognize rhinitis and localization to intertriginous and peri- clinically because vesicles may not be present. orificial areas, acutely tender skin and occurrence This type of widespread involvement is generally in newborns or infants suggest the diagnosis of associated with very severe neurologic disease. SSSS. Definitive diagnosis depends on the histo- Multinucleated giant cells should be demonstrable logic location of the blister; in TEN the separation on Tzanck smears of vesicular lesions (3). is subepidermal, and full-thickness epidermal ne- crosis is noted (8). Syphilis Congenital syphilis may cause diffuse erythe- Metabolic/nutritional disorders ma and scaling. This presentation is most typically The diseases in this category need to be con- seen in infants at 6 to 8 weeks of age, in whom sidered in an infant who is ill or not thriving, and the exposure to Treponema pallidum occurred either dermatitis begins in the periorificial area before it very late in pregnancy or at the time of delivery. generalizes. Although the etiologies of these dis- Superficial erosions or bullae over the hands or orders differ, the clinical manifestations are strik- feet of the newborn, together with a diffuse scaling ingly similar, possibly because there is a common dermatitis should alert to the possibility of syphilis. link in the pathogenesis at the level of protein or Infiltrated mucosal papules and plaques (condy- keratin biosynthesis. Epidermal turnover is more lomata lata) are most often seen in the perianal rapid on mucous membranes, which could explain region. Periosteal changes of long bones as well the periorificial predilection of many of these dis- as hepatosplenomegaly, lymphadenopathy, ane- orders as well as profound diarrhea seen in some mia and thrombocytopenia are additional features of them (8). (3,27). Acrodermatitis enteropathica Drug reactions is a classic example of a nutri- Drug induced erythrodermas in children are tional or metabolic cause of neonatal erythroder- commonly observed with sulphonamides, iso- ma. Acrodermatitis enteropathica is an autosomal niazid, streptomycin, NSAIDs, and antiepileptic recessive disorder thought to be due to impaired drugs. If the incriminating drug(s) are withdrawn intestinal absorption of zinc. The initial lesions are and symptomatic treatment instituted, these cases vesiculobullous, crusted or psoriasiform and de- have an excellent prognosis (1). velop usually in the perioral and perianal areas. Toxic epidermal necrolysis Skin lesions are accompanied by diarrhea, failure to thrive, alopecia, recurrent infection, photopho- Toxic epidermal necrolysis (TEN) is an acute bia and irritability. Secondary infection of the skin severe bullous cutaneous disease characterized with Candida is not uncommon (8). In addition to by extensive areas of skin necrosis accompanied low serum zinc levels, serum alkaline phospha- by a systemic toxic condition. TEN is usually a dis- tase levels are also reduced, as this enzyme is ease of adults and is less common in childhood. zinc dependent (30). The of The vast majority (80%-95%) of children with TEN acrodermatitis enteropathica can also appear in have a drug reaction implicated as the cause. Sul- other disorders associated with secondary zinc phonamides, anticonvulsants, non-steroidal anti- deficiency, including malabsorption syndromes inflammatory drugs (NSAIDs) and are and long-term use of zinc-deficient parenteral nu- most frequently implicated. Several cases of TEN trition (31). The response to zinc therapy is rapid in infants have been described in association with and dramatic. Klebsiella pneumoniae (28) and Staphylococcus aureus sepsis (8). In most children, TEN develops An acrodermatitis-like symptom complex with in the form of blistered erythematous patches and perioral dermatitis, failure to thrive, diarrhea and plaques that evolve within hours to extensive ar- low zinc concentrations has been reported in chil- eas of skin necrosis, with loss of sheets of epider- dren with acquired immune deficiency syndrome mis. About 90% of patients will have involvement (AIDS) (32). of the mucosa with painful erosions and hemor- rhagic crusts. TEN is a severe disease with a high Essential fatty acid deficiency mortality rate of 30% to 70% (29). Essential fatty acids (EFA), such as linoleic and Differentiation from SSSS is necessary. High linolenic acids, must be supplied by the diet as the fever and occurrence in older children favor the body cannot synthesize them. EFA deficiency can

