Chapter XXII.7. Neonatal Rashes
Amity Tran
December 2022

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The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2014 second edition Dr. Jessica M. Donigan and Dr. Douglas W. Johnson. This current third edition chapter is a revision and update of the original authorís work.


In the newborn nursery, a mother of a two day old female notes that her newborn has a rash on her face and chest. According to the patientís mother, the rash started as red spots, but now there are pus bumps too. She notes that the infant does not seem to be bothered by the rash.

On exam, the infant has normal vital signs and measurements. The skin exam reveals erythematous macules on the face and trunk, some of which have tiny pustules in the center. She is otherwise well-appearing.

You make a clinical diagnosis of erythema toxicum neonatorum, and reassure the mother that this is a benign condition that is self-limited and will resolve within the week.


Neonatal skin differs from adult skin as it is 40% to 60% thinner, less hairy, has a weaker attachment between the epidermis and dermis, has less sweat and sebaceous gland secretions, and makes up a greater amount of the body surface area to weight ratio (1). As a result, newborn skin is less equipped to handle external stress, so it is common for neonates to develop a cutaneous disorder. Premature and low birth weight infants are at increased risk of infection, dehydration, injury, and toxic absorption due to their under developed skin being an ineffective barrier (2). Many of these lesions are idiopathic while others may be due to maternal hormones, the immaturity of the newbornís epidermis, or infection. Application of emollients on infant skin can improve barrier function, prevent hypersensitivity reactions, and lower risk of infection (2).

Note to the reader of this chapter. It is difficult to describe rashes purely in words. Pictures are very useful. Photos of these lesions are difficult to obtain due to consent requirements and maintaining the organization of these images. By entering the names of each of these entities into an internet search and selecting the images option will yield many photographs of these conditions. Keep in mind that not all of these are correct so the viewer should look for some consistency with the descriptions in this text and the majority of the photos that are displayed.

Erythema toxicum neonatorum (ETN) is an idiopathic condition that tends to occur during the first few days of life. The true incidence is unknown. It is characterized by asymptomatic erythematous macules, papules, and tiny pustules that may occur anywhere on the body, but sparing the palms and soles. The lesions tend to appear at 24 to 48 hours of age, beginning as 1 cm to 3 cm erythematous macules that may develop tiny (but occasionally larger) vesicles or pustules within the center (3). Rarely, the lesions appear as late as 10 days after birth. The cause of ETN is not well understood, but it has been suggested it is an immune response to microbial colonization of the skin (1). Biopsy is rarely needed for the diagnosis as ETN is usually diagnosed clinically. However, histologically, the lesions contain eosinophils. If the center is punctured superficially, then touched to a glass slide, a Wright stain will also show a ball of eosinophils, and the CBC may show peripheral eosinophilia. No treatment is necessary, as ETN is usually asymptomatic and spontaneously resolves without sequelae within 7 to 10 days (2). Rarely, the lesions persist for 2 to 3 weeks.

Sebaceous hyperplasia is due to maternal androgen stimulation and commonly occurs during the first few weeks of life (1). This is characterized by multiple pinpoint, yellow to flesh-colored macules or papules on the nose, cheeks, and upper lips of full-term infants (1). These lesions tend to spontaneously resolve within the first few weeks of life, but may persist for up to 6 months.

Acne neonatorum is another condition that is due to maternal hormone stimulation. It resembles acne vulgaris seen in adolescents (1). Neonatal acne presents with erythematous papules and pustules on the face. Treatment other than gentle washing is usually unnecessary. However, in more severe cases, keratolytics or topical antibiotics can be used. Severe or treatment-resistant cases should be further evaluated for underlying androgen excess (1).

