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 nail dystrophy and, months and in 80% of cases fades by the age most importantly, destruction of the of six months (2). Linear warty lesions may underlying bone of the terminal phalanx. appear on the back of the hands and feet, The lytic lesions may occur secondary to particularly on the fingers and toes. Warty pressure from the overlying tumors or lesions around the nails with underlying lytic represent primary bone manifestation of IP bone lesions have occurred in adolescence (3). (4). They are highly evocative on the scalp. Palmoplantar hyperhidrosis can also be Late onset of focal verrucous lesions has present (2). Supernumerary nipples have been reported (10). been reported (10). In over half of the reported cases, organs other than the skin The third stage, unrelated to the sites of the or its appendages have been involved (4). previous stages, consists of brownish linear Skull defects such as microcephaly, cleft and whorled streaks that follow the lines palate, cleft lip and ear abnormalities are of Blaschko, with a wide range of encountered (11). involvement mainly on the trunk (2). The Skeletal malformations include: syndactyly, pigmentation ranges in color from blue-gray or hemiatrophy, shortening of arms and legs, slate to brown. The bizarre “splashed” or dwarfism and spina bifida (9). “Chinese figure” distribution is diagnostic. Dental abnormalities are the most common Multiple linear and macular teleangiectasias non-cutaneous manifestation of IP, occurring have occasionally been present (4). in more than 80% of all patients, with nearly 65% presenting major anomalies. These A fraction of patients (about 14%) exhibits a findings have substantive diagnostic fourth stage which appears as a residual importance because they persist for life, in hypopigmentation in the areas of the previous contrast to the skin abnormalities. Both the hypepigmentation, without atrophy; 28% of the deciduous and permanent dentinion may be patients show only small, hairless, atrophic affected (3). Delayed dentition (18%), partial patches (2) that may be anhidrotic (4). The anodontia (43%) and cone or peg-shaped teeth most common distribution is on the extremities (30%) are the most usual (4). in 77% of cases with predilection for posterior Ocular defects are found in about 40% of the calves and very infrequent involvement of the cases, many patients being blind. torso. Side lighting may be used for better Asymmetric involvement is the most common, visualization of atrophic patches whereas although bilateral ocular lesions may occur as Wood's lamp examination may assist in the well (3). The defects include strabismus, diagnosis of hypopigmented streaks (3). Such cataract, conjuctival pigmentosa uveitis, optic lesions might be the only remaining sign of atrophy, retinal vascular abnormalities, blue childhood disease and may then be of sclerae, exudative chorioretinitis and a condition importance, in counseling parents who resembling retrolental fibroplasia. Microphthalmia already have an affected child (4). The hair is also occurs (2, 4, 7, 12). usually normal but in about 25% of the cases,

Stavrianeas NG, Kakepis ME. Incontinentia Pigmenti. Orphanet Encyclopedia. April 2004. http://www.orpha.net/data/patho/GB/uk-incontinentia-pigmenti.pdf 3

Retinal lesions may affect the peripheral retina release eosinophil chemotactic factor of or the macula and generally appear to be a anaphylaxis and by the release of eotaxin by result of vaso-occlusive events and activated keratinocytes (4). After ischemia with subsequent compensatory degranulation, eosinophilic proteases may vasoproliferation. They become evident cause degradation of tonofilaments and between the neonatal period and 1 year of age, desmosomes, resulting in spongiosis and emphasizing the need for frequent ophthalmologic eventual blister formation. evaluation during this time. The prognosis for Recurrences frequently occur after the onset normal vision in a child without demonstrable of a febrile illness, during which circulating findings within the first year of life is generally inflammatory cytokines tend to increase and considered good. However, once established, may therefore trigger a second episode (3). the retinal changes may evolve slowly during Eosinophil chemotactic activity has been many years or progress quickly to retinal demonstrated in patients with IP in the blister detachment and blindness during the course fluid and in eluates of crusted scales overlying of weeks (3). the lesions (3, 13). In the warty lesions the Central nervous system (CNS) disorders hyperkeratosis is further increased and within occurs in about 25% of cases. They include the irregularly acanthotic epidermis hyaline seizures, mental retardation, spasticity, bodies represent individual cell keratinization cerebral atrophy, hemiparesis and (4). Focal dyskeratosis occurs very early, encephalopathy (4). persists until the onset of stage 4 lesions and There has been one report of seizures is clearly determined to be related to presenting as the initial disorder (6). They keratinocyte apoptosis (10).The pigmented occur early in life and are associated with patches show diminution or absence of ocular defects (2, 4, 8, 12). Eosinophilia up to pigment in the basal cells and large quantities 50% in the peripheral blood is usual when of melanin in melanophages in the upper acute inflammatory skin changes are present. dermis. The epidermis may be normal or The highest levels are documented at 3 to 5 slightly acanthotic (4). weeks of life. There is evidence of both Stage 4 presents as atrophic epidermis with a neutrophil and lymphocyte dysfuncton; altered loss of rete ridges and dermal sweet coils. The immunological reactivity is observed in some only remnants of the pilosebaceous apparatus patients (4). are orphaned erector pili muscles. Basal melanocytes are structurally normal but are Course and prognosis significantly reduced in quantity. Colloid The prognosis is generally good and depends on bodies similar to Civatte bodies of lichen extracutaneous manifestations. There is a poor planus and lupus erythematosus have also prognosis and developmental delay in patients been identified in the upper dermis, by means with seizures during the first weeks of life. of electron microscopy (3). In all three stages, Absence of seizures and normal developmental melanophages are present (4). milestones appear to predict a good prognosis (4). Intensity of skin manifestations and Differential diagnosis eosinophil count are not related to more The combination of bullae with linear, severe visceral involvement and have no nodular or warty lesions in a female infant is prognostic value (10). pathognomonic (4). Peripheral eosinophilia and radiographic changes of distal phalanges are Pathology suggestive signs in early stages (5). Other The bullae are situated beneath the horny diseases to take into consideration are shown layer or within a spongiotic epidermis. The in Table 1 dermis shows non-specific inflammatory changes with a cellular infiltrate, including numerous eosinophils. The infiltrate extends into the epidermis and the contents of the bullae may consist predominantly of eosinophils. The lichenoid papules show hyperkeratosis, acanthosis and oedema of the basal layer, many cells of which are degenerated. Macrophages laden with melanin are present in the upper dermis. The presence of eosinophils in epidermal and dermal infiltrates can be explained by the presence in the early vesicular stage of basophils which

