April 2001

A 3-day-old female infant was transferred to the Scott & White NICU from an outside hospital for an evaluation and treatment of a vesicular rash on her scalp, trunk and inner thighs, first noted on the second day of life. She was born at 39 weeks gestation by C-section for failure to progress. Membranes were ruptured approximately 8 hours prior to delivery. The fluid was clear and Apgar scores were 7 and 9 at 1 and 5 minutes, respectively. The baby’s blood and urine was cultured because of maternal fever (up to 102° F) and antibiotic therapy begun, but discontinued after 48 hours of negative cultures at the referring hospital. On the day of transfer, the patient was feeding well and vital signs were normal. Maternal cultures and lab tests, including VDRL, hepatitis B and HIV were all negative, and there was no history of maternal herpes simplex virus (HSV) infection.

Physical exam confirmed normal vital signs and revealed a mildly jaundiced infant with an erythematous, vesicular rash in whorl patterns over the parietal and occipital area of the scalp, the trunk and inner thighs, sparing the face (figures 1-6). The remainder of the exam was normal.

The patient had viral, bacterial and fungal cultures and stains performed on the lesions, and was empirically treated with intravenous acyclovir for the possibility of neonatal HSV infection. Bacterial and fungal stains were negative. The patient was monitored in the NICU and otherwise treated normally.

Dermatology obtained a biopsy of one of the lesions that showed numerous eosinophils within the superficial dermis and an area of hyperkeratosis.

What's Your Diagnosis?

1. Neonatal herpes simplex virus infection
2. Neonatal candidiasis
3. Erythema toxicum
4. Incontinentia pigmenti

Answer

This case turned out to be incontinentia pigmenti (IP), an X-linked dominant disorder with mortality in males, also known as Bloch-Sulzberger syndrome. Females with IP are mosaics. Variable presentation among patients is thought to be due to Lyonization. The term IP describes the histologic feature where there is incontinence of the melanocytes in the basal layer of the epidermis into the superficial dermis.

IP has manifestations in multiple body systems.

Cutaneous manifestations

Stage 1 is characterized by erythema, vesicles and/or pustules, which develop at birth or within a few weeks of birth. These lesions typically clear within 4 months. This phase is an inflammatory process with massive infiltration of eosinophils into the epidermis and marked leukocytosis with eosinophilia in up to 65% of patients. Stage 2 is noted by hyperkeratotic lesions that sometimes go unnoticed. Stage 3 is the hallmark of IP. It is characterized by hyperpigmentation, most often over the trunk, and occurring in whorls or streaks. These typically fade by the end of the second decade. Pale, hairless patches or streaks characterize stage 4. Nail involvement is variable. Dystrophy of the nails is noted in some as well. Hair is lusterless and coarse in about 50% of patients with occasional areas of alopecia.

Ophthalmologic manifestations

Avascular areas noted on the retina are the hallmark findings. These are due to abnormalities of the developing retinal vessels and underlying pigmented cells. The process usually stops without treatment. Approximately 10% of patients develop visual problems, which are typically unilateral in nature.

CNS manifestations

The central nervous system (CNS) is involved in approximately 30% of patients with IP. CNS manifestations include seizures, microcephaly, spasticity and mental retardation. Seizures during the neonatal period are indicative of a poor prognosis. Magnetic resonance imaging findings when present include hypoplasia of the corpus callosum, neuronal heterotopies and vessel occlusion in both large and small vessels. These occlusive events are thought to be similar to those seen in the retina.

Dental manifestations

Eighty percent of patients with IP have dental involvement, which persist through life. Findings noted are hypodontia, delayed eruption, impaction and malformation of the crowns. Teeth quality is usually normal.

Obtaining further history, the mother did report that she was diagnosed with IP as an infant and that her mother had it as well. Mother also stated that her older daughter also has IP and is doing well. Pediatric ophthalmology evaluated the patient and noted peripheral avascular retina bilaterally consistent with IP. Genetics consult was obtained and supported the diagnosis of IP through the given family history. The rash began to resolve prior to discharge. This infant did well and was discharged home on hospital day 3 (day 6 of age) with all cultures being negative and with the diagnosis of IP. Soon after discharge, the patient moved out of the area and was lost to follow-up.

Differential

Regarding the other choices, neonatal herpes simplex virus (HSV) infection is a legitimate concern in a newborn with a vesicular rash, and early treatment with acyclovir is essential. Even though it tends to appear 7 to 10 days of age rather than 3 days, and may have a positive prenatal history, neither of these features can rule out HSV. The lesions can look identical to those of IP.