Neonatal cephalic pustulosis, is an acneiform condition that has been associated with Malassezia fungal species (3). It is characterized by pinpoint papules and pustules on the forehead, cheeks, and chin (1). Although the terms neonatal cephalic pustulosis and neonatal acne are often used interchangeably, the latter has a comedonal eruption as opposed to the pustule kind seen in the former (3). These lesions respond to topical antifungal agents such as ketoconazole; however, treatment is usually unnecessary as the disease tends to be self-limited and resolve within several weeks. Oils in baby oil, cream, and ointment may aggravate the condition (3).

Seborrheic dermatitis is discussed elsewhere in Eczematous Dermatitis of this book. However, it is worth mentioning again as it is a common condition. It is thought that seborrheic dermatitis is due to a hypersensitivity response to Malassezia which is a common fungus found on the skin. This condition occurs in areas where there is a high density of sebaceous glands, termed seborrheic areas which include the scalp, face, ears, trunk, and intertriginous areas. On the scalp, the condition is referred to as "cradle cap". It is characterized by erythematous plaques with greasy yellow scales. The lesions are usually asymptomatic and the diagnosis is clinical. Seborrheic dermatitis is best managed by frequent shampooing with medicated shampoos that contain ketoconazole, selenium sulfide, zinc pyrithione, or coal tar. Low potency topical corticosteroids and topical antifungals can also be helpful.

Milia resemble white dots within pores that are most easily seen on the nose of the newborn. They are caused by keratin retention within the dermis. Milia most commonly occur on the face, but may also be seen on the upper trunk, limbs, penis, or mucous membranes. When on the hard palate, these lesions are called Epsteinís pearls. Milia are characterized by multiple pinpoint to 2 mm pearly white or yellow papules. They generally do not require any therapy and tend to spontaneously resolve after three or four weeks of life, but may persist for a few months (1). If persistent milia present in a widespread or unusual distribution, it may be indicative of underlying condition such as hereditary trichodysplasia, epidermolysis bullosa, Bazex or Rombo syndrome, or type 1 oral-facial-digital syndrome (1).

Miliaria is common in neonates and is caused by sweat retention due to the incomplete differentiation of the epidermis and its appendages (e.g., eccrine ducts). Eccrine ducts become plugged with keratin resulting in a collection of sweat beneath the obstruction which presents as vesicles. The two main types of miliaria seen in infants are miliaria crystallina and miliaria rubra. Miliaria crystallina presents as pinpoint clear vesicles without an inflamed border while maliaria rubra is characterized by erythematous papules, vesicles, or both (1). Management of miliaria involves avoiding excess heat and humidity.

Diaper dermatitis is a non-specific diagnosis. The three most common types of diaper dermatitis are chafing dermatitis, irritant contact dermatitis, and candidiasis (candida diaper rash) (3). Atopic dermatitis should also be considered (1). As the name implies, chafing dermatitis is due to friction and occurs in areas where this is highest, including the medial aspects of the thighs, genitalia, buttocks, and abdomen. It presents as mild erythema and scaling. Treatment includes frequent diaper changes. Irritant contact dermatitis is due to contact with urine and feces, and chemicals in soaps, detergents, and topical preparations (3). Excessive heat and moisture also play a role (3). This disorder tends to involve the buttocks, vulva, perineum, lower abdomen, and proximal thighs, sparing the intertriginous creases (3). Treatment includes frequent diaper changes, non-irritating diaper wipes, and topical therapies such as petrolatum, zinc oxide, and hydrocortisone cream (1). Diaper candidiasis may present as widespread, beefy red, shiny and moist erythema on the buttocks, lower abdomen, and medial thighs (1). The diagnostic hallmark of diaper cadidiasis is beefy red satellite lesions. Other characteristic features are a raised edge and sharp marginization with white scales at the border. This condition can occur as a sequela of systemic antibiotic therapy or as a secondary infection of pre-existing diaper dermatitis. Diagnosis can be confirmed with potassium hydroxide (KOH) preparation of skin scrapings which reveals budding yeast, hyphae, or pseudohyphae. Skin scrapings can also be cultured on Sabouraudís agar; however, this usually takes 48 to 72 hours to confirm the diagnosis. Treatment includes frequent diaper changes, gentle cleansing of affected area with moist and fragrant-free wipes, or use of zinc-oxide/petrolatum-based product to form a barrier between the skin and urine/feces (3). Topical anti-yeast agents (e.g., nystatin, miconazole, clotrimazole) are fairly effective and are sometimes used concomitantly with low-strength topical corticsteroids (1,3).

