Xeroderma Pigmentosum with a Rapidly Proliferating Squamous Cell Carcinoma in a 4-Year Old Kid: A Rare Entity in Indian Subcontinent

Abstract

Xeroderma pigmentosum is a rare autosomal recessive genetic disorder, affecting nucleotide excision repair against ultraviolet radiation. This genodermatosis (a hereditary skin disorder) is distinguished by photosensitivity, alterations in cutaneous pigmentation, premature aging of the skin, and the typically observed onset of cutaneous and internal malignancies towards the conclusion of the first decade of life. In this article, we present a case involving a 4-year-old girl from North India who was born to non-consanguineous parents and developed an extensive fungating growth on her face. Subsequent diagnosis revealed the presence of squamous cell carcinoma, resulting in significant facial disfigurement. While xeroderma pigmentosum is a recognized condition, its occurrence in India, particularly in the northern region, is relatively rare. This report also underscores a noteworthy observation—the emergence of a cutaneous malignancy at such a tender age.

Introduction

Xeroderma pigmentosum (XP) is a rare autosomal recessive condition caused by a faulty DNA repair mechanism. Clinically characterized by progressing pigmentary anomalies, increased photosensitivity, and a heightened risk of developing malignancies in sun-exposed skin and mucous membranes. In India, XP prevalence is undocumented, but most cases are in the southern region due to increased consanguineous marriages [1]. Conversely, in northern India, XP is notably rare, and reports regarding its occurrence are scarce.

Case Report

A 4-year-old girl, born to non-consanguineous parents, presented at the hospital with a history of photosensitivity and numerous hypopigmented and hyperpigmented lesions across her body, primarily in sun-exposed areas since birth. In the past three months, a large fungating mass appeared on her philtrum, along with smaller lesions on her face, upper back, and scalp. Discussions with the mother revealed a history of photophobia but no conjunctivitis, eye redness, or hearing loss. Born prematurely at 30 weeks, weighing 1 kg, the child cried immediately after birth but experienced global developmental delay. Anthropometry indicated severe stunting and microcephaly. On skin examination, diffuse hyperpigmented macules resembling freckles, as well as areas of hypopigmentation, were observed on the face, neck, chest's 'V' area, arms, forearms, and back, along with hyperpigmented macules on both legs. An ulcero-proliferative lesion measuring 5 × 5 cm was observed at right philtrum of lip and was seen extending towards right nasal mucosa, causing obstruction of the nostril (Fig. 1). The lesion was partially necrotic from within and bled upon touch. Additionally, it was accompanied by the presence of purulent discharge and emitted an unpleasant odour. Ophthalmological evaluation unveiled presence of photophobia. Blood count, liver, and renal tests were normal. Vitamin D levels were deficient (8 ng/ml). Skeletal survey and brain MRI were normal. Lesion located on the nose was sent for histopathological analysis. Microscopic examination of the lesion revealed prominent hyperkeratosis, papillomatosis, and focal parakeratosis within the epidermal layer (Fig. 2a). Notably, there were distinct regions displaying blunt projections of squamous epithelium and pushing margin. The underlying dermal tissue exhibited malignant squamous cells, demonstrating mild-to-moderate nuclear pleomorphism and abundant eosinophilic cytoplasm (Fig. 2b,c). Additionally, focal regions exhibited intra and intercellular keratin deposits, accompanied by formation of keratin pearls (Fig. 2d). A final diagnosis of squamous cell carcinoma was given. Parents were counseled on the importance of sun protection and proper use of broad-spectrum sunscreens. The treatment plan included syrup Acitretin at 0.4 mg/kg/day, along with vitamin D supplementation, and neoadjuvant chemotherapy was recommended. The patient was referred to pediatric oncology for ongoing care but tragically succumbed to the illness within a week of starting chemotherapy.

Fig. 1.

Clinical image showing an ulcero-proliferative growth over the right philtrum of the lip, extending into right nasal mucosa and obstructing the right nostril. Numerous hyperpigmented macules and regions of hypopigmentation on face, neck, ‘V’ area of chest, extensor aspects of arms, forearms and back

Fig. 2.

a Histopathological image of the lesion showing prominent hyperkeratosis, papillomatosis, focal parakeratosis within the epidermal layer along with distinct region displaying blunt projections of squamous epithelium and pushing margin (HE 40x); b–d Underlying dermal tissue showing malignant squamous cells, demonstrating mild to moderate nuclear pleomorphism and abundant eosinophilic cytoplasm along with a focus showing keratin pearl formation in a background of chronic inflammation (HE 200x, 400x, 400x)

