NeoQuest November 2021: A Blistering Neonatal Rash

A term male infant born via planned caesarean section has neck and buttock skin findings at birth (Figure 1). Based on a family history of similar lesions, as well as a skin biopsy with immunofluorescence testing revealing IgG antibodies, the dermatologist counsels the family that the lesions are expected to resolve spontaneously by one month of age with supportive wound management.

Figure 1. Mientus A, Duncan S. Skin erosions in a newborn. Neoreviews. 2021;22(11):e76. doi:10.1542/neo.22-11-e76

What intervention should be recommended to this mother to decrease the risk of similar skin findings in future children?

A. Administer topical and systemic corticosteroids during future pregnancies
B. Avoid delivering vaginally with subsequent pregnancies
C. Collect third trimester nasal swabs for microbiological cultures in future pregnancies
D. Obtain a rapid plasma reagin test prior to conception and during pregnancy
E. Refer for pre-conception genetic counseling and testing

Answer: A. Administer topical and systemic corticosteroids during future pregnancies

Explanation:

Figure 1 illustrates superficial skin erosions with central granulation tissue at the nape of the infant’s neck and buttocks. The differential diagnosis of skin blisters and erosions in a neonate is vast and includes infectious, immune-mediated, and genetic etiologies. Given the family history of similar lesions, a skin biopsy notable for IgG antibody presence on immunofluorescence testing, and anticipated spontaneous resolution with minimal intervention, these lesions are most consistent with neonatal pemphigus vulgaris (PV).

Neonatal PV is a rare transient blistering skin condition that occurs when a fetus is exposed to maternal IgG autoantibodies from a pregnant woman with PV. PV is an autoimmune bullous disorder characterized by the loss of cell adhesion in the intraepithelial layer due to IgG autoantibodies against desmoglein-1 (Dsg1) and/or desmoglein-3 (Dsg3), which are glycoproteins integral in maintaining tissue integrity.² When maternal autoantibodies against Dsg1 and Dsg3 are present during pregnancy, they can passively cross the placenta and bind to the fetal epidermis, resulting in bullae, blisters, and skin erosions at birth. Diagnosis of neonatal PV requires a high clinical suspicion and can be confirmed on skin biopsy utilizing hematoxylin and eosin stains, as well as direct or indirect immunofluorescence to identify autoantibodies.³ The degree of severity of the neonatal presentation and outcome are independent of the maternal disease burden.^3–6 Unlike other etiologies of blistering, most neonatal PV resolves within 3–4 weeks with supportive care focused on wound healing and infection prevention.⁶ Typically, neonatal therapy does not require systemic immunosuppressive agents.⁶ Although neonatal PV has an overall favorable prognosis, fetal outcomes in a pregnancy complicated with PV can include spontaneous abortion, stillbirth, preterm birth, and low birth weight.⁷ Therefore, antenatal surveillance, discontinuation of teratogenic PV medications (eg, methotrexate, cyclophosphamide), and initiation of non-teratogenic PV treatment (topical and systemic corticosteroids, intravenous immunoglobulin, or plasmapheresis) are highly recommended (Option A) (Figure 2).⁷

Figure 2. Pre-conception and intrapartum management and treatment strategies in women with PV. ABSIS, Autoimmune Bullous Skin Disorder Intensity Score; ELISA, enzyme-linked immunosorbent assay; IVIg, intravenous immunoglobulin therapy; MMF, mycophenolate mofetil; MTX, methotrexate; PDAI, Pemphigus Disease Area Index. Permission granted for image reproduction from: Genovese G, Derlino F, Berti E, Marzano AV. Treatment of autoimmune bullous diseases during pregnancy and lactation: a review focusing on pemphigus and pemphigoid gestationis. Front Pharmacol. 2020;11:583354.⁷

Like immune-mediated disorders, infectious etiologies such as herpesvirus (HSV), Staphylococcus aureus (S. aureus), and congenital syphilis can also present with various degrees of neonatal blistering and skin erosion, although this infant’s rash is not typical for these infections (Table).⁸ In addition, dermatology notes a favorable prognosis with spontaneous resolution of this infant’s lesions, which is not consistent with HSV, S. aureus, or syphilis, as these infections require curative antiviral or antibiotic therapy. Additionally, positive immunofluorescence testing for IgG antibodies makes an underlying autoimmune process most likely.

