NeoQuest December 2023: Preterm Newborn with a Rash

A preterm male infant is born with skin lesions on a finger, back, and abdomen after birth (Figure 1A and 1B). The pregnancy was complicated by maternal Chlamydia trachomatis and Trichomonas vaginalis infections, fetal cerebral ventriculomegaly with suspected Dandy-Walker malformation noted on prenatal ultrasound, and premature rupture of membranes.

 
Figure 1. A. Skin lesion on the left fourth digit. B. Erythematous skin erosions and peeling on lower back and abdomen. Image from: Hanford J, Liu C, Elkeeb A, Byland R. Rash at birth in a preterm neonate. Neoreviews. 2023;24(12):e809–e813¹

Question: Which of the following features is most likely associated with this condition?

1. Chorioretinal scars
2. Blisters from minor friction trauma
3. Eosinophilia
4. Mutations in genes for keratin
5. Transplacental transfer of pathogenic maternal IgG antibodies

Answer: A. Chorioretinal scars

Explanation:

The infant in this vignette presents with an intact tense, serous bulla (Figure 1A) and skin erosions (Figure 1B) at birth in the setting of a pregnancy complicated by maternal sexually transmitted infections, congenital intracranial anomalies, and premature rupture of membranes. This constellation of signs and symptoms should raise suspicion for an intrauterine infection such as herpes simplex virus (HSV).

Neonatal HSV can be acquired in utero (< 5%), peripartum (85%), or after birth (10%).^2–4 In rare cases of intrauterine transmission, HSV in the pregnant person infects the fetus via transplacental spread through the hematogenous route or an ascending infection from a colonized genital tract.^5,6 As a result, an intrauterine HSV infection presents with a range of multiorgan manifestations at birth or within the first 48 hours after birth.^5,6 In contrast, the more common peripartum HSV infection usually presents with symptoms between 5 to 14 days after birth. Mucocutaneous lesions, severe central nervous system disease (eg, microcephaly, hydrocephalus, hydranencephaly, and encephalomalacia), and ophthalmologic findings (eg, chorioretinitis [Option A] and microphthalmia) are features seen in the classic triad of intrauterine HSV.^5,6 Of note, this clinical triad of symptoms are seen in only 30% of patients with intrauterine HSV.⁷ Particular attention should be made to the onset and type of skin lesions that are exhibited in 90–95% of infants with intrauterine HSV—preexisting bullae, erosions, skin denudement, and scarring at birth or shortly after delivery.⁸ These skin lesions differ from the classic dermatologic findings in peripartum acquired infections—grouped vesicular lesions that typically present within 1 to 3 weeks after birth.^2–4 Intrauterine HSV is associated with high neonatal morbidity and mortality; thus, a high index of suspicion for HSV infection in neonates born with bullae or erosions is important.^5,6 Timely sepsis evaluation, including HSV testing and an investigation for Toxoplasmosis, Other (syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirus, and Herpes infections (TORCH), should be performed to rule out alternative infectious etiologies that may manifest in a similar manner. Prompt recognition of HSV and treatment with intravenous acyclovir may prevent further disease progression.²

Figure 2. Tense bullae (A) and peeling erosions (B) seen in epidermolysis bullosa. Images from: Ahmad RS, O’Regan GM, Bruckner AL. Blisters and erosions in the neonate. Neoreviews. 2011;12(8):e453–462²

Figure 3. Dystrophic nails exhibited in an infant with severe junctional EB. Images from: Lucky AW, Whalen J, Rowe S, et al. Diagnosis and care of the newborn with epidermolysis bullosa. Neoreviews. 2021;22(7):e438–e451⁹