Transient neonatal pustular melanosis is an idiopathic disorder that is less common than erythema toxicum neonatorum, and seen most commonly in neonates with darkly pigmented skin, particularly African-American infants (2,3). It presents at birth, or soon after, as pustules and vesicles that resolve within 48 hours and leave a fine, white collarette scale around hyperpigmented macules that can take months to resolve. Lesions also have a tendency to cause benign hyperpigmentation that can persist for months (2). Pustules can also rupture prior to birth, resulting in variable presentation of pustules and macules or hyperpigmentation at birth (3). These lesions can occur anywhere (including the palms and soles), but are most commonly found on the forehead and mandible (1). Although unnecessary, histological evaluation demonstrates subcorneal pustules that are not folliculo-centric, with neutrophils being the primary inflammatory cell. Treatment is not necessary, as this is a benign, self-limited disorder.

Infantile acropustulosis is another idiopathic disorder that may present between birth and 2 years of age. While the exact cause of this condition is unknown, arthropod bites (e.g., scabies) should be ruled out (1). This condition is characterized by recurrent, 1 mm to 2 mm pruritic vesiculopustules found on the palms and soles, and less commonly on the other aspects of the extremities. Histology reveals large numbers of neutrophils and occasionally eosinophils (1). Recurrences are normal, but each episode will decrease in intensity with complete resolution within 2 to 3 years (2). Although infantile acropustulosis will subside, therapy is often required due to the intensely pruritic nature of the lesions. Antihistamines and topical corticosteroids are recommended for patients with severe pruritus (1). Dapsone is also recommended for severe cases; however, due to the risk-benefit concerns, it should be used with caution (1).

Eosinophilic pustular folliculitis (EPF) is an idiopathic disorder that can be seen in adults as well as infants. It has been suggested that EPF and infantile acropustulosis are related disorders. Lesions most commonly occur on the scalp and extremities. As the name implies, the disease is characterized by follicular pustules. These lesions tend to be recurrent, like those seen in infantile acropustulosis. Histological evaluation demonstrates folliculo-centric pustules with an eosinophilic infiltrate. There may also be peripheral eosinophilia on CBC. Although EPF tends to be idiopathic, it is occasionally the presenting sign of hyperimmunoglobulinemia E syndrome. EPF is a self-limited condition that tends to resolve by 3 years of age. Treatment is symptomatic and includes topical corticosteroids and antihistamines. Topical tacrolimus is recommended for cases that do not respond to topical corticosteroids (1).

Sucking blisters are seen in newborns and are a result of sucking in utero. They present as 0.5 cm to 2 cm bullae or erosions on the dorsal aspect of the fingers, thumbs, wrists, lips, or radial forearms. Lack of vesicles or erosions elsewhere helps to make this diagnosis. These lesions resolve quickly.

Epidermolysis bullosa (EB) refers to a group of uncommon, inherited mechanobullous disorders that result from genetic defects of structural proteins necessary for the attachment and integrity of the epidermis. Patients with EB develop vesicles and bullae as a result of very minor trauma. There are several types of EB with forms characterized by blisters localized to the hands and feet, to severe generalized forms that are lethal before two years of age. Whole-exome sequencing has largely replaced immunofluorescence mapping as the method used to confirm EB diagnosis and to determine the subtype (1). Electron microscopy is generally not useful, except for rare subtypes (1). Treatment involves wound care and infection control, and expertise by a clinician experienced in the care of these patients.

