Xeroderma pigmentosum with multiple skin carcinoma and a homogenous XPC mutation: A case report from China and literature review

Abstract

Xeroderma pigmentosum is a rare autosomal recessive genetic disorder characterized by hypersensitivity to ultraviolet radiation and increased risk of skin cancer. Impaired DNA repair mechanisms are considered to be involved in the occurrence and development of this distinct disorder. We present the case of a 48-year-old Chinese woman with facial and chest tumors; these lesions had been rapidly growing over the past 6 months. Pathological biopsy and immunohistology indicated malignant melanoma in facial and chest tumors and squamous cell carcinoma in chest tumors. Using whole-exome sequencing, a site mutation c.2218_2220del (p.Glu)740del in the XPC gene was confirmed. To treat the infection and skin carcinoma, antibiotics and plastic surgery were employed. The identified XPC variant has not been previously reported in Chinese or global populations, expanding the mutational spectrum of this gene and providing valuable data for genetic counseling of affected families.

Introduction

Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder that involves impaired DNA repair mechanisms. It affects nucleotide excision repair (NER), causing an increased sensitivity to ultraviolet (UV) radiation and a high risk of skin cancer. To date, eight genes related to XP DNA damage repair defects have been identified: XPA, XPB (ERCC3), XPC, XPD (ERCC2), XPE (DDB2), XPF (ERCC4), XPG (ERCC5), and XPV (POLH), which encode the components of the NER pathway and DNA polymerase.^1,2 Based on the specific gene mutations involved and disease severity, XP can be classified into eight subtypes. Each XP subtype has a distinct genetic basis and demonstrates characteristic progression and degree of neurological involvement.^3–7 The incidence of XP varies worldwide, estimated to range from 1/10,000 to 1/300,000, with a relatively higher prevalence in Japan, North Africa, and the Middle East as well as in populations with a high degree of consanguinity. ⁸

The etiology of XP is complex and multifactorial, involving both genetic and environmental factors. The XP group C (XPC) is located on chromosome 3p25, with a relative molecular mass of 106,000, including 15 exons and 14 introns. XPC protein and HHR23 B protein form a dimer complex and polymerize in the nucleus, which can recognize DNA damage and be used for NER. XPC protein is involved in DNA damage recognition and NER, and XPC mutation can affect its function and increase the probability of cancer.^9,10 However, environmental factors, such as sun exposure and/or chemical exposure, can also contribute to this disease. UV radiation present in sunlight ¹¹ and chemical mutagens such as benzo[a] pyrene, ¹² aromatic amines, ¹³ and polycyclic aromatic hydrocarbons, ¹⁴ which are commonly found in cigarette smoke and industrial pollutants, can also induce DNA damage.

With clinical manifestations largely depending on the severity and type of mutations, XP is often characterized by increased sun sensitivity, skin xerosis, premature skin aging, and abnormal skin pigmentation, particularly in sun-exposed areas of the body. Patients with XP also have a high susceptibility to multiple types of skin cancer, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma, with an approximately 1000-fold higher risk than that in the general population. ¹⁵ The diagnosis of XP is based on clinical findings, family history, and laboratory tests. Due to the genetic mutation of XP, whole-exome sequencing (WES) is a practical and rapid method for molecular diagnosis. WES has enabled the identification of several mutations in XP, thereby facilitating the diagnosis and understanding of XP development.^16,17 Although the concrete mechanism underlying XP development remains unclear, different gene site mutations reported in WES results might provide valuable knowledge for further research.

Here, we report the case of a Chinese woman with facial and chest tumors. She suffered from multiple skin carcinomas including facial melanoma, eye melanoma, and chest SCC after photosensitivity and hyperpigmentation that first presented during her childhood. During the treatment, Aeromonas caviae and Proteus mirabilis were found in the infectious site of chest and facial tumors, while pathological results indicated malignant melanoma in facial and chest tumors and SCC in chest tumors. Gene sequencing using WES revealed a mutation site c.2218_2220del (p.Glu)740del in the XPC gene, which further confirmed the diagnosis of XP. To treat the infection and skin carcinoma, antibiotics and plastic surgery were used. Furthermore, to improve the understanding of XP and enhance early recognition of this disorder by clinicians, a literature review was performed.

Case presentation

Patient characteristics

A Chinese female patient in her late 40s was admitted to the Department of Plastic and Aesthetic Surgery, Affiliated Dermatology Hospital of Hainan Medical University, Haikou, Hainan Province, China, in October 2022 for evaluation and treatment of tumors on her face and chest wall.

