Clinical and histologic features of incontinentiapigmenti in adults with nuclear factor-kB essential

modulator gene mutations

Smaıl Hadj-Rabia, MD, PhD,a,b Aude Rimella, MD,a Asma Smahi, PhD,b Sylvie Fraitag, MD,c

Dominique Hamel-Teillac, MD,a Jean-Paul Bonnefont, MD, PhD,d Yves de Prost, MD, PhD,a

and Christine Bodemer, MD, PhDa,b

Paris, France

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Background: Incontinentia pigmenti (IP) is a multisystem disorder, in which cutaneous symptoms can beaccompanied by dental, ocular, and central nervous system defects. In adults, the clinical diagnosis of IP isbased principally on the late onset of stage 4 lesions and their association with dental, nail, ocular, orcentral nervous system anomalies. Nevertheless, these lesions are often unrecognized.

Objectives: Our aim was assessment of IP manifestations in adults to clarify diagnostic criteria for mild formsof the disease, to help physicians detect adult IP in the presence of subtle lesions and avoid misdiagnosis.

Method: We conducted clinical and histologic examination of 25 adults with IP and nuclear factor-kBessential modulator gene rearrangement or mutations.

Results: Linear atrophic, hypopigmented, and hairless lesions (stage 4) are constant in adults. Apoptotickeratinocytes in the epidermis or dermis and atrophic hair follicles, with absence of arrector pili muscles,are frequently observed. In contrast, nipple anomalies are rare.

Limitations: We were unable to determine the age of the onset of IP stage 4 lesions.

Conclusion: Skin manifestations are constant in adult patients with IP. Histology is characteristic and couldbe considered as a minor diagnostic criterion of IP. Nipple anomalies also may be considered as a minorcriterion. Detection of such subtle manifestations can evoke IP in patients with repeated miscarriages orunexplained neurologic manifestations. ( J Am Acad Dermatol 2011;64:508-15.)

Key words: clinics; histology; incontinentia pigmenti; NEMO mutation.

Abbreviations used:

EDA: ectodermal dysplasia anhidrotic formIP: incontinentia pigmentiNEMO: nuclear factor-kB essential modulatorNF: nuclear factor

The nuclear factor (NF)-kB signaling path-way is a multicomponent pathway thatregulates the expression of hundreds of

genes that are involved in diverse key cellular andorganismal processes including cell proliferation,survival, stress response, innate immunity, and in-flammation. Not surprisingly, misregulation of theNF-kB pathway is involved in many human diseases,

the Centre National de Reference des Maladies Genetiques a

pression Cutanee (MAGEC) and the Department of Derma-

logy,a Institut National de la Sante et de la Recherche

edicale (INSERM) U-781,b Department of Pathology,c and

epartment of Genetics,d Unite de Formation et de Recherche

FR) Necker-Enfants Malades Hospital, Universite Paris V,

ssistance Publique-Hopitaux de Paris (APHP).

first two authors contributed equally to this article.

ing sources: None.

licts of interest: None declared.

Accepted for publication January 6, 2010.

Reprint requests: Christine Bodemer, MD, PhD, Centre MAGEC,

Departement de Dermatologie, Hopital Necker-Enfants

Malades, 149 rue de Sevres 75015 Paris, France. E-mail:

christine.bodemer@nck.aphp.fr.

Published online January 21, 2011.

0190-9622/$36.00

ª 2010 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2010.01.045

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especially those associated with chronic inflamma-tion, immunodeficiency, and cancer. In 2000, incon-tinentia pigmenti (IP), or Bloch-Sulzbergersyndrome (IP, Mendelian inherritance in man,308300) was the first human disease in which amutation of a component of this pathway wasdetected. IP is a rare, X-linked dominant genoder-

CAPSULE SUMMARY

d Incontinentia pigmenti may be detectedduring adulthood (13 of our 25 cases).

d Linear atrophic, hairless, andhypopigmented lesions followingBlaschko lines (stage 4) are constant andlocalization on the limbs is typical (100%of cases).

d Histologic anomalies at stage 4 consistof: (1) an atrophic epidermis, withmarkedly decreased melanin in the basallayer; (2) persistence of apoptotic bodiesin the epidermis or papillary dermis; andabove all (3) complete absence ofpilosebaceous units and eccrine glands.These histologic findings should beconsidered to be minor additionaldiagnostic criteria.

d Recurrence of stage 1 lesions may beobserved during adulthood.

