Incontinentia Pigmenti Authors: Prof Nikolaos G. Stavrianeas1,2, Dr Michael E. Kakepis Creation date: April 2004 1Member of The European Editorial Committee of Orphanet Encyclopedia 2Department of Dermatology and Venereology, A. Sygros Hospital, National and Kapodistrian University of Athens, Athens, Greece. [email protected] Abstract Keywords Definition Epidemiology Etiology Clinical features Course and prognosis Pathology Differential diagnosis Antenatal diagnosis Treatment References Abstract Incontinentia pigmenti (IP) is an X-linked dominant single-gene disorder of skin pigmentation with neurologic, ophthalmologic, and dental involvement. IP is characterized by abnormalities of the tissues and organs derived from the ectoderm and mesoderm. The locus for IP is genetically linked to the factor VIII gene on chromosome band Xq28. Mutations in NEMO/IKK-y, which encodes a critical component of the nuclear factor-kB (NF-kB) signaling pathway, are responsible for IP. IP is a rare disease (about 700 cases reported) with a worldwide distribution, more common among white patients. Characteristic skin lesions are usually present at birth in approximately 90% of patients, or they develop in early infancy. The skin changes evolve in 4 stages in a fixed chronological order. Skin, hair, nails, dental abnormalities, seizures, developmental delay, mental retardation, ataxia, spastic abnormalities, microcephaly, cerebral atrophy, hypoplasia of the corpus callosum, periventricular cerebral edema may occur in more than 50% of reported cases. Ocular defects, atrophic patchy alopecia, dwarfism, clubfoot, spina bifida, hemiatrophy, and congenital hip dislocation, are reported. Treatment of cutaneous lesions is usually not required. Standard wound care should be provided in case of inflammation. Regular dental care is necessary. Pediatric ophthalmologist or retinal specialist consultations are essential. Seizures should be treated with anticonvulsants. Abnormal fibrovascular proliferation can be treated with photocoagulation. Keywords Bloch-Sulzberger syndrome, skin pigmentation disorders, factor VIII gene, NEMO/IKK-y mutations, (NF-kB) signaling pathway Definition dermis during the third, pigmentary stage of the Incontinentia pigmenti (IP), sometimes termed disease (2). Bloch-Sulzberger syndrome, is a rare X-linked, dominantly hereditary disorder of the developing Epidemiology organs and tissues of ectodermal and Although its prevalence is unknown, more than mesodermal origin (1). The name derives from the 700 cases have been reported in the world incontinence of melanin in the superficial literature up-to-date. Most cases have been Stavrianeas NG, Kakepis ME. Incontinentia Pigmenti. Orphanet Encyclopedia. April 2004. http://www.orpha.net/data/patho/GB/uk-incontinentia-pigmenti.pdf 1 described in white persons, although other races a position 200 kilobases proximal to the factor are affected as well. The occurrence of IP in VIII locus. NF-kB essential modulator male patients is unusual, with a worldwide total mutations impair NF-kΒ activation and cause of 28 cases found in a recent literature review IP (7). When activated, NF-kB controls the (3). expression of multiple genes including cytokines and chemokines and protects cells against Etiology apoptosis (3). A severely truncated NEMO It seems that there is a genetic background in protein will leave the cells susceptible to the pathogenesis of this syndrome. About 50% of proapoptotic signals. This explains why in IP the IP cases have a positive family history (2). the functionally aberrant cell clone is There must be an X-linked dominant trait that is eliminated by apoptosis and why the skin usually lethal in males. More than 95% of the lesions containing apoptotic cells at birth reported cases are females, the few males eventually heal after elimination of NEMO- affected being probably result of spontaneous defective cells. It is obvious that such a mutations (4). These mutations are suspected deleterious mutation of a vital gene can only to produce a failure of immune tolerance in survive in a mosaic state. Hemizygous male ectodermal tissues, resulting in an autoimmune- embryos die in utero because of severe like reaction in heterozygote girls and a fetal graft apoptosis. Apparently, the inflammatory and versus host like disease in homozygous boys vesicular stage, occurring during the neonatal (5). period, reflects apoptosis that eliminates the Five infant boys with the disease also had functionally aberrant cell clone. It is important evidence of Klinefelter's syndrome (47, XXY) to realize, however, that this elimination is not that may have played a role in their survival complete because inflammatory stages because the second X chromosome protected characterized by