She had no symptoms until the age of 5 years. At the age of 5 years, photosensitivity, itching, and hyperpigmentation were first recognized. Pigmented macules and erythematous plaques were observed over the areas exposed to sunlight or UV radiation. At the age of 36 years, she underwent right eye enucleation for malignant melanoma of the right eye at another hospital, followed by chemotherapy. At the age of 38 years, she underwent skin grafting after surgical resection of malignant melanoma on the lower eyelid of the left eye, which gradually increased in size.

Two prothorax lesions, 1.5 cm × 1.5 cm ×0.5 cm each in size, without itching or pain were first discovered 3 years ago. Six months ago, these lesions grew rapidly, reaching 8 cm × 5 cm × 1 cm (upper) and 5 cm ×4.5 cm × 1 cm (lower) in size, respectively (Figure 1(a)). Itching and erosion occurred in the skin around these lesions. Meanwhile, black maculopapular rash and erythematous scaly plaques were also present on the face, and some erythematous surfaces were eroded and crusted. The patient had not exhibited any neuropsychiatric symptoms until the time of writing this report.

Figure 1.

(a) Clinical images of the patient with XP. (b) Anterior chest wall lesions and (c–e) face lesions.

Family history revealed no history of consanguineous marriage or similar syndrome in her parents or son. However, her older brother had a history of similar pigmented macules and erythematous plaques.

Physical examination

Physical examination revealed the following. Two irregular cauliflower-like reddish tumors, measuring approximately 8 cm ×5 cm × 1 cm (upper position in the anterior chest wall) and 5 cm × 4.5 cm × 1 cm (lower position in the anterior chest wall) in size, were observed in the anterior chest. The surface of these tumors was uneven, with ulcers, purulent secretions, foul smell, and hard texture. When extruding the base of the tumors, a small amount of purulent secretion was observed, accompanied with easy bleeding. Diffuse erythema was observed on the skin around the tumors, and erosion and scabbing were observed on the surface of some erythematous lesions (Figure 1(b)). Dozens of black plaques and reddish plaques of different sizes were observed on the face, with the largest measuring approximately 3.5 cm × 3.0 cm and the smallest approximately 0.5 cm × 0.3 cm. The plaques were irregular in shape and had clear boundaries; some erythematous plaques had erosions and scabs on the surface, and depigmented plaques and telangiectasia were observed around them. Black plaques had waxy luster on the surface, and melanin was unevenly distributed in the plaques. An old white skin graft flap, approximately 3 cm × 2 cm in size, was observed on the lower eyelid of the left eye. A subcutaneous nodule, approximately 1 cm × 1 cm in size, was palpable behind the left neck. Multiple reddish, macular, and black lesions were disseminated throughout the body (Figure 1(c) to (e)).

Laboratory and imaging tests

Complete blood count showed anemia, with a hemoglobin level of 101 g/L; other parameters were as follows: hematocrit, 32.9%; mean corpuscular volume (MCV), 63.9 fL; mean corpuscular hemoglobin (MCH), 19.6 pg; and mean corpuscular hemoglobin concentration (MCHC), 307 g/L.

Bacterial culture for purulent secretions in the skin lesions showed suspected infected bacteria as follows: (a) A. caviae, which was sensitive to ciprofloxacin, meropenem, amikacin, tobramycin, piperacillin, imipenem, cefepime, ceftazidime, gentamicin, piperacillin/tazobactam, polymyxin B, and cefoperazone/sulbactam and (b) P. mirabilis, which was sensitive to amikacin, minocycline, imipenem, cefepime, ceftazidime, piperacillin/tazobactam, and cefoperazone/sulbactam.

Chest X-ray showed suspicious nodules with slightly high density in the middle zone of the right upper lung field and in the middle zone of the left middle lung field. To rule out pulmonary metastasis, an additional chest CT scan was performed, which showed a few fibrous lesions in the medial segment of the right middle lobe and the lower lingual segment of the left upper lobe as well as the foci of soft tissue density in the anterior chest wall. These findings were consistent with chronic fibrous changes rather than metastatic disease.

Surface ultrasonography for the subcutaneous nodule behind the left neck revealed a subcutaneous hypoechoic nodule, indicating the presence of a schwannoma.

Histopathological investigation

To determine the nature of the tumors, tissue biopsy was used for further histopathology and immunohistochemistry. Skin samples taken from tumors in the margin of the lower left eyelid, in front of the right ear, and prothorax wall as well as normal skin from abdominal wall were analyzed.

