Erythroderma in children

INTRODUCTION — Erythroderma is a generalized and persistent erythema of the skin involving at least 90 percent of the body surface [1]. Although relatively uncommon in infants, erythroderma may be the presenting feature of a wide range of acquired and inherited diseases, including infections, inflammatory skin diseases, ichthyoses, and congenital immunodeficiencies.

This topic will review the causes of erythroderma in children and the approach to the diagnosis and management. Erythroderma in adults is discussed separately. (See "Erythroderma in adults".)

ETIOLOGY — Neonatal and infantile erythrodermas are associated with a wide range of underlying cutaneous and systemic disorders, including [1-3]:

●Infectious diseases (eg, staphylococcal scalded skin syndrome, congenital cutaneous candidiasis, syphilis)

●Inflammatory diseases (eg, atopic dermatitis, seborrheic dermatitis, psoriasis)

●Inherited ichthyoses

●Primary immunodeficiencies

●Inborn errors of metabolism

●Drug hypersensitivity reactions

Determining the underlying cause of erythroderma is rarely possible without laboratory, histologic, microbiologic, or molecular genetic testing. The choice of the appropriate laboratory studies is based upon history and clinical presentation.

Infectious diseases

Staphylococcal scalded skin syndrome — In neonates and infants, diffuse erythema with superficial desquamation and/or bullae not involving the mucous membranes suggests staphylococcal scalded skin syndrome (SSSS) (picture 1A-B) [4]. SSSS is a toxin-mediated illness caused by infection with phage group II Staphylococcus aureus, which produces the exfoliative toxins A and B [5]. These toxins bind to the desmosomal adhesion protein desmoglein-1 and induce cleavage of the epidermis at the level of the granular layer, resulting in acantholysis and blister formation (picture 2).

The diagnosis is usually clinical, but bacterial cultures should be obtained from the nasopharynx, axillary skin, urine, and blood. SSSS is a life-threatening condition that often evolves rapidly. Prompt diagnosis and institution of therapy is crucial to avoid poor clinical outcomes. (See "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Staphylococcal scalded skin syndrome' and "Staphylococcal scalded skin syndrome".)

Staphylococcal toxic shock syndrome — Staphylococcal toxic shock syndrome may infrequently cause erythroderma in neonates and infants [6]. (See "Staphylococcal toxic shock syndrome".)

Neonatal toxic shock syndrome-like exanthematous disease — Neonatal toxic shock syndrome-like exanthematous disease (NTED) is a newly described disease that has been reported in neonates in Japan and France who are colonized with methicillin-resistant S. aureus, producing the toxic shock syndrome toxin 1 [7-9]. NTED typically presents in the first few days of life with fever and generalized macular erythema that tends to coalesce. Thrombocytopenia (<150,000/microL) and low positive level of C-reactive protein (1 to 5 mg/dL) are also present.

The disease appears to be less severe than toxic shock syndrome and usually regresses spontaneously in neonatal patients without active treatment.

Congenital cutaneous candidiasis — Congenital cutaneous candidiasis presents at birth or in the first few days of life with small, diffuse, erythematous macules and pustules, often involving the palms and soles (picture 3A-B) [10]. Widespread crusting and erosions and a generalized erythema may also be present. The infection can be acquired in utero via ascending infection from maternal vulvovaginal area or at birth.

Infants with this presentation do not appear ill and usually do not have systemic disease. However, mucocutaneous Candida infection can be seen in neonates with primary immunodeficiencies [11]. Premature neonates, usually between one to three weeks of age, can present with diffuse scaling, crusting, and erosions as a manifestation of neonatal candidiasis. Premature infants are at increased risk for developing candidemia and multiple organ infection.

Diagnosis is confirmed by appropriate laboratory investigations, such as potassium hydroxide (KOH) examination, which reveals the typical pseudohyphae and clusters of oval or round yeast cells (picture 4), histopathology (when indicated), and culture. In every case, evaluation for the possibility of systemic infection must be kept in mind and should be guided by clinical considerations. (See "Clinical manifestations and diagnosis of Candida infection in neonates".)

Syphilis — Early congenital syphilis may present with widespread erythema and superficial scaling in the first six to eight weeks of life (picture 5). Palm and sole involvement with bullae and/or localized desquamation associated with more widespread desquamation should alert the clinician to the possibility of this infection [12-14]. Additional clinical findings include fever, hepatomegaly, splenomegaly, and generalized lymphadenopathy. Condylomata lata can also be seen in these children (picture 6).