vesiculation and eosinophilia them from intrauterine death. Also, hypomorphic may recur even in adult patients (8). alleles may play a role on the survival of males with IP, with less deleterious mutations and Clinical features presentations along a proposed continuum The clinical presentations of IP vary from IP to anhidrotic ectodermal dysplasia with considerably even among family members. immunodeficiency (3). The rare occurrence of IP They range from subtle cutaneous and dental in males can be explained by one of the following involvement, recognized after the diagnosis, in a three mechanisms: half chromatid hypothesis, relative to severe and incapacitating neurological unstable permutations or higher rate of de and ophthalmological manifestations. Those novo germ line mutations (6). In general, cases differences in expressivity have been attributed to IP in male patients should be attributed to lyonization in females, resulting carefully investigated and chromosomal in functional mosaicism. analysis should be performed, to run out an Severity of the disease process in the small alternate diagnosis (3). number of live-born male patients is It is now recognized that during early generally not greater than that in the embryogenesis of mammalian female affected females. Many male patients have organism, X chromosome inactivation or disease expression limited to cutaneous lyonization results in a mosaic population of cells: involvement of one or two limbs (3). The skin some cells have an active paternal X changes evolve in stages in a fixed chromosome whereas others have an active chronological order. maternal X chromosome. It has been hypothesized that the segmental and streaked The first stage is present in 90% of the patients manifestations of IP may be consequential to at birth or within the first two weeks of life (2). It tissue mosaicism from random X inactivation, is possible that earlier inflammatory stages with the normal X chromosome active in can occur in utero and not progress after uninvolved skin and the IP X chromosome birth. Clear, tense bullae on inflammatory bases active in involved skin (1). In female patients, in linear groups develop on the limb in the clinical findings may be subtle, reflecting recurrent crops; less often, they are extreme lyonization. generalized (4). They tend to follow the lines It is now known that IP is caused by the NEMO of Blaschko (3, 9). Recurrence of stage 1 gene, which encodes a regulatory component of lesions can be seldom observed. The the I kappa Β kinase, required to activate the frequency of such late recurrences, sometimes nuclear factor-kappa B (NF-kB) pathway (1). The several years after the neonatal period, locus of IP has been found close to the factor remains unknown. Thus, a diagnosis of IP VIII gene on chromosome Xq28. The gene for could be considered in the case of a child, NF-kΒ essential modulator has been mapped to presenting recurrent inflammatory lesions of Stavrianeas NG, Kakepis ME. Incontinentia Pigmenti. Orphanet Encyclopedia. April 2004. http://www.orpha.net/data/patho/GB/uk-incontinentia-pigmenti.pdf 2 unknown origin along the Blaschko lines (10). patches of cicatricial alopecia resembling The bullae are accompanied or followed by pseudopelade, are present from birth, or smooth, red nodules or plaques, often irregularly develop in infancy at or near the vertex (4). It linear, on the limbs and trunk. The plaques may often follows inflammation and vesiculation in be extensive and may precede the bullae. the area (3). Two cases of whorled scarring They may be bluish purple in color and may alopecia associated with IP that follow the ulcerate (4). The face is usually spared, lines of Blaschko, have been reported. They although scalp lesions are quite common (3). reflect functional X-chromosome mosaicism Lesions on the extremities frequently progress (7). to stage 2 of the disease, with a possibility of scarring during the fourth (atrophic) stage: The nails are usually normal but may be small those on the torso typically heal without and dystrophic (7). Nail pitting, onychogryposis atrophy. Recurrences may be accompanied by and subungual hyperkeratosis have been pruritus. However, such recurrences are usually observed (10). Subungual and periungual short-lived and less severe than the original keratotic tumors may appear at a later eruption. stage, typically between puberty and the third decade, although one case has been The second stage, which is marked by linear reported in a 10-year old. Fingers arc are verrucous lesions similar to the first stage affected more often than toes. The tumors pattern, follows usually between the second may regress spontaneously but usually and sixth weeks of life. It persists for a few continue to grow, causing