For the tumor in the lower left eyelid, hematoxylin–eosin (HE) staining revealed an ulcerated skin surface with separated epidermal and dermal layers and suspected formation of subepidermal blister-like structures. Atypical melanocytes were distributed throughout the epidermis and superficial dermis in a nested and single-cell pattern. No distinct in situ melanoma component was identified. Degenerative necrosis of the epidermis was noted. Lymphocyte infiltration and a small amount of eosinophil infiltration were observed around the small vessels in the dermis, consistent with melanoma recurrence.

For the tumors in front of the right ear, malignant melanoma was detected via HE staining (Figure 2(a) and (b)). For the tumor in the chest wall (upper), SCC (moderated differentiated) was detected via HE staining (Figure 2(c) and (d)).

Figure 2.

Histopathology of the tumor in front of the right ear, showing malignant melanoma on HE staining ((a) 40× and (b) 400×). Histopathology of the tumor in the upper chest wall, demonstrating moderately differentiated SCC on HE staining ((c) 100× and (d) 400×). Histopathology of the tumor in the lower chest wall ((e) 40× and (f) 400×). HE: hematoxylin–eosin; SCC: squamous cell carcinoma.

For another tumor in the chest wall (lower), HE staining showed actively proliferating spindle-like cells in the tumor with commonly seen mitotic figures in the microscopic field.

The tumor was suspected to be malignant (Figure 2(d) and (e)). Further immunohistochemical (IHC) testing was recommended for confirmation. According to the IHC results, the tumor showed negative expression of cytokeratin (CK), P63, CK5/6, smooth muscle actin (SMA), and desmin (Des) and positive expression of vimentin, S100, Ki-67 (∼30%), melanoma antigen recognized by T cells 1 (Melan-A), and human melanoma black 45 (HMB-45). These results confirmed the diagnosis of malignant melanoma (Figure 3(a) to (e)).

Figure 3.

Immunohistochemical staining of the chest wall tumor. Tumor cells showed positive staining for Melan-A ((a) 100×), HMB45 ((b) 200×), S100 ((e) 100×), and vimentin ((d) 100×). Ki67 proliferation index was approximately 30% ((c) 100×). Melan-A: melanoma antigen recognized by T cells 1; HMB45: human melanoma black-45.

For the pigmented plaque from the abdominal wall, HE staining showed that significant melanin granule deposition was observed in the basal layer of the epidermis; in the dermis, local small vessels were dilated with a few lymphocytes infiltrated around the vessels. No malignant lesions were observed.

Together, the immunohistopathological results demonstrated multiple skin carcinomas in the patient, namely SCC and malignant melanoma. Notably, given her history of melanoma in the right eye, melanoma in the left lower eyelid, skin symptoms (photosensitivity, itching, and hyperpigmentation) since childhood, and similar symptoms in her older brother, the disease is highly likely to be genetic.

Mutation analysis

To further confirm the diagnosis, WES was performed for the patient and her son at the Beijing Mygenostics Co., Ltd. Blood samples were collected after obtaining written informed consent from the patient. A pathogenic variant of XPC gene chr3 (14190344-14190346): NM_004628.5; exon 12: c.2218_2220del (p.Glu740del) was identified as homozygous in the patient and heterozygous in her son. The son’s heterozygous carrier status was consistent with autosomal recessive inheritance and indicated that he was clinically unaffected. Other family members, including the patient’s parents and older brother (who reportedly had similar symptoms), did not provide samples for genetic testing. This variant of XPC has been reported as heterozygous in another XP patient; however, the pathogenetic mechanism of this c.2218_2220del (p.Glu740del) variant has not been fully confirmed in a homozygous case. ¹⁸ Furthermore, another mutation in the HBB gene chr11:5247993-5247996: NM_000518.5; exon 2: c.126-129del (p.phe42Leufs Ter19) was reported as heterozygous both in this patient and her son. ¹⁹ Based on WES results, a diagnosis of XP was confirmed.

Clinical treatment

Due to the infectious status in the two chest tumors and facial tumor, amikacin (topically, bid) and cefoperazone/sulbactam (2 g, intravenous infusion (ivgtt), bid) were used with regular dressing therapy according to the abovementioned antibiotic drug sensitivity test. After 7-day usage of antibiotics and dressing therapy, the infection was restrained, which provided an opportunity for surgical treatment. Subsequently, plastic surgery was performed to remove the SCC and malignant melanoma in her chest, recurrent melanoma at the margin of the left eyelid, and melanoma in front of the right ear. Due to the malignancy of SCC and malignant melanoma in the chest, tumor area was determined according to the base of both tumors. To ensure complete resection of the malignant tumors, the surgical margin was extended 2 cm beyond the visible tumor area, with a resection depth >2 cm below the tumor. Two split-thickness skin grafts were collected using a roller dermatome along the right inner thigh to seal the surgical excision wound. To ensure graft survival, compression bandaging and vacuum suction devices (VSDs) were applied immediately after skin grafting. Compression bandaging and VSDs were removed 7 days postoperatively. The graft was shown to survive well 28 days postoperatively. In response to the patient’s need for facial cosmetology, the recurrent melanomas at the margin of left eyelid and melanoma in front of the right ear were excised with a 0.5-cm margin from the enlarged tumor margin and directly pulled and sutured after resection.