matosis that affects mostlyfemale patients and is usuallylethal for male fetuses inutero. IP is a multisystemdisorder, in which cutaneoussymptoms can be accompa-nied by dental, ocular, andcentral nervous system disor-ders such as seizures, spasticparalysis, microcephaly, andmental retardation.1 The typ-ical phenotype results from afunctional mosaicism, whichby itself is a consequence oflyonization.2 The identifica-tion of NF-kB essential mod-ulator (NEMO) as thedisease-causing gene, andthe skewing of X-chromo-some inactivation, are pow-erful tools for the diagnosisof unusual forms of IP. In 80%of IP cases, the disease iscaused by a large-scale dele-tion of NEMO exons 4 to

10.3,4 Nevertheless, the diagnosis of IP is based ona thorough clinical examination. Landy and Donnai5

have defined criteria that are useful for the clinicaldiagnosis of IP (Table I). The skin lesions may occurin 4 successive diagnostic stages: erythema, thenvesicles and pustules (stage 1); verrucous lesions(stage 2); linear hyperpigmentation (stage 3); anddepigmentation and scarring (stage 4). The lesionsfollow the Blaschko lines and individual stages mayeither overlap or be absent. In a previous study, wehave reported the frequency of IP manifestations in aseries of 40 affected children. We also proposed toinclude the characteristic histologic features as amajor criterion for the diagnosis of pediatric IP.6

The association of unusual ocular and neurologicmanifestations and frequent and late miscarriages inyoung women could be explained by the diagnosisof IP. However, its detection may be difficult consid-ering the paucity of detailed data in adults. Stage1 and 2 lesions are usually absent, and persistentstage 3 lesions are often inconstant and discrete.7-12

In adults, the clinical diagnosis of IP is principallybased on the late onset of stage 4 lesions and their

association with dental, nail, ocular, or central ner-vous system anomalies.13,14 Even so, these lesionsare often unrecognized.

The aim of our study was to assess the clinicaland histologic findings in a series of 25 women withmolecular confirmation of IP. In doing so, wedemonstrated the importance of a careful examina-

tion. We also describe un-usual but helpful histologicfeatures that suggest the di-agnosis of IP in adults.

METHODSAll women (ie, aged [ 18

years) with genetically con-firmed IP (n = 60) from thegenetic registry of our hospi-tal were contacted by mail.During a 1-hour consultation,the following informationwas collected using a stan-dardized case record form:personal and familial historyconcerning the cutaneous,ocular, dental, neurologic,and infectious manifestationsand their evolution; gyneco-logic history was also noted.When necessary, data werecollected through differentspecialists who had followedup the patients. All patients

were closely examined by a senior dermatologist (S.H-R. or C. B.). The clinical examination was partic-ularly focused on skin, hair, nail, teeth, breast,nervous system, and eye anomalies. When skinlesions were observed, a skin biopsy was systemat-ically proposed and realized after informed consentof the patient. The samples were all examined by thesame dermatopathologist (S. F.). Standard thick sec-tions were cut and stained with hematoxylin-eosinfor routine histologic examination, which focused onmelanin (Fontana-Masson staining), elastic fibers(orcein staining), and melanocytes (Mart-1 orMelan-A) staining according to standard immunohis-tochemical techniques.15

RESULTSIn all, 25 patients were included (response rate

42%). The confirmed molecular diagnosis consistedof the common rearrangement, for 22 patients, or analternative mutation for the 3 others in NEMO gene.Fifteen patients belonged to 8 families; the other 10were sporadic cases. The median age of the patients

Table I. Clinical and histologic criteria for diagnosisof incontinentia pigmenti

No incidence of IP in at least

1 first-degree female relative

Evidence of IP in at least 1 first-

degree female relative

Major criteriaTypical neonatal rash Suggestive history or

evidence of typical rashErythema, vesicles,

eosinophiliaSkin manifestation of IP

Typical hyperpigmentation HyperpigmentationMainly on trunk ScarringFollow Blaschko lines Hairless streaksFading in adolescence Alopecia at vertexLinear, atrophic, hairless

lesionsAnomalous dentition

Wooly hairRetinal diseaseMultiple miscarriages of

male fetusesMinor criteria (supportive evidence)

Dental involvementAlopeciaWooly hair, abnormal nailsHistologic features (ie,

apoptotic keratinocytes)*Nipple anomalies*

At least 1 major criterion is necessary to make firm diagnosis of

sporadic IP. Minor criteria, if present, will support diagnosis;

because of their high incidence, complete absence should

induce degree of uncertainty.

