AN UNUSUAL NEWBORN RASH

Rima Sanka, DO, and Mudra Kumar, MD u University of South Florida School of

Medicine,Tampa, Florida, USA

CASE REPORT

A 2-week-old African American girl is brought to the Emergency Departmentbecause of a worsening rash. The rash had been present since birth and was nowmore ‘‘bumpy and spreading.’’ The baby was eating well with normal urine andstool output. There was no history of fever or fussiness. Birth weight was 2.3 kgand perinatal history was uneventful.

On examination, the infant’s temperature was 99.3 F, pulse 150 per min andrespiratory rate 40 per min with no acute distress.Weight was 2.7 kg. She did notappear toxic. Neonatal re£exes and activity were normal. There were no coarsefacial features or organomegaly. Her scalpwas covered with several honey-crusted,oozing pustules, especially over the occipital area. Her skinwas peeling extensively,revealing hypopigmented skin on all four extremities and trunk but sparing theface, palms, and soles.The denuded skin followed a swirling pattern on the trunk.There were numerous erythematous nodules in the antecubital and poplitealfossae and inguinal folds, some verrucous in nature. None of the lesions appearedpainful.

Laboratory analysis revealed white blood cell count (WBC) of 19:4�103=mm3, with 39% neutrophils,10% band forms, 32% lymphocytes,11%monocytes,and 8% eosinophils. The hemoglobin was 14.9 g=dL and platelet count941�103=mm3. Due to the bandemia and rash of unknown origin in this neonate,bacteremia and sepsis were considered. Blood culture, skin culture for bacteriaand viruses, and herpes simplex virus (HSV) by polymerase chain reaction(PCR) from the skin were sent. The infant was admitted to the hospital forobservation and possible antibiotic therapy.

The di¡erential diagnoses for vesiculobullous and verrucous lesions in a2-week-old female were considered. These included bacterial and viral infectionsas staphylococcal scalded skin, herpes simplex, bullous impetigo, varicella, candi-diasis, syphillis, and other intrauterine=perinatally acquired infections; atopic der-matitis with superinfection, acrodermatitis enteropathica, erythema multiforme;

Special thanks to Dr. Sharon Dabrow for editing skills and Dr. Mudra Kumar for the photo contribution.Address correspondence to Rima Sanka, DO, University of South Florida School of Medicine,Tampa, FL,

USA. E-mail: rimasanka@yahoo.com

Fetal and Pediatric Pathology, 23: 275^279, 2004Copyright#Taylor & Francis Inc.ISSN: 1522-7952 print / 1523-4525 onlineDOI: 10.1080/15227950490923750

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neoplastic such as mastocytosis and histiocytosis; pigmentary disorders such ascongenital dyskeratosis, acropustulosis of infancy, epidermolysis bullosa, ichthyosis,and bullous pemphigoid. Since the infant appeared well clinically, it was decidednot to start empiric antibiotics but to continue observation in the hospital.

DISCUSSION

All cultures were negative. Skin analysis by HSV PCRwas negative. Giemsastain revealed abundant eosinophils. The negative infectious work-up and thestable, afebrile condition of the baby throughout the 3-day hospital stay suggestedthat the baby most likely had a noninfectious etiology for her rash.

The following day, a friend of the family mentioned that the mom, now in herearly 20s, had had a similar rash when she was an infant. The friend describedthat at birth, the mother’s entire body had peeled and developed warty lesionsthat eventually resolved, leaving a dark pigmentation.Themother also hasmissha-pen front teeth and a small area of alopecia on her scalp.Wewere further informedthat in the Caribbean island where the mother was born, many female babieswere bornwith these ‘‘rashes’’ that changed over time andeventually resolved with-out intervention. These rashes are so common that they are accepted as a‘‘normal’’ newborn condition.

Subsequently, our patient was diagnosedwith incontentia pigmenti (IP) on thebasis of family history, physical exam, and absence of support for other etiologies.This was later con¢rmed by DNA analysis that was positive for the NEMO genedeletion mutation on locus Xq28. IP (also known as Bloch-Siemens-Sulzbergersyndrome) is classi¢ed as a genodermatosis and is a rare, multisystem ectodermaldisorder with dermatologic, dental, skeletal, and ocular abnormalities with anexon deletion of an X-linked dominant gene.

Characteristically in most, IP evolves in several stages with variable onset andduration. The ¢rst stage is evident at birth or the ¢rst few weeks of life. It consistsof erythematous streaks and plaques of vesicles most pronounced on the limbsincluding the palms and soles and circumferentially on the trunk (Figure 1). Theunique linear con¢guration and the whorled pattern of distribution followingBlashko’s lines are pathgnomonic (Figure 2).The second stage occurs at 3 weeks to6 months with blisters on the distal limbs becoming hyperkeratotic with verrucousplaques.This stage is accompanied by abnormal tooth eruption and dytrophic nailformation.

By approximately 6 months of age, stage three develops with epidermal hyper-plasia, papillomatosis, and hyperpigmentation. The axillae and groin are mostcommonly a¡ected followed by the trunk, and limbs. These pigmented lesionsfade by early adolescence and usually disappear by 16 years of age. In the fourthstage, hypopigmented, hairless patches or streaks occur on the lower legs, trunkand arms in the areas that were previously hyperpigmentated.This stage may notoccur in all patients.