Case summary

We report a rare case of a 48-year-old Chinese woman with multiple skin carcinoma and homogenous XPC mutation diagnosed as XP. Due to the rarity of XP, the patient was first diagnosed with multiple skin carcinoma at another hospital. However, according to the early occurrence of photosensitivity, itching, and hyperpigmentation since childhood and her history of melanoma in the right eye and melanoma in the left lower eyelid, this multiple skin cancer could be attributed to a genetic disorder. Family history revealed that her older brother exhibited similar skin symptoms, while her other siblings remained asymptomatic. Based on WES, an XPC mutation (c.2218_2220del (p.Glu740del)) was identified as homozygous in this patient and heterozygous in her sibling.

In clinical treatment, pathohistological investigation is necessary to determine whether a tumor is benign or malignant. Based on the pathohistological results, the surgical plan for skin cancer can be determined. Notably, in the treatment of skin cancer in XP, surgical principles are based on the malignancy of each cancer.

Together, clinical manifestations, individual history, family history, pathohistological tests, and WES play important roles in the diagnosis of XP. In addition, early recognition of this disorder facilitates the diagnosis. Therefore, to enhance awareness and understanding of this rare disease, a literature review is presented.

Literature review

As a rare autosomal recessive genetic disorder, XP was first described by Moriz Kaposi and Ferdinand Hebra in 1874; they reported a patient with an unusual skin disorder characterized by excessive freckling and skin cancers. In the following decades, significant progress was made in understanding the molecular basis of XP.^20–22

Etiology

The etiology of XP is primarily attributed to genetic mutations that affect the DNA repair mechanisms responsible for eliminating the damage caused by UV radiation and other environmental mutagens.^11–14 To date, several genes have been identified as causes of XP: XPA, XPB, XPC, XPD, XPE, XPF, XPG, and XPV. XPC and XPE are the most common types of XP, accounting for approximately 50% and 20% of cases, respectively. ²³ Among them, patients with XP-A type tend to have severe neurological symptoms, while those with XP-C, XP-E, and XP-V rarely exhibit severe sunburn reactions and neurological symptoms. NER pathways are involved in maintaining genome stability, and defects in these pathways can result in mutations and genomic instability.^24,25

Manifestations

XP is a multisystem disorder that manifests with a range of clinical features affecting the skin, eyes, and, in some cases, the nervous system. Typically, it first presents during early childhood, and XP patients exhibit extreme sensitivity to sunlight and UV radiation. ²⁶ XP patients often develop freckles on sun-exposed areas at an early age and actinic keratoses which are precursors to skin cancers. The risk of developing skin cancers increases with aging, with affected individuals typically developing their first skin cancer by the age of 10 years and an average of over 20 skin cancers in their lifetime. ²⁷

Ophthalmic manifestations due to sun damage are also observed in this disease. In severe cases, XP can cause progressive vision loss or blindness.^28,29 Similarly, in this case, the patient had malignant melanomas in her right eye and lower left eyelid, which eventually led to right eye enucleation and recurrence of melanoma in the lower left eyelid.

Some individuals with XP may experience neurological abnormalities, although they are less common than cutaneous symptoms. Neurological manifestations can include progressive neurological degeneration, cognitive impairment, developmental delays, hearing loss, and poor coordination. Neurological abnormalities such as cognitive impairment and progressive ataxia are also common, particularly in patients with XP-C and XP-D.^30,31

Diagnosis

Diagnosis of XP is typically based on clinical features, family history, and laboratory testing. Clinical evaluation typically involves detailed history taking and physical examination, including assessment of sun exposure and a complete skin examination. Family history and genetic counseling are critical components of the diagnostic workup, as XP is inherited in an autosomal recessive manner. Laboratory testing for XP typically involves one or more DNA damage assays, such as the DNA synthesis assay,^32–34 flow cytometry, or comet assay. Deficient DNA repair or lack of repair ability strongly suggests the presence of XP. ³⁴ As XP can also affect the central nervous system, neurological evaluations may be conducted.