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be seen in individuals with severe fat malabsorp- thetase deficiency, methylmalonic and propionic tion. EFA deficiency leads to increased suscepti- acidemia (3,36,37). bility to infection, growth impairment, and a char- Methylmalonic and propionic acidemia may acteristic generalized and periorificial cutaneous be associated with a variety of cutaneous mani- eruption consisting of dry, thickened, erythema- festations such as superficial scalded skin, pso- tous, desquamating plaques (8,31). riasiform desquamation after metabolic decom- pensation, and chronic periorificial acrodermatitis Cystic fibrosis dermatitis enteropathica-like dermatitis (36). A well-known complication of cystic fibrosis (CF) is protein-energy , characterized Multiple carboxylase deficiency by hypoproteinemia, edema and anemia. Sweat Biotin-responsive multiple carboxylase defi- chloride level is usually elevated. However, con- ciency (MCD) is a potentially lethal disorder which firmation of the diagnosis is complicated by the may manifest in early infancy with metabolic aci- fact that the sweat test can be falsely negative in dosis, central nervous system dysfunction, and edematous infants (33). recurrent infections. MCD is an autosomal reces- Cutaneous manifestations of malnutrition are sive disorder of metabolism in which the function rare in patients with CF and have been attributed of mitochondrial biotin-dependent carboxylase en- to deficiencies of protein, zinc and EFA, particu- zymes are impaired (propionyl CoA carboxylase, larly linoleic acid. Zinc and EFA have reciprocal β-methylcrotonyl CoA carboxylase, and pyruvate metabolic interactions that alter both the produc- carboxylase) with non-functional branched-chain tion of prostaglandins from linoleic acid and their amino acid and carbohydrate metabolism (38). subsequent metabolism (31). The neonatal form of MCD presents in the first Failure to thrive, hypoproteinemia, edema, and weeks of life, due to deficient holocarboxylase cutaneous eruption can be present before the synthetase enzyme, with sharply margined der- onset of pulmonary and gastrointestinal symp- matitis on the scalp, eyebrows and eyelashes that toms and before the diagnosis of CF is confirmed spreads to the perioral, perianal and other flexural (8,34). The clinical and histologic appearance of areas. Secondary candidiasis is common. The hair the rash in infants with CF most closely resembles thins and there can be associated and acrodermatitis enteropathica. Infants with CF can keratoconjunctivitis with photophobia. If untreated, develop widespread, scaly erythematous lesions profound lactic acidosis, ketosis, and death result. as a manifestation of global malnutrition during the Early recognition and therapy with oral biotin may first 3 or 4 months of life (3). completely reverse all of the manifestations of the disorder (6,38). Amino acid disorders The juvenile form is milder than the neonatal In different amino acid disorders, dermatitis form and presents between the ages of 3 weeks similar to acrodermatitis enteropathica can appear and 2 years. It is caused by total or partial defi- due to dietary over-restriction of branched-chain ciency of the enzyme biotinidase. Dermatologic amino acids. Patients with maple syrup urine dis- symptoms are the same as in the neonatal form of ease are unable to metabolize three branched- MCD. These children also develop hearing loss, chain amino acids: leucine, isoleucine and valine seizures, ataxia and coma (6,38,39). Immediate (3). A diet low in branched-chain amino acids is treatment and lifelong management using phar- indicated. Overly strict adherence to this diet may macological doses of biotin supplements may pre- result in deficiency of these amino acids and ex- vent many of these complications. foliative erythroderma (8). Erythematous scaling eruption that becomes erosive begins primar- Immune disorders ily in the periorificial distribution within days after Because of the protective effect of maternal im- initiating dietary therapy (35). Treatment requires munity, congenital immunodeficiency syndromes diligent attention to dietary restriction so that suf- are rarely symptomatic at birth. Graft-versus-host ficient branched-chain amino acids are delivered reaction from maternal lymphocyte engraftment (8). Presumably, adequate concentrations of may, however, occur even during intrauterine de- amino acids are needed for normal keratinization velopment. (36). Graft-versus-host disease (GVHD) Similar eruptions have also been noted in neo- GVHD is seen mainly in children with T cell natal citrullinemia and carbamoyl phosphate syn- immunodeficiency, but can occur in immunocom-

