OVERVIEW: What every practitioner needs to know

Are you sure your patient has incontinentia pigmenti? What are the typical findings for this disease?

Incontinentia pigmenti (IP) is an X-linked dominant disorder named for its distinctive skin findings, which are present late in the disease and are caused by a mutation in the gene for nuclear factor kappa B (NF-kB) essential modulator (official abbreviation is IKBKG; also sometimes referred to as NEMO). However, IP is a syndrome that also affects the central nervous system, teeth, eyes, and occasionally other organ systems.

It is found almost exclusively in female infants because boys die in utero; however, several confirmed cases of boys being born with IP do exist. The clinical manifestations of IP are highly variable, from subclinical or asymptomatic in individuals who are diagnosed only after testing because of an affected family member, to severe and disabling symptoms that manifest at birth.

The skin findings in IP are traditionally described as progressing through four stages. Note that not all stages are readily apparent, and stages may have variable presentation, overlap with other stages, occur out of order, or be absent completely:

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Stage 1

This stage, known as the vesiculbullous, vesicular, or inflammatory stage, is typically discovered during the first 2 weeks of life, but has also been reported to occur in utero in up to 10% of cases. Lesions are erythematous vesicles or blisters that frequently appear in a linear pattern on the limbs and trunk but usually spare the face. Vesicles can crust and heal and be replaced by new vesicles. These vesicles can resemble and often are mistaken for zoster. Lesions are characterized by eosinophilic infiltration of the skin and can be accompanied by leukocytosis with eosinophilia of peripheral blood.

Stage 1 is noted in up to 90% of individuals with IP and lasts from 2 weeks to several months, but has been noted to recur in a milder form, particularly with febrile illnesses. There are also reported cases in which stage 1 has been described to first occur later in infancy or in a young toddler.

Stage 2

Stage 2, the verrucous stage, is characterized by warty, hyperkeratotic-appearing lesions that replace stage 1 vesicles. Verrucal areas may occur in areas previously unaffected by stage 1 vesicles and tend to be relatively more distal. Stage 2 begins from 2 weeks-2 months of age and will usually resolve by 6 months of age. Stage 2 is present in approximately 80% of patients with IP. Similar to stage 1, it has also been noted to occur in utero.

Stage 3

Stage 3 is the stage from which IP gets its name, and is the stage that is present at some point in almost every patient diagnosed with IP. As with the other stages and features of IP, the presentation can vary between subtle and striking. This stage is characterized by hyperpigmented areas on the torso and extremities, particularly the groin, axillae, and nipples. They can appear brown or gray, with a classic pattern of “whorls and streaks”; patterns of findings like these that follow the lines of Blaschko are often described.

Hyperpigmented areas do not necessarily overlap with the locations previously affected in stages 1 and 2, and are therefore not thought to represent postinflammatory hyperpigmentation. The onset of stage 3 is typically between 3 and 6 months of age and persists for many years, usually fading sometime between puberty and the third decade of life.

Stage 4

Stage 4 is usually known as the atrophic stage and has at times also been called the “burnt out” phase. This stage is characterized by patches of mildly hypopigmented and hairless skin, most commonly on the posterior calves. Lesions can be faint and frequently missed without careful examination and the aid of a Wood lamp. Stage 4 usually begins before the resolution of stage 3, and is considered permanent.

Noncutaneous manifestations of IP

The teeth are the most commonly affected organ system after the skin and are abnormal in approximately 70%-90% of individuals with IP. Abnormalities are varied and include delayed dentition, extra or (more commonly) missing teeth, and conical or pegged-shaped teeth.

Abnormalities in the central nervous system (CNS) and the eyes are not universally present in IP but typically account for the most morbidity. Ocular complications occur in about one third of cases and include vascular retinopathy that may affect one or both eyes, optic atrophy, and retinal detachment. Eye misalignment is also common as are, less commonly, cataracts, microphthalmia, and nystagmus.

CNS disease is closely linked with ocular manifestations. Seizures of various types are present in about 25% of patients and seem to be associated with relatively poorer neurologic outcome, with intellectual deficits and/or cerebral palsy in approximately 10% of total cases of IP. Also reported is microcephaly, cerebellar ataxia, and hemiparesis. Imaging abnormalities of the brain can be detected as early as the first week of life and include heterotopias, atrophy, abnormalities of the corpus callosum and periventricular white matter, restricted diffusion representing ischemic processes, and hemorrhagic necrosis.

The hair and nails in IP are frequently affected. Alopecia at the vertex of the scalp is seen with IP in 40%-70% of patients and can often help suggest the diagnosis when other manifestations are subtle. Eyelash and eyebrow alopecia is also reported. Nail abnormalities such as ridging and pitting has been reported in approximately one fourth of cases.

It is important to note that infants with IP can have findings that are suggestive of nonaccidental trauma, such as retinal hemorrhages and brain ischemia with generalized edema. In this context, the skin findings can be misinterpreted as further evidence of abuse. Obtaining a detailed family history will often identify other female relatives with IP, and the pattern and evolution of skin findings in these children should lead to the diagnosis of IP, especially in consultation with neurologic and dermatologic specialists.

What other disease/condition shares some of these symptoms?

IP is frequently confused with hypomelanosis of Ito (HI), which was previously called incontinentia pigmenti type 1 or incontinentia pigmenti achromians. Like IP, HI is also characterized by pigmentary abnormalities with swirling patterns seen in infancy and also affects multiple organ systems such as the CNS, eyes, and teeth. However, there is no inflammatory stage preceding the abnormal pigmentation in HI. However, HI can be difficult to distinguish from IP if a history of vesicles or verrucal lesions is not present.

