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Special Feature
April 04, 2011

Picture of the Month—Diagnosis

Author Affiliations



Copyright 2011 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2011

Arch Pediatr Adolesc Med. 2011;165(4):368. doi:10.1001/archpediatrics.2011.23-b
Denouement and Discussion: Incontinentia Pigmenti

Skin histology revealed hyperkeratosis with scale crust, dyskeratosis, a chronic inflammatory infiltrate within the superficial dermis, and eosinophilic spongiosis. These findings, combined with the clinical findings of a linear array of vesicles and verrucous papules in a boy with Klinefelter syndrome (47, XXY) confirmed the diagnosis of incontinentia pigmenti (IP).

Incontinentia pigmenti is an X-linked dominant genodermatosis best characterized as an ectodermal dysplasia. Approximately one-third of patients have an affected first-degree relative. Incontinentia pigmenti results from mutation of the nuclear factor κB essential modulator gene (NEMO) on chromosome Xq28. Incontinentia pigmenti occurs largely in girls, and is typically lethal for boys in utero. Girls demonstrate skewed X inactivation, as cells expressing the mutated X chromosome are eventually eliminated through apoptosis.1

Rarely, male children with IP may survive. In boys with Klinefelter syndrome, the additional X chromosome provides protection from the deleterious effects of a mutated NEMO gene.2,3 Hypomorphic alleles, where NEMO function is reduced but not fully lost, also result in survival in boys. Boys with these less deleterious mutations present with immunodeficiency and ectodermal dysplasia as opposed to the typical features of IP. Somatic mosaicism secondary to postzygotic mutation of the NEMO gene may also explain male survival with IP.35

Classically, the cutaneous manifestations of IP progress through 4 stages.6,7 Every stage may not occur in every affected individual, and stages may overlap. The first stage appears at birth or within the first several weeks of life and consists of a linear configuration of blisters following the Blaschko lines of ectodermal development on the limbs and torso, often preceded by erythema. These blisters typically resolve by 4 months of age. In the second stage, hyperkeratotic verrucous papules and plaques develop predominantly on the extremities; these begin to involute by 6 months of age. In the third stage, hyperpigmented linear streaks and whorls appear predominantly on the torso; although these usually fade by adolescence, some hyperpigmentation may be permanent. The fourth stage, which develops in only 30% to 50% patients, occurs in late adolescence and consists of hypopigmented atrophic macules that typically appear on the lower leg.7 Compared with girls, boys with IP are more likely to initially manifest localized, unilateral involvement; however, many later develop more widespread, bilateral disease and other systemic abnormalities, suggesting that initial unilateral involvement is not a prognostic indicator for milder disease in boys.8

Incontinentia pigmenti also affects other ectodermal structures. Nail involvement, which is usually mild, ranges from mild pitting to onychogryphosis and occurs in 10% to 40% of patients.7 Hair abnormalities include lusterless, thin, and/or coarse hair, with vertex alopecia present in 20% to 40% of patients. Ophthalmologic findings include retinal vascular and pigment abnormalities in up to 40% of patients, although other ophthalmologic abnormalities may occur. Dental abnormalities occur in most patients, and unlike many other features of IP, may persist throughout life. These anomalies include delayed tooth eruption, hypodontia, impaction, conical teeth, and other malformations. Approximately one-third of patients with IP will have associated neurological disease including seizures, spastic paralysis, microcephaly, motor delays, and mental retardation. Seizures are the most prominent manifestation, developing in 77% of patients with neurologic symptoms.7 In addition, there have been case reports of anomalies of the breasts, skeletal system, and ears in IP. Overall, similar frequencies of CNS and ocular manifestations have been observed in affected boys compared with girls.8

The diagnosis of IP is largely clinical. Blood eosinophilia may be present during the neonatal period.7 Skin biopsy performed during the first stage is diagnostic and demonstrates eosinophilic spongiosis of the epidermis, often with dyskeratotic keratinocytes.7 Histologic features of the later stages may be nonspecific; dyskeratosis and dermal melanophages are seen in the second and third stages, while cutaneous atrophy predominates in the fourth stage. Chromosomal analysis should be performed on all male patients with IP. In addition, patients should be referred for ophthalmologic and neurologic evaluation.

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Article Information

Correspondence: Todd A. Florin, MD, Division of Pediatric Emergency Medicine, The Children's Hospital of Philadelphia, 34th Street and Civic Center Blvd, Philadelphia, PA 19104 (

Author Contributions:Study concept and design: Florin and Shah. Acquisition of data: Shah. Analysis and interpretation of data: Shah. Drafting of the manuscript: Florin. Critical revision of the manuscript for important intellectual content: Florin and Shah. Study supervision: Shah.

Financial Disclosure: None reported.

Additional Contributions: The authors would like to thank Albert Yan, MD, for his review of the manuscript and providing the photographs for this article.

Smahi  ACourtois  GVabres  P  et al. The International Incontinentia Pigmenti (IP) Consortium, Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. Nature 2000;405 (6785) 466- 472
Ormerod  ADWhite  MI McKay  EJohnston  AW Incontinentia pigmenti in a boy with Klinefelter's syndrome. J Med Genet 1987;24 (7) 439- 441
Kenwrick  SWoffendin  HJakins  T  et al. International IP Consortium, Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome. Am J Hum Genet 2001;69 (6) 1210- 1217
Fusco  FFimiani  GTadini  GMichele  DUrsini  MV Clinical diagnosis of incontinentia pigmenti in a cohort of male patients. J Am Acad Dermatol 2007;56 (2) 264- 267
Pacheco  TRLevy  MCollyer  JC  et al.  Incontinentia pigmenti in male patients. J Am Acad Dermatol 2006;55 (2) 251- 255
Landy  SJDonnai  D Incontinentia pigmenti (Bloch-Sulzberger syndrome). J Med Genet 1993;30 (1) 53- 59
Hadj-Rabia  SFroidevaux  DBodak  N  et al.  Clinical study of 40 cases of incontinentia pigmenti. Arch Dermatol 2003;139 (9) 1163- 1170
Ardelean  DPope  E Incontinentia pigmenti in boys: a series and review of the literature. Pediatr Dermatol 2006;23 (6) 523- 527