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Histopathology

The presence of numerous dyskeratotic keratinocytes, often in clusters, inassociationwith spongiotic dermatitis in an infant is virtually diagnostic of inconti-nentia pigmenti. In the acute phase, epidermal edema with perivascular in£am-matory in¢ltrate and eosinophil-¢lled intraepidermal vesiculation are present.Eosinophils in¢ltrate the epidermis and dermis with up to 65% peripheral eosino-philia.The verrucous stage is characterized by hyperkeratosis and acanthosis.Thelast stage lesions show epidermal thinning with vacuolar degeneration of epidermalbasal cells and heavy accumulation of melanophages in the upper dermis. Thelack of, or ‘‘incontinence of pigment,’’ is responsible for the name of the disease.

Other Manifestations

Alopecia or texture changes such as wiry coarse hair occur in up to 40% ofpatients and may accompany thin, spoon-shaped striated nails. About 80% havedental anomalies with late dentition, hypodontia, or conical teeth. Neurologicalproblems include developmental delay, seizures, microcephaly, spasticity, andparalysis in up to 33% of all children. There is a 30% risk of retinal detachmentand other ocular anomalies such as cataracts, strabismus, and optic atrophy. Skele-tal anomalies such as microcephaly, syndactyly, extra ribs, and shortened extremi-ties may occur.

FIGURE 1 Hyperpigmented lesions in a linear distribution on the extremities with nodule formation.

AnUnusual Newborn Rash 277

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Genetics

IP is caused by a randomX inactivation of an X-linked dominant gene namedthe NEMOgene that has been mapped to locus Xq28. Approximately 70^80% ofpatients with IP, including our patient, have this deletion mutation [2]. Southernblot testing has an 80% detection rate [7]. Many cases seem to occur sporadicallywithout familial background, suggesting a substantial mutation rate. Since thismutation is usually lethal in males, the genotype of surviving o¡spring from ana¡ected mother is approximately1=3 a¡ected females, 1=3 una¡ected females, and1=3 una¡ected males. IP occurs 20 times more often in females.

Late reactivation of IP skin lesions was reported in a case series of 5 patientswith IP. The reactivation was always preceded by an infectious episode and itoccurred months or years after resolution of the initial rash.This suggests that themutatedcells persist in epidermis. It is also possible that proin£ammatory cytokinesmay act as a trigger for reactivation [4].

The work-up includes a skeletal survey, screening by a retinal specialist every 6months to a year, dental monitoring, DNA for the IP mutation (to con¢rm), andreferral to early intervention. Genetic counseling and DNA testing are indicated

FIGURE 2 Hyperpigmented lesions in awhirling pattern on the truck with verrucae formation.

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for at-risk family members to facilitate family planning for carriers and preventivescreening.

For pregnancies of womenwith IP, prenatal diagnosis is available if her IKBKGgene mutation has been identi¢ed. The ¢rst step is to determine the fetal sex bychromosomal analysis (amniocentesis or chorionic villus sampling). If the fetalkaryotype is 46 XY, counseling should include discussion of increased risk ofmiscarriage of a¡ected males after the ¢rst trimester. If the fetus is found to befemale, molecular genetic testing can be o¡ered [7].

Recent research has indicated a spectrum of pigmentary disorders that followBlashko’s lines called ectodermal dysplasia [5].They are linked by the IKBKGmuta-tion that is thought to impair NF-kappaB signaling causing an abnormal cellresponse to TNF-a and other cytokines, ultimately impairing T and B cellfunction.The immunode¢ciency has been observed in males as an X-linked, reces-sive hypohidrotic ectodermal dysplasiawith dysgammaglobulinemia and recurrentinfections [6].

REFERENCES

1. V|cente-V|lla A, LamasJV, Pascual AM, Cuesta DL, et al. Incontinentia pigmenti: areport of ten cases. EurJ Pediatr 2001;160(1):64^65.

2. Smahi A, Courtois G, Vabres P, et al. Genomic rearrangement in NEMO impairsNF-kappaB activation and is a cause of incontinentia pigmenti. The InternationalIncontinentia Pigmenti (IP) Consortium. Nature 2000;405(6785):466^472.

3. Online Mendelian Inheritance in Man (OMIM). Familial incontinentia pigmenti (IP2)Identi¢er 308300.

4. Bodak N, et al. Late recurrence of in£ammatory ¢rst-stage lesions in incontinentiapigmenti. Arch Derm 2003;139.

5. Do⁄nger R, et al. X-linked anhidrotic ectodermal dysplasiawith immunode¢ciencyis caused by impaired NF-kappaB signaling. Nat Genet 2001;27:277^285.

6. Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, Shapira SK,Farndon PA, Wara DW, Emmal SA, Ferguson BM. A novel X-linked disorder ofimmune de¢ciency and hypohidrotic ectodermal dysplasia is allelic to incontinentiapigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet2000;67:1555^1562.

7. http:==www.geneclinics.com funded by NIH, HRSA, and DOE.

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