Incontinentia Pigmenti

Incontinentia pigmenti is an X-linked dominant neurocutaneous syndrome with cutaneous, neurologic, ophthalmologic, and dental manifestations. Garrod reported the first probable case of incontinentia pigmenti 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.

Incontinentia pigmenti 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 incontinentia pigmenti 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 incontinentia pigmenti 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 incontinentia pigmenti.

Incontinentia pigmenti 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 incontinentia pigmenti. The proliferation of surviving IKK-positive cells may result in the production of the verrucous lesions seen in stage 2 of incontinentia pigmenti. 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 incontinentia pigmenti 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 incontinentia pigmenti.[2]

The pathophysiology underlying the CNS manifestations in incontinentia pigmenti are unknown, but inflammation resulting from loss of NEMO/IKK -gamma activity may contribute to the development of vascular occlusive events. Increased expression of tumor necrosis factor receptor-1 and elevated oxidative stress markers have been reported in a neonate with IP and encephalopathy.[3]  

Females with hypomorphic mutations in NEMO/IKK -gamma may have few clinical manifestations of incontinentia pigmenti.

A single mutation in NEMO/IKK -gamma involving the deletion of exons 4 through 10 accounts for most (80%) incontinentia pigmenti mutations.

The NEMO gene is part of a segmental duplication or low copy repeat (LCR), which contains both NEMO and its pseudogene IKBKGP. A local high frequency of microhomologies, macrohomologies, tandem repeats, and repeat/repetitive sequences contribute to a high rate of nonallelic homologous recombination involving NEMO, resulting in the development of de novo deletion mutations.[4]

Numerous different point mutations in NEMO have also been reported in patients with incontinentia pigmenti, including 21 recently described point mutations that are predicted to result in complete or partial loss of function through one of the following mechanisms: premature stop codon, missense, splicing, or frameshift.[5]

Hypomorphic mutations in the zinc-finger domain of NEMO/IKK -gamma result in X-linked recessive ectodermal dysplasia and immunodeficiency. A family history of incontinentia pigmenti 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 incontinentia pigmenti 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 incontinentia pigmenti patients.[6, 7]

Genetic testing for NEMO/IKK -gamma mutations is available through the Baylor College of Medicine Medical Genetics Laboratories.

There are rare reports of patients with the clinical features of IP but without identifiable mutations in NEMO. In one report, the authors identified a heterozygous deletion of PAK6, a p21-activated serine/threonine kinase and a heterozygous duplication of AIFM1, a mitochondrial flavin adenine dinucleotide-dependent oxidoreductase, as additional candidate genes.[8]

Frequency

United States

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

International

Incontinentia pigmenti 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.

Race

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

Sex

Incontinentia pigmenti is an X-linked dominant, male lethal syndrome. More than 95% of reported cases of incontinentia pigmenti occur in females. Incontinentia pigmenti 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.[9, 10]

Age

Characteristic skin lesions compatible with the early, vesicular and/or verrucous stages of incontinentia pigmenti 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 incontinentia pigmenti is occasionally reported in older infants. Neurologic and ophthalmologic sequelae often manifest during early infancy.

The prognosis is variable and depends on the degree of involvement of organ systems other than the skin, in particular the presence of neurodevelopmental complications. There are generally no significant sequelae secondary to the cutaneous manifestations. Morbidity and mortality primarily result from neurologic and ophthalmologic complications, including mental retardation, seizures, and vision loss. Patients with structural brain abnormalities and neonatal seizures are at greater risk for motor and intellectual impairment.

Inform parents that delayed eruption of both deciduous and permanent teeth is common. Reassure parents that if no evidence of CNS involvement or seizures is seen in their infant, the neurodevelopmental prognosis is excellent. Genetic counseling should be offered to the family. Counsel parents on the expected course of cutaneous manifestations.

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, central nervous system abnormalities, and dental abnormalities, may not be recognized until infancy or early childhood.

