What is the differential diagnosis for an 8-day-old male presenting with a bullous/vesicular rash with desquamation on the fingertips, glans penis, abdomen, and pubic region, who is afebrile with stable vital signs and has a negative cerebrospinal fluid (CSF) result for herpes simplex virus (HSV)?

Differential Diagnosis for Bullous/Vesicular Rash in an 8-Day-Old Male

Despite the negative CSF HSV PCR, neonatal herpes simplex virus infection remains the most critical diagnosis to consider, as vesicular rash is present in only approximately 60% of neonates with CNS or disseminated disease, and skin-limited HSV can occur without CNS involvement. 1

Primary Differential Considerations

Neonatal Herpes Simplex Virus (Most Critical)

• Localized skin, eye, and mouth (SEM) disease accounts for approximately 40% of neonatal HSV cases and typically presents at 10-11 days of age with vesicular lesions 1
• The distribution involving fingertips, glans penis, abdomen, and pubic region is consistent with HSV, which can affect any skin surface 1
• Critical pitfall: A negative CSF HSV PCR does not exclude cutaneous HSV disease, as only 60% of neonates with skin disease have CNS involvement 1
• Vesicles contain clear fluid with infectious viral particles that burst and form shallow ulcers with desquamation, matching this presentation 1
• Immediate action required: Obtain cultures from skin vesicles, blood, mouth/nasopharynx, eyes, urine, and stool/rectum to confirm diagnosis 1, 2
• Direct immunofluorescence from lesion scrapings can provide rapid diagnosis 1

Staphylococcal Scalded Skin Syndrome (SSSS)

• Presents with bullous lesions and desquamation in neonates, typically involving perioral, periorbital, and flexural areas
• Usually accompanied by fever and irritability, which this patient lacks
• The afebrile presentation and stable vital signs make this less likely, but bacterial culture should be obtained

Bullous Impetigo

• Caused by Staphylococcus aureus producing exfoliative toxins
• Presents with flaccid bullae that rupture easily leaving denuded areas
• Can affect any body surface including genitals
• The well-appearing, afebrile status is consistent with localized impetigo
• Gram stain and culture of vesicular fluid would be diagnostic

Epidermolysis Bullosa (EB)

• Genetic blistering disorder presenting at or shortly after birth
• Bullae develop at sites of minor trauma (fingertips consistent with this)
• Typically involves extremities, but can affect any area
• Family history and distribution pattern help distinguish from infectious causes
• Skin biopsy with immunofluorescence mapping is diagnostic

Incontinentia Pigmenti (Stage 1)

• X-linked dominant disorder presenting with vesicular eruptions in first weeks of life
• Lesions typically follow Blaschko's lines in linear distribution
• The described distribution doesn't clearly follow this pattern, making it less likely
• More common in females; males are rarely affected

Diagnostic Algorithm

Step 1: Immediate HSV Testing (Highest Priority for Morbidity/Mortality)

• Obtain viral cultures from vesicle fluid, blood, mouth, eyes, urine, and stool 1, 2
• Direct immunofluorescence from lesion scrapings for rapid results 1
• Even with negative CSF, skin-limited HSV requires 14 days of IV acyclovir at 20 mg/kg/dose three times daily 1, 2

Step 2: Bacterial Evaluation

• Gram stain and bacterial culture from vesicular fluid
• Blood culture if any concern for systemic involvement
• Consider Staphylococcus aureus PCR for rapid identification

Step 3: Consider Non-Infectious Causes if Infectious Workup Negative

• Dermatology consultation for suspected epidermolysis bullosa
• Skin biopsy with immunofluorescence if genetic blistering disorder suspected
• Genetic testing if clinical features suggest incontinentia pigmenti

Critical Management Points

Empiric IV acyclovir should be strongly considered while awaiting culture results given the catastrophic consequences of untreated neonatal HSV 1, 2

• The well-appearing status does not exclude HSV, as 40% of neonatal HSV presents as localized skin disease 1
• Neonates with skin lesions may have cutaneous recurrences during the first 6 months even after successful treatment 1, 2
• Positive cultures from skin, mouth, eyes, urine, or stool obtained >48 hours after birth indicate viral replication rather than intrapartum contamination 1

Common Pitfalls to Avoid

• Do not rely solely on negative CSF HSV PCR to exclude neonatal herpes—skin-limited disease is a distinct entity 1
• Do not delay acyclovir therapy while awaiting culture results if HSV is suspected, as early treatment dramatically improves outcomes 1, 2
• Do not assume the well-appearing status excludes serious infection—80% of children with localized skin, eye, or mouth HSV disease have vesicular rash and may appear well initially 1
• Vesicular rash on the glans penis in a newborn should always prompt consideration of HSV acquired during delivery 1