Infants with suspected congenital syphilis should be evaluated with a quantitative nontreponemal test (rapid plasma reagin [RPR] or Venereal Disease Research Laboratory [VDRL]) performed on infant serum; if reactive, the infant should be examined thoroughly for evidence of congenital syphilis [15]. Darkfield examination or direct fluorescent antibody (DFA) staining of skin lesions and/or mucous membrane samples can demonstrate thin, corkscrew-shaped organisms with rigid, tightly wound spirals (picture 7). (See "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis".)

Herpes simplex — Herpes simplex virus (HSV) infection in neonates and infants primarily results from intrapartum exposure to maternal cervical or vaginal lesions. Lesions are not usually present at birth but develop in the first few weeks of life. Infants typically present with discrete areas of pustules and/or vesicles (picture 8A-B).

In rare cases, the infection can be acquired in utero. Newborns may present with more diffuse erythema with scales and erosions (picture 9) [16]. Intrauterine HSV infection may be associated with involvement of the central nervous system, eyes, and viscera, including adrenal glands, liver, and lungs.

Comprehensive laboratory evaluation should be performed in infants with suspected HSV infection, including culture and histologic examination of affected tissues, DFA of swabs/scrapings of skin or mucous membrane lesions, and HSV DNA polymerase chain reaction (PCR) of the blood and cerebrospinal fluid. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis".)

Human T lymphotropic virus type 1 — Infective dermatitis is a severe, chronic, relapsing dermatitis associated with human T lymphotropic virus (HTLV) type 1 [17]. First described in Jamaican children, infective dermatitis has been recognized in several endemic areas, including Brazil, Japan, and the Caribbean. One of the most common transmission modes is mother-to-child vertical transmission, primarily through breast feeding.

Infective dermatitis is characterized by a severe erythematous and exudative dermatitis with scaling and crusting primarily affecting the scalp, forehead, eyelids, paranasal area, neck, retroauricular areas, external ear, axillae, and groin. The onset is usually in early childhood, and the condition tends to improve with age. Rarely, infective dermatitis may present as exfoliative erythroderma in infants [18]. (See "Human T-lymphotropic virus type I: Disease associations, diagnosis, and treatment", section on 'Infective dermatitis'.)

Scabies — In newborns and infants, a very itchy eruption with erythroderma and hyperkeratotic areas may be the presentation of crusted (or Norwegian) scabies, which means a heavy infestation by mites probably due to decreased immune defenses in newborns and infants. (See "Scabies: Epidemiology, clinical features, and diagnosis", section on 'Crusted scabies'.)

Inflammatory diseases

Atopic dermatitis — Atopic dermatitis, although a common condition in the general population, is unusual in neonates. However, atopic dermatitis can be seen during infancy and may present with diffuse erythroderma (picture 10).

Clues to the diagnosis of atopic dermatitis include the presence of pruritus, scratching (in infants old enough to scratch), and involvement of skin sites usually affected by the infantile form of atopic dermatitis such as the face, torso, and extremities. Typically, the diaper area is spared due to moisture and occlusion. A family history of atopy is usually present.

Erythrodermic atopic dermatitis should be differentiated from other eczematous and inflammatory skin diseases, including seborrheic dermatitis, psoriasis, immunodeficiency syndromes, and Netherton syndrome. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

Psoriasis — One percent or less of all cases of psoriasis occur in infants [19,20]. Infantile psoriasis commonly presents with involvement of the diaper area and often other areas, such as the scalp, axillae, and extremities. The skin of the diaper area, including the folds, appears glossy and erythematous and may show superficial erosions (picture 11) [21]. Pustular psoriasis can also be seen during infancy. In some cases, especially if associated with bone disease, it can be an indicator of the rare genetic autoinflammatory syndromes DIRA (deficiency of interleukin-1 receptor antagonist) and DITRA (deficiency of the interleukin-36 receptor antagonist) [22,23]. (See "Psoriasis in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Pustular and erythrodermic psoriasis' and "The autoinflammatory diseases: An overview".)

Congenital erythrodermic psoriasis is exceedingly rare [24,25]. Erythroderma may be the presentation of infantile psoriasis or may occur later in childhood. Patients present with generalized erythema and thickening of the skin. Localized or diffuse sterile pustules may be seen on the background erythema.

The clinical diagnosis is difficult. A skin biopsy may show typical features of psoriasis, including psoriasiform hyperplasia, laminated parakeratosis, spongiform pustula, and mild dermal lymphocytic infiltrate [26]. (See 'Skin biopsy' below.)