A family history of incontinentia pigmenti in the mother is reported to occur in 25-35% of patients. In most patients (65-75%), the syndrome occurs sporadically. Male patients with incontinentia pigmenti generally appear to have the 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 incontinentia pigmenti, only five had evidence of a 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%). Transmission of a NEMO mutation from an affected father to a daughter has been reported due to germline mosaicism.[11, 12]

Diagnostic criteria for incontinentia pigmenti have been proposed. In the absence of a family history, the presence of at least one major criterion is necessary. The presence of minor criteria supports the diagnosis of incontinentia pigmenti.

Major criteria are as follows:

• Typical neonatal vesicular rash with eosinophilia
• Typical blaschkoid hyperpigmentation on the trunk, fading in adolescence
• Linear, atrophic hairless lesions

Minor criteria are as follows:

• Dental anomalies
• Alopecia
• Wooly hair
• Abnormal nails

With a definitive family history, the presence of any major criterion strongly supports the diagnosis of incontinentia pigmenti.

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

Revised criteria for the diagnosis of incontinentia pigmenti suggest that the typical cutaneous manifestations be considered major criteria, whereas the presence of dental anomalies, ocular anomalies, CNS anomalies, alopecia or abnormal hair, abnormal nails, palate anomalies, nipple and breast anomalies, a history of multiple male miscarriages, and typical features on cutaneous histology be considered minor criteria.[13]

If NEMO mutation status is unknown, and incontinentia pigmenti is not present in a first-degree female relative, at least 2 major criteria or 1 major and at least 1 minor criteria are required to make the diagnosis of sporadic IP.

If NEMO mutation status is unknown but incontinentia pigmenti is present in a first-degree female relative, then any single major criteria or 2 minor criteria are required to make the diagnosis.

If NEMO mutation has been confirmed, the presence of any 1 major or minor criteria is required to make the diagnosis.

Significant clinical heterogeneity exists in incontinentia pigmenti with regard to ectodermal, ophthalmologic, and neurologic abnormalities, even within families.[14] The cutaneous findings generally progress through four 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 one or two limbs.

Anomalies other than those categorized below that have been reported to occur with increased frequency in patients with incontinentia pigmenti include supernumerary nipples, nipple hypoplasia, and breast hypoplasia.

Ectodermal changes

Skin features occur in four 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. A neonate with confirmed incontinentia pigmenti who presented with verrucous and hyperpigmentation without the characteristic vesicular lesions has been reported.[15] The vesicular stage resolves within several months. Rarely, self-limiting episodes of recrudescence of vesicular lesions have been reported to occur in older infants and children with incontinentia pigmenti in association with an intercurrent febrile illness or after routine immunization.[16, 17, 18, 19]

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 incontinentia pigmenti 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 incontinentia pigmenti 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 incontinentia pigmenti patients.

See the images below.

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 features[20] 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 incontinentia pigmenti 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.[21, 22, 23, 24, 25] The fingers are most commonly affected. Rarely, subungual squamous cell carcinoma has been reported.[26, 27]

Dental and oral abnormalities[28, 29, 30, 31] are seen in 50-80% 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 eruption of dentition, partial anodontia, hypodontia, and conical or pegged teeth are the most common dental findings (see the image below). Poor enamel quality leading to an increased incidence of dental caries and early dental loss has been reported historically, but this association has been questioned. The most common oral anomalies are cleft palate and high-arched palate. An increased prevalence of dental malocclusion and facial asymmetry has also been reported.[32]

Ophthalmologic findings

Ophthalmologic findings occur in 20-35% of patients, and asymmetric involvement is common.[33, 34, 35, 36, 37]

Retinal vascular changes, optic atrophy, and developmental defects may be seen.[38] Loss of visual acuity and blindness are significant complications. Blindness has been reported to develop in 7% of incontinentia pigmenti 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. A bimodal distribution of retinal detachment has been reported, with tractional detachment occurring at a median age of 1.5 years and rhegmatogenous detachment occurring in adults with a median age of 31.5 years.[39]

Nonretinal manifestations include strabismus, optic nerve atrophy, conjunctival pigmentation, microphthalmia, vortex ("whorl-like") keratitis, cataracts, iris hypoplasia, nystagmus, and uveitis.

