Incontinentia Pigmenti: Do You Know the Signs?

IN THIS ARTICLE

• Presenting stages
• Diagnostic criteria
• Management of IP

A 21-year-old woman with type 1 diabetes is admitted for recurrent diabetic ketoacidosis. Physical exam reveals hypopigmented, linear, streaky patches on the medial aspects of the bilateral lower legs (Figure 1A). The patient denies tenderness, pruritus, or paresthesia. There is obvious symmetrical hair loss on the lateral aspects of the eyebrows, as well as slightly wooly male-pattern hair distribution with patchy alopecia on the vertex of the head (Figure 1B). She has very poor dentition with hypodontia and malformed teeth (Figure 1C). Her fingernails and toenails appear normal, with no visible atrophy (Figure 1D). What explains her condition?

Incontinentia pigmenti (IP), also known as Bloch-Sulzberger syndrome, is a rare, X-linked dominant genodermatosis involving the cutaneous, ophthalmic, neurologic, and dental systems.^1-3 It results from X-inactivation due to mutations in the NF-kappaB essential modulator (NEMO) gene with deletion of exons 4-10 in most cases. The NEMO gene encodes a regulatory component of the IkappaB kinase complex required to activate the NF-kappa B pathway, which is important for many immune, inflammatory, and apoptotic processes.^4-6 This deletional mutation is typically lethal in normal 46,XY male karyotypes. Male fetuses with this mutation usually die in utero, making the reported cases predominantly female.^4,7

The estimated incidence of IP is between 1/10,000 and 1/100,000.⁴ Due to the rarity of the condition, IP may be underrecognized and underdiagnosed.

CLINICAL PRESENTATION

Characteristic skin lesions of IP begin to develop at birth or in utero, in an evolving pattern that consists of four stages:

• The vesicular stage (stage I) is characterized by linear erythematous papules and blisters that manifest in newborns.
• The verrucous stage (stage II) begins as the blisters start to heal—usually after several weeks—and is distinguished by hyperkeratotic warty papules in linear or swirling distribution. This stage resolves on its own within months.
• The hyperpigmentation stage (stage III) is when swirling macules or patches develop. This hallmark stage of IP tends to remain static until adolescence.
• The hypopigmentation stage (stage IV) manifests with faded streaky patches, which may be subtly atrophic. This final stage usually develops in the second or third decade of life.^2,3

All these cutaneous lesions follow Blaschko lines—invisible lines believed to result from embryonic cell migration that become visible with the manifestation of cutaneous or mucous lesions.⁶

Other associated cutaneous findings include patchy alopecia, nail dystrophy, and oral/dental anomalies such as hypodontia, oligodontia, and tooth deformities. In addition, ophthalmologic involvement can result in strabismus, cataracts, and retinal vascular changes that can lead to blindness. Central nervous system manifestations include seizures, cognitive impairment, and spastic paralysis.³

DIFFERENTIAL DIAGNOSIS

Because IP is uncommon, it may be easily overlooked or misdiagnosed as another, similar cutaneous manifestation. Cutaneous sarcoidosis, for example, is a skin lesion of noncaseating granuloma. It can present as patches, papules, ulcers, scars, ichthyosis, and alopecia. The development of cutaneous sarcoidosis can be idiopathic or iatrogenic, particularly in patients using anti-TNF therapy. The diagnosis is made clinically and can be confirmed pathologically.⁸

Stage I IP can also be confused with neonatal herpes simplex virus-1 (HSV-1) infection, given the similarities in vesicular morphology and linear distribution. The diagnosis of HSV-1 can be made based on history, physical exam, and pathology. Given the serious sequelae of neonatal HSV-1 infection, antiviral therapy should not be delayed until confirmation of the diagnosis in infants with vesicular eruptions.⁹

Erythema multiforme (EM) is another dermatologic condition frequently encountered in children and young adults. Its characteristic round target lesion usually has two rings surrounding the dusky-appearing central zone. Atypical lesions can be bullous or crusty, mimicking the appearance of stage I or II IP. EM is usually a self-limiting condition, but specific treatment may be required if the infectious agent is identified.¹⁰

Vitiligo, the development of white patches due to the loss of melanocytes, is another item in the differential. Although it most commonly involves the skin, the hair may also be affected. The diagnosis is made clinically and can be confirmed with skin biopsy if needed.¹¹