Diagnosis of IP is likely in first-degree female relative of affected

female patient if any mentioned minor criteria are present, alone

or in combination.

*We propose to add histologic features and nipple anomalies as

minor criteria. In situations of hidden nuclear factor-kB essential

modulator mutations, histology can be very helpful for

confirmation of IP.

According to Landy and Donnai.5

IP, Incontinentia pigmenti.

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was 38 years and 3 months (range, 23-69 years).Median age at diagnosis was 16 years and 2 months(range, birth-65 years). It was unknown for only onepatient. The diagnosis of IP was made during adult-hood for 13 patients (52%).

Dermatologic manifestationsFrequency and topography of dermatologic le-

sions are reported in Table II. All patients (100%)presented skin lesions on clinical examination.Typical stage 4 lesionswerepresent in all the patients,sometimes in a very subtle way, especially in patientswith light skin. All the lesions were hairless, enhanc-ing the hypopigmented aspect. The surrounding skinusually appeared normal, except for 3 patients with amarked hairiness on erythematous, inflamed skinnear the lesions. The hair was thick and rough inthese areas, different from the hairiness of the rest of

the body. The patients reported accelerated hairgrowth in these areas. There was no sign of hyper-androgenism. Interestingly, these 3 patients also hadneurologic manifestations of IP.

Unilateral predominance of stage 4 lesions wasseen in most of the patients (19 of 25; 76%). Most ofthese were on the left side (15 of 19; 79%). Stage1 lesions in the neonatal period were reported by 17patients (68%) and 5 patients (20%) reported stage 2lesions in infancy. Recurrence of stage 1 lesionsduring infancy was reported by 3 patients (17%).Only one 27-year-old patient showed a stage 2hyperkeratotic lesion on clinical examination. Thelesion was overlying a stage 3 hyperpigmentedmacule on the left leg (Fig 1, E). The patient reportedthat the lesion was preceded by first-stage vesiclesand recurred frequently. The recurrence alwaysoccurred in the same location and was alwaystriggered by an infectious episode, sun exposure,or emotional stress. One patient had a subungualkeratotic tumor.

Extracutaneous manifestationsIn all, 23 patients (92%) had dental abnormalities:

partial anodontia (18 patients; 72%), conical incisors(15 patients; 60%), persistence of deciduous teeth(14 patients; 56%), delayed dentition (7 patients;28%) (Fig 2, C and D), and an ectopic tooth in thehard palate (3 patients; 12%). Enamel defects werenot detected. All patients reported increased decaydevelopment in spite of early dental care. Onepatient had focal gingival hypoplasia and 4 patientsreported chronic gingivitis.

Ophthalmologic abnormalities were present in 17patients (68%). Myopia was noted in 5 patients. Theremaining 12 patients had unilateral ophthalmologicabnormalities consisting of strabismus during child-hood that was corrected by ocular re-education orsurgery (5 patients), left cataract (3 patients), leftretinal weakness requiring laser treatment (2 pa-tients), left retinal detachment (1 patient), and uni-lateral right visual loss caused by optic nerve atrophy(1 patient).

Neurologic abnormalities were reported in 3 pa-tients (12%). One patient had left cerebral atrophy,right spastic hemiparesis, motor retardation, andmild mental retardation. She had right optic nerveatrophy and refractory focal epilepsy. The secondpatient had a convulsive disorder during the first 5days of life with tonicoclonic movement of the rightarm and leg. Infectious disease was excluded and notreatment was effective. The disorder spontaneouslyabated at day 5 and never recurred. She had mod-erate mental retardation with some slowness andlearning difficulties. The third patient had right leg

Table II. Cutaneous manifestations in 25 adults with incontinentia pigmenti

Topography

Cutaneous lesions Frequency (n = 25) Arms Legs Trunk Back

Stage 3 44% (11) 24% (6)* 16% (4) 24% (6)y 24% (6)y

Stage 4 100% 88% (22) 100% 28% (7) 8% (2)z

Telangiectasia 72% (18) 72% (18)Nail dystrophy§ 92% (23)Excessive sweatingk 16% (4)Alopecia 60% (15)Unruly hair and slow growth 40% (10)Sparse eyebrows/eyelashes{ 76% (19)

Stage 3 lesions consisted of hairless linear or reticulate hyperpigmented macules. Stage 4 lesions consisted of linear, reticulate, or patchy

atrophic hypopigmented lesions along Blaschko lines (Fig 1, A and B).