However, during erythrodermic flares, histology often shows nonspecific inflammatory features. In such cases, and especially in the absence of family history of psoriasis, the diagnosis is made later in the course of the disease, when the classic presentation with sharply demarcated, deep red plaques with overlying white or "silvery" scale becomes apparent (picture 12). (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)

Seborrheic dermatitis — Commonly seen during the neonatal and infantile ages, seborrheic dermatitis presents with erythematous patches and plaques with "greasy" scales that more prominent over typical locations, such as the scalp, face, axillae, and groin (picture 13A-B). Occasionally, seborrheic dermatitis may present as erythroderma; in most cases, this presentation occurs in association with immunodeficiency and failure to thrive.

The distinction between erythrodermic seborrheic dermatitis and psoriasis or atopic dermatitis may be difficult, and the two conditions may overlap in some patients [5]. The spontaneous improvement of seborrheic dermatitis over weeks to months helps to differentiate it from atopic dermatitis or psoriasis, which usually have a chronic, prolonged course. (See "Cradle cap and seborrheic dermatitis in infants".)

Pityriasis rubra pilaris — Pityriasis rubra pilaris is exceedingly rare during the neonatal or infantile ages. It presents with scaling follicular papules with or without palmoplantar keratoderma (picture 14A-B) [5]. A family history of this condition may be found.

The diagnosis is based upon the combination of characteristic clinical and histopathologic features. Histology shows orthokeratosis with spotty parakeratosis, epidermal acanthosis, and a mild dermal lymphohistiocytic infiltrate but also may be nondiagnostic. (See "Pityriasis rubra pilaris: Pathogenesis, clinical manifestations, and diagnosis".)

Diffuse cutaneous mastocytosis — In the neonate, the clinical finding of diffusely infiltrated (thickened) skin with erythema and episodes of vesiculation or blistering should raise the suspicion of diffuse cutaneous mastocytosis (picture 15) [27-29]. This condition is a rare variant of cutaneous mastocytosis that typically presents at birth or in early infancy.

A skin biopsy is necessary to confirm the diagnosis. Histology shows a dense, band-like infiltrate of mast cells with a granulated cytoplasm in the upper dermis. Granules are not visible with routine stains but may be seen with a Giemsa stain.

Symptoms include flushing, itching, vesiculation, diarrhea, gastrointestinal bleeding, abdominal pain, vomiting, and hypotension. The clinical course can be severe and even life-threatening, due to the potential for circulatory compromise and anaphylactoid reactions from sudden mast cell degranulation.

Systemic involvement may occur but is rare. Unexplained peripheral blood abnormalities, hepatomegaly, splenomegaly, or lymphadenopathy indicate systemic involvement [30].

The utility of serum tryptase levels for the diagnosis of diffuse cutaneous mastocytosis is not entirely clear but can help point toward the need for evaluation of other sites of involvement, such as bone, bone marrow, or gastrointestinal tract [31,32]. (See "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis".)

Inherited ichthyoses — Neonatal erythroderma may be the clinical presentation of several nonsyndromic and syndromic congenital ichthyoses (table 1A-B). (See "Autosomal recessive congenital ichthyoses".)

Nonsyndromic — The nonsyndromic autosomal recessive congenital ichthyoses (ARCI), which include lamellar ichthyosis, congenital ichthyosiform erythroderma, and Harlequin ichthyosis, present at birth as erythroderma with or without a collodion membrane (picture 16 and table 2) [33]. When the membrane is shed, the severity of long-term skin involvement is unpredictable based upon the neonatal presentation. The majority of infants with ARCI develop a diffuse erythema with fine white scale. The other phenotype seen after the shedding of the collodion membrane has less erythema and a thicker lamellar-type of scale.

At birth, epidermolytic ichthyosis (EI) often presents with erythroderma and features similar to epidermolysis bullosa. Neonates have areas of erosive epidermal loss mixed with hyperkeratotic skin without involvement of the mucous membrane (picture 17). Over time, the blistering subsides, erythroderma becomes more obvious, and hyperkeratosis may become prominent, particularly at the flexures (picture 18A-B). The diagnosis is based upon characteristic findings on histopathologic examination of a skin biopsy, which include epidermal hyperplasia with compact hyperorthokeratosis and ostia plugs, normal or thickened granulosus layer, and little or absent lymphocytic infiltrate [26].