Apart from HSV and other TORCH infections, it is important to acknowledge that there are several less common, non-infectious etiologies responsible for blisters and erosions in a neonate that should be considered during diagnostic evaluation (eg, epidermolysis bullosa, incontinentia pigmenti, epidermolytic ichthyosis, and pemphigus vulgaris). Epidermolysis bullosa (EB) refers to a group of rare hereditary blistering skin diseases that have been linked to multiple genes that code for structural proteins involved in maintaining the integrity of the basement membrane.^2,9 The inheritance pattern can vary depending on the type and subtype of EB, with the majority of EB cases following an autosomal dominant pattern. This condition leads to extremely fragile skin, resulting in friction-induced blisters (Option B), tense bullae (Figure 2A), and erosions (Figure 2B) at birth, mimicking intrauterine HSV.^2,9 In addition to mechanically fragile skin, the presence of nail abnormalities (Figure 3), including dystrophic nails (48.6%), anonychia (43.2%), and pachyonychia (40.5%), is frequently exhibited in patients with EB. This occurs as a  result of similar protein expression found in the basement membranes of nail structures and normal skin. Thus, individuals with EB who have gene abnormalities affecting integral proteins crucial for the structure and function of the dermoepidermal junction may present with abnormalities in both the skin and nail.¹⁰ Although infants with EB can have multiorgan involvement consisting of infectious, respiratory, genitourinary, and gastrointestinal comorbidities, neurologic issues are not associated with EB. The neonate in the vignette has no family history of dermatologic conditions and presents with normal nails (Figure 1A) and intracranial abnormalities, which are not consistent with EB.

Figure 4. Incontinentia pigmenti rash evolution over time. A. Presentation of vesiculobullous skin lesions distributed along the lines of Blaschko during the 2^nd week of age. B. Skin lesions evolving into hyperpigmented brownish macules and papules that follow the lines of Blaschko distribution by the 3^rd week of age. Images from: Pal S, Jain A, Chopra A, et al. A newborn with a changing rash. Neoreviews. 2019;20(12):e740–e743¹¹

Incontinentia pigmenti (IP) is a rare, X-linked multisystem disease that is lethal for males but has a variable phenotype in female neonates.^2,11 The cutaneous abnormalities observed in IP may appear as early as birth and evolve over time in four stages: vesicular, verrucous, hyperpigmented, and hypopigmented.¹¹ The only skin findings that manifest in the neonatal period are vesicular lesions seen in stage 1 IP, which can be mistaken for HSV blisters. Specifically, stage 1 lesions are erythematous blisters that form within the first two weeks after birth along the lines of Blaschko, which are pathways of mesodermal and epidermal cell migration during fetal development (Figure 4A and B).^2,11 Although these lesions may resemble HSV vesicles, newborns with IP typically are well-appearing at birth, where infants with perinatal HSV infections are often ill-appearing.^2,11 Patients with IP have multisystem involvement, affecting the eyes, oral cavity, teeth, and central nervous system. Ocular disease in IP can present as a wide spectrum of retinal and nonretinal involvement that include avascularity, neovascularization, hemorrhages, retinal detachments, optic nerve atrophy, strabismus, and cataracts.¹² Common central nervous system features include microcephaly, seizures, intellectual disability, and motor dysfunction.¹¹ Another classic feature of IP is eosinophilia in the blood (Option C). The neonate in the vignette is male with skin lesions at birth that do not follow the lines of Blaschko, which makes IP unlikely in this case.

Figure 5. Sharply demarcated, superficial erosions seen in epidermolytic ichthyosis. Image from: Ahmad RS, O’Regan GM, Bruckner AL. Blisters and erosions in the neonate. Neoreviews. 2011;12(8):e453–462²

Epidermolytic ichthyosis (EI), formerly known as bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a rare autosomal dominant dermatologic disorder involving genes that encode for keratin 1 or keratin 10 (Option D).² Hallmark characteristics of EI include widespread erythroderma, poorly functioning skin barrier, and the gradual transition from severe blistering at birth to hyperkeratosis (Figure 5).²  In contrast to other forms of ichthyosis, EI is the only type to appear as blisters and erosions in the newborn period, posing a challenge in differentiating it from other bullous skin conditions.² However, EI is unlikely in this case due to the absence of a family history of EI, the presence of a congenital brain malformation, and intact skin integrity in unaffected areas.