*The lesions are located in armpits.yAs shown in Fig 1, D.zAs shown in Fig 1, C.§Smooth nails with linear vertical striations, fragile extremities or onycholysis (Fig 2, A).kFollowing pregnancy.{The eyebrows are sparse on their external end and the inferior eyelashes are rare (Fig 2, B). One patient had an aspect of trichorrhexis

nodosa.

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atrophy with intermittent limping, but the origin wasnever investigated. Neurologically, she had no ap-parent mental or motor retardation. These last twopatients had no ocular anomalies. Seven patients(30%) had breast anomalies: inverted nipples withbreast-feeding incapacity (6 patients), supernumer-ary nipple (2 patients), symmetric breast hypoplasia(2 patients), and agalactia (2 patients). Early sponta-neous abortion was reported by 14 patients (56%).History of repeated infections was negative for all thepatients.

Histologic findingsSkin samples were obtained from 22 patients.Stage 4 lesion biopsy specimens were obtained

from 21 patients (Fig 3, A and B). They showedapoptotic bodies in the epidermis or in the papillarydermis (Civatte bodies, 17 of 21 patients; 81%),absence of pilosebaceous units in 19 of 21 patients(90%), and absence of eccrine glands in 18 of 21patients (85%). A slight atrophic and pale epidermiswas seen with almost complete absence of melaninin the basal layer after Fontana-Masson staining (allof 21 patients). Melan-A staining showed that thenumber of melanocytes had decreased in the basallayer. The distribution of melanocytes was irregular(all of 10 patients).

The dermis was pale, fibrous, and sometimesedematous with a flattened papillary profile (16 of 21patients; 76%), whereas elastin fibers were normalafter orcein staining. Total absence of pigmentaryincontinence and inflammation in the papillary der-mis (all of 21 patients) and the presence of ectaticvessels (10 of 21 patients; 47%) were also noted.

Stage 3 lesions were obtained from 7 patients(Fig 3, C ). Analysis demonstrated large deposits offree or intramacrophagic melanin in the papillarydermis with a slight inflammatory infiltrate.Apoptotic Civatte bodies in the epidermis and/or inthe papillary dermis, and absence of pilosebaceousand sudoral units were also constant features.

A stage 2 lesion overlying a stage 3 lesion wasobtained from the 27-year-old patient (seeDermatologic Manifestations section). It revealedsignificant verrucous hyperplasia of the epidermiswith orthokeratotic hyperkeratosis, acanthosis, andpapillomatosis. Many apoptotic cells were observedin the epidermis. Papillary fibrous dermis was asso-ciated with vascular hyperplasia and a mononuclearinfiltrate without eosinophilia. Deposits of free orintramacrophagic melanin were observed. Reticulardermis was dense, fibrous, and totally devoid ofpilosebaceous units and sweat glands.

DISCUSSIONClassically, the diagnosis of IP is based on the 4

successive, sometimes overlapping, stages of therash. During childhood, stages 1 and 2 are almostconstant.6 However, in adults the paucity and sub-tleness of skin features may lead to IP being over-looked. To pinpoint the importance of such clinicalfeatures, 25 women with molecular confirmation ofIP (ie, from the register of the department of genet-ics) were systematically re-evaluated.

Interestingly, the diagnosis of IP was not madeuntil adulthood in 52% of these patients. This latediagnosis corresponded to the detection of IP in theasymptomatic, or paucisymptomatic, relatives of a

Fig 1. Skin manifestations of incontinentia pigmenti in adults. Varied clinical appearance ofstage 4 lesions: Blaschko linear hypopigmented atrophic hairless lesions associated withtelangiectasia on leg (black arrow) (A), patchy hypopigmented lesions on arm (black arrow)(B), reticulated hypopigmented lesions on back (black arrow) (C). D, Stage 3 linear reticulatedhyperpigmented macules. E, Stage 2 hyperkeratotic lesion overlying stage 3 hyperpigmentedmacule on inferior limb.

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proband. Our findings emphasize the underesti-mated frequency of the disease in the general pop-ulation. Moreover, the constant detection ofdermatologic features underlines the importance ofcareful skin evaluation in women with recurrentmiscarriages, reported in 56% of the cases in ourseries.

