eMedicine Specialties > Dermatology > Pediatric Diseases

Incontinentia Pigmenti

Author: Kara N Shah, MD, PhD, Assistant Professor, Department of Pediatrics, Section of Dermatology, Children's Hospital of Philadelphia
Contributor Information and Disclosures

Updated: Feb 18, 2008

Introduction

Background

Incontinentia pigmenti (IP) is an X-linked dominant neurocutaneous syndrome with cutaneous, neurologic, ophthalmologic, and dental manifestations. Garrod reported the first probable case of IP in 1906 and described it as a peculiar pigmentation of the skin in an infant. Subsequently, Bloch and Sulzberger further defined the condition in 1926 and 1928, respectively, as a clinical syndrome with a constellation of unique features that includes typical cutaneous manifestations.

Pathophysiology

IP is an X-linked dominant genodermatosis characterized by abnormalities of the tissues and organs derived from the ectoderm and neuroectoderm and represents a type of ectodermal dysplasia. Involvement of the skin, hair, teeth, and nails is seen in conjunction with neurologic and ophthalmologic anomalies. In female IP patients, lyonization results in functional mosaicism of X-linked genes, which is manifested by the blaschkoid distribution of cutaneous lesions.¹ Cells expressing the mutated X chromosomes selectively eliminate around the time of birth; therefore, females with IP have an extremely skewed X-inactivation pattern. Normal X chromosomes are active in unaffected skin, and mutated X chromosomes are active in skin affected with IP.

Frequency

United States

No incidence or prevalence data are available on IP in the US population.

International

IP is an uncommon disease. Up until 1987, only 700 cases had been reported in the literature. The disease is probably underreported because many mild or uncomplicated cases are likely unrecognized.

Mortality/Morbidity

The prognosis depends on the presence and severity of associated extracutaneous manifestations. Morbidity and mortality primarily result from neurologic and ophthalmologic complications, including mental retardation, seizures, and vision loss.

Race

IP has a worldwide distribution. IP appears to be more common among white patients, but it has also been reported in blacks and Asians.

Sex

IP is an X-linked dominant, male lethal syndrome. More than 95% of reported cases of IP occur in females. IP may rarely occur in males with Klinefelter syndrome (XXY syndrome) or as a result of somatic mosaicism or hypomorphic (less deleterious) mutations in the NEMO gene.^2,3

Age

Characteristic skin lesions compatible with the early, vesicular and/or verrucous stages of IP are present at birth or develop in the first few weeks of life in approximately 90% of patients. The cutaneous manifestations of the hyperpigmented stage develop during infancy and persist during childhood. The hyperpigmented lesions usually fade during adolescence. The cutaneous manifestations of the atrophic/hypopigmented stage develop during adolescence and early adulthood and persist indefinitely. Hair, nail, and dental anomalies often first manifest during infancy and are permanent. Late-onset IP is occasionally reported in older infants. Neurologic and ophthalmologic sequelae often manifest during early infancy.

Clinical

History

In most patients, cutaneous manifestations are present at birth or occur within the first 2 weeks of life. The cutaneous manifestations usually appear in a characteristic, chronologic sequence. Other systemic manifestations, including ocular defects, CNS abnormalities, and dental abnormalities, may not be recognized until infancy or early childhood.

A family history of IP in the mother is reported to occur in 28% of patients. In most patients (62%), the syndrome occurs sporadically. Germline mutations inherited from the father have been reported in over 80% of cases of sporadic IP. Male patients with IP generally appear to have a sporadic form. The development of postzygotic mutation and resulting somatic mosaicism is the likely mechanism in most male patients. In a study of 42 boys with IP, only 5 had evidence of NEMO gene mutation. The male phenotype is similar to that of the female phenotype, although unilateral presentation is a more common occurrence in boys (15%).