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petent newborns as the result of transplacental passage of maternal lymphocytes or in the post- natal period (exchange transfusions) (2). Clinical manifestations include fever, morbilliform rash that gradually progresses to erythroderma, eosino- philia, lymphocytosis, hepatosplenomegaly, and lymphadenopathy (4,8,40). The diagnosis should be suspected in any young infant with erythro- derma and frequent infections, chronic diarrhea, and failure to thrive. Clinical presentation may re- semble Omenn‘s syndrome, but the skin eruption is usually less eczematous in GVHD. Infiltration of activated cytotoxic T cells into the skin is the common pathogenic mechanism for both skin le- sions (41). In contrast, in the immunocompetent newborn with a small number of transferred cells, Figure 10. Graft-versus-host disease that devel- clinical symptoms are minimal and may involve oped in an 11-month-old infant with severe com- only transient macular rash (2). bined immunodeficiency (SCID) after allogeneic Histologic examination usually reveals signifi- bone marrow transplantation. cant lymphocytic infiltration and keratinocytic ne- crosis with satellite lymphocytes. These findings, both humoral and cellular immune defects are however, are not specific for GVHD since similar seen. A gene defect has been identified that maps changes are found in Omenn‘s syndrome (18). to chromosome 11 (3, 41). Karyotyping and histocompatibility typing can help The etiology of Omenn’s syndrome is unknown, detect maternal engraftment in an immunodeficient however, unlike other forms of SCID, patients with infant, which will suggest the diagnosis of GVHD Omenn’s syndrome have activated T lymphocytes (41). Histology findings can rule out Netherton‘s in their circulation capable of non-MHC restricted syndrome and CIE as other possible causes of cytotoxic function (41). It is characterized by exfo- neonatal and infantile erythroderma. liative erythroderma with the onset at birth or in the early neonatal period. It is associated with diffuse Severe combined immunodeficiency alopecia, pronounced lymphadenopathy, hepa- Severe combined immunodeficiency (SCID) tosplenomegaly, recurrent infections, and failure represents a heterogeneous group of genetic to thrive (2). Marked leukocytosis, eosinophilia, disorders characterized by a profound defect in anemia, elevated serum IgE levels, hypogamma- T cell differentiation or function, accompanied by globulinemia and depressed T-cell immunity are secondary B cell depletion or dysfunction (42). It other characteristics. Skin biopsy may confirm is inherited as an autosomal dominant or X-linked the diagnosis and help in differentiating it from recessive trait. The impaired cellular and humoral Netherton’s syndrome. necrosis with immunity predispose these infants to a variety of satellite lymphocytes and significant lymphocytic serious infections and sometimes to the develop- or eosinophilic infiltration of the skin are highly ment of GVHD due to engraftment of transplacen- suggestive of an immnodeficiency syndrome (10). tally acquired maternal T cells (1). The main clini- Although it is mostly fatal, cyclosporine and bone cal manifestations of SCID include predisposition marrow transplantation can be effective therapies to infections, growth retardation, and chronic di- (1,3,8). arrhea. Cutaneous manifestations include muco- cutaneous infections, viral exanthemas and, most Hypogammaglobulinemia importantly, acute GVHD which usually occurs Patients with hypogammaglobulinemia can within the first months of life (Fig. 10) (43,44). present with neonatal erythroderma. An infant who is apparently normal at birth subsequently Omenn’s syndrome/familial reticuloendo- develops fever, diarrhea and rapidly progressive theliosis with eosinophilia generalized exfoliative dermatitis (erythroderma). Omenn’s syndrome is a rare autosomal reces- Monthly replenishment by intravenous infusion of sive combined immunodeficiency. Although the gammaglobulins alleviates fever and erythema condition is primarily due to T-cell dysregulation, (1,8,40).

ACTA DERMATOVENEROLOGICA CROATICA 187 Kotrulja et al. Acta Dermatovenerol Croat Neonatal and infantile erythroderma 2007;15(3):178-190

