Are You Confident of the Diagnosis?
Characteristic findings on physical examination
The diagnosis of neonatal cephalic pustulosis is primarily a clinical one in which scattered inflammatory papules and pustules are found on the face, scalp, and neck in infants days to weeks old (Figure 1). Most often, the cheeks and forehead are affected. Comedones, nodulocystic lesions and follicular localization are absent.
Many consider a distinction between neonatal acne and neonatal cephalic pustulosis academic and group the two conditions together.
Neonatal cephalic pustulosis is considered by many to be an acne variant (splitters) and others consider it the sole cause of neonatal acne (lumpers), unless you use a potassium hydroxide preparation (KOH) to see the organism, the clinical appearance is so similar that it is difficult to differentiate the two. Since both resolve over time, the distinction is generally not necessary.
Expected results of diagnostic studies
No diagnostic studies are usually needed or recommended. In situations in which other differential diagnoses of infantile pustulosis may be entertained, several bedside tests may be helpful.
Smear of a pustule for Tzanck and KOH preparation, and Gram stain may help rule out herpes infection, candidiasis, dermatophyte infection, or bacterial cause. Culture of pustule for bacteria, fungi, and viruses is also recommended when diagnosis is in question.
In neonatal cephalic pustulosis, examination of a pustule smear will reveal a majority of neutrophils and, rarely, eosinphils, basophils, and/or lymphocytes. Culture from a pustule may reveal Malassezia organisms if plated on appropriate culture media to facilitate growth of these organisms.
Biopsy of a representative lesion reveals enlarged sebaceous follicles and glands. Oval single-budding yeast may be observed most densely in the ostium; 2-4µm spores in aggregates can also be found throughout the entire follicle. Malassezia spores are visible on routine histology as well as periodic acid-Schiff (PAS) stain, with PAS strongly staining Malassezia cell walls.
Neonatal cephalic pustulosis can occasionally be confused with miliaria rubra, candidiasis, neonatal herpes simplex, tinea faciei, eosinophilic pustular folliculitis, or erythema toxicum neonatorum.
Miliaria rubra is caused by obstruction of eccrine sweat glands, presenting with pruritic erythematous papules and pustules. Lesions most often appear on the neck, axilla, and groin in neonates and will self resolve.
Cutaneous candidiasis can present with bright erythematous patches, with peripheral papules and pustules. Congenital candidiasis is a rare condition, acquired in utero or during vaginal birth, and is associated with paronychia. KOH and Gram stain show hyphae, pseudohyphae, and budding yeast.
Neonatal herpes simplex classically presents with grouped vesicles and pustules on an erythematous base and/or erosions. Neonates are exposed during vaginal delivery from an infected mother or in utero during a primary infection. Infants often exhibit systemic symptoms such as irritability, lethargy, fever, or poor feeding. Multinucleated giant cells with eosinophilic intranuclear inclusion bodies are evident on Tzanck smear of a vesicle.
Tinea faciei appears as pruritic, annular, or serpiginous scaly plaques with an active border composed of papules, pustules, or crusts, most commonly found on the cheeks. Both Microsporum and Trichophyton organisms can be the causative agent. KOH preparation shows septate branching hyphae. Although uncommon in young infants, it may be acquired from contact with infected pets or other family members.
Eosinophilic pustular folliculitis presents with recurrent, pruritic follicular papules and pustules. Clinically, confluent lesions can become indurated, with central clearing and peripheral extension. In children, the scalp is almost universally involved, although the trunk and extremities can also be affected. On laboratory testing, peripheral leukocytosis with elevated eosinophil counts can be present. PAS staining shows eosinophilic infiltration of hair follicles.
Erythema toxicum neonatorum is a benign self-limited eruption characterized by small papules, vesicles, and occasional pustules, with surrounding edematous erythematous halos. Lesions can appear anyway, although are most commonly found on the face, trunk, and proximal extremities, with centripetal spread. Gram stain of a pustule shows predominance of eosinophils.
Who is at Risk for Developing this Disease?