Figure 6. Skin erosion over the sacrum of a neonate with pemphigus vulgaris. Image from: Mientus AM, Duncan SD. Skin erosions in a newborn. Neoreviews. 2021;22(11);e786-789¹³

Neonatal pemphigus vulgaris (PV) is a rare and transient autoimmune blistering skin condition where pathogenic maternal IgG antibodies (Option E) cross the placenta and attack the fetal Dsg1 and/or Dsg3 glycoproteins in the epidermis, resulting in blisters and erosions at the time of birth.¹³ These lesions (Figure 6) begin as flaccid bullae and typically heal in 3 to 4 weeks as the maternal antibodies degrade and wane.^2,13 The presentation of neonatal pemphigus vulgaris classically occurs in infants born to mothers with active disease, and thus, a thorough maternal health history can reveal the diagnosis.^2,13 The patient in this vignette has a tense bullous lesion that is not typical of PV, and there is no maternal history of skin lesions, making the diagnosis of PV less likely for this patient.

Did you know?

Unlike HSV encephalitis in infants over 3 months old, which has a predilection for focal temporal lobe involvement, neonatal HSV can affect various regions of the brain, often involving multiple areas simultaneously.⁴

What dermatological manifestation is seen in trisomy 21, Cornelia de Lange syndrome, and homocystinuria?

To find the answer, please read the following article: Goodarzi H, Wu TT, Wang J, Teng JM. Neonatal dermatology: the normal, the common, and the serious. Neoreviews. 2021;22(1):e40–51.³

NeoQuest December 2023 Authors:

Allison N. J. Lyle, MD, MA, University of Louisville
Neena Jube-Desai, MD, MBA, University of Maryland

References:

1. Hanford J, Liu C, Elkeeb A, Byland R. Rash at birth in a preterm neonate. Neoreviews. 2023;24(12):e809–e813
2. Ahmad RCS, O’Regan GM, Bruckner AL. Blisters and erosions in the neonate. Neoreviews. 2011;12(8):e453–e462
3. Goodarzi H, Wu TT, Wang J, et al. Neonatal dermatology: the normal, the common, and the serious. Neoreviews. 2021;22(1):e40–e51
4. Kimberlin DW. Herpes simplex virus infections in neonates and early childhood. Semin Pediatr Infect Dis. 2005;16(4):271–281
5. Marquez L, Levy ML, Munoz FM, et al. A report of three cases and review of intrauterine herpes simplex virus infection. Pediatr Infect Dis J. 2011;30(2):153–157
6. Knox AT, Powell SB, Logan LK. Intrauterine herpes simplex virus infection in a monochorionic twin gestation. J Pediatric Infect Dis Soc. 2012;1(2):157–159
7. Drumm C, Caufield M, DeKlotz C, et al. Intrauterine herpes simplex virus infection presenting as a zosteriform eruption in a newborn. AJP Rep. 2018;08(01):e33–e36
8. Cliff S, Ostlere LS, Haque K, et al. Segmental scarring following intrauterine herpes simplex virus infection. Clin Exp Dermatol. 1997;22(2):96–98
9. Lucky AW, Whalen J, Rowe S, et al. Diagnosis and care of the newborn with epidermolysis bullosa. Neoreviews. 2021;22(7):e438–e451
10. Pastrana‐Arellano E, Morales‐Olvera D, García‐Romero MT. Nail involvement in patients with epidermolysis bullosa: a systematic review. Skin Health Dis. 2023;3(1):e183
11. Pal S, Jain A, Chopra A, et al. A newborn with a changing rash. Neoreviews. 2019;20(12):e740–e743
12. Goldberg MF, Custis PH. Retinal and other manifestations of incontinentia pigmenti (Bloch-Sulzberger syndrome). Ophthalmology. 1993;100(11):1645–1654
13. Mientus AM, Duncan SD. Skin erosions in a newborn. Neoreviews. 2021;22(11):e786–e789