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, 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:
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Typical neonatal vesicular rash with eosinophilia
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Typical blaschkoid hyperpigmentation on the trunk, fading in adolescence
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Linear, atrophic hairless lesions
Minor criteria are as follows:
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Dental anomalies
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Alopecia
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Wooly hair
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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:
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Suggestive history or evidence of typical rash, hyperpigmentation, or atrophic hairless lesions
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Vertex alopecia
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Dental anomalies
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Retinal disease
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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.
Physical Examination
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.
Complications
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]
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A 19-day-old female neonate with incontinentia pigmenti. Clean tense vesicles in linear groups are seen extending from the inner aspect of the right knee to the posterior aspect of the right leg and right sole.
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A 40-day-old female infant who first presented with incontinentia pigmenti when she was aged 19 days. The vesicles have disappeared, leaving a brownish pigmentation with verrucous lesions.
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A 20-day-old female neonate with incontinentia pigmenti. Bullae, vesicles, and verrucous lesions are seen on the lower extremities and buttocks.
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A 27-day-old female neonate who first presented with incontinentia pigmenti when she was aged 20 days. Note the verrucous eruptions with brownish pigmentation in a streaky linear pattern on the left leg.
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Histologic features of a vesicle in a 20-day-old female neonate who presented with incontinentia pigmenti. The epidermis shows acanthosis, spongiosis, and vesicles, which contain an inflammatory infiltrate that includes eosinophils. The epidermis between the vesicles also shows dyskeratotic cells, either singly or in small clusters (hematoxylin and eosin, original magnification X100).
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A 7-month-old female infant with incontinentia pigmenti. Brownish pigmentation in a linear whorled or reticular pattern is present on the trunk.
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A 1-year-old girl who first presented with incontinentia pigmenti when she was aged 7 months. Note that the pigmentation on the left thigh and leg is similar to that on the trunk.
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A 6-year-old girl who first presented with incontinentia pigmenti when she was aged 7 months. Note that the brownish pigmentation on the trunk has largely disappeared, and a small area of pigmentation is left.
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Histologic features of the pigmented skin from a 6-year-old girl with incontinentia pigmenti. An inflammatory infiltrate that includes eosinophils is present in the epidermis. Many melanophages are seen in the upper part of the dermis (hematoxylin and eosin, original magnification X100).
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Typical bullous eruption in a neonate with incontinentia pigmenti.
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Blaschkoid hyperpigmentation in an infant with incontinentia pigmenti.
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Conical teeth in an infant with incontinentia pigmenti.