Linear atrophic, hairless, and hypopigmentedlesions following Blaschko lines (stage 4) (Fig 1, Ato C ) are constant. Localization on the limbs is classic(100% of cases) but also frequent on the trunk (28%).Characteristic stage 4 lesions have been reported in27 relatives of IP proband.13 These lesions may bedifficult to detect in women with light skin, but nodifferential diagnosis can be evoked. In a few cases,IP presents as subtle patchy hairless lesions. The age

of onset is difficult to determine. In a previousretrospective study, stage 4 lesions were reportedin 22.5% of 40 affected children.6 During childhood,these lesions may be more frequent but hidden bystage 1 to 3 lesions. Moreover, in adults, increasedhair density around the lesions may highlight thehairless lesions in stage 4. Considering that 32% ofour patients did not report typical neonatal stage1 lesions, it may be difficult to recognize such subtlestage 4 lesions and detect sporadic cases in adults.Unilateral, mostly left-sided predominance of stage 4lesions was also a striking element. It might suggestthat NEMO-deficient cells could be present very earlyin development, when lateralization occurs. Genesimplicated in lateralization may be among NF-kBregulatory targets during skin development.

Fig 2. Appendages and dental anomalies in incontinentia pigmenti. Nail dystrophy withlongitudinal striations (A); sparse eyebrows (B); hypodontia, conical superior incisor, andretained deciduous teeth (C); panoramic dental radiograph showing anodontia, conicalincisors, and retained deciduous teeth (D). Patients C and D are different individuals.

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As already observed, linear hyperpigmentationlesions (stage 3) (Fig 1, D) are present in folds. Theyfade after puberty. In adults, isolated hyperpig-mented linear lesions may be mistaken for otherpigmentation disorders.11 This fact had led us tocarefully research their association with stage 4lesions. This association is highly characteristic ofIP (44% of our series).

Our results confirm, even in adults, the possiblelate recurrence of stage 1 lesions (17%).7,8,16,17 In ourparticular patient, lesions were always triggered by aninfectious episode, sun exposure, or emotional stress.The frequency and significance of such late recur-rences remain unknown. A trigger factor is frequentlyreported.18 This phenomenon could be explained bythe persistence of residual NEMO-deficient cellsgiving rise to hyperproliferation, inflammation, andapoptosis until there is a complete elimination ofthe mutated cells from the skin.19 The role of proin-flammatory cytokines such as tumor necrosis factor(TNF)-a has been discussed.20,21 IP should be con-sidered in patients presenting with recurrent inflam-matory or hyperkeratotic lesions of unknown originalong Blaschko lines.

One of our most important findings is the persis-tence of highly diagnostic histologic features in skinbiopsy specimens from adults with IP. A previousstudy has underlined the characteristic aspect of thehistologic pattern observed at different stages of theclassic eruption in children.6 Interestingly, in ouradult series, we observed constant, highly

characteristic histologic anomalies in stage 4 skinbiopsy specimens. The features were detected, afterserial histologic sections, even in biopsy specimensof subtle stage 4 lesions. The main characteristicfeatures consist of the association of: (1) an atrophicepidermis, massive reduction of melanin in the basallayer; (2) the persistence of apoptotic bodies in theepidermis or papillary dermis; and above all (3) thecomplete absence of pilosebaceous units and ec-crine glands. The absence of fibrosis and the normalelastic network ruled out scar tissue (Fig 3, A andB).14 The remarkable and unusual ectatic vesselsmay explain the vascular appearance of some le-sions. Moreover, stage 3 hyperpigmented lesions andstage 2 verrucous lesions were also hairless (Fig 3,C ). These constant hairless lesions associated withthe absence of pilosebaceous units and traces ofscarring emphasize the role of NF-kB in epidermaldifferentiation and the previously demonstratedlinks between IP and anhidrotic ectodermal dyspla-sia (EDA). It was also interesting to observe thineyebrows and eyelashes (Fig 2, B) in 76% of ourpatients, as seen in EDA.22,23

Many reports have demonstrated that NF-kB hastwo major roles in the epidermis. It protects keratino-cytes from apoptosis and controls their proliferationand differentiation during the last step of epidermalmaturation.24 Functional blockade of NF-kB by ex-pressing dominant-negative NF-kB inhibitory pro-teins in transgenic murine and human epidermisproduced hyperplasic epithelium in vivo with

