HISTORICAL INSIGHTS Xeroderma Pigmentosum in Four Siblings With Three Different Types of Malignancies Simultaneously in One Mohammed El-Hayek, MD,* Giles G. Lestringant, MD,† and Philippe M. Frossard, MD‡ Abstract: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease characterized by marked sensitivity to ultraviolet radiation that leads to the development of multiple skin malignancies. The authors describe four XP siblings in a consanguineous Pakistani family. The first patient was a boy who died at age 2 years. The second and third siblings were girls who died at age 2 and 7 years, respectively. The fourth sibling, the propositus, was a boy diagnosed with XP at age 7 years. He developed three different types of malignancies simultaneously and died at age 13. The authors conclude that it is important to be aware of multiple malignancies of different types in the same patient with XP. Key Words: xeroderma pigmentosum, squamous cell carcinoma, basal cell carcinoma, DNA damage, skin neoplasms, genetics (J Pediatr Hematol Oncol 2004;26:473–475) X eroderma pigmentosum (XP) is a rare genetic disorder clinically characterized by extreme skin sensitivity to sunlight and photophobia. Genetic and molecular analyses have revealed that the repair of ultraviolet-induced DNA damage is impaired in these patients due to mutations in genes that form part of a DNA repair pathway known as nucleotide excision repair.1,2 This provides an opportunity for mutant malignant growth. Compared with the normal population, XP patients have a more than 1,000-fold increased risk of developing cancer on sun-exposed skin areas.3 There are few reported patients in the literature who presented with two different malignancies simultaneously. We describe one patient who presented with squamous cell carcinoma of the left lower eyelid, basal cell Received for publication December 9, 2003; accepted March 26, 2004. From the *Department of Pediatric Hematology/Oncology, Tawam University Hospital and Faculty of Medicine and Health Sciences, Al Ain, United Arab Emirates; †Department of Dermatology, Tawam University Hospital and Faculty of Medicine and Health Sciences, Al Ain, United Arab Emirates; and ‡Department of Pathology, Tawam University Hospital and Faculty of Medicine and Health Sciences, Al Ain, United Arab Emirates. Reprints: Mohammed El-Hayek, MD, Department of Pediatric Hematology/Oncology, Tawam Hospital, Al Ain, United Arab Emirates (e-mail: mohhayek@emirates.net.ae). Copyright © 2004 by Lippincott Williams & Wilkins J Pediatr Hematol Oncol • Volume 26, Number 8, August 2004 carcinoma of the right ear, and multiple nodular malignant melanomas over the back and the forehead simultaneously. CASE REPORT The patient was a 7-year-old Pakistani boy who developed sensitivity to sunlight manifested by freckles and darkened skin all over the body, with some particularly hyperpigmented areas, and small tumors over the left lower eyelid and right ear that had developed over the few months before admission. The tumor on the left eyelid was removed, and histology showed squamous cell carcinoma. The other tumor from the right ear was also removed, and histology showed basal cell carcinoma. Six months later, while he was an inpatient, other tumors appeared over the forehead, right orbital area, right preauricular area, face, neck, and back, with necrotizing and infected ulcers. The tumor from the forehead and the back were malignant melanomas (Figs. 1–4). Although he had no neurologic abnormalities at presentation, neurologic deterioration developed later, progressively manifested as blindness, hearing loss, ataxia, and seizures due to tumor involvement of his orbit and skull. The patient was protected from ultraviolet radiation by using sunblocks; seizures were controlled with phenytoin (5 mg/kg/d). Accutane (13-cis retinoic acid) at 2 mg/kg/d orally and 5-fluorouracil cream were started. Surgical excision of the tumors was done with skin grafting from non-light-exposed areas. The child had many admissions for infections and neurologic complications. Despite all efforts, his clinical condition deteriorated progressively and he died at age 13. The family history disclosed that the parents were first cousins and that there had been three previous siblings with XP, all of whom died of malignant melanomas (Fig. 5). DISCUSSION The genetic background for XP is complex. The products of the XP genes are proteins involved in the different steps of nucleotide excision repair (NER) and comprise three damage-recognition proteins, two helicases, and two nucleases. The two helicases, XPB and XPD, are components of the basal transcription factor, which has a role in NER and in the initiation of transcription. Different mutations in these genes can 473 El-Hayek et al FIGURE 1. Face of the patient with XP. Note the sunlightinduced dermatologic abnormalities and the well-defined, red, scaling, thickened patches at the eyelid areas (squamous cell carcinoma). affect NER and transcription differentially, and this accounts for the different phenotypes.4 The XPC patients characteristically have a mutation in the XPC gene, and they develop skin cancers at a very early age. Studies have recently shown the association between XPC, the p53 gene mutation, and the increased frequency of skin melanomas5 up to 90% in skin cancers of patients with XP.6 Basal cell carcinoma and squamous cell carcinoma of the skin occur in 45% and melanomas in 5% of patients with XP.7 In our patient, all three types of malignancy occurred simultaneously. It is of great importance to be aware of the possibility of multiple and different malignancies at the same time in patients with XP. This is well known in adults, but only a few cases have been reported in children. We describe this patient who had XP and three different skin tumors that did not respond to any kind of treatment. FIGURE 2. Trunk of the patient, with mottled hyperpigmented areas typical of XP. 474 J Pediatr Hematol Oncol • Volume 26, Number 8, August 2004 FIGURE 3. Right ear basal cell carcinoma: a raised, smooth, pearly bump. Early detection of these tumors is necessary because they grow rapidly and may metastasize quickly, leading to death. Surgical removal of the tumors with skin grafting from non-light-exposed areas is mandatory as the first line of treatment. Chemotherapy is ineffective, and radiotherapy may induce new tumors.8 XP is an uncommon neurocutaneous disorder manifested by severe neurologic problems, infections, and malignancy, usually with a fatal outcome. It is important to be aware of the possibility that several different skin malignancies may be present at the same time in the same patient, even in children. Affected children should be totally protected from ultraviolet radiation, and genetic counseling of affected families is important. Amniocentesis for prenatal diagnosis of XP and termination of pregnancy may be discussed in areas where religion allows it. There is, however, the promising possibility of in vitro fertilization with implantation of unaffected embryos.9–12 FIGURE 4. Malignant melanoma on the back, a brown- to black-pigmented lesion. © 2004 Lippincott Williams & Wilkins J Pediatr Hematol Oncol • Volume 26, Number 8, August 2004 Simultaneous Malignancies in Xeroderma Pigmentosum FIGURE 5. Family tree. 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