REFERENCES

1. Boer A, Misago M, Wolter M, Kiryu H, Wang XD, Ackerman AB.

Prurigo pigmentosa: new observations and comprehensive

review. Available from: URL:http://www.derm101.com. Ac-

cessed April 15, 2006.

2. Boer A, Misago N, Wolter M, Kiryu H, Wang XD, Ackerman AB.

Prurigo pigmentosa: a distinctive inflammatory of the skin.

Am J Dermatopathol 2003;25:117-29.

3. Boer A, Ackerman AB. Prurigo pigmentosa (Nagashima

disease), textbook and atlas of a distinctive inflamma-

tory disease of the skin. New York: Ardor Scribendi Ltd;

2004.

4. Daneshpazhooh M, Safar F, Barikbin B, Safee-naraghi Z, Asgari

M, Chams-Davatchi C. Vesicular prurigo pigmentosa in a

16-year-old girl. Nouv Dermatol 2004;23:599-603.

5. Requena Caballero C, Nagore E, Sanmartin O, Botella-Estrada R,

Serra C, Guillen C. Vesiculous prurigo pigmentosa in a 13-year-

old girl: good response to isotretinoin. J Eur Acad Dermatol

Venereol 2005;19:474-6.

6. Nagashima M, Ohshiro A, Shimizu N. A peculiar pruriginous

dermatosis with gross reticular pigmentation [in Japanese].

Jpn J Dermatol 1971;81:38-9.

7. Nagashima M. Prurigo pigmentosaeclinical observations of our

14 cases. J Dermatol 1978;5:61-7.

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136 Brief reports

Incontinentia pigmenti in a boy with XXYmosaicism detected by fluorescence

in situ hybridization

Luis M. Franco, MD,a Jennifer Goldstein, PhD,a Neil S. Prose, MD,b M. Angelica Selim, MD,c

Carlos A. Tirado, PhD,a Melissa M. Coale, MD,d and Marie T. McDonald, MDa

Durham and Greensboro, North Carolina

We report the case of a male infant with incontinentia pigmenti (MIM 308310) and low-grade XXYmosaicism. Fluorescence in situ hybridization may reveal the underlying genetic alteration in male patientswith incontinentia pigmenti and a normal karyotype. ( J Am Acad Dermatol 2006;55:136-8.)

Familial incontinentia pigmenti (IP) (MIM308310) is an X-linked dominant genetic con-dition that usually is lethal in males. Individ-

uals with IP develop characteristic skin lesions alongthe lines of Blaschko that progress through variousstages (vesicular, verrucous, hyperpigmented, andatrophic). Retinal dysplasia and abnormalities ofteeth, hair, and nails also are common. Some indi-viduals exhibit neurologic problems including men-tal retardation and seizures. Diagnostic criteria forIP have been published.1

From the Division of Medical Genetics, Department of Pediatrics,a

and the Departments of Dermatologyb and Pathology,c Duke

University Medical Center, Durham; and the Dermatology

Group of the Carolinas, Greensboro.d

Funding sources: None.

Conflicts of interest: None identified.

Reprint requests: Marie T. McDonald, MD, Division of Medical

Genetics, Department of Pediatrics, Duke University Medical

Center, 246B, Bell Bldg, Durham, NC 27710. E-mail: mcdon035@

mc.duke.edu.

0190-9622/$32.00

ª 2006 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2005.11.1068

The gene for IP was mapped to chromosomeXq28 by linkage analysis2 and subsequently found toencode the nuclear factor kappa B essential modu-lator (NEMO).3 Approximately 80% of patients withIP have a deletion involving exons 4 to 10 of theNEMO gene.3

Although IP usually is lethal in males, cases ofmale patients with IP have been reported.4 We reporta 4-month-old Hispanic boy with IP whose survivalmay be explained by XXY mosaicism.

CASE REPORTThe patient’s mother noticed multiple vesicles in

a linear distribution on the patient’s calf at 5 daysof age. The vesicles gradually disappeared, leavingbehind residual hyperpigmentation that persisted(Fig 1). At 1 month of age, the patient was evaluatedby a dermatologist, and the possibility of IP wasconsidered. A punch biopsy specimen of the lesionsshowed slight, verrucous, epidermal hyperplasiawith mild hyperkeratosis, hypergranulosis, and ne-crotic keratinocytes (Fig 2, A). Some lichenoid

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Brief reports 137

inflammatory infiltration was seen at the dermoepi-dermal junction, composed mainly of lymphocytes,although scattered eosinophils were seen (Fig 2, B).Melanoderma was present in the absence of quan-titative alteration of melanocytes. Although the con-stellation of epidermal acanthosis, hyperkeratosis,and dyskeratinocytes can be seen in epidermal nevi,a diagnosis of IP in an early verrucous stage wasmade on the basis of the clinical presentation. Therewas no family history of multiple miscarriages, andthere were no other individuals in the family withreported signs of IP.