Fig 3. Histologic features of incontinentia pigmenti. A,Stage 4 lesion biopsy specimen showing atrophic paleepidermis with flattened papillae, pale, fibrous dermis,total absence of pilosebaceous units, ectatic vessels, andabsence of inflammation. B, Stage 4 lesion biopsy speci-men showing apoptotic keratinocytes in epidermis (blackarrow) and Civatte bodies in papillary dermis (blackcircle). C, Stage 3 lesion biopsy specimen showing largedeposit of free melanin and Civatte body formation inpapillary dermis, with absence of pilosebaceous units andeccrine glands. (A to C, Hematoxylin-eosin stain; originalmagnifications: A, 340; B, 3250; C, 3100.)

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absenceofhair follicles.21,25 Pharmacologic inhibitionof NF-kB leads to the same observation.26 Thus theabsence of hair follicles in patients with IP might be adevelopmental skin defect. Attentive histologic anal-ysis of early stage lesions (1 and 2) will allow confir-mation of this hypothesis. At least, it will improveknowledge of the process of the differentiation of thepilosebaceous unit from infancy to adulthood.

Moreover, large-scale deletion of the NEMO geneis now routinely identified. This corresponds to 80%

of IP mutations. In the remaining 20%, the mutationis hidden by the second copy of the NEMO gene andthe presence of a highly homologous NEMO pseu-dogene. In cases of hidden mutations, histology is ahighly helpful tool for the confirmation of the IPdiagnosis.4 In our opinion, histologic features mustbe considered as a true minor criterion (Table I).

In our practice, histology was helpful to diagnosean affected pregnant woman with no NEMO rear-rangement or skewed X-chromosome inactivation.Her mother, who was initially considered unaffected,presented with hypopigmented atrophic macules onher legs, which were confirmed by histology to be IPlesions. Thus the prenatal diagnosis was made on thebasis of segregation analysis of microsatellitemarkers flanking the NEMO gene on the Xq28chromosome.

Our series confirms that dental (92%) (Fig 2, C andD), nail (92%), and hair and nipple (30%) involve-ment are minor but useful criteria for IP diagnosis inadults. Alopecia was more frequent in our series thanpreviously reported (60% vs 38%).1,5 Unruly hair wasless frequent (10%). Rare and thin eyelashes, eye-brows, or both (76%) are frequent. Nail anomalieswere also more frequent than reported elsewhere(92% vs 40%) (Fig 2, A), as were nipple anomalies(30%), which may be added as a minor criterion forIP diagnosis. Moreover, functional anomalies werefrequently reported, ie: agalactia (8%) or feedingincapacity (24%). These nipple anomalies must alertthe gynecologist, particularly in women with fre-quent miscarriages.1,5 Absence of clinical manifesta-tions of immunodeficiency (ie, repeated infections)is explained by the nature of NEMO gene mutationsrelated to IP.27

Ocular complications are common. Their severityis variable. Bilateral involvement is exceptional.Neurologic complications are less frequent but se-vere. However, the onset of seizures in infancy isfrequently resistant to conventional antiepileptictreatments.6 Because of the major role of TNF inthe occurrence of inflammatory reactions and laterecurrences of skin lesions, we speculate that thiscytokine may play a key role in the onset of seizures.Therefore, anti-TNF medications might be of interestfor treatment of seizures.

ConclusionIn adults, careful skin examination enables the

detection of constant, but sometimes subtle, linearatrophic, hypopigmented, and hairless lesions of IP.

Our results show that skin biopsy specimen ishelpful for physicians confronted with such unex-plained and refractory clinical manifestations asophthalmologic, neurologic, and gynecologic

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anomalies. Histologic features should be consideredas minor criteria. They are persistent and highlyspecific. Apoptotic keratinocytes are a constant fea-ture at any stage of the disease. Nipple anomaliesneed also to be included as a minor diagnosticcriterion of IP. One benefit of establishing the diag-nosis of IP in an adult is genetic counseling andfamily planning.

In previous studies we established and empha-sized the link between IP and EDA. Both belong tothe same clinical and molecular spectrum.28 Thisstudy confirms the strong association between thetwo entities. New advances in that field lead us toreconsider previous classifications; thus, X-linkeddominant EDA IP type appears to be an appropriateterminology.29 More information is needed to deter-mine the role of the NF-kB pathway in early fetaldevelopment and its implication in the unilateralpredominance of IP manifestations.

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