lncontinentia Pigmenti, A Chromosomal instability Syndrome, Is Associated With Childhood Malignancy

W. MARK ROBERTS, MD," JESSE J. JENKINS, MD,t EDWARD L. MOORHEAD, II, MD,$ AND EDWlN C. DOUGLASS, MD'

Incontinentia pigmenti (IP) is a rare hereditary disorder that has recently been classified as a chromosomal instability syndrome. As in Fanconi anemia and ataxia telangiectasia, spontaneous and inducible chro- mosomal aberrations primarily of the chromatid type are increased in patients with IP. Both Fanconi anemia and ataxia telangiectasia are genetic diseases that predispose to cancer. A case report of an infant with IP and malignancy (rhabdoid tumor of the kidney) is presented, and five previously reported cases of this association are reviewed. The malignancies in all of these cases occurred before age three, whereas malignancy associated with Fanconi anemia and ataxia telangiectasia tends to appear in late childhood or in adulthood. The chromosomal instability seen with IP may increase the risk for malignancy in young children.

Cancer 62:2370-2372, 1988.

NCONTINENTIA PIGMENT1 (IP), d S O known as Bloch- I Sulzberger syndrome, is a rare hereditary syndrome characterized by a distinctive, triphasic cutaneous erup- tion and variable malformations often including the skel- eton, teeth, eyes, and central nervous system.*-3 The di- agnosis is obvious in infancy because of the striking cu- taneous involvement. An erythematous, vesiculobullous rash typically appears during the first 2 weeks of life and is followed by verrucous growths and, ultimately, bizarrely pigmented lesions that may become atrophied and de- pigmented. Incontinentia pigmenti is generally assumed to represent an X-linked dominant mutation and is usu- ally lethal in affected hemizygous males. 1-3

Increased chromosomal breakage or chromosomal in- stability has been reported in several families with IP! The spontaneous chromosomal aberrations in somatic cells of patients with IP are remarkably similar to those in both Fanconi anemia and ataxia telangiectasia, which suggests that there are similar defects of DNA replication in these three chromosomal instability syndrome^.^-^ Fanconi anemia and ataxia telangiectasia are genetic

From the Departments of *Hematology-Oncology and ?Pathology and Laboratory Medicine, St. Jude Children's Research Hospital, Mem- phis, Tennessee, and the Division of Hematology/Oncology, Department of Pediatrics, The University of Tennessee, Memphis, College of Med- icine, Memphis, Tennessee and $Butterworth Hospital, Grand Rapids, Michigan.

Supported in part by the American Lebanese Syrian Associated Char- ities (ALSAC).

Address for Reprints: W. Mark Roberts, MD, St. Jude Children's Re- search Hospital, 332 N. Lauderdale, Memphis, TN 38101.

Accepted for publication June 6, 1988.

diseases clearly associated with an increased risk for cancer.'-' *

We describe a case of rhabdoid tumor of the kidney in an infant with IP. Although no association of IP and ma- lignancy has been suggested in previous reports, a litera- ture review revealed five additional cases of malignancy in young children with IP. Thus, the chromosomal insta- bility associated with this syndrome appears to lead to an increased risk of early childhood malignancy.

Case Report

A 6-month-old asymptomatic white female infant was referred to St. Jude Children's Research Hospital for evaluation of a right-sided abdominal mass. The patient was the second child of a 27-year-old mother. The patient, a female sibling, and their mother all were diagnosed with IP with typical cutaneous find- ings. Four previous pregnancies had ended in early miscarriage. Figure 1 shows the pedigree for the occurrence of IP in this family.

Physical examination disclosed a 2-cm, round, deeply pig- mented lesion in the left inguinal region. The skin was atrophied, and marked depigmentation in a whorled pattern was present in both axillae and in the medial aspects of both upper legs and inguinal regions. There were no apparent ocular, skeletal, or neurologic abnormalities. Ultrasonography and computed to- mographic scans of the abdomen revealed an 8-cm solid tumor arising from the lateral aspect of the right kidney. Chest roent- genograms disclosed multiple bilateral pulmonary nodules.

The right kidney and mass were excised. The histologic find- ings (Fig. 2) were diagnostic of malignant rhabdoid tumor of the kidney. Antineoplastic therapy, initially consisting of cisplatin and etoposide followed by vincristine, dactinomycin, and doxo- rubicin failed to induce a response. The patient died of pro- gressive pulmonary disease 10 weeks after diagnosis.