It is widely recognized that there are 3 general categories of neonatal herpes infection: skin-eye-mouth disease, disseminated disease and isolated CNS disease. The clinical presentation is determined by the type of HSV infection, from overwhelming sepsis to a relatively asymptomatic vesicular rash, and everything in between. The timing of the rash in this patient, the lack of maternal history of herpes, the appearance of the lesions in “whorls,” the well being of the baby and the presence of eosinophils in the lesion make herpes unlikely. However, I cannot emphasize enough the importance of empiric treatment with acyclovir until the diagnosis is confirmed NOT to be HSV infection.

Congenital candidiasis or neonatal candidiasis is an infection of the newborn with Candida albicans (figures 7-10), depending on whether the baby acquires the infection in utero or postnatally. Figure 11 is a smear of a lesion showing the budding yeast typical of Candida. Ophthalmologic exam and urine fungal cultures can be used to look for evidence of dissemination. When this condition is diagnosed in a newborn, most experts recommend treating the baby with amphotericin B. We have adopted the use of liposomal amphotericin B in almost all patients, which is associated with less toxicity. Additionally, one can give much larger doses (up to 5 mg/kg/day) allowing for potentially shorter course of therapy. Figures 12 and 13 show the same baby after therapy with amphotericin B.

Erythema toxicum is a papulopustular rash of newborns (figures 14 and 15). The lesions typically are on erythematous bases, but not always, and tend to appear by day 2 of age. They are usually located on the trunk, but can occur anywhere, but usually not the palms and soles. They tend to last about 5 days with new lesions appearing for up to 2 weeks of age. The underlying cause is unclear, but it is self-limiting and requires no treatment except reassurance. The Gram’s stain is negative as well as the culture, but the fluid usually contains some eosinophils, as in IP.

IP is an uncommon disease that causes a vesicular rash in neonates. This diagnosis should be considered in any female neonate who presents with a vesicular rash. However, it is also important to rule out the infectious causes of vesicular rashes in neonates, which can be life threatening.

Neonatal HSV infection does share some features with IP but with a careful history and physical exam, differentiation between the 2 entities should be possible. The differences found include maternal and family history, the pattern and age of onset of the rash, and clinical stability of the patient. The rash in HSV is typically vesicular and usually has its onset after day 4 of life. The infant with HSV usually has signs of clinical instability. In IP, there is typically a positive family history. The rash is noted to be in whorls following a dermatomal distribution and may be present from birth. Clinically, these patients are stable.

The diagnosis of HSV or IP does not rule out the other diagnosis; however, and completion of the work-up for the cause of the rash is necessary because these 2 illnesses can coexist in the same patient. As seen in our patient, the rash was noted within the first 2 days of life and dermatomal in distribution. She was clinically stable and there was a positive family history of IP that helped direct us to the correct diagnosis. Patients with IP deserve early diagnosis so that they can be followed for the development of any of the other medical problems related to the disease.

Acknowledgment: Thanks go to Charles Oltorf, MD, Neonatologist at Scott & White for his assistance with this case.

For more information:

• Avery GB, Fletcher MA, MacDonald MG, eds. Neonatology: Pathophysiology and Management of the Newborn. 5th edition. Philadelphia: Lippincott, Williams and Wilkins, 1999.
• Landy SJ, Donnai D. Incontinentia pigmenti (Bloch-Sulzberger syndrome). J Med Genet. 1993;30:53-59.
• Lee AG, Goldberg MF, Gillard JH, et al. Intracranial assessment of incontinentia pigmenti using magnetic resonance imaging, angiography, and spectroscopic imaging. Arch Pediatr Adolesc Med. 1995;149:573-580.
• Menkes JH, Sarnat HB, eds. Child Neurology, 6th edition. Philadelphia: Lippincott, Williams and Wilkins, 2000.
• Scully RE, Mark EJ, McNeely WF, McNeely BU. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises. N Engl J Med. 1989;320:1399-1410.
• Stitt WZD, Scott GA, Caserta M, Goldsmith LA. Coexistence of incontinentia pigmenti and neonatal herpes simplex virus infection. Pediatr Dermatol. 1998;15:112-115.
• Taeusch HW, Ballard RA, eds. Avery’s Diseases of the Newborn. 7th edition. Philadelphia: W.B. Saunders, 1998.