Xeroderma pigmentosum is an autosomal recessive disease in which the patients develop a high frequency of skin cancer, internal tumors, and neurological abnormalities (20–30% of the patients) (Menck and Munford, 2014). The tumor susceptibility is due to germline mutations that impair the processing of DNA lesions by nucleotide excision repair (NER) or by the translesion synthesis (TLS) pathway. The initial recognition step distinguishes two subpathways of NER. The transcription-coupled repair (TCR), in which the recognition occurs on the transcribed strand by the arrest of the RNA polymerase, and the nontranscribed genome is repaired by the global genomic repair (GGR) pathway (Hanawalt, 2002). These pathways are responsible for correctly cleaning up the DNA from lesions induced mainly by the ultraviolet radiation (UVR) from sunlight. Deficiency in this process leads to genetic instability, mutagenesis, and tumor progression (Kraemer et al., 1994).

XP has a wide range of symptom severity and clinical features among the eight complementation groups (XP-A to XP-G and XP-V). Patients mutated at one of the seven genes from XPA to XPG are NER-deficient, while mutations at POLH/XPV lead to a deficiency in TLS, a pathway involved with damage tolerance (Menck and Munford, 2014). XP-C cells lack an essential step of the DNA damage recognition at the GGR, and the XP variant (XP-V) type is NER proficient, but lacking the DNA polymerase eta function of bypassing the UV-induced lesions. The difference in which the mechanism is not working is directly linked to the phenotype of the patient. Therefore, molecular diagnosis is critical for the management of their prognosis (Fassihi et al., 2016; Lehmann and Fassihi, 2020). XP-C, XP-E, and XP-V are mainly affected by skin and eye tumors with no neurological abnormalities. XP-C patients are seriously affected with aggressive skin tumors and more than 1,000-fold increased risk of hematological malignancies, while XP-E and XP-V patients present a milder phenotype (Fassihi et al., 2016; Sarasin et al., 2019b; Oetjen et al., 2020).

This work identified a total of 13 patients (9 alive and 4 deceased) with a clinical diagnosis of XP in the city of Montanhas (state of Rio Grande do Norte-RN-, Brazil), leading to an estimated XP frequency of 1/1,120 inhabitants, considering the total population as 11,200 inhabitants in that city (Brazilian Institute of Geography and Statistics). Three patients did not participate in the study, and probably the XP incidence is underestimated due to a stigmatization effect. The denial of the disease impairs diagnosis, medical care, genetic counseling, and prevention practices reducing their quality and life expectancy. By performing the next-generation sequencing (NGS) with a specific panel of DNA repair genes, we identified homozygous mutations in two different genes: POLH (six patients) and XPC (one patient). This is the second XP genetic cluster described in Brazil (Munford et al., 2017), but the first to identify two different mutated XP genes in such a small community.

We provided the molecular diagnosis for 7 XP patients, out of 13, at Montanhas, a small city in the south of Rio Grande do Norte (RN), Brazil. Different from the genetic cluster previously reported at Araras (Goiás, Brazil) (Munford et al., 2017), Montanhas is not an isolated community. Natal, the state capital, is 60 miles away from Montanhas (approximately 1 h and a half of paved road by car) where patients receive medical care (Figure 1).

The majority of the patients were born from consanguineous marriages. All of them presented the typical clinical phenotype of XP with no neurological abnormalities: photosensitivity, actinic keratosis, basal and squamous cell carcinomas (BCC and SCC), freckling, hyper- and hypopigmentation, and ophthalmologic abnormalities as ocular lesions and blurred vision (Figure 2 and Table 2). None of them reported sunburn after sun exposure. The different clinical symptoms comparing patient XP07RN.br and the other XPs call attention, as one would expect the same mutation affecting all patients in this small community.

Molecular genetic analysis revealed two mutations, each one in two different genes. Most of the patients (six) carry a homozygous insertion that leads to a frameshift mutation in the POLH gene and are, thus, XP-V (OMIM #278750). The map location of the mutation according to GRCh37/hg19 sequence reference is NC_000006.11: g.43568736_43568737insT; NM_006502.2: c.672_673insT; NP_006493.1: p.Leu225Serfs*33. The patient XP07RN.br, however, carries a homozygous mutation at a canonical splice site in the XPC gene (NC_000003.11: g.14190232C > G; NM_004628.4: c.2251-1G>C) and, therefore, is XP-C (OMIM #278720).

The mean age of the XP-V patients was 63 years old (range: 37–89 years), with the first symptoms (skin lesions) at 16 years (range: 12–20 years). Only one of them developed melanoma at 72 years. The oldest XP-V patient (XP03RN.br) died in 2019 at 89 years old. According to his medical record, he went to the Hospital bedridden due to a stroke. Approximately 2 weeks before, he developed edema with nodulation in the right submandibular angle, suspected of melanoma metastasis. He was treated with amoxicillin–clavulanate and died a few months later, probably not related to the XP phenotype. In October of 2021, the patient XP08RN.br died (38 years), and we did not have access to the cause of death.

The XP-C patient, XP07RN.br, presented an aggressive phenotype with the first symptoms before the first year of life with extreme photophobia and ophthalmologic sensitivity. Around 3–4 months of age, her eyes used to water a lot, with difficulties to open in bright environments. At 7 months of age, there was a medical concern about the blood result test from serum thyroid-stimulating hormone level (TSH) of 9.35 mIU/L (reference from 0 to 11 months: 0.8–6.3 mIU/L). However, the follow-up showed that the level decreased 3 months later to 4.95 mIU/L and 1 month later to 3.59 mIU/L. In 2020, at 8 years of age the level is 6.83 mIU/L, in the limit of the normal reference. Freckles got intense after 1 year old, and at 4 years, she had her first tumor onset in the left eye. As her family had to wait 1 year for the surgery due to the lack of medical assistance available in the location, the tumor grew rapidly, and unfortunately, the eye had to be enucleated.

In October 2020 (7 years), she presented a melanoma onset at the glabella region and nasal dorsum. The lymph node was not evaluated. The surgery completely removed the melanoma and she is being treated with interferon (10.000 UI/m²) three times a week for a total of 48 weeks. There was an excellent response to the treatment. An improvement was observed in the behavior of the child, who now is more willing to talk and interact in the clinic.

In this work, we reported a small city in the Northeast region of Brazil (Montanhas, RN), with patients mutated at the XPC or POLH gene. The prognosis of the disease varies according to the mutated gene, the affected repair pathway, and the level of individual photoprotection. The XP-C patient had the most severe symptoms, which appeared before the first year of life, and a melanoma onset at 7 years old. For the XP-V patients, the mean age for the first symptoms was 16 years, and one developed melanoma at 73 years. The patients report minimal photoprotection using sporadic sunscreen when they have it. The mother of the XP-C is the most informed and worried about protection and prevention, mainly due to the high photosensitivity of the child. The difficulty in accessing medical care at the locality exacerbates the worst prognosis of a disease such as XP, especially the XP-C group, with an urgent need for continuous care and tumor excision. It should be noted that the low latitude of the location, near the equator line (approximately 445 miles), implicates high levels of DNA damage by sunlight (Schuch et al., 2012). There is an imperative demand on investing in prevention, providing them physical photoprotection and educational support, more importantly, facilitating access to medical care and prioritizing urgency for these patients.