Neurologic abnormalities

Neurologic complications occur in 30% of incontinentia pigmenti patients and often manifest within the neonatal period. They are a major cause of morbidity and mortality in affected patients.[38, 40]

Seizures are the most common neurologic complication; they are reported in 20% of patients and usually develop within the first few weeks of life. Neonatal seizures may present days to months before the development of the characteristic cutaneous features.[41, 42]

Neurologic complications may result in part from microvascular vaso-occlusive ischemic events involving the CNS, and recurrent acute stroke may occur.[43, 44] Extensive cerebral infarction involving small and medium-sized cerebral arteries may result in destructive encephalopathy.[1, 45, 46] Involvement of the cerebral hemispheres, cerebellum, and corpus callosum may occur.[47] Progressive periventricular hemorrhagic infarcts have been reported. Other reported brain MRI abnormalities include periventricular and subcortical white matter disease, hypoplasia of the corpus callosum, cerebral atrophy, and cerebellar hypoplasia.[38] In addition to ischemic vascular insult, inflammation and apoptosis are believed to contribute to the development of neurologic sequelae.

Interestingly, resolution of cortical and subcortical white-matter destructive lesions have been reported in several infants with incontinentia pigmenti.[48, 49]

Other neurodevelopmental manifestations include developmental delay, mental retardation, learning disabilities,[50]  ataxia, spastic paralysis, microcephaly, porencephaly, and periventricular cerebral edema. 

Secondary bacterial infection can develop during the vesicular stage, but this is rare. Seizures and mental retardation are common in patients with structural brain malformations or evidence of ischemic brain injury. Ophthalmologic complications can lead to reduced visual acuity and blindness. Keratinocytic malignancies, including squamous cell carcinomas and cutaneous and subungual keratoacanthomas, have been reported to develop within affected areas of hyperpigmentation and hyperpigmentation.[21, 22, 23, 24, 25, 26, 27, 51, 52] Although in the absence of neurologic complications many affected children are normal from a neurodevelopmental perspective, learning disabilities have been reported in a significant number of those affected.[50, 53]

Leukocytosis and eosinophilia may be noted. When acute inflammatory skin changes are present, eosinophilia (≤80%) may be seen in the peripheral blood. Evidence of neutrophil dysfunction (defects in chemotaxis), lymphocyte dysfunction (decreased proliferation in response to mitogen stimulation), and altered immunologic reactivity has been reported in some patients. Quantitative immunoglobulin levels and lymphocyte subpopulation counts are normal.

Head CT scanning and brain MRI[54] may demonstrate cerebral edema, hydrocephalus, structural brain abnormalities, cerebral infarctions, and hypointense areas or hypoattenuation.

Magnetic resonance spectroscopy and angiography have demonstrated reduced cerebral blood flow and elevated cerebrospinal fluid lactate levels, consistent with cerebral ischemia secondary to cerebrovascular occlusive events.[55]

Single-photon emission CT scanning may show decreased cerebral blood flow.[56]

EEG is helpful for localizing CNS lesions and epileptogenic foci in patients with seizures.

Karyotype analysis is recommended in male infants with incontinentia pigmenti in order to detect Klinefelter syndrome (XXY syndrome).

Genetic testing for NEMO/IKK -gamma mutations is available through the Baylor College of Medicine Medical Genetics Laboratories.

Skin biopsy may be diagnostic if performed during the early vesicular and verrucous stages of incontinentia pigmenti (stages 1-2).