Management of children with neo- 3. Levy ML, Spraker MK. Erythrodermas: the red natal and infantile erythroderma scaly baby. In: Eichenfiled LF, Frieden IJ, Ester- ly NB, eds. Textbook of neonatal dermatology. Irrespective of its cause, neonatal and infantile Philadelphia: WB Saunders Company;2001. erythroderma is a potentially life threatening con- pp. 260-75. dition. Erythrodermic neonates and infants are at a risk of hypernatremic dehydration and hyper- or 4. Scheimberg I, Harper JU, Malone M, Lake hypopyrexia. These infants need a warm, humid BD. Inherited ichthyoses: a review of the his- environment to minimize their metabolic demands tology of the skin. Pediatr Pathol Lab Med (3). Maintaining adequate oral or parenteral fluid 1996;16:359-78. intake and monitoring serum electrolytes are 5. Taϊeb A, Boralevi F. Common transient neona- therefore mandatory. Topical application of emol- tal dermatoses. In: Harper J, Oranje A, Prose lients, such as white paraffin, hydrates the skin N, eds. Textbook of pediatric dermatology, 2nd and prevents fissuring. Blisters and erosions, seen ed. London: Blackwell Publishing Ltd.; 2006. in bullous ichthyosiform erythroderma, SSSS, and pp. 55-65. cutaneous mastocytosis, should be treated with a 6. Lucky AW. Transient benign cutaneous lesions topical astringent, such as 0.01% potassium per- in the newborn. In: Eichenfiled LF, Frieden IJ, manganate soaks, and systemic antibiotics should Esterly NB, eds. Textbook of neonatal derma- be given if necessary. As transcutaneous absorp- tology. Philadelphia: WB Saunders Company; tion is profoundly increased, additives such as sal- 2001. pp. 88-102. icylic acid or lactic acid should be strictly avoided 7. Bonifazi E, Meneghini CL. Atopic dermatitis in in the young infant, and topical steroids are to be the first six months of life. Acta Derm Venereol used cautiously and only after the establishment Suppl (Stockh) 1989;144:20-2. of a diagnosis warranting their use (2). 8. Connelly EA, Spraker MK. Differential diag-

nosis of neonatal erythroderma. In: Harper J, Conclusion Oranje A, Prose N, eds. Textbook of pediatric In neonates and infants numerous diseases dermatology, 2nd ed. London: Blackwell Publis- can present with erythroderma. These can be hing Ltd.; 2006. pp. 105-18. transient, benign dermatoses, primary cutaneous 9. Menni S, Piccinno R, Baietta S, Ciuffeda A, diseases, however, more serious infectious, meta- Scotti L. Infantile : a se- bolic and immune diseases should also be con- ven year follow-up and some prognostic crite- sidered. Recognition of these diseases, i.e. early ria. Pediatr Dermatol 1989;6:13-5. and precise diagnosis is important for it can spare 10. Pruszkowski A, Bodemer C, Fraitag S, Teil- a healthy child with transient, benign dermatosis lac-Hamel D, Amoric JC, de Prost Y. Neona- from unnecessary or invasive evaluation, antibi- tal and infantile erythrodermas. Arch Dermatol otic treatment and hospitalization. On the other 2000;136:875-80. hand, recognition of potentially serious diseases that demand early treatment is mandatory. Delay 11. Henriksen L, Zachariae H. Pustular psoriasis in the establishment of the correct diagnosis can and arthritis in congenital psoriasiform erythro- be fatal. Differential diagnosis of erythroderma is a derma. Dermatologica 1972;144:12-8. multi-step procedure that involves clinical assess- 12. Salleras M, Sanches-Regaña M, Umbert P. ment, knowledge of any relevant family history, Congenital erythrodermic psoriasis: case re- and certain laboratory investigations. port and literature review. Pediatr Dermatol 1995;12:231-4. 13. Larrègue M. Les érythrodermies néonatales: References évolution conceptuelle sur cent ans: de 1889 à 1989. Ann Dermatol Venereol 1989;116:931- 1. Sehgal VN, Srivastava G. Erythroderma/ge- 40. neralized exfoliative dermatitis in pediatric 14. Farber EM, Jacobs AH. Infantile psoriasis. Am practice: an overview. Int J Dermatol 2006;45: J Dis Child 1977;131:1266-9. 831-9. 15. Harrison PV, Cook LJ, Lake HJ, Shuster S. 2. Hoeger PH, Harper JI. Neonatal erythroderma: Diffuse cutaneous mastocytosis: a report of differential diagnosis and management of the neonatal onset. Acta Derm Venereol (Stockh) “red baby”. Arch Dis Child 1998;79:186-91. 1979;59:541-43.

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By rain, wind and snow use Nivea cream; year 1935. (from the collection of Mr. Zlatko Puntijar)

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