Discussion

Xeroderma pigmentosum can manifest in individuals from diverse racial and ethnic backgrounds. Nine complementation groups, each tied to mutations in a corresponding gene, have been identified. These mutations can affect any of genes, with XPA and XPC being the most frequently affected, followed by other genes including XPB, DDB2, ERCC1, ERCC2, ERCC4, ERCC5, and POLH1 [2, 3]. Clinical presentation and severity of disease are contingent upon both cumulative ultraviolet radiation exposure and specific complementation group involved. Clinical manifestations encompass degenerative and progressive alterations in skin, including hyper-hypopigmentation, skin atrophy, actinic keratosis, and development of cutaneous malignancies like basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma [3]. Cutaneous symptoms usually appear in children under 2 years old, with around 60% eventually developing malignancies. Patients face a substantially elevated risk, with a 10,000-fold increased likelihood of developing non-melanoma skin cancer and 2,000-fold increased risk of developing melanoma [4]. BCC and SCC are the most frequently occurring carcinomas in photo-exposed areas (face, head, and neck) [5]. Kramer et al. conducted a comprehensive assessment involving approximately 830 XP patients, typically exhibiting photosensitivity between ages of 1 to 2 years [6]. Moreover, median age for the onset of the first cutaneous neoplasm was 8 years, a remarkable 50-year difference compared to general population.⁶ In contrast, our patient presented with the development of skin cancer at the remarkably early age of 4 years. The ocular system is affected in 40–80% of patients, leading to manifestations such as conjunctivitis, keratitis, photophobia, eyelash loss, eyelid hyperpigmentation, and increased malignancy risk [1]. Approximately 30% of XP patients exhibit neurological abnormalities, manifesting as loss of fine motor control, spasticity, hearing loss, ataxia, and progressive mental retardation [7]. In the present case, global developmental delay was observed.

The Xeroderma pigmentosum group G (XPG) and Xeroderma pigmentosum group D (XPD) genes play vital roles in the nucleotide excision repair pathway. Any modification in these genes can hinder the efficiency of DNA repair, leading to genomic instability and the potential for carcinogenesis. Both XPG and XPD genes may contain single nucleotide polymorphisms (SNPs), many of which could influence the development of Oral Squamous Cell Carcinoma (OSCC) through synergistic effects [8]. Therefore, it is essential to assess any intra-oral lesions that are present and to schedule a biopsy accordingly. Xeroderma pigmentosa/Cockayne syndrome complex (XP/CS) is a rare variant, combining features of both XP and CS. Individuals with XP/CS exhibit symptoms like photosensitivity, short stature, microcephaly, cachexia, abnormal development, retinal degeneration, sensorineural deafness, and progressive neurological dysfunction. Notably, while neurological degeneration in CS is often attributed to demyelination, in XP, it stems from neuronal degeneration [9]. The present case had some features reminiscent of both conditions; however, XP/CS was excluded as MRI brain exhibited normal findings, and our patient also presented with SCC, a rare occurrence in the XP/CS syndrome. Approximately, 2/3rd of untreated patients succumb to the condition before reaching age of 20. Clever and Revert reported that children residing in regions with high sun exposure who neglect photoprotective measures face a significantly reduced life expectancy of approximately 10 years. Hence, it is imperative to provide patients with comprehensive counseling and education on the significance of photoprotective measures. Patients should be advised to strictly avoid exposure to UV radiation sources, including sunlight, halogens, and fluorescent lights and encouraged to wear protective clothing, employ UV-absorbing eyewear, and utilize sunscreens with a high sun protection factor. Patients who rigorously shield themselves from sunlight may be at risk of vitamin D deficiency, necessitating appropriate supplementation. Surgical excision remains the preferred approach for managing cutaneous neoplasms in these individuals. Notably, the administration of oral 13-cisretinoic acid has demonstrated a reduction in the incidence of new cancers in this patient population [10].

Conclusion

Treatment of xeroderma pigmentosum is quite challenging as DNA damage is cumulative, irreversible and majority of patients eventually develop cutaneous malignancies. Early, accurate diagnosis, rigorous sun protection, and vigilant skin malignancy monitoring are crucial to prevent early-age morbidity and mortality.

Author Contributions

Dharitree Senapati contributed to conceptualization, project writing and management, extensive literature search, operative work (clinical), manuscript preparation and manuscript editing. Md Ali Osama contributed to conceptualization, project writing and management, extensive literature search, practical work (laboratory work), manuscript editing, guarantor. Suparna Das contributed to conceptualization, project writing and management, defining the study, operative work (clinical), manuscript preparation, manuscript editing and manuscript review. Vibhu Mendiratta contributed to conceptualization, defining the study, operative work (clinical), manuscript editing and manuscript review. Smita Singh defining the study, practical work (laboratory work), manuscript editing and manuscript review.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article

Declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Consent to Participate

The authors certify that they have obtained the appropriate consent from the patient’s parents. The patient’s parents have given their consent for the images and other clinical information to be reported in the journal. The patient’s parents understand that the name and initials will not be published, and due efforts have been made to conceal the same.