Background
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.
Pathophysiology
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.
Etiology
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]
Epidemiology
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.
Prognosis
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 intellectual disability, seizures, and vision loss. Patients with structural brain abnormalities and neonatal seizures are at greater risk for motor and intellectual impairment.
Patient Education
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.
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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.