Stage 1 (vesicular)

Spongiotic dermatitis with eosinophil-filled intraepidermal vesicles and an eosinophilic epidermal and dermal infiltrate are seen. The epidermis often contains dyskeratotic cells, either singly or in small clusters.

Stage 2 (verrucous)

Acanthosis, papillomatosis, and hyperkeratosis with increased numbers of dyskeratotic cells, which sometimes form whorled collections,[57] are seen. Basal cells show vacuolization and a decrease in melanin content. Eosinophils can persist in the epidermis and dermis, and melanophages are often present in the papillary dermis.

Stage 3 (hyperpigmented)

Melanin deposition in melanophages within a thickened papillary dermis is seen. Colloid bodies in the papillary dermis, dyskeratotic cells in the epidermis, and basal cell layer vacuolar changes may be seen. The histologic findings are often suggestive of incontinentia pigmenti but are not specific.

Stage 4 atrophic/hypopigmented)

Atrophic epidermis with loss of the normal rete ridge pattern and dermal eccrine structures and hair follicles with a reduction in basal melanocytes are seen. Colloid bodies and scattered apoptotic bodies in the epidermis may also be seen. Although the histologic findings are nonspecific, they may be helpful in confirming a diagnosis of incontinentia pigmenti in an adult female with a suggestive clinical history.[58]

Note the images below:

While the cutaneous manifestations of incontinentia pigmenti may be dramatic, the main concerns with regard to short- and long-term morbidity are related to ophthalmologic and neurologic sequelae.

Treatment is not usually required for the cutaneous lesions, although use of topical tacrolimus and topical corticosteroids has been reported to hasten the resolution of the inflammatory stage.[59, 60] The vesicles of the inflammatory stage should be left intact, and the skin should be monitored for the development of secondary bacterial infections. Emollients and topical antibiotics may be used as needed. As there is a risk for the development of cutaneous malignancy, in particular subungual keratinocytic tumors and tumors within areas of hyperpigmentation and hypopigmentation, periodic skin examinations with attention to skin cancer screening are warranted.

Oral hygiene and regular dental care is necessary, and dental restoration may be indicated.

Seizures should be treated with anticonvulsants. Additionally, routine neurodevelopmental assessments should be made, with referral to occupational and physical therapists as warranted. The use of systemic corticosteroids has been reported to reduce neurologic symptoms, including seizure frequency, in neonates with encephalopathy.[61, 62] Of note, in a mouse model of incontinentia pigmenti, intravenous administration of an adenovirus-associated vector containing a normal NEMO gene was associated with a reduced incidence and a delayed onset of seizures.[63]

Frequent ophthalmologic evaluations are required, especially during the first year of life, in order to diagnose and treat potential ophthalmologic complications.

Abnormal retinal fibrovascular proliferation can be treated with xenon laser photocoagulation or cryosurgery.[64, 65]

Retinal detachments may be treated using vitreoretinal surgery.

Consultation with the following specialists may be needed:

• Dermatologists may help in the initial evaluation and can perform a skin biopsy to aid in diagnosis.

• Ophthalmologists can perform regular ophthalmologic examinations and manage any ophthalmologic sequelae.

• Neurologists can perform a complete initial neurologic examination (including imaging studies and EEG), initiate and monitor anticonvulsant therapy in patients with seizures, and facilitate neurodevelopmental evaluation and intervention.

• General dentists can provide regular dental care, screening for dental complications, and restorative dental care.

• Geneticists can provide appropriate genetic counseling and genetic testing for the patient and his or her family.

The presence of variable disease expression in an affected family makes monitoring for potential complications important. Regular follow-up with a neurologist, ophthalmologist, dentist, and dermatologist should be coordinated as needed.

In patients with seizures, anticonvulsant drugs are used. These agents have central and peripheral anticholinergic effects and sedative effects. They also block the active reuptake of norepinephrine and serotonin. A variety of anticonvulsants are available, and they should be selected at the discretion of the neurologist.