Protection

Limiting exposure to both UV radiation and chemical mutagens is critical for protecting individuals with XP from developing skin cancer. Strategies to reduce exposure to UV radiation include avoiding the sun during peak hours, wearing protective clothing, hats, and using broad-spectrum sunscreens. ¹¹ In addition to these strategies, there is increasing interest in developing novel interventions to reduce the risk of developing XP and other skin cancers. One such intervention is the use of photoprotective agents, which can modulate the skin’s response to UV radiation. ³⁵ Several studies have identified natural compounds such as green tea polyphenols, which have photoprotective effects and can reduce the incidence of skin cancer in animal models.^36,37 Other interventions, such as DNA repair enzymes and antioxidants, are also being studied for their potential in preventing XP and other skin cancers.^38,39 Routine skin examinations by a dermatologist are essential for early detection and protection of skin cancers or precancerous lesions. ⁴⁰ Genetic counseling should be provided to individuals with XP and their families to discuss inheritance patterns, recurrence risks, and the availability of prenatal genetic testing options.^41,42

Treatments

There is currently no specific cure for XP, and management is focused on minimizing exposure to UV radiation and early detection and treatment of skin cancers.

Surgical removal is a direct method to excise skin cancer. Radical resection with free margin, which is based on the lateral extension of skin incision, is recommended.^25,42 Biopsy of the margin could be a predictive parameter for metastasis.^25,39 Photodynamic therapy is widely used in dermatology to treat benign and premalignant skin lesions. The reactive oxygen species generated by photosensitizer, light, and oxygen lead to cell apoptosis and necrosis, which eventually eradicate tumor cells. ⁴³ Cryotherapy is a treatment option for certain types of skin cancer, including BCC, SCC, and some types of precancerous skin lesions. ⁴⁴

The use of pharmacotherapy is based on the type of cancer. For melanoma, several therapies have been developed to stimulate antitumor systems, including immunotherapy (such as interleukin 2, which is used for metastatic melanoma), ⁴⁵ immune checkpoint inhibitors (such as PD-1 inhibitor, PD-L1 inhibitor, and CTLA-4 inhibitor),^46,47 and target inhibitors (such as BRAF inhibitor and mitogen-activated extracellular signal–regulated kinase (MEK) inhibitor).^48,49 For SCC, EGFR-targeted therapy and interferon are used as conventional chemotherapy, while immune checkpoint inhibitors are used for unresectable or metastatic SCC. ⁵⁰ For BCC, hedgehog signaling inhibitors have proven effective for unresectable or metastatic BCC. ⁵¹

Unlike the majority of reported XPC mutations, which are frameshifts or nonsense variants leading to complete protein loss, the c.2218_2220del mutation is a rare in-frame deletion that removes only a single amino acid (glutamic acid at position 740) while preserving the reading frame. ⁵² The deleted amino acid is located within the highly conserved C-terminal region (amino acids 520–870), which contains critical binding sites for DNA and repair proteins. ⁵³ To the best of our knowledge, this specific variant has not been previously reported in Chinese or global XP-C cohorts. This finding expands the mutational spectrum of the XPC gene and may contribute to a better understanding of genotype–phenotype correlations in Chinese XP-C patients. The reporting of this study conforms to the Case Report (CARE) guidelines. ⁵⁴

Notably, this specific variant has not been previously reported in Chinese or global XP-C cohorts. Our findings thus expand the mutational spectrum of the XPC gene and contribute to a better understanding of genotype–phenotype correlations in Chinese XP-C patients. Importantly, identification of this novel variant enhances molecular diagnosis capabilities and facilitates genetic counseling for affected families, particularly regarding carrier screening and reproductive risk assessment.

Conclusion

This case report emphasizes the importance of the combined use of clinical manifestations, family and individual histories, histopathology, and WES to diagnose XP. Although XP is a rare autosomal recessive genetic disorder, WES facilitates the diagnosis of XP. In addition, the literature review will facilitate better clinical understanding and early awareness of this rare disease.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605261416735 - Supplemental material for Xeroderma pigmentosum with multiple skin carcinoma and a homogenous XPC mutation: A case report from China and literature review

Supplemental material, sj-pdf-1-imr-10.1177_03000605261416735 for Xeroderma pigmentosum with multiple skin carcinoma and a homogenous XPC mutation: A case report from China and literature review by Feng Gao, Ruiye Huang, Yang Lu, Ziyu Guo, Min Li, Weiwei Wu and Wen Li in Journal of International Medical Research