The proposed diagnostic criteria for IP are as follows:

• In the absence of a family history, the presence of at least 1 major criterion is necessary. The presence of minor criteria supports the diagnosis of IP.
  • Major criteria
    • Typical neonatal vesicular rash with eosinophilia
    • Typical blaschkoid hyperpigmentation on the trunk, fading in adolescence
    • Linear, atrophic hairless lesions
  • Minor criteria
    • Dental anomalies
    • Alopecia
    • Wooly hair
    • Abnormal nails
• With a definitive family history, the presence of any major criterion strongly supports the diagnosis of IP.
• Other characteristic features include the following:
  • Suggestive history or evidence of typical rash, hyperpigmentation, or atrophic hairless lesions
  • Vertex alopecia
  • Dental anomalies
  • Retinal disease
  • Multiple male miscarriages

Physical

Significant clinical heterogeneity exists in IP with regard to ectodermal, ophthalmologic, and neurologic abnormalities, even within families. The cutaneous findings generally progress through 4 distinct characteristic stages, although some stages may overlap temporally and some may not occur at all in individual patients. Affected males often have limited involvement of 1 or 2 limbs.

• Ectodermal changes
  • Skin features occur in 4 stages.
    • Stage 1 (vesicular) is characterized by the development of red papules and vesicles on an erythematous base that follow Blaschko lines. Lesions are seen predominantly on the extremities but may also occur on the trunk or on the head and neck. The vesicular stage has been reported to occur in 90-95% of patients. In most patients (>90%), lesions are present at birth or develop within the first 2 weeks of life. They resolve within several months. Rarely, self-limiting episodes of recrudescence of vesicular lesions have been reported to occur in older infants and children with IP in association with an intercurrent febrile illness.
    • Stage 2 (verrucous) is characterized by thickened, warty-appearing linear and whorled plaques on an erythematous base that follow Blaschko lines. In general, lesions develop on the extremities and trunk but may also be seen on the head and neck. Verrucous lesions have been reported to occur in 70-80% of IP patients. In most patients, verrucous lesions develop in the first few weeks to months of life and subsequently resolve over weeks to months.
    • Stage 3 (hyperpigmented) is characterized by the development of streaks and whorls of brown or slate-gray pigmentation along Blaschko lines; this occurs in 90-98% of IP patients. Hyperpigmented lesions usually involve the trunk but may also involve the extremities, the skin folds, or the head and neck. The location of the hyperpigmented lesions does not appear to correlate with areas of prior skin involvement during the earlier vesicular and verrucous stages. Hyperpigmented lesions generally develop within the first few months of life and resolve slowly by adolescence.
    • Stage 4 (atrophic/hypopigmented) is characterized by hypopigmented, atrophic, and reticulate or linear patches observed on the lower extremities, usually involving the calves. Atrophic lesions usually develop during adolescence and persist into adulthood. Atrophic lesions have been reported to occur in 30-75% of IP patients.
  • Abnormal dermatoglyphic patterns have also been reported.
  • Hair changes include scarring alopecia and are seen in 28-38% of patients. An absence or hypoplasia of the eyebrows and eyelashes has also been reported. Finally, hair is sparse in early childhood; later, it has a lusterless, wiry, and coarse appearance.
  • Nail features⁴ include nail dystrophy, which ranges from mild pitting or ridging of the nail plate to hyperkeratosis and onycholysis. This is observed in 7-40% of IP patients, and usually multiple fingernails and toenails are affected. Nail dystrophy may improve with age. Subungual and periungual keratotic tumors associated with pain, bony deformities, and lytic lesions involving the underlying phalanges also may be seen, usually in older children and adults.^5,6,7 The fingers are most commonly affected.
  • Dental abnormalities^8,9 are seen in 80% of patients and can involve both deciduous and permanent teeth. Dental anomalies are permanent and thus serve as a very useful diagnostic finding in older patients. Delayed dentition, partial anodontia, and conical or pegged teeth are the most common dental findings. Poor enamel quality leading to an increased incidence of dental caries has been reported historically, but this association has been questioned.
• Ophthalmologic findings^10,11
  • Ophthalmologic findings occur in 20-35% of patients, and asymmetric involvement is common. Loss of visual acuity and blindness are significant complications. Blindness has been reported to develop in 7% of IP patients.
  • Ophthalmologic manifestations may become evident within the first few weeks to months of life and may progress rapidly to permanent visual deficits.
  • Retinal vaso-occlusive events with resultant ischemia are believed to be the primary mechanism underlying ocular pathology.
  • Retinal manifestations include retinal detachment, proliferative retinopathy, fibrovascular retrolental membranes, foveal hypoplasia, vitreous hemorrhages, and atrophy of the ciliary body.
  • Nonretinal manifestations include strabismus, optic nerve atrophy, conjunctival pigmentation, microphthalmia, keratitis, cataracts, iris hypoplasia, nystagmus, and uveitis.
• Neurologic abnormalities
  • Neurologic complications occur in 30% of IP patients and often manifest within the neonatal period.
  • Seizures are the most common neurologic complication and usually develop within the first few weeks of life.
  • Neurologic complications may result in part from microvascular vaso-occlusive ischemic events involving the CNS. Involvement of the cerebral hemispheres, cerebellum, and corpus callosum may occur.¹² Progressive periventricular hemorrhagic infarcts have been reported.
  • Other neurodevelopmental manifestations include developmental delay, mental retardation, ataxia, spastic paralysis, microcephaly, cerebral atrophy, porencephaly, hypoplasia of the corpus callosum, and periventricular cerebral edema.
• Other anomalies that have been reported to occur with increased frequency in patients with IP include supernumerary nipples, nipple hypoplasia, and breast hypoplasia.

