Incontinentia Pigmenti Presenting as Seizures

Jason N. Hubert, M.D., and Jeffrey P. Callen, M.D.

Department of Medicine, Division of Dermatology, University of Louisville, Louisville, Kentucky

Abstract: Incontinentia pigmenti is a rare disorder that may affect manysystems including the skin, central nervous system, bone, and eyes. Wedescribe a 13-day-old girl who developed seizures on day 1 of life and wasplaced on antiseizure medication. On approximately day 4 of life, shedeveloped a vesicular rash on her trunk and extremities. The pediatric teamprescribed intravenous acyclovir and diphenhydramine cream. These wereused without improvement. At dermatology consultation, linear and swirledvesicular lesions were seen. A skin biopsy specimen revealed eosinophilswithin intraepidermal vesicles consistent with a diagnoses of incontinentiapigmenti. This case of incontinentia pigmenti is of interest in that the initialsymptom was a seizure disorder.

Incontinentia pigmenti (IP) is an X-linked disorderthat has characteristic cutaneous lesions along withnumerous associated systemic findings (1). The skineruption usually proceeds through multiple stagesincluding vesicular, verrucous, and pigmentary changes.We found that instances of seizures occurring as thepresenting sign of IP are rare but have been reported inthe literature (2, 3).We describe a newborn infant whosefirst manifestation was a convulsive disorder and wholater developed other findings of IP.

CASE REPORT

A 3.0 kg female infant was born to a 30-year-old motherwhose pregnancywas uncomplicated. Themother’s onlyother pregnancy was also uncomplicated, and the siblingis a healthy young boy. Neither the mother nor son haveneurologic or cutaneous abnormalities, and there is nofamily history of these types of abnormalities. At 12hours following birth, the infant girl had a generalizedseizure with convulsive motor activity. Phenobarbitalwas administered without effect. On her third day oflife she was transferred to our pediatric hospital for

treatment of uncontrolled seizures. No cutaneousabnormalities were noted on the physical examination atadmission. Evaluation includedblood cultures, completeblood count, urinalysis, arterial blood gas, and lumbarpuncture, all of which were normal. The neurologicexamination revealed no focal abnormalities. Electro-encephalogram (EEG) was abnormal and showedmultifocal spikes in both the frontal and right occipitalregions. Head computed tomography (CT) showed amoderate subarachnoid hemorrhage and bilateralscattered foci of encephalomalacia that was thought torepresent scattered areas of ischemia or localized edema.Ampicillin and gentamicin were started on admission

and were discontinued 2 days later when no evidence ofinfection was found (see Table 1 for the time frame ofevents). The phenobarbital was continued, and shereceived one dose of fosphenytoin on the fourth day oflife. Approximately 8 hours after the dose of fosphenyt-oin, the infant was first noted to have a rash. The fos-phenytoin was discontinued because the rash wasthought to have possibly been an adverse drug reaction.She was started on diphenhydramine cream and wasnoted to have great improvement in her cutaneous lesion

Address correspondence to Jeffrey P. Callen, M.D., 310 EastBroadway, Suit 2A, Louisville, KY 40202, or e-mail: jefca@aol.com

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over the next 3 days.Her eruption returned on the fourthday after discontinuation of the fosphenytoin. At thispoint the pediatric team felt the vesicular nature of herlesions suggested a diagnosis of herpes simplex virusinfection and intravenous acyclovir was begun. Thelesions were not cultured nor was a Tzanck smear per-formed. Since she continued to experience seizures, shewas restarted on fosphenytoin.Dermatology was first called to see the patient on

day 13 of life, when cutaneous examination revealedvesicles on erythematous bases in a swirling pattern onher upper and lower extremities (Fig. 1). The acyclovirand diphenhydramine were discontinued. Skin biopsywas performed and the specimen demonstrated intra-epidermal vesicles and a spongiotic dermatitis. Thesevesicles were filled with eosinophils and a superficiallymphocytic infiltrate was also noted. These findings

were consistent with the diagnosis of incontinentiapigmenti.Ophthalmologic examination revealed no abnormal-

ities except mild conjunctivitis. A geneticist was consul-ted who provided information for the family about therisk of IP in future pregnancies. The number and severityof the infant’s seizures gradually declined while undertreatment with phenobarbital and phenytoin. Thesemedications were continued after she was discharged,which was on day 17 of life. At that time, the cutaneouslesions were relatively unchanged.Skin examination 2 months after birth revealed

vesicular and bullous lesions located in linear whorls,extending up the medial aspects of her feet onto herlegs and thighs. The mother reports that the infantexperienced the verrucous stage of this disorder pre-dominately on her hands and feet during the third andfourth months of life. Eight months after birth she wasnoted to have tan-colored pigmentation in a whorledpattern on her lower extremities. Since the initialhospitalization, she has been rehospitalized once forseizures and was started on adrenocorticotropic hor-mone (ACTH), with further improvement in seizureactivity. This medication was discontinued after 2months, and she has remained free of seizures sincethat time. She has also been seen at regular intervals byan ophthalmologist, who has found no abnormalities.At 1 year of age she is within normal limits for size andweight, but the mother reports that her daughter hashad a patch of alopecia for the past few months inthe occipital region, has no teeth, and appears to beslightly developmentally delayed in reaching her walk-ing milestone.