Syndromic — Erythroderma can be the presenting symptom of several syndromic forms of ichthyosis (table 1B), including Netherton syndrome, Sjögren-Larsson syndrome (SLS), and Conradi-Hünermann-Happle syndrome. (See "Autosomal recessive congenital ichthyoses" and "Netherton syndrome".)

SLS is caused by mutations in the ALDH3A2 gene, which codes for fatty acid aldehyde dehydrogenase and is inherited in an autosomal recessive fashion [34]. Affected children can have a phenotype similar to ARCI but ultimately develop spasticity and intellectual disability. The characteristic glistening dots on the retina of these patients are not uniformly seen. (See "Sjögren-Larsson syndrome".)

Conradi-Hünermann syndrome (chondrodysplasia punctata type 2) is an X-linked dominant disorder caused by mutations in the EBP gene (emopamil-binding protein) encoding an 8-7 sterol isomerase involved in cholesterol metabolism. Affected female neonates present at birth with a diffuse or linear scaling erythema. Ultimately, ichthyosis with hyper- or hypopigmentation develops along the lines of Blaschko. Additional findings include follicular atrophoderma and scarring alopecia. Extracutaneous signs include dwarfism, cataracts, and psychomotor retardation. Stippled epiphyses should be sought by plain radiographs at birth in suspected cases. (See "Skeletal dysplasias: Specific disorders", section on 'Chondrodysplasia punctata'.)

Erythroderma can also be seen in cases of keratitis-ichthyosis-deafness (KID) syndrome due to mutations in connexin 26 gene (GJB2). Newborns with neutral lipid storage disease (Chanarin-Dorfman syndrome) may present with either erythroderma or a collodion membrane. Infants with ichthyosis prematurity syndrome may appear identical to those with KID syndrome at birth but do not have associated keratitis and deafness. (See "Overview and classification of the inherited ichthyoses", section on 'KID syndrome' and "Metabolic myopathies caused by disorders of lipid and purine metabolism", section on 'Neutral lipid storage diseases'.)

Netherton syndrome — Netherton syndrome is an autosomal recessive disorder caused by mutations in the SPINK5 gene, which encodes a kinase known as LEKTI [3,35]. Netherton syndrome should be considered in any infant with diffuse inflammatory skin disease and failure to thrive (picture 19). Most, but not all, patients will also show abnormally brittle hair (picture 20).

The examination of hairs for the typical "bamboo-hair" deformity known as trichorrhexis invaginata (picture 21) is helpful for the clinical diagnosis. Immunostaining of a skin biopsy with a specific monoclonal antibody against the serine protease inhibitor LEKTI can be used to establish the diagnosis [26]. (See "Netherton syndrome".)

Immunodeficiency — Newborns and infants with persistent and diffuse dermatitis or erythroderma and failure to thrive must bring to mind the possibility of primary immunodeficiencies [36-38]. In the United States, many states now include screening for T cell immunodeficiencies in their newborn screening programs. T cell receptor excision circles (TRECs) are the basis of these tests and measure new and naïve T cells [39,40]. (See "Severe combined immunodeficiency (SCID): An overview" and "Newborn screening for inborn errors of immunity".)

Severe combined immunodeficiency — Severe combined immunodeficiency (SCID) syndromes are a heterogeneous group of disorders arising from a disturbance in the development and function of both T and B cells (cellular and humoral immunity) due to mutation in multiple genes, including interleukin receptor common gamma chain, recombinase activating gene (RAG) 1 or 2, adenosine deaminase, and Janus kinase 3. (See "Severe combined immunodeficiency (SCID): Specific defects".)

Omenn syndrome is a form of SCID, due to hypomorphic mutations in RAG1 and RAG2, characterized by a T-negative, B-negative, natural killer (NK)-positive phenotype. Newborns with Omenn syndrome present with erythroderma, lymphadenopathy, hepatosplenomegaly, profound eosinophilia, chronic persistent diarrhea, and failure to thrive. Some infants born with SCID will present with graft-versus-host disease due to maternal engraftment (transplacental passage of alloreactive maternal T cells). (See 'Graft-versus-host disease' below.)

In suspected cases, complete evaluation of the immune function should be done, including the measurement of immunoglobulin levels, absolute numbers and percentages of lymphocyte subsets (T, B, and natural killer), and assessment of T cell function. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Diagnosis'.)