Causes

IP is caused by mutations in the NEMO/IKK -gamma gene, which is located on chromosome Xq28. NEMO/IKK -gamma is the regulatory subunit of the inhibitor kappa kinase (IKK) complex and is required for the activation of the transcription factor NF-kappaB (NF-kB). NF-kB is central to many immune, inflammatory, and apoptotic pathways.

Activation of NF-kB prevents apoptosis in response to the tumor necrosis factor family of cytokines. NF-kB  activity is normally regulated via the inhibitor kB protein. Tumor necrosis factor receptor activation results in phosphorylation and inactivation of inhibitor kB by IKK, thus resulting in activation of NF-kB. Loss of IKK activity results in deficient NF-kB  activity and increased susceptibility to apoptosis.

Cells that retain IKK activity may produce additional cytokines that trigger apoptosis in neighboring IKK-deficient cells, thus creating an amplification loop that eventually results in the death of all of the IKK-deficient cells. This mechanism is believed to produce the cutaneous manifestations of the vesicular stage of IP. The proliferation of surviving IKK-positive cells may result in the production of the verrucous lesions seen in stage 2 of IP. The pathophysiology of the hyperpigmented cutaneous findings seen in stage 3 and the atrophic/hypopigmented manifestations of stage 4 remains unknown. Inflammation and subsequent postinflammatory changes may play a role.

• The peripheral eosinophilia seen in the early stages of IP may result from the production of eotaxin, an eosinophil-selective cytokine, during the inflammatory cascade that results from a loss of NEMO/IKK -gamma activity. Activation of eosinophils with subsequent release of cellular proteases may trigger the development of the vesicular stage of IP.¹³
• The pathophysiology underlying the CNS manifestations in IP are unknown, but inflammation resulting from loss of NEMO/IKK -gamma activity may contribute to the development of vascular occlusive events.
• Females with hypomorphic mutations in NEMO/IKK -gamma may have few clinical manifestations of IP.
• A single mutation in NEMO/IKK -gamma involving the deletion of exons 4 through 10 accounts for most (80%) IP mutations.
• Hypomorphic mutations in the zinc-finger domain of NEMO/IKK -gamma result in X-linked recessive ectodermal dysplasia and immunodeficiency. A family history of IP may be elicited. Such mutations result in decreased but not absent IKK activity and thus allow for low-level NF-kB  activation.
• Hypomorphic mutations in the stop codon of NEMO/IKK -gamma result in the X-linked dominant ectodermal dysplasia osteopetrosis lymphedema syndrome.
• Confirmation of NEMO/IKK -gamma mutations in males is difficult due to the high rate of post-zygotic mosaicism.
• NEMO/IKK -gamma knockout mice manifest a cutaneous phenotype similar to female IP patients and develop neurologic sequelae, although they do not develop dental or ocular abnormalities. They also develop diffuse apoptosis of splenic and thymic lymphocytes, which does not occur in human IP patients.^14,15
• Genetic testing for NEMO/IKK -gamma mutations is available through the Baylor College of Medicine Medical Genetics Laboratories.

• Search for CME/CE on This Topic »

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