What are the differential diagnoses for a newborn presenting with a blister on the shaft or glans of the penis?

Differential Diagnoses for Penile Blisters in Newborns

In a newborn with a blister on the penile shaft or glans, the primary differential diagnoses include neonatal herpes simplex virus infection, epidermolysis bullosa, staphylococcal scalded skin syndrome, transient neonatal pemphigus from maternal autoimmune disease, hand-foot-and-mouth disease, and traumatic blistering from birth or instrumentation.

Infectious Causes

Neonatal Herpes Simplex Virus (HSV)

• HSV is the most critical diagnosis to exclude due to its life-threatening nature and potential for devastating neurological sequelae if untreated 1, 2.
• Newborns born to mothers with genital herpes during pregnancy or those presenting with vesicles, vesicular rash, or crusts on skin should be tested for HSV 3.
• Vesicles contain clear fluid with high viral particle concentrations, which burst to form shallow ulcers or erosions that crust and heal without scarring 4, 5.
• Laboratory confirmation is essential as clinical diagnosis alone is unreliable; collect vesicular fluid for viral culture, PCR (most sensitive), or immunofluorescence 6, 3.
• HSV typically presents within 2-10 days of exposure (up to 4 weeks), though neonatal acquisition usually occurs perinatally during passage through an infected birth canal 3, 2.

Staphylococcal Scalded Skin Syndrome (SSSS)

• Caused by exfoliative toxins (type A or B) from Staphylococcus aureus that induce proteolysis and separation of the granular epidermis layer 7.
• Presents with skin redness and formation of bubbles filled with serous or serous-bloody content 7.
• Bacteriological testing of blister fluid is mandatory to identify or exclude staphylococcal infection 8.

Hand-Foot-and-Mouth Disease (HFMD)

• HFMD in the genital region presents with maculopapular eruptions progressing to vesicles containing clear fluid with high viral concentrations 4.
• Vesicles burst forming shallow ulcers that heal without scarring, distinctly different from diaper rash 4.
• Key distinguishing feature: HFMD typically has associated lesions on hands, feet, or oral mucosa, unlike isolated genital HSV 4.
• May be misdiagnosed as genital herpes due to similar vesicular appearance 4.

Autoimmune/Immunologic Causes

Transient Neonatal Pemphigus

• Results from transplacental passage of maternal pemphigus IgG antibodies in mothers with pemphigus vulgaris, pemphigus foliaceus, or bullous pemphigoid 7.
• Critical history: maternal autoimmune blistering disease should prompt consideration of this diagnosis 8.
• Presents with multiple blisters filled with serous or serous-bloody content, often widespread 7.
• Diagnostic testing: serum IgG and IgA antibody levels in the neonate, plus immunofluorescence of skin biopsy to detect antibodies 7.
• Generally has good prognosis except for linear IgA bullous dermatosis, which requires aggressive treatment 8.

Inherited Genodermatoses

Epidermolysis Bullosa (EB)

• A group of rare genetic disorders characterized by fragile skin that blisters with minimal trauma 9.
• Suspect when: family history of genodermatoses or consanguinity is present 8.
• Classification updated in 2020, now based primarily on genetic rather than clinical features 9.
• Diagnostic approach: next-generation sequencing panel for all EB types, with immunofluorescence and electron microscopy of skin biopsies in special circumstances 9.
• Can affect genitourinary system as an associated comorbidity 9.

Non-Infectious Causes

Traumatic Blistering

• May occur from birth trauma, instrumentation during delivery, or friction 8.
• Usually isolated lesion without systemic symptoms or progression 8.
• History of difficult delivery or instrumentation is key diagnostic clue.

Diagnostic Algorithm

Immediate steps for any newborn with penile blistering:

1. Obtain detailed maternal history: genital herpes during pregnancy, autoimmune blistering diseases, family history of genodermatoses or consanguinity 3, 8, 7.

2. Collect vesicular fluid immediately before lesions rupture:

   • Open vesicles with sterile needle 3
   • Swab for viral culture, PCR (HSV), and bacterial culture 3, 8
   • Apply to microscope slide for immunofluorescence 3

3. Initiate empiric acyclovir if HSV cannot be excluded, given the life-threatening nature and effectiveness of early treatment 1, 2.

4. Examine for additional lesions: hands, feet, oral mucosa (HFMD), widespread skin involvement (pemphigus, EB, SSSS) 4, 8, 7.

5. Laboratory workup:

   • Neonatal serum IgG and IgA antibody levels if maternal autoimmune disease suspected 7
   • Skin biopsy with immunofluorescence if autoimmune or inherited causes considered 8, 7, 9
   • Genetic testing if EB suspected based on family history 9

Critical Pitfalls to Avoid

• Never rely on clinical diagnosis alone for genital ulceration in newborns, as HSV, HFMD, and other causes appear similar 6, 4.
• Do not delay empiric acyclovir while awaiting HSV test results if clinical suspicion exists, as outcomes depend on early treatment 1, 2.
• Do not assume isolated genital lesions exclude systemic infection; neonatal HSV can present with localized skin lesions before dissemination 1, 2.
• Maternal antibody titers and clinical condition do not predict severity of transient neonatal pemphigus 7.
• Extensive skin damage from any blistering cause creates infection risk and disrupts thermoregulation and fluid-electrolyte balance, requiring aggressive supportive care 7.