Because of the presence of features of IP in a boy,we considered the possibility of Klinefelter’s syn-drome. The patient’s lymphocytes were cultured andharvested by using standard cytogenetic techniques.A 500-band level karyotype showed a normal malechromosome complement (46,XY); 30 cells wereanalyzed.

To investigate the possibility of mosaicism forKlinefelter’s syndrome (XXY mosaicism), dual-colorfluorescence in situ hybridization was performedwith the use of an X centromere and a Y satellite IIIprobe cocktail (DXZ1, DYZ1) (Vysis Inc, DownersGrove, Ill). A total of 200 interphase nuclei wereevaluated, of which 185 (92.5%) showed signals forone X chromosome and one Y chromosome, and 13(6.5%) showed signals for two X chromosomes andone Y chromosome. These findings indicated low-level XXY mosaicism. The International System forHuman Cytogenetic Nomenclature for the fluores-cence in situ hybridization result in this patient isnuc ish Xcen (DXZ1x2), Yq12 (DYZ1x1) {13}/Xcen(DXZ1x1), Yq12 (DYZ1x1) {185}.

Analysis of the NEMO gene was carried out onperipheral blood lymphocyte DNA by looking fordeletion of exons 4 to 10. Sequence analysis of theNEMO gene also was undertaken. No mutationswere identified.

Fig 1. Hyperpigmented macule in linear distribution attime of presentation.

DISCUSSIONThe clinical, histopathologic, and cytogenetic

findings in this patient are consistent with the diag-nosis of IP with low-level XXY mosaicism. To ourknowledge, this is the first reported case of thisoccurrence. In previously reported cases of malepatients with IP, their survival had been explained byeither Klinefelter’s syndrome with a 47,XXY karyo-type, which creates heterozygosity for the muta-tion,4-10 or somatic mosaicism for a NEMO mutation.6

Scheuerle4 reviewed previously reported cases ofmale patients with IP, 14 of whom had undergonekaryotype analysis. Of these, 5 had Klinefelter’ssyndrome and 9 had a normal karyotype. Thepresence of Klinefelter’s syndrome in some malepatients with IP has led to the recommendation ofkaryotype analysis in all men and boys with IP.4,7-10

However, because a karyotype can miss low-levelmosaicism, we believe that fluorescence in situhybridization studies should be carried out on malepatients with IP who have a normal karyotype. It ispossible that some of the previously reported casesof male patients with IP and a normal karyotype are,in fact, low-level XXY mosaics.

Various mechanisms could explain the clinicalsigns of IP in our patient. One would be that he

Fig 2. A, Epidermal acanthosis with marked melaninincontinence (arrowhead ) and mild chronic inflammation.B, High magnification of specimen highlights abundantdyskeratinocytes (asterisk) and eosinophils (arrowhead ).(Hematoxylin-eosin stain; original magnifications: A, 310;B, 340.)

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138 Brief reports

carries a NEMO mutation in only his XXY cells.X inactivation would then create two functionallydifferent XXY cell populations, one in which theX chromosome with the normal NEMO gene is activeand one in which the X chromosome with theabnormal gene is active. The effects of X inactivationwould manifest clinically along the lines of Blaschko,as has been proposed for female patients with IP.11,12

The presence of a normal NEMO gene in the patient’sXY cells would have allowed his survival. A secondpossibility is that the altered NEMO gene is present inall cells but that X inactivation in the XXY cells, whichare heterozygous for the mutation, has alloweda normal copy of the NEMO gene to be expressed.Considering the low level of mosaicism that wasdetected in the patient’s lymphocytes, it seems likelythat too few cells would express a normal NEMOgene for him to survive. However, if the level of XXYmosaicism was higher in other tissues, the number ofcells expressing the normal gene may have beensufficient for survival. Finally, it is possible that XXYmosaicism and IP occurred independently. In thiscase, our patient could be mosaic for the NEMOmutation or could have a hypomorphic mutationas has been described for other male patients withIP who do not have Klinefelter’s syndrome.6,13-15

Because reported male patients with hypomorphicmutations in the NEMO gene have atypical forms ofIP,13-15 with recurrent infections and ectodermal dys-plasia, we believe that this possibility is less likely.

Knowledge that a male patient with IP is mosaicfor Klinefelter’s syndrome helps to provide an expla-nation for the presence of clinical symptoms of acondition that usually is lethal in male patients andallows the family and health care provider to preparefor possible complications related to Klinefelter’ssyndrome.

We appreciate the help of Drs Dian Donnai and RudolfHapple in reviewing this case, and of Drs Richard Lewis andDavid Nelson for sequence analysis of the NEMO gene.

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