TABLE 1. Time Frame of Events

Date Medication changes Cutaneous findings

7/4 Phenobarbital started for seizure control.7/5 Upon transferring, started on ampicillin

and gentamycin.No findings noted upon initial physicalexamination at the pediatric hospital.

7/6 Started fosphenytoin and lorazepamas required.

‘‘Rash’’ appeared approximately 8 hours afterthe first dose of fosphenytoin.

7/7 Ampicillin and gentamycin discontinuedbecause of negative sepsis workup.Fosphenytoin stopped secondary to concernsof an adverse drug reaction.Diphenhydramine cream started.

Improvement of ‘‘rash’’ over the next 3 days.

7/11 Acyclovir (IV) started for suspected herpessimplex virus.

Fosphenytoin restarted since rash not likelya drug reaction.

‘‘Rash’’ worsened and was noted to havea vesicular component.

7/15 Acyclovir and diphenhydramine discontinued. Dermatology consult found the cutaneous findings consistentwith the diagnosis of IP.

7/19 Continued phenobarbital and phenytoin(switched from fosphenytoin) at the timeof discharge from the hospital.

Cutaneous findings unchanged from 7/15.

Figure 1. Linear vesicular eruption.

Hubert and Callen: IP Presenting with Seizures 551

DISCUSSION

Since IP is an X-linked dominant disorder, it affectspredominately females. Genetic analysis has indicatedXq28 to be the major locus for familial IP (4). It hasrecently been shown that most cases of IP are due tomutations in the gene for NEMO (NF-kappaB essen-tial modulator)/IKKgamma (IkappaB kinase-gamma).This gene product is critical for the activation ofNF-kappaB, which is a transcription factor involvedin many immune, inflammatory, and apoptotic path-ways (5). These mutations are presumed to be lethal tomale fetuses in utero. It is thought that the rareinstances of males with IP can be explained by one ofthree mechanisms: the half-chromatid hypothesis,unstable premutations, and a higher rate of denovogermline mutations (6). In our case, the mother hadno history or evidence of the disorder and her earlierpregnancy resulted in a normal, healthy son. Themother is currently considering genetic testing forherself and her daughter, but it has not been perfor-med to date.There are many abnormalities associated with IP,

and our patient first presented with central nervoussystem (CNS) manifestations, which appear in appro-ximately 10–30% of patients (1,7). Seizures are themost common CNS finding, but others include mentalretardation, microcephaly, and motor retardation(1,7). It has been reported that up to 13% of patientswith IP may have a convulsive disorder (7). The timeframe in which these seizures occur is not wellreported in the literature. Our patient actually hadseizures as her presenting abnormality, and this clinicalpicture may represent a very small minority of cases ofIP, especially as approximately 92% of patients havethe characteristic rash by the age of 2 weeks (7). Ourpatient also had head CT findings consistent withscattered areas of ischemia or localized edema, andthis association of IP and stroke or ischemic lesionshas been reported in the literature (8). In these reports,

the children with stroke and ischemic lesions were notnoted to have seizure activity (8).Because of all the associated manifestations, it is

important to have the patient see various physicians forevaluation and management of the different problems(9). It is recommended that they have neurologic, oph-thalmologic, and dental examinations on a regular basisand be followed closely by their pediatrician. In the fewpatientswith IP reported topresentwith seizures,CTandMRI abnormalities have been noted, but none of thosecases displayed the same pattern as our patient. Inaddition, our case is another illustration that specialattention should be given to the skin examination for anysigns of IP in infants presenting with seizure activity.

REFERENCES

1. Cohen PR. Incontinentia pigmenti: clinicopathologiccharacteristics and differential diagnosis. Cutis 1994;54:161–166.

2. Yang JH, Ma SY, Tsai CH. Destructive encephalopathy inincontinentia pigmenti: a case report. J Dermatol 1995;22:340–343.

3. Hardart G. A 2-day-old girl with seizures and a rash. CurrOpin Pediatr 1994;6:454–458.

4. Woffendin H, Jakins T, Jouet M, et al. X-inactivation andmarker studies in three families with incontinentia pigmenti:implications for counselling and gene localisation. ClinGenet 1999;55:55–60.

5. Smahi A, Courtois G, Vabres P, et al. Genomic rearrange-ment in NEMO impairs NF-kappaB activation and is acause of incontinentia pigmenti. Nature 2000;405:466–472.

6. Shastry BS. Recent progress in the genetics of incontinentiapigmenti (Bloch–Sulzberger syndrome). J Hum Genet2000;45:323–326.

7. Carney RG. Incontinentia pigmenti: a world statisticalanalysis. Arch Dermatol 1976;112:535–542.

8. Kasai T, Kato Z, Matsui E, et al. Cerebral infarction inincontinentia pigmenti: the first report of a case evaluated bysingle photon emission computed tomography. Acta Paedi-atr 1997;86:665–667.

9. Sahn EE, Davidson LS. Incontinentia pigmenti: three caseswith unusual features. J Am Acad Dermatol 1994;31:852–857.

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