Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by extreme sensitivity to ultraviolet (UV) radiation due to defective DNA repair mechanisms. It significantly increases the risk of skin cancers at an early age and is also associated with ocular disease and progressive neurodegeneration.1,2 Clinical manifestations include severe photosensitivity, early freckling, poikiloderma, and multiple skin cancers, including melanoma and nonmelanoma skin cancers.3,4 The disease results from mutations in genes involved in the nucleotide excision repair pathway, which is essential for repairing UV-induced DNA damage.2,4 Management includes rigorous photoprotection, early detection, and treatment of skin lesions. Investigational therapies are currently being explored; however, life expectancy is often reduced due to skin cancers and neurodegenerative complications.1,5

Hedgehog pathway inhibitors (HHIs), such as vismodegib and sonidegib, have demonstrated efficacy in the treatment of locally advanced and metastatic basal cell carcinoma (BCC) caused by aberrant activation of the Hedgehog signaling pathway. Moreover, these drugs have been successfully used to manage multiple BCCs in patients with Gorlin syndrome.6 However, evidence regarding the use of these therapies in XP is limited, highlighting the need for further research in this patient population.

We report the case of a 68-year-old man with XP treated with sonidegib. The patient had been diagnosed with XP through genetic testing 30 years earlier. Throughout his life, he had developed more than 100 BCCs on the face and trunk, 2 superficial spreading melanomas on the trunk, 1 porocarcinoma on the left lower eyelid, and more than 10 squamous cell carcinomas (SCCs).

The patient had undergone numerous surgical procedures, particularly on the face. Furthermore, he had received oral acitretin at variable doses (10–25mg/day) for 15 years (1995–2010) and oral nicotinamide (500mg every 12h) for 2 years (2015–2017). However, neither treatment successfully reduced the development of cutaneous neoplasms.

During follow-up, the number and size of lesions compatible with BCC, particularly on the face, rendered surgery unfeasible. The patient underwent treatment with intralesional interferon-α and topical imiquimod, with variable success over the years, according to his preference to avoid further surgical interventions. Consequently, treatment with sonidegib was initiated in December 2023 at a dose of 200mg/day according to prescribing guidelines. At treatment initiation, the patient had 17 BCCs located on several areas, including the face (Fig. 1), trunk, and lower extremities.

Fig. 1.

Multiple lesions compatible with basal cell carcinoma before initiation of treatment with sonidegib in the facial region.

Two months into therapy, significant improvement was observed in lesions compatible with BCC, and no new lesions developed. The patient experienced several adverse effects, including asthenia, myalgia, dysgeusia, weight loss, headache, bradypsychia, diarrhea, and nausea. Notably, the patient also stopped smoking during this period. Because of poor tolerability, the dosing schedule was initially adjusted to every 48h and later to every 72h. Ultimately, after 4 months of treatment, the regimen was modified to 1 week on treatment (200mg/day) followed by 3 weeks off treatment, based on an ongoing clinical trial protocol (NCT04806646: Tailored Sonidegib Schedule After Complete Response in BCC [SONIBEC], available at www.clinicaltrials.gov).

Under this adjusted schedule, the patient reported no further adverse effects except for persistent weight loss. After 24 months of treatment, the patient presented no suspicious malignant lesions, with complete resolution of preexisting lesions and no development of new lesions. Moreover, a notable improvement in cutaneous hyperpigmentation and chronic photodamage was observed (Fig. 2).

Fig. 2.

Absence of lesions compatible with basal cell carcinoma after 12 months of treatment with sonidegib in the facial region.

Currently, only 2 cases have reported the use of HHIs, particularly vismodegib, in patients with XP. One case involved a 21-year-old woman treated with vismodegib who showed a 61% reduction in lesion diameter after 16.5 months. However, after 18.5 months, a persistent lesion showed progression with metatypical characteristics. Adverse events included persistent alopecia, muscle cramps, dysgeusia, and amenorrhea. Despite these adverse effects, vismodegib demonstrated potential in treating BCCs in patients with XP by reducing existing lesions and preventing the development of new lesions.7

Another case described the use of vismodegib in an 8-year-old Chinese boy with XP who presented with a nodular BCC on the nasal tip. Vismodegib was administered at a dose of 150mg/day, leading to complete clinical clearance after 4 months. During a 21-month follow-up period, the patient's nose remained free of tumors. This case underscores the effectiveness of vismodegib in pediatric XP patients, achieving tumor regression while avoiding cosmetic and functional disfigurement.8

Some reports have suggested an association between HHIs and the development of cutaneous squamous cell carcinoma (cSCC). The exact mechanism remains unclear, but it has been proposed that vismodegib may select tumor cells that use alternative signaling pathways, such as the Ras/MAPK pathway. However, a retrospective cohort study reported no increased risk of cSCC compared with standard BCC treatments, with an adjusted HR, 0.57.9

The use of HHIs appears promising for the treatment of BCCs in patients with XP. Clinical reports have demonstrated substantial tumor reduction and prevention of new lesions, although adverse effects and persistent lesions have occasionally been observed. The broader efficacy of HHIs across various cancers further supports their potential role in XP treatment and warrants additional studies to optimize therapeutic strategies and improve management of adverse effects.10

Sonidegib may represent a new therapeutic option for patients with XP. A regimen consisting of 1 week of treatment followed by 3 weeks of rest may be considered in patients who experience intolerable adverse effects. To our knowledge, this is the first reported case of a patient with XP successfully treated with sonidegib.