Neonatal cephalic pustulosis affects approximately 10%-20% of infants, although a study by Bernier et al. reported an incidence of 66%. There does not appear to be a genetic predisposition. Average age of onset ranges from 12 to 22 days, regardless of birth history (preterm vs. term vs. posterm pregnancy).
There are no known risk factors for developing neonatal cephalic pustulosis. Malasseszia colonization may play a role in development of neonatal cephalic pustulosis. In one study of neonatal intensive care unit patients, use of lambs wool, paper tape, op-site tape, and incubators were associated with higher rates of colonization.
What is the Cause of the Disease?
Neonatal cephalic pustulosis was once thought to be caused by endogenous and maternal hormonal stimulation of sebaceous glands.
Alternatively, a correlation with Malassezia yeast species has been observed. A study of microscopic examination of pustules revealed the presence of Malassezia furfur, although overall skin colonization rates were similar between case and control groups. Another species, Malassezia sympodialis, was significantly associated with severe cases of neonatal cephalic pustulosis, but not with mild or moderate cases.
Another study found that infants with moderate cephalic pustulosis were more likely to be colonized by Malassezia species (M. sympodialis, M.globosa) than unaffected controls. However, a study by Katsambas et al, failed to identify any Malassezia species on microscopic examination of pustules. Thus, the relationship between Malassezia and neonatal cephalic pustulosis is likely one of association, not causation.
Malassezia is a lipophilic saprophyte found on normal human skin of children and adults. Certain conditions, such as sebaceous gland activity, corticosteroid usage, and higher humidity can promote this yeast into its mycelia phase causing common skin conditions such as tinea versicolor or seborrheic dermatitis.
Colonization rates increase with age, with Malassezia found on the skin of 7%-50% of infants by 7 days of life. More than 90% of the adult population is chronically colonized.
Systemic Implications and Complications
There are no known associated systemic disorders or etiologies associated with this diagnosis. No further work-up is necessary once the diagnosis is made.
Topical ketoconazole 2% cream twice a day for 7-14 days
Optimal Therapeutic Approach for this Disease
1. Topical ketoconazole 2% cream twice a day for 7-14 days
The majority of lesions will improve within 7 days of treatment without erythema or scaling. Physicians may want to consider treatment if the cutaneous eruption is more severe or extensive or does not improve after several weeks of observation.
Lesions should resolve within 4 months of their first appearance. If the lesions do not resolve in a timely matter, a smear of a pustule for Tzanck preparation (to visualize prominent eosinophils in eosinophilic pustular folliculitis [EPF]), use of KOH preparation (to visualize Malassezia), and a Gram stain/culture will help direct further therapy and diagnosis.
Sterile pustules with eosinophils would suggest EPF, especially if the lesions were pruritic, caused fussiness in the child, and erupted in crops. Clinically, the pustules in EPF tend to rupture and develop a yellow crust quickly.
Providers should explain the benign nature of this condition to concerned parents and families, with reassurance that pustules and papules will resolve with therapy or on their own without sequelae. Side effects of topical ketoconazole include an allergic reaction, contact dermatitis, pruritus, or irritation.
Alternatively, parents can just employ observation, and the lesions will resolve within 4 months.
Unusual Clinical Scenarios to Consider in Patient Management
In cases of neonatal cephalic pustulosis refractory to treatment, alternative diagnoses should be considered. In a review of literature, refractory pustules in one infant showed eosinophilic folliculitis on skin biopsy.
In the author’s experience, a severe case of neonatal cephalic pustulosis in a premature, immunocompromised female infant with thrombocytopenia and absent radius syndrome was treated with intravenous fluconazole, with resolution of the eruption within 2 weeks. There are no reports or studies of fluconazole for the treatment of neonatal cephalic pustulosis to date in the literature.
What is the Evidence?
