Dermatology Quiz and Case Discussion
From The Child's Doctor, Fall 2011
- Jennifer Sorrell, MD
- Dermatology Resident, Northwestern University Feinberg School of Medicine
- Disclosure: Dr. Sorrell has no industry relationships to disclose and does not refer to products that are still investigational or not labeled for the use in discussion.
- Amy Paller, MD
- Attending physician, Dermatology, Ann & Robert H. Lurie Children's Hospital of Chicago; Walter J. Hamlin Professor and Chair of Dermatology, Professor of Pediatrics, Northwestern University Feinberg School of Medicine
- Disclosure: Dr. Paller has no industry relationships to disclose and does not refer to products that are still investigational or not labeled for the use in discussion.
Other Disclosure Information
At the conclusion of this activity, participants will be able to:
Recognize the disorder described in the vignette and shown in the photograph
Describe the clinical features and causes of the condition
Discuss the management approaches
1. The most likely diagnosis is:
a. Herpes simplex
b. Varicella zoster
c. Incontinentia pigmenti
d. Neonatal candidiasis
2. Diagnosis can be confirmed by which of the following tests?
a. Skin biopsy
b. Viral culture
c. Potassium hydroxide examination
d. Testing for Darier sign
3. In addition to Dermatology, important consultations for team care include all of the following EXCEPT:
Answers: 1c, 2a, 3c
Discussion: Incontinentia pigmenti (IP) often presents with characteristic cutaneous abnormalities during the first month of life, although lesions may be present at birth. Early diagnosis is particularly important, given the early association with neurologic and ophthalmologic complications. Four stages of skin lesions have been described, although these stages often overlap and the minority of affected individuals have all stages. Lesions usually occur in a curvilinear pattern, following the lines of Blaschko, lines of embryologic development of the ectoderm.
The patterning of lesions is the best clue to diagnosis, although the “line” is often the “best fit” pattern of lesions. The initial lesions are vesicular and inflammatory, reflecting the intraepidermal collection of eosinophils seen by routine histologic evaluation of lesional skin. Lesions may appear pustular if the eosinophilic infiltration is extensive. Typically, peripheral eosinophilia accompanies the intraepidermal eosinophils, with levels of eosinophils as high as almost 90%. As these clear during the next weeks to months, verrucous papules and plaques may be noted, which may persist for up to 6 months. The third stage is characterized by hyperpigmented streaks and whorls along Blaschko’s lines, which usually fade by adolescence, although persistence of localized areas of hyperpigmentation into adulthood is not unusual. The minority of patients show streaks of atrophy, alopecia and/or hypopigmentation, which has been considered the fourth stage of IP. In up to 10% of patients, verrucous lesions or even pigmentary streaks are seen without a known history of preceding lesions, suggesting in utero vesiculation. The inflammatory stage may recur with illness, such as upper respiratory infections in infancy, childhood and even young adulthood.
While the cutaneous manifestations are key to making the diagnosis of IP, it is important to recognize the other systems that can be involved. The central nervous system has been reported to be affected in anywhere from less than 10% to up to 30% of patients and may manifest as seizures and developmental delay. Given the early appearance of vesicles in neonates with associated seizures, neonatal herpes is often considered, leading to administration of acyclovir after cultures are obtained. Although the lesions of herpes simplex (and certainly varicella zoster) may show a dermatomal distribution, the multiple lesions in their curvilinear array are typical of IP.
Eye findings can be seen in about one-third of patients and the hallmark finding is abnormal retinal vessels, which in the minority of affected individuals can lead to blindness or retinal detachment. Eye changes can also include strabismus, microphthalmia and myopia; however the overwhelming majority of patients with IP have normal vision. Some babies with IP have been misdiagnosed as abused, given the sometimes purplish appearance of the inflammatory lesions, especially with darker skin, the retinal vessel abnormalities suggesting shaken baby, and seizures.
Dental anomalies are a later manifestation and are reminiscent of those of hypohidrotic ectodermal dysplasia, with partial anodontia, delayed dentition and conical teeth. Onychodystrophy (ie, malformed or discolored nails) and focal areas of cicatricial alopecia are not uncommon manifestations.
IP is an X-linked dominant disorder that affects predominantly females. Because the disorder is usually lethal in males without a normal X-chromosome, an affected mother may report a history of miscarriages. Male individuals may survive because of the presence of 1 or more extra X chromosomes (Klinefelter syndrome) or post-zygotic mosaicism. The disorder results from mutations in the gene at chromosome Xq28 encoding nuclear factor kappa B (NF-kB) essential modulator (also called NEMO or IKBKG, inhibitor of kappa light polypeptide gene enhancer in B cells, kinase gamma). The gene product of NEMO activates NF-kB, a transcription factor that protects cells from apoptosis. The disappearance of the cutaneous lesions of IP is thought to result from the selective survival advantage of normal skin cells vs. the cells with the mutation. Approximately 85% of individuals with IP have NEMO mutations that lead to a deletion from exon 4 through exon 10. However, NEMO mutations (usually missense) in exon 10 can also cause IP in girls. These “hypomorphic” mutations are associated with the occurrence of hypohidrotic ectodermal dysplasia with immunodeficiency in their male offspring.
Fortunately, the cutaneous manifestations of IP largely clear by childhood. Affected individuals occasionally show 1 or more persistent streaks of hyperpigmentation or atrophy, and sometimes have recurrences, especially of the vesicular lesions and usually with viral infections. Nevertheless, the ocular and neurologic sequelae can be devastating, emphasizing the importance of early recognition based on the skin manifestations. Neurologic consultation is not necessary if there is no evidence of neurologic abnormalities, but early ophthalmologic evaluation is critical, since findings may not be otherwise discovered.
[1.] Fryssira H, Kakourou T, Valari M, et al. Incontinentia pigmenti revisited. A novel nonsense mutation of the IKBKG gene. Acta Paed 2011;100(1):128-133.
[2.] Berlin AL, Paller AS, Chan LS. Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol 2002;47(2):169–187.
[3.] Bodak N, Hadj-Rabia S, Hamel-Teillac D, et al. Late recurrence of inflammatory first stage lesions in incontinentia pigmenti: an unusual phenomenon and a fascinating pathologic mechanism. Arch Dermatol 2003;139(2):201-204.
[4.] Phan TA, Wargon O, Turner AM. Incontinentia pigmenti case series: clinical spectrum of incontinentia pigmenti in 53 female patients and their relatives. Clin Experim Dermatol 2005;30(5):474-480.
[5.] Minic S, Novotny GE, Trpinac D, et al. Clinical features of incontinentia pigmenti with emphasis on oral and dental abnormalities. Clin Oral Investig 2006;10(4):343-347.
[6.] Pacheco TR, Levy M, Collyer JC, et al. Incontinentia pigmenti in male patients. J Am Acad Dermatol 2006;55(2):251-255.