Hyperimmunoglobulin E syndrome — Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency characterized by elevated serum immunoglobulin E (IgE), skin eruption, and recurrent bacterial infections of the skin and lung [41]. There are two forms of HIES, caused by distinct genetic mutations, which are inherited in an autosomal dominant or recessive fashion. Both forms of the disease show classic features of eczema that is often diffuse or erythrodermic (picture 22), skin abscesses, respiratory infection, marked elevation in serum IgE, mucocutaneous candidiasis, and eosinophilia [42].

Autosomal dominant HIES (Job syndrome) is the most frequent form. It is caused by mutations in the signal transducer and activator of transcription 3 gene (STAT3). These patients have predominantly bacterial infections of the skin, but sinopulmonary and skeletal infections are also common. Additional clinical features include hyperextensible joints, skeletal abnormalities, osteoporosis, and coarse facies. (See "Autosomal dominant hyperimmunoglobulin E syndrome".)

Dedicator of cytokinesis 8 (DOCK8) deficiency, caused by loss-of-function mutations in the DOCK8 gene, was previously classified as the autosomal recessive form of HIES, but many patients do not have elevated serum IgE [43,44]. It is suspected in patients with eczematous skin disease accompanied by severe cutaneous viral infections, such as herpes simplex, molluscum contagiosum, or varicella zoster [42,45]. Some patients may develop aggressive squamous cell carcinoma and cutaneous T cell lymphoma [42,45]. (See "Combined immunodeficiencies: Specific defects", section on 'DOCK8 deficiency'.)

Wiskott-Aldrich syndrome — Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disorder characterized by thrombocytopenia, pyogenic infections, and a diffuse eczematous dermatitis [36]. It is caused by mutations in the gene encoding the Wiskott-Aldrich protein (WASp), which is involved in actin cytoskeleton remodeling and is widely expressed in the hematopoietic cell lines.

Affected male infants present with extensive eczema and thrombocytopenia, which can result in bleeding and a hemorrhagic appearance of the dermatitis (picture 23). Patients may also have epistaxis, gastrointestinal, or central nervous system hemorrhage. Bacterial, viral, and opportunistic infections due to Pneumocystis can be seen [37]. Lymphoproliferative disorders and autoimmune diseases have been reported in patients with WAS.

Laboratory findings include decreased number of T cells, elevated immunoglobulin A (IgA) and IgE levels, and thrombocytopenia associated with abnormally small platelets. (See "Wiskott-Aldrich syndrome".)

DiGeorge syndrome — DiGeorge syndrome (DGS) is a disorder characterized by a constellation of signs and symptoms associated with defective development of the pharyngeal pouch system. It is caused by a heterozygous chromosomal deletion at 22q11.2 [46]. Most patients with DGS have impaired T cell production and normal humoral immunity. Other abnormalities include cleft palate, heart defects, dysmorphism, and hypoparathyroidism, depending on the size of the deletion.

A subset of patients with profound T cell deficiency presents with or develops a form of SCID referred to as atypical complete DGS. Skin findings include a papular or eczematous dermatitis that can be diffuse and erythrodermic [37]. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

IPEX — Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a rare, severe, autoimmune lymphoproliferative disorder caused by mutations in the gene for the transcription factor FOXP3 (FOXP3), with result in quantitative or functional deficiency of regulatory T cells [47]. Skin manifestations include diffuse erythema and eczematous or psoriasiform dermatitis. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)

Metabolic disorders — Acrodermatitis enteropathica is a recessively inherited partial defect in intestinal zinc absorption. It is the result of mutations in the SLC39A4 gene, which encodes a protein that appears to be involved in zinc transportation.

Acrodermatitis enteropathica may rarely present as erythroderma in neonates [3,5,48]. Most often, it presents later in infancy with a periorificial dermatitis (picture 24) or with a diffuse, scaling erythema. Other clinical symptoms include alopecia, brittle hair, diarrhea, failure to thrive, and irritability.

Cutaneous features similar to acrodermatitis enteropathica can be seen in disorders of biotin metabolism, such as multiple carboxylase deficiency, and in other organic acidemias. Newborns with organic acidemias typically present with neurologic symptoms (eg, hypotonia, lethargy), poor feeding, and/or acidemia. The specific diagnosis is suggested by measurement of organic acids in the urine and confirmed by demonstration of deficient enzyme activity in skin fibroblasts or peripheral blood leukocytes. (See "Zinc deficiency and supplementation in children" and "Organic acidemias: An overview and specific defects".)