Ayhan, M, Sancak, B, Karaduman, A, Arikan, S, Sahin, S. “Colonization of neonatal skin by Malassezia species: relationship with neonatal cephalic pustulosis”. J Am Acad Dermatol. vol. 57. 2007. pp. 1012-8. (A study of 104 neonates, in which 25% of subjects developed neonatal cephalic pustulosis. Skin colonization rates with Malassezia increased with age (5% at 1 week, 30% at 2-4 weeks). Development and severity of neonatal cephalic pustulosis was not associated with higher rates skin colonization.)
Bergman, JN, Eichenfield, LF. “Neonatal acne and cephalic pustulosis: is Malassezia the whole story”. Arch Dermatol. vol. 138. 2002. pp. 255-7. (An editorial summarizing pertinent articles [published prior to 2002] on the relationship between Malassezia and neonatal cephalic pustulosis.)
Bernier, V, Weill, FX, Hirigoyen, V, Elleau, C, Feyler, A, Labreze, C. “Skin colonization by Malassezia species in neonates: a prospective study and relationship with neonatal cephalic pustulosis”. Arch Dermatol. vol. 138. 2002. pp. 215-8. (A series of 102 neonates and their mothers, which reported neonatal cephalic pustulosis present in 66% of infants. At birth and 3 weeks, 11% and 52% of neonates and 35% and 32% of mothers, respectively, had skin colonization with Malassezia. Of those with neonatal cephalic pustulosis, only 62% had positive Malassezia cultures. Thus, despite the strong correlation a definitive causation could not be proven.)
Katsambas, AD, Katoulis, AC, Stavropoulos, P. “Acne neonatorum: a study of 22 cases”. Int J Dermatol. vol. 38. 1999. pp. 128-30. (A study of twenty-two infants with neonatal acne. Of six biopsies taken, all were negative for yeast. However, it is unclear whether the distinction between neonatal cephalic pustulosis and neonatal acne was made in selecting subjects.)
Koseki, S, Takahashi, S. “Serial observation on the colonization of Pityrosporum orbiculare (ovale) on the facial skin surface of newborn infants”. Jpn J Med Mycol. vol. 29. 1988. pp. 209-15. (A report [in Japanese] of skin colonization rates in 410 neonates. At birth, 1 week, and 2-6 weeks, 54%, 86%, and 99% of infants, respectively, were colonized with Pityrosporum. Although skin colonization rates were similar between case and control groups, infants with neonatal cephalic pustulosis had significantly more spores with hyphae on microscopic review.)
Niamba, P, Weill, FX, Sarlangue, J, Labreze, C, Couprie, B, Taieb, A. “Is common neonatal cephalic pustulosis (neonatal acne) triggered by Malassezia sympodialis”. Arch Dermatol. vol. 134. 1998. pp. 995-8. (Approximately 12% of neonates had neonatal cephalic pustulosis in this study. Of nineteen controls and nineteen affected neonates, there was no difference in skin colonization rates of Malassezia furfur. However, infants with severe neonatal cephalic pustulosis were more likely to be colonized with Malassezia sympodialis.)
Rapelanoro, R, Mortureux, P, Couprie, B, Maleville, J, Taieb, A. “Neonatal Malassezia furfur pustulosis”. Arch Dermatol. vol. 132. 1996. pp. 190-3. (Approximately 10% of neonates had neonatal cephalic pustulosis. Malassezia was found in eight of thirteen cases examined; there was no corresponding control group to examine rates of skin colonization. Ketoconazole 2% cream was effective at treating this benign condition after twice daily use for 1 week.)
Raval, DS, Barton, LL, Hansen, RC, Kling, PJ. “Congenital cutaneous candidiasis: case report and review”. Pediatr Dermatol. vol. 12. Dec 1995. pp. 355-8. (This report examined features associated with congenital cutaneous candidiasis, which is on the differential diagnosis of any infant presenting with neonatal cephalic pustulosis. )
Smolinski, KN, Shah, SS, Honig, PJ, Yan, AC. “Neonatal cutaneous fungal infections”. Curr Opin Pediatr. vol. 17. 2005. pp. 480-93. (A report summarizing common fungal infections in neonates)
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