Impetigo can present in newborns as early as 2 or 3 days after delivery. It presents as vesicles, pustules, or bullae or honey crust on an erythematous base (1). Vesicles and bullous lesions are easily denuded leaving superficial erosions with a bordering collarette, usually lacking crust formation (1). Impetigo tends to occur in moist areas such as the groin, axillae, and neck folds. Lesions are commonly due to Staphylococcus aureus (bulla), occasionally group A streptococci (honey crust) may be the causative organism (1). Neonates with localized lesions and no systemic symptoms can be treated in the outpatient setting with no need for further evaluation of a serious bacterial illness (1).

Neonatal pustulosis, also known as S. aureus pustulosis, presents with small pustules on an erythematous base, most commonly in the diaper area. These lesions denude easily leaving superficial erosions. These should be cultured for diagnosis and antibiotic sensitivity (1).

Congenital toxoplasmosis is due to transplacental transmission of Toxoplasma gondii, a protozan commonly transmitted from cat feces. The most common cutaneous manifestation is a rubella-like maculopapular rash sparing the face, palms, and soles. Other skin findings include scarlatiniform eruptions, subcutaneous nodules, or blueberry muffin lesions. Blueberry muffin lesions are blue-red macules or papules that represent extramedullary erythropoeisis. Skin findings tend to develop in the first weeks of the illness, last for a week, and are followed by desquamation or hyperpigmentation. Diagnosis made by serologic testing and should be treated promptly due to ophthalmologic complications such as chorioretinitis and blindness may occur (1). Other congenital infections that also present with these distinctive blueberry muffin lesions are rubella, cytomegalovirus, and herpes simplex virus (2). Histiocytosis, neuroblastoma, leukemia cutis, transient myeloproliferative disorder, mastocytosis, and multifocal vascular lesions can also produce lesions that resemble blueberry muffin lesions (2).

Congenital varicella syndrome occurs as a result of maternal varicella infection during the first 20 weeks of gestation. The incidence of this syndrome is somewhat rare due to the fact that most women either acquire immunity from a childhood infection or the varicella vaccine. Cutaneous manifestations include depressed and pigmented vesicles and/or scars in a dermatomal distribution (1).

Neonatal varicella occurs due to a maternal varicella infection during the last few weeks of pregnancy or the early postpartum period. Skin findings include disseminated erythematous papules, vesicles, and erosions. Neonates who were born to mothers who contracted varicella 5 days prior to or 2 days after delivery, should receive varicella-zoster immune globulin. These neonates should also receive intravenous acyclovir.

Congenital rubella syndrome (CRS) occurs as a result of maternal rubella infection during the first 16 to 20 weeks of gestation. This syndrome has become less common since the advent of the rubella vaccine. The classic cutaneous manifestation of CRS is blue-red infiltrative papules and nodules called blueberry muffin lesions. These lesions are usually present at birth or developed within 24 hours. Other cutaneous findings in CRS include a generalized maculopapular rash, reticulated erythema of the face and extremities, hyperpigmentation, and recurrent urticaria. Treatment is supportive therapy with frequent ophthalmologic examinations.

Congenital cytomegalovirus (CMV) infection usually occurs as a result of primary maternal infection. Cutaneous manifestations of congenital CMV infection include jaundice, petechiae, purpura, a generalized maculopapular rash, blueberry muffin lesions, and rarely, vesicular lesions.

Neonatal herpes simplex virus (HSV) infection is most commonly acquired during vaginal delivery, but can also result from an ascending infection in utero, or occur post partum via contact with people who are infected. Recently, HSV-1 has been the causative agent in a majority of genital herpes and neonatal herpes infections (1). The risk of infection acquired during vaginally delivery is higher in mothers with primary genital herpes than in those with recurrent infection. The typical cutaneous manifestation of neonatal HSV is grouped vesicles on an erythematous base distributed on the presenting part of the neonate (most commonly the scalp and face). After 24 to 48 hours, the vesicles will become pustular and crust or ulcerate (1). Pustules and erosions may also be present. Other skin findings that may be present are purpuric, petechial, or zosteriform lesions. Large bullae similar to those of epidermolysis bullosa may also be present (1). Tzanck smear, direct fluorescent antibody assays, viral cultures, and/or skin biopsy can be used to confirm neonatal HSV infection if skin lesions are present. PCR is helpful for rapid diagnosis. This is a serious infection and requires intravenous acyclovir or vidarabine.