Other metabolic disorders that can cause erythroderma in newborns and infants include cobalamin deficiency, maple syrup urine disease, carbamoyl phosphate synthetase deficiency, cystic fibrosis, essential fatty acid deficiency, holocarboxylase synthetase deficiency, and biotinidase deficiency. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features".)

Graft-versus-host disease — Acute graft-versus-host disease (GVHD) may occur in neonates with SCID and may occasionally be the first clinical manifestation of SCID [49,50] (see 'Severe combined immunodeficiency' above). In these infants, GVHD is caused by maternal engraftment (transplacental passage of alloreactive maternal T cells) or transfusion of blood products containing viable lymphocytes. Other causes of GVHD in infants include allogenic hematopoietic stem cell transplantation and solid organ transplantation.

The skin, gastrointestinal tract, and liver are the principal involved organs in acute GVHD. Severe acute GVHD presents with generalized erythroderma with desquamation, bullae, or extensive skin detachment (table 3). Mucosal involvement is frequent.

A skin biopsy shows interface dermatitis with focal vacuolization of the basal layer, spongiosis, and epidermal apoptotic keratinocytes; a mild lymphocytic infiltrate is present in the papillary dermis (picture 25). (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

Drug-induced erythroderma — Drug reactions are an infrequent cause of erythroderma in neonates and infants [5]. Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) has been rarely reported as well. If there is clinical suspicion of SJS/TEN, a skin biopsy should be taken to confirm the diagnosis. Histology typically shows subepidermal blistering, full-thickness necrosis of the epidermis, and a mild perivascular infiltrate of lymphocytes containing a variable amount of eosinophils. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

PATIENT EVALUATION AND DIAGNOSIS — The evaluation of the erythrodermic baby involves a detailed personal and family history, physical examination, and appropriate laboratory tests [48]. In some cases, a skin biopsy may be helpful in diagnosing the underlying disease [26]. In approximately 10 percent of cases, the cause of erythroderma remains unknown. The approach to the differential diagnosis of erythroderma in neonates and infants is illustrated in the algorithms (algorithm 1A-B).

History — A detailed history is of key importance in the evaluation of the neonate or infant with erythroderma. The clinician should obtain the parents' history of atopy (eg, asthma, allergic rhinitis, contact allergies), psoriasis, ichthyosis, and immunodeficiency. Was newborn screening performed? If so, what type? Parents' consanguinity should also be ascertained. For many of the inherited causes of erythroderma such as immunodeficiencies, ichthyoses, or metabolic diseases, family history may provide information on the inheritance pattern. A history of severe or repeated common infections may suggest a primary immunodeficiency disorder.

Physical examination — An accurate assessment of weight and rate of weight gain and growth is crucial because failure to thrive is associated with several conditions presenting with erythroderma at birth or in the first months of life (algorithm 1A-B). Poor feeding, hypotonia, hepatomegaly, and acidosis may indicate a metabolic disorder. Clinical signs of hypocalcemia (ie, tetany, seizures) suggest DiGeorge syndrome.

Examples of cutaneous findings that may help to determine the underlying cause of erythroderma include:

●Periorificial scaling and erythema, suggesting a metabolic disorder

●Involvement of the diaper area, suggesting psoriasis

●Diffuse, recalcitrant eczema that spares the diaper area, suggesting atopic dermatitis or immunodeficiency

Laboratory and imaging tests — Laboratory testing is based upon the clinical presentation and clinical suspicion. The initial evaluation of the erythrodermic baby may include (algorithm 1A-B):

●Complete blood count – Blood count abnormalities such as abnormal neutrophil indices (elevated or depressed absolute neutrophil count and elevated ratio of immature to total neutrophil counts), hypereosinophilia, or lymphopenia may indicate infection, atopic dermatitis, or immunodeficiency. As an example, hypereosinophilia is associated with atopic dermatitis but, in more severe cases, may be a marker of Omenn syndrome or Netherton syndrome. (See "Severe combined immunodeficiency (SCID): An overview".)

●Chest radiograph – The absence of a thymic shadow on chest radiography is a typical finding in infants with severe combined immunodeficiency (SCID). (See "Severe combined immunodeficiency (SCID): An overview".)

●Serum electrolytes – Because of the skin barrier impairment and insensible water loss through the erythrodermic skin, neonates are at risk of hypernatremic dehydration (weight loss ≥12 percent of birth weight and serum sodium concentration ≥150 mEq/L). (See "Fluid and electrolyte therapy in newborns", section on 'Electrolyte disorders'.)

