We herein present a patient from a consanguineous family with recurrent facial chemotherapy-resistant SCC lesions. The child was not diagnosed with XP until his last admission at 7 years of age, although he had typical salt-and-pepper appearance of the sun-exposed areas and UV-exposure related recurring SCCs. We emphasize that clinical recognition of this condition is possible and essential. WES is a practical tool for determining the underlying genetic defect in single-gene disorders with genetic heterogeneity and allowed for the definition of a novel splice site mutation, c.2250 + 1G>A, in the present patient.
Under the age of 20 years, the risk of nonmelanoma skin cancer has increased 10,000-fold, and that of melanoma has increased 2000-fold, in XP . The most common cancers in patients with XP are BCC and SCC, mainly affecting the face, head, and neck . Early detection of these malignancies is essential as they grow fast, metastasize in early phases, and even lead to death . Accordingly, major causes of mortality in XP are metastatic malignant melanoma and SCC, caused by ultraviolet-induced skin hypersensitivity .
Children with XP develop multiple cutaneous malignancies at a young age , similar to our case, who developed SCC at the age of 2. Generally, significant tissue damage occurs by the time of diagnosis, and most untreated patients die before the age of 20 years . XP is ultimately fatal, though life expectancy can be prolonged by minimizing sun exposure. Early diagnosis and treatment of these skin lesions and malignancies will reduce morbidity and mortality of the disorder .
Compared with the healthy population, patients with XP are at a several thousand-fold increased risk of skin cancer , and apart from skin cancers, there is also a 50-fold increased risk of systemic malignancy . DNA damage plays a significant role in carcinogenesis by promoting cellular transformation . Being an inherited disease, a radical cure today is unexpected in XP disorder, and cancer is the major cause of mortality and morbidity in these patients. There is no standard therapy for skin cancer of XP . Chemotherapeutics might cause substantial organ toxicity and usually need to be used in reduced doses, which decrease the survival rates. Thus, immune checkpoint inhibitors were reported to increase response rates, maintain durable responses, and improve outcomes. They also might help prevent chemotherapy-related side effects if they were to be used at the first-line regimen. Our patient used six cycles of cisplatin–fluorouracil chemotherapy before surgical excision. Programmed death-ligand 1 (PDL-1) antibody nivolumab produces a complete response to progressive disease. One important feature of the patient was the complete response obtained with reused nivolumab after relapse. There was no resistance to the drug given for the second time, and the patient is well with no new lesion or any systemic sign of metastasis. Immune checkpoint inhibitors mainly target PD-1 and PDL-1, and they improve outcomes in many cancers, as well as SCC in XP .
XP means “dry pigmented skin” and is characterized by mucocutaneous and ocular hypersensitivity to UV radiation with irreparable DNA damage, and also by progressive neurological degeneration in some subjects , including cognitive impairment and progressive hearing loss . Approximately 25% of patients with XP have progressive neurological degeneration leading to a shortened lifespan [2, 15]. Excessive sensitivity to sunlight result in severe sunburn and photophobia . In addition to sunburn, the first finding in patients is usually lentiginosis (marked freckle-like pigmentation of the face) , which is first noticed around the age of 2, like in our patient, progressively settling in sun-exposed areas. Over time, the number of lentigines increases, and photoaging, xerosis, skin laxity, and poikiloderma (dyspigmentation) appear [1, 2, 7]. With multiple hypo- and hyperpigmented lesions all over his body, our patient was also affected with hemorrhagic crusted plaques and nodules over both superior eyelids. It is common for patients with XP, as the present patient, to have ocular abnormalities, such as photophobia and keratitis [2, 7], caused by ultraviolet-induced DNA alteration to epithelial cell conjunctiva, the cornea, and the eyelid [5, 7].
XP is a hereditary autosomal recessive disorder, with a prevalence of 1:1,000,000 in the USA and 1:100,000 in Japan . The prevalence is higher in Middle Eastern countries such as Turkey, Israel, and Syria because of the high frequency of consanguineous marriages [11, 16]. Recent Turkish Demographic and Health Surveys reported the rate of consanguineous marriages as 22–24% in Turkey . In a demographic study among patients with XP by Akdeniz et al. , the parental consanguinity rate was 86.7%, which is consistent with previous reports by Khatri et al. (92.8%) , Metin et al. (100%) , and Gül et al. (83.3%) . The parents of the present patient were first cousins, and they were heterozygous carriers of the relevant mutation. Genetic counseling should emphasize the importance of avoiding further consanguineous marriages for prevention .
XP can result from mutations in any one of eight genes (XPA, XPB, XPC, XPD, XPE, XPF, XPG, and XPV). From XPA to XPG, the encoded proteins are involved in repairing UV-induced photoproducts in DNA by the process of NER . The NER system is capable of repairing DNA damage resulting from UV radiation . Each of these genes corresponds to clinically different complement subgroups. For example, neurological symptoms are observed in diseases caused by mutant XPA, XPD, and XPG, but not in others generally. Sunburn is also observed in XPA, XPB, XPD, and XPG, while not in the others . However, it is still not possible to distinguish these subgroups on the basis of only clinical findings; mutation analysis is required. In the present patient, the c.2250 + 1G>A splice site mutation of the XPC gene was detected when WES analysis was performed. XPC is the most common complement type in the USA, Europe, and North Africa .
Over the past decade, WES has afforded an efficient and straightforward diagnosis method for patients with Mendelian disorders, and it has been helpful for inferring pathogenesis [25, 26]. While first-generation sequencing of all exons is difficult and time consuming , next-generation sequencing, specifically WES, is more efficient than first-generation sequencing approaches, with similar costs . Besides offering a rapid and effective manner of genetic analysis, WES allows the detection of novel genes involved in pathogenesis [7, 21, 28]. In our case, WES analysis was performed with Ion Proton next-generation sequencing platform, and a novel pathogenic homozygous mutation in the XPC gene was identified.