Congenital syphilis has been increasing over the last 60 years (1). Caused by the spirochete Treponema pallidum, the risk of congenital syphilis is highest in mothers with untreated primary syphilis. Manifestations are divided into early congenital syphilis (prior to 2 years of age) and late congenital syphilis (after 2 years of age). Cutaneous manifestations of early congenital syphilis include maculopapular dermatitis on the palms and soles (most common), condylomata lata (commonly in the moist areas), intractable diaper dermatitis, and mucous patches (fissures at mucocutaneous junctions). Another early diagnostic finding is "barber-pole umbilical cord" or necrotizing funisitis, which is a spiral pattern of red and blue discoloration interspersed with white streaks on the umbilical cord (1). Skin findings of late congenital syphilis include gummas and rhagades (perioral fissuring). The treatment of congenital syphilis is parenteral penicillin G.


Questions
1. How do erythema toxicum neonatorum and transient neonatal pustular melanosis differ?

2. How do erythema toxicum neonatorum and eosinophilic pustular folliculitis differ?

3. What are the three most common types of diaper dermatitis?

4. Do erythema toxicum neonatorum, acne neonatorum, transient neonatal pustular melanosis, milia, or sebaceous hyperplasia require treatment?

5. What congenital infection is most commonly associated with a blueberry muffin baby?

6. What other congenital infections can present with blueberry muffin lesions?


References
1. Mancini AJ, Paller AS. Chapter 2. Cutaneous Disorders of the newborn. In: Mancini AJ, Paller AS (eds). Hurwitzís Clinical Pediatric Dermatology: a Textbook of Skin Disorders of Childhood & Adolescence, 6th edition, 2022. Elsevier, St. Louis. pp:11-41.
2. Sidbury R. Chapter 103. Newborn Skin Development: Structure and Function. In: Gleason CA, Juul SEJ (eds). Averyís Disease of the Newborn, 10th edition, 2018. Elsevier, Philadelphia. pp:1468-1474.
3. Chadha A, Jahnke M. Common Neonatal Rashes. Pediatr Ann. 2019;48(1):16-22.


Answers to questions
1. Erythema toxicum neonatorum (ETN) does not have a racial predilection, as opposed to transient neonatal pustular melanosis (TNPM) which is more common in newborns with darkly pigmented skin. The pustules of TNPM are not surrounded by erythema, like in ETN, and in TNPM, there are hyperpigmented macules that appear after the resolution of the pustules. Additionally, histologic evaluation of ETN shows an folliculo-centric pustules with an abundance of eosinophils, whereas in TNPM the pustules are not centered around the follicles and neutrophils are the primary inflammatory cell.
2. Both erythema toxicum neonatorum (ETN) and eosinophilic pustular folliculitis (EPF) can present with follicular pustules that show an eosinophilic infiltrate histologically. ETN can occur anywhere on the body (sparing the palms and soles), whereas EPF tends to occur on the scalp and extremities. Unlike the lesions of ETN which resolve within a couple of weeks, the pustules seen in EPF are recurrent and can take up to three years to completely resolve.
3. Diaper dermatitis has many different causes with the three most common types being chafing dermatitis, irritant contact dermatitis, and diaper candidiasis.
4. No. Many of the most common lesions seen in newborns are transient and do not require treatment. These include erythema toxicum neonatorum, acne neonatorum, transient neonatal pustular melanosis, milia, and sebaceous hyperplasia.
5. Congenital rubella. However, other congenital viral infections can have a rash that is similar.
6. Toxoplasmosis, Cytomegalovirus. Enterovirus and Parvovirus B19 can do this but these were not mentioned in the chapter.


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