●Routine serum biochemistry – Including glucose, liver function tests, and albumin.

●Bacterial, fungal, or viral cultures – Nasopharyngeal umbilical, perianal, and maternal vaginal cultures should be obtained if infection is suspected. Infections with common or uncommon organisms may suggest a primary immunodeficiency.

Specific tests that may be helpful in determining the underlying cause of erythroderma are performed based upon the clinical symptoms:

●TREC/KREC testing – T cell receptor excision circles (TRECs) test or kappa-deleting recombination excision circles (KRECs) test in infants with suspected SCID or other primary immunodeficiency. (See "Newborn screening for inborn errors of immunity".)

●Measurement of serum ionized calcium – Hypocalcemia may suggest hypoparathyroidism due to hypoplastic or absent parathyroids in the DiGeorge syndrome. (See "Neonatal hypocalcemia", section on 'When to test for hypocalcemia'.)

●Arterial blood gases – A low serum bicarbonate, low arterial pH, and increased anion gap are features of metabolic acidosis and suggest an inborn error of metabolism.

Skin biopsy — As with any case of erythroderma, the skin biopsy may be nonspecific. However, the presence of a predominant histopathologic pattern may be helpful for the diagnosis of the underlying disorder (algorithm 1A-B) [26]:

●Spongiotic pattern – The spongiotic pattern, with lymphocyte exocytosis and a mild to intense lymphocytic infiltrate of the upper dermis with or without eosinophils can be seen in atopic dermatitis, primary immunodeficiencies, and graft-versus-host disease (GVHD). The association of a spongiotic reaction pattern with keratinocyte necrosis suggests the diagnosis of immunodeficiency or GVHD.

●Psoriasiform pattern – The psoriasiform pattern, with epidermal hyperplasia, parakeratosis, and mild lymphocytic infiltrate can be seen in psoriasis and Netherton syndrome. Spongiform pustule and Munro abscess are typical of psoriasis, whereas little or no inflammation is present in Netherton syndrome. Immunohistochemistry with LEKTI antibody showing absence of stain is diagnostic of Netherton syndrome.

●Ichthyosiform pattern – The ichthyosiform pattern, with epidermal hyperplasia, compact hyperorthokeratosis, and hypergranulosis without inflammation are typically seen in ichthyoses.

●Acantholysis – The presence of a cleavage plane below the granular layer with acantholytic cells and a few inflammatory cells is characteristic of staphylococcal scalded skin syndrome. Full-thickness epidermal necrosis and subepidermal bullae are features of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). (See 'Drug-induced erythroderma' above.)

Genetic testing — Genetic testing is available for a growing number of primary immunodeficiencies, and neonatal screening for various forms of SCID is available in some states in the United States (US) and some other countries [51]. Information for laboratories that provide genetic test services is available at the Genetic Testing Registry website. Genetics services can be located by searching the American College of Medical Genetics website by city or state.

TREATMENT

Initial management — The "red baby" with generalized erythroderma should be hospitalized for initial evaluation and treatment. Regardless of the specific etiology, the initial management involves:

●Monitoring of fluids and electrolytes – Because of the increased insensible water loss, erythrodermic neonates and infants are at risk of hypernatremic dehydration (weight loss ≥12 percent of birth weight and serum sodium concentration ≥150 mEq/L). (See "Fluid and electrolyte therapy in newborns".)

●Monitoring of body temperature – The transepidermal water loss is always accompanied by heat loss, resulting in hypothermia and increased metabolic rate. Neonates and infants should be placed in a warm and humid environment to minimize insensible water loss and hypothermia.

●Ensuring adequate nutrition – Exfoliation of the skin may result in significant protein loss and hypoalbuminemia. The increased metabolic rate is associated with an increased caloric expenditure. The caloric and protein supplementation must meet the requirements of normal growth and development and hypermetabolic state.

●Prevention and treatment of infection – Cutaneous colonization and infection with S. aureus, Streptococcus, or gram-negative bacteria are common in erythrodermic babies [35]. (See "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation".)

●Skin care – Skin care is a critical component of the management of erythroderma. The impaired barrier function of erythrodermic skin is responsible for fluid and electrolyte imbalance, temperature instability, and susceptibility to skin colonization and infection. Regular bathing in plain water and topical, liberal application of a petrolatum-based ointment multiple times per day may be helpful in restoring the skin barrier function.