2370

No. 11 IP ASSOCIATED WITH CHILDHOOD MALIGNANCY - Roberts et al. 237 1

I i 27 yr 27 yr r

A A A A A a FIG. 1. Pedigree for the occurrence ofin- t hero peut ic 1-1 3 y r patient

abortion continentia pigmenti.

1 st t ri mes ter misca rriages

Affected female 0 Unaffected female 0 Unaffected male A Abortions-sex unknown

Literature Review Fanconi anemia is associated with an increased risk of acute leukemia, especially the myelomonocytic type.' ' Ataxia telangiectasia, a primary genetic immunodefi- ciency disease, clearly predisposes to malignancy, usually of the lymphoid system (estimated to occur in 12% to 40% of cases).'-' This link to lymphoid cancer may reflect

positions where the immunoglobulin and T-cell receptor genes have been mapped.' It is interesting that hetero- zygous camers of the ataxia telangiectasia gene also have an excess risk of cancer, particularly breast cancer in women.'"

We could find no reports of malignancy in patients with IP who were older than 3 years. In five of the six identified cases malignancy developed during infancy; the

Wilms, tumor, a malignancy of embryonal origin, at years of age. Thus, whereas both Fanconi anemia and ataxia telangiectasia predispose to malignancies in late

A search of the medical literature revealed five cases of IP in children who developed malignancy. Two female children with IP developed retinoblastoma in their first year of life; neither had a family history of this t ~ m o r . ~ ~ , ~ ~

ophthalmologic, and developmental abnormalities de- veloped bilateral Wilms' tumor. l 5 Acute myelocytic leu- kemia was diagnosed in a 4-month-old female infant with IP.16 She survived for 3 years despite relapse of her leu- kemia. In a male infant with IP, paratesticular rhabdo- myosarcoma was diagnosed at birth and treated with or- chiectomy alone. l7 This patient had extremely severe neurologic involvement typical of the few surviving males

monocytic leukemia, which proved fatal. Autopsy findings indicated unsuspected Wilms' tumor in a horseshoe kidney.

A 2-year-01d with IP and the fact that preferred chromosomal breakpoints are at

with IP" At years Of age he acute mye1o- remaining patient was diagnosed as having bilateral

Discussion

Incontinentia pigmenti involves chromosomal aber- rations remarkably similar to those in Fanconi anemia and ataxia telangiectasia-chromosomal instability syn- dromes that are associated with increased rates of malig- n a n ~ y . ~ - ' ~ A 1976 review of the world literature revealed no malignancies in 653 patients with IP,' and a subsequent longitudinal study in 15 patients produced similar find- ings." The case described here, in which a 6-month-old female infant with IP presented with malignant rhabdoid tumor of the kidney, combined with the five cases found in our literature review represents a total of six children with IP and malignancy. Thus, like ataxia telangiectasia and Fanconi anemia, IP appears to predispose to cancer.

childhood or adulthood, the increased risk of cancer as- sociated with IP appears to be limited to the first 2 years of life. It may be that in IP embryonal tissues are more sensitive to the chromosomal aberrations that produce malignant transformation, a sensitivity that may be lim- ited to early childhood.

Although the specific biochemical basis for the chro- mosomal instability in IP remains unknown, the finding that aberrations are primarily of the chromatid type in- dicates that the mutations, like those in ataxia telangi- ectasia and Fanconi anemia, arise in connection with DNA replication6; defects in DNA repair have been re- ported in the two latter syndromes and in Bloom syn- drome.16

The six cases reviewed here support the suggestion that

2312 CANCER December 1 1988 Vol. 62

FIG. 2. Loosely cohesive sheets of large tumor cells. Cytoplasmic. eosinophilic inclusion-like bodies and prominent nucleoli are distinctive for malignant rhabdoid tumor of the kidney (H & E, X480).

the chromosomal instability in IP leads to an increased incidence of cancer in early childhood. To date, approx- imately 800 patients with IP have been reported. However, because of probable underreporting, the precise risk of malignancy in young children with IP cannot yet be de- fined. The identification of a specific biochemical defect in DNA repair would help to explain the chromosomal instability reported with IP. Such findings would aid in understanding the mechanism of cancer proneness in young children with IP.

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