The dental abnormalities are a key feature of IP, which may help distinguish IP from HI when the preceding inflammatory lesions cannot be confirmed. Please see the chapter on HI for more information.

The general skin manifestations seen in stage 1 and stage 2 are not unique to IP. The vesicles of stage 1 can be very similar to those seen in herpes simplex virus or varicella zoster virus infections. Also, any skin disease characterized by vesicles, bullous-type lesions, or verrucal lesions can present like IP.

When stages 1 and 2 are absent or have resolved, the pigmentation seen in stage 3 can mimic several disorders other than HI. They include X-linked dominant chondrodysplasia punctata, Naegeli-Franceschetti-Jadassohn syndrome, dermatopathia pigmentosa reticularis, and linear and whorled nevoid hypermelanosis.

What caused this disease to develop at this time?

As an X-linked dominant disorder, there is no specific predisposing factor apart from family history. A careful family history and examination of the mother and other female relatives should reveal overt or subtle manifestations of IP. A history of miscarriages is frequently present. Interestingly, members of the same family can have dramatically variable manifestations, including when IP is present in identical twins. (Also see section on “what causes this disease and how frequent is it?”)

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Genetic testing: The diagnosis can be confirmed with genetic testing of IKBKG. More than 80% of cases of IP are caused by one specific IKBKG, testing for which is available in the United States through Baylor College of Medicine (https://www.bcm.edu/geneticlabs/test_detail.cfm?testcode=6036). If testing provides negative results but the suspicion of IP is high, testing of the entire IKBKG gene is available in Europe and Israel (see http://www.ncbi.nlm.nih.gov/sites/GeneTests/) or through specialty research laboratories.

Other laboratory tests: Many children with IP will have a leukocytosis with eosinophila during the early stages of the disease. Skin biopsy findings of lesions during any of the phases are nonspecific and will not alone lead to a definitive diagnosis of IP. However, biopsies can help to support the diagnosis through exclusion of other diagnoses when genetic testing is unavailable or nonconfirmatory.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not particularly indicated unless as directed by an abnormal examination. Brain imaging is needed if there are neurologic abnormalities such as seizures, developmental delay, weakness, hypertonia/hypotonia, spasticity, or retinal findings. Magnetic resonance imaging is the preferred modality, and computed tomography should be avoided to prevent unnecessary radiation unless there is concern for an acute process that needs urgent evaluation. If there is evidence of retinal ischemic processes, angiography of the brain should be considered.

If you are able to confirm that the patient has this disease, what treatment should be initiated?

Currently, there is no specific treatment for IP, and any treatment should be directed at particular symptoms. The vesicular lesions of stage 1 can be treated with dressings to help prevent infection. The characteristic skin findings of the other stages do not require treatment. Other skin manifestations such as of the nail and hair should be referred to a dermatologist for evaluation. A comprehensive eye examination with a pediatric ophthalmologist and retinal specialist is critical at diagnosis, with frequent follow-up particularly during infancy, although there are currently no uniform guidelines.

If present, any neurologic complications, such as seizures, delay, or spasticity, are treated with conventional methods. There are little to no data about whether any particular antiepileptic medication is more effective than others for the treatment of seizures in individuals with IP.

A history and examination should be performed on all at-risk relatives to identify others with IP for surveillance purposes and possibly genetic counseling if indicated.

What are the possible outcomes of this disease?

The prognosis for individuals with IP is broad. Some will have subclinical or mild symptoms, whereas others can be profoundly affected, with global developmental delay, seizures, and blindness accounting for the worst morbidity.

What causes this disease and how frequent is it?

The incidence of IP is debated but is presumed to occur in approximately 1/40,000 individuals. It is caused by abnormal functioning caused by genetic mutation of the NF-kB essential modulator (IKBKG) protein. This gene is located on the X chromosome at Xp28, and most mutations are a result of a deletion of exons 4-10, which results in truncated protein.

NF-kB is a transcription factor that is involved in several inflammatory and apoptotic cascades, and IKBKG is necessary for the activation of NF-kB. Because of X-linked inactivation, which occurs early in gestation, each cell in patients with IP will express either a normal X chromosome or the one carrying the mutated IKBKG. The pattern of skin findings in IP that occur along the lines of Blaschko, is evidence of the lineage of the two populations of cells.

How do these pathogens/genes/exposures cause the disease?

A review of the cellular physiology underlying the skin lesions seen in IP is beyond the scope of this text, but an excellent discussion can be found in Berlin et al (see references).

How can this disease be prevented?

Women with IP should be advised to have genetic counseling if they are considering pregnancy. There is no other specific prevention strategy.

What is the evidence?

Tanaka, K, Kambe, N, Fujita, M. “Incontinentia pigmenti in identical twinswith separate skin and neurological disorders”. Acta Derm Venereol. vol. 70. 1990. pp. 267-8. (A case report of IP in identical twins that emphases that the clinical manifestations of IP can vary widely from case to case.)

Berlin, AL, Paller, AS, Chan, LS. “Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology”. J Am Acad Dermatol. vol. 47. 2002. pp. 169-87; quiz 188-90. (Avery well written, complete, and readable review of IP, withphotographs and a nice discussion on the putative molecular pathwaysinvolved in IP.)

Ongoing controversies regarding etiology, diagnosis, treatment

There is some uncertainty as to the epidemiology and constellation of findings in IP as described in the older literature. This is due to the fact that it is now widely believed that many patients who were previously included in case series and reports of IP instead actually had HI.