Table. Summary of common infectious etiologies of neonatal blisters and erosions. Table from: Ahmad R, O'Regan G, Bruckner A. Blisters and Erosions in the Neonate. Neoreviews. 2011;12: e453-462.⁸

If a neonate is positive for HSV lesions, maternal antenatal surveillance for active lesions during future pregnancies and labor is critical. In the presence of active genital ulcers at the onset of labor, it is recommended to avoid vaginal delivery. In this situation, delivery via cesarean section without labor or rupture of membranes would be helpful to decrease the risk of the neonate contracting HSV and developing clinical symptoms (Option B).⁹

Toxins released by S. aureus can cause bullous impetigo, and in more severe cases, staphylococcal scalded skin syndrome (SSSS). One prospective study noted an increased neonatal S. aureus carriage risk to those born vaginally to pregnant women with culture-proven vaginal S. aureus.¹⁰ However, there is no evidence that S. aureus nasal swab screening or decolonization of a mother is an effective intervention in preventing skin lesions from forming in future children (Option C).

Syphilis must be evaluated in all pregnant women, especially in women who have previously given birth to a child with congenital syphilis. Obtaining a rapid plasma reagin (RPR) test during future pregnancies will detect if a woman is reinfected and aid in the prevention of vertical transmission to her fetus (Option D).

Inherited skin conditions like epidermolysis bullosa, bullous congenital ichthyosiform erythroderma, and incontinentia pigmenti must be considered in any neonate with bullous and ulcerative lesions. In these conditions, the type of blister formation, extent of disease, and prognosis can vary, depending on the mutation or defect. Thus, genetic counseling and testing for these aforementioned inherited skin conditions will provide guidance in the care of the neonate affected and assist in determining the risk of recurrence in future offspring (Option E). Generally, even mild presentations of inherited skin disorders do not resolve completely (in contrast to the dermatologist’s prognosis), and individuals may have cutaneous and/or multisystemic effects into adulthood. As PV is an immunologic disorder, rather than an inherited skin disorder, genetic counseling and testing are not routinely recommended.

Did you know?

• Neonatal PV typically presents with a diffuse distribution of lesions affecting both skin and mucosa, which contrasts with adult PV where lesions tend to localize to the mucosa. This difference in presentation is a direct result of the variation in expression of Dsg3 in neonates (diffuse distribution throughout the entire epidermis) and adults (localized expression in the deep layers of the epidermis).¹¹
• If there is a strong suspicion for neonatal PV based on maternal history, testing the neonate’s serum for Dsg1 and Dsg3 antibodies via enzyme-linked immunosorbent assay may help establish a diagnosis when the option to perform a skin biopsy is limited or unavailable.^{5, 6}

A neonate is noted to have multiple skin erosions and red-brown papules in the diaper region. What key feature on skin biopsy aids in the diagnosis of this skin finding? Once a diagnosis is made, what further systemic evaluation must be performed?

To learn more about this and other etiologies of blisters and skin erosions, read the following article:

• Ahmad R, O'Regan G, Bruckner A. Blisters and erosions in the neonate. Neoreviews. 2011;12(8):e453–462.

NeoQuest November Authors
Neena Jube-Desai, MD, MBA, FAAP, University of Maryland
Elizabeth V. Schulz, MD, FAAP, Uniformed Services University

References:

1. Mientus A, Duncan S. Skin erosions in a newborn. Neoreviews. 2021;22(11):e76. doi:10.1542/neo.22-11-e76
2. Foster ML, Spaulding RT, Schadt CR. Neonatal pemphigus vulgaris. JAMA Dermatol. 2021;157(2):220
3. Turrentine JE, Sokumbi O, Agim NG. Blisters and erosions in a neonate. JAMA Dermatol. 2014;150(11):1223–1224
4. Fenniche S, Benmously R, Marrak H, Dhaoui A, Ammar FB, Mokhtar I. Neonatal pemphigus vulgaris in an infant born to a mother with pemphigus vulgaris in remission. Pediatr Dermatol. 2006;23(2):124–127
5. Gushi M, Yamamoto Y, Mine Y, et al. Neonatal pemphigus vulgaris. J Dermatol. 2008;35(8):529–535
6. Zhao CY, Chiang YZ, Murrell DF. Neonatal autoimmune blistering disease: a systematic review. Pediatr Dermatol. 2016;33(4):367–74
7. Genovese G, Derlino F, Berti E, Marzano AV. Treatment of autoimmune bullous diseases during pregnancy and lactation: a review focusing on pemphigus and pemphigoid gestationis. Front Pharmacol. 2020;11:583354
8. Ahmad R, O'Regan G, Bruckner A. Blisters and erosions in the neonate. Neoreviews. 2011;12(8):e453–462
9. Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA. 2003;289(2):203–209
10. Campo-Voegeli A, Muñiz F, Mascaró JM, et al. Neonatal pemphigus vulgaris with extensive mucocutaneous lesions from a mother with oral pemphigus vulgaris. Br J Dermatol. 2002;147(4):801–805