Treatment of underlying conditions — After the underlying etiology of erythroderma has been determined, appropriate treatment of the underlying condition should be added to the initial management measures:

●Infections – Treatment of staphylococcal scalded skin syndrome consists of prompt administration of intravenous penicillinase-resistant penicillin. (See 'Staphylococcal scalded skin syndrome' above.)

In full-term infants, congenital cutaneous candidiasis tends to run a benign, self-limited course that can be managed with careful observation. Topical or systemic antifungal agents can be used if needed. (See "Treatment of Candida infection in neonates".)

The evaluation and management of infants with congenital syphilis is discussed in detail separately. (See "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis" and "Congenital syphilis: Management and outcome".)

In neonates with suspected intrauterine herpes simplex virus (HSV) infection, supportive measures and appropriate antiviral therapy should be started empirically, pending laboratory investigations. (See "Neonatal herpes simplex virus infection: Management and prevention".)

●Inflammatory diseases – The treatment of erythroderma caused by atopic dermatitis includes emollients and topical corticosteroids; oral antihistamines may aid in relieving night itch. In very rare cases, infants with severe, refractory disease may require systemic corticosteroids or other immunosuppressants, such as cyclosporine or methotrexate, in addition to supportive measures. However, other causes of erythroderma should be carefully considered before resorting to use of systemic immunosuppression in an infant or young child. (See "Treatment of atopic dermatitis (eczema)".)

Treatment of erythrodermic seborrheic dermatitis includes emollients and topical corticosteroids. (See "Cradle cap and seborrheic dermatitis in infants".)

Infants with pityriasis rubra pilaris are usually treated with topical corticosteroids and emollients. Systemic retinoids may be necessary in severe cases [52]. (See "Pityriasis rubra pilaris: Pathogenesis, clinical manifestations, and diagnosis".)

The management of diffuse cutaneous mastocytosis involves the use of oral antihistamines and oral sodium cromoglycate [27,53,54]. Very severe cases require neonatal intensive care unit (NICU) admission for sedation because of anaphylactoid status. (See "Cutaneous mastocytosis: Treatment, monitoring, and prognosis".)

●Ichthyoses – The management of neonates and infants with ichthyosis involves diligent skin care with regular bathing in plain water (without excessive soap) and application of emollients as often as necessary, in addition to the initial management measures described above [55]. Severe cases of lamellar ichthyosis, congenital ichthyosiform erythroderma, and Harlequin ichthyosis may require systemic retinoids [56]. (See "Autosomal recessive congenital ichthyoses", section on 'Care of the neonate with autosomal recessive congenital ichthyoses' and "Inherited ichthyosis: Overview of management".)

●Immunodeficiencies – Infants with severe combined immunodeficiency will need aggressive management in specialized centers, which involves avoidance of any potentially contagious contact, immune globulin replacement therapy, and prompt treatment of infection [57]. Bone marrow transplantation is the only curative therapy available for many primary immunodeficiencies. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

PROGNOSIS — Mortality from erythroderma in neonates or infants can be significant, particularly in those with immunodeficiency. Mortality rates of 16 and 26 percent have been reported in two case series [35,58]. Sepsis, hypernatremic dehydration, and hyperpyrexia or hypothermia are the main causes of death.

SUMMARY AND RECOMMENDATIONS

●Definition and etiology – Erythroderma is an extensive and persistent erythema of the skin involving at least 90 percent of the body surface. In neonates and infants, erythroderma may be the clinical presentation of a wide range of acquired and inherited diseases, including inflammatory skin diseases, infections, ichthyoses, and congenital immunodeficiencies. (See 'Introduction' above and 'Etiology' above.)

●Evaluation and diagnosis – The evaluation of the erythrodermic neonate or infant involves detailed personal and family history, physical examination, and appropriate laboratory tests (algorithm 1A-B). A skin biopsy may be helpful in diagnosing the underlying disease in many patients. However, in approximately 10 percent of cases, the cause of erythroderma remains unknown. (See 'Patient evaluation and diagnosis' above and 'Skin biopsy' above.)

●Initial management – The "red baby" with generalized erythroderma should be hospitalized for initial evaluation and treatment. Regardless of the specific etiology, the initial management involves the monitoring of fluids and electrolytes, maintenance of the body temperature, and nutritional support. The application of petrolatum-based ointment multiple times per day may be helpful in improving the skin barrier function. (See 'Initial management' above.)

●Treatment of the underlying condition – After the etiology of erythroderma has been determined, appropriate treatment of the underlying condition should be added to the initial management measures. (See 'Treatment of underlying conditions' above.)