Stavrianeas NG, Kakepis ME. Incontinentia Pigmenti. Orphanet Encyclopedia. April 2004. http://www.orpha.net/data/patho/GB/uk-incontinentia-pigmenti.pdf 4

Table 1. Differential diagnosis of with appropriate anticonvulsant therapy and Incontinentia Pigmenti usually do not result in other impairment of the Stage Differential diagnosis CNS or mental retardation if late in onset. of IP Therefore, parents should be reassured of First Infectious: Bullous impetigo, herpes good prognosis if neurological deficits do not simplex, varicella, Langerhans cell develop during infancy (3). histiocytosis. Immune-mediated: Dermatitis References herpetiformis, epidermolysis bullosa 1. Ezughah F, Heagerty A. Incontinentia acquisita, bullous systemic lupus Pigmenti. Midlands Dermatology Society erythematosus, linear IgA bullous autumn meeting, Solihull hospital, 7th dermatosis, bullous pemphigoid, pemphigus vulgaris, heritable November 2001, Book of epidermolysis bullosa, bullous abstracts.Rook/Wilkinson/Ebling Textbook of mastocytosis. Dermatology, Fifth edition 1992, pp.1580-2. Child abuse. 2. Parish LC, Brenner S. Women's Second Verrucae vulgaris, linear epidermal Dermatology. From infancy to maturity 2001, nevi. pp. 89-92. Third Linear and whorled nevoid hypomelanosis, dermatopathia 3. Berlin A. Paller A, Chan L. Incontinentia pigmentosa reticularis, Naegeli- pigmenti: A review and update on the Francoshett-Jadessohn syndrome, molecular basis of pathophysiology. J Am Acad X-linked dominant Dermatol 2002; 47: 169-84. chondrodysplasia punctata. pigment 4. Rook/Wilkilson/Ebling Textbook of mosaicism. Dermatology, Fifth edition 1992, pp. 1580-2. Various Goltz syndrome. 5. Kane KKS-M, Ryder JB, Johnson RA, Baden HP, Stratigos A. Color atlas & synopsis

Antenatal diagnosis of Pediatric Dermatology. pp. 292-5. As IP is a X-linked dominant disease, a family 6. Hubert JN, Callen JP. Incontinentia counseling should be offered (4). A single Pigmenti, presenting as seizure. Ped Dermatol mutation of NEMO gene, resulting in the deletion 2002; 19: 550-2. of exons 4 through 10, is found to account for 7. Chan Y-C, Happle R, Giam Y-C. Whorled more than 80% of all IP cases. The high frequency of this specific deletion facilitates scarring alopecia: A rare phenomenon in mutational detection for the majority of families incontinentia pigmenti? J Am Acad Dermatol and offers a possibility of prenatal diagnosis (3). 2003; 49: 929-31. 8. Happle R.A fresh look at Incontinentia Treatment Pigmenti. Arch Dermatol 2003; 139: 1206-7. The inflammatory lesions, particularly if 9. Braun-Falco O, Plewig G, Wolff HH, denuded, should be treated with standard wound care to avoid secondary infections (5). Burgdorf WHC. Dermatology, Second Spontaneous improvement and resolution of skin completely revised edition 2000, pp.1021-2. lesions is the general rule. The use of lasers in 10. Rabia SH, Froidevoux D, Bodak N, the treatment of hyperpigmentation should be Teillac DH, Smahi A, Freitag S, De Prest Y. discouraged because it has been reported to Clinical study of 40 cases of Incontinentia trigger an extensive vesiculobullous eruption. Pigmenti. Arch Dermatol 2003; 139: l163-70. Concerning the teeth, referral for radiologic evaluation and dental intervention by the age of 11. Fitzpatrick TB, Eisen AZ, Wolff K, 2 years is appropriate. Freedberg IM, K. Austen KF. Dermatology in Regular visits to a pediatric ophthalmologist or General Medicine, Third edition 1987, pp.856- a retinal specialist familiar with retinopathy of 8. prematurity, are essential during the fist 12. Arnold/Odom/James/Andrews year of life. A complete neurologic Diseases of the skin. Clinical Dermatology, examination is warranted for all infants with newly diagnosed IP. Neonatal seizures are Eighth edition 1990. an important prognostic indicator and may 13. Elder D, Elenitsas R, Jaworsky C, predict developmental delay. Seizures Johson B. Miller and Miller Lever's occasionally develop in later childhood or Histopathology of the skin, 8th edition 1997 adolescence, but are generally easy to control

Stavrianeas NG, Kakepis ME. Incontinentia Pigmenti. Orphanet Encyclopedia. April 2004. http://www.orpha.net/data/patho/GB/uk-incontinentia-pigmenti.pdf 5