Atypical Clinical Presentation of Xeroderma Pigmentosum in a Patient Harboring a Novel Missense Mutation in the <b><i>XPC</i></b> Gene: The Importance of Clinical Suspicion

Abstract

Background: Xeroderma pigmentosum (XP) is a genodermatosis caused by abnormal DNA repair. XP complementation group C (XPC) is the most frequent type in Mediterranean countries. We describe a case with a novel mutation in the XPC gene. Case: A healthy Caucasian male patient was diagnosed with multiple primary melanomas. Digital follow-up and molecular studies were carried out. Results: During digital follow-up 8 more additional melanomas were diagnosed. Molecular studies did not identify mutations in CDKN2A, CDK4 or MITF genes. Two heterozygous mutations in the XPC gene were detected: c.2287delC (p.Leu763Cysfs*4) frameshift and c.2212A>G (p.Thr738Ala) missense mutations. Conclusion: The p.Thr738Ala missense mutation has not been previously described. Missense mutations in the XPC gene may allow partial functionality that could explain this unusual late onset XP. Atypical clinical presentation of XPC could be misdiagnosed when genetic aberrations allow partial DNA repair capacity.

Xeroderma Pigmentosum with Severe Neurological Manifestations/De Sanctis–Cacchione Syndrome and a Novel XPC Mutation

“…The majority of reported XPC mutations result in Premature Termination Codons (PTCs) [ 36 , 39 – 42 ]. There are few reports of missense type mutations in the XPC gene [ 41 , 43 – 45 ].…”

Lentigo maligna in a patient with xeroderma pigmentosum, variant type: A case report with dermoscopic findings and review of the literature

“…However, only five reports with six patients have been reported regarding the utility of dermoscopy for diagnosing skin lesions in XP patients. 1,[5][6][7][8] Here, we report a rare case of XP variant type (XPV) with dermoscopic findings of lentigo maligna. In addition, we conducted a literature review for relevant articles regarding the use of dermoscopy in XP.…”

“…To the Editor, Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder affecting the DNA repair system, which is vital to mend the damage caused by ultraviolet (UV) radiation. 1,2 XP patients usually develop multiple skin tumors including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma (MM), and angiosarcoma. 3,4 However, the diagnosis of these tumors is often difficult due to severe actinic damage caused by the UV radiation.…”

A novel missense variant and multiexon deletion causing a delayed presentation of xeroderma pigmentosum, group C

“…Functional testing of UV-induced DNA repair synthesis (UDS) in his skin fibroblasts was ∼40% of normal after a UVR dose of 10 Jm-2 suggesting that the XPC protein was partially functional, demonstrating the pathogenicity of the observed missense variants (Fassihi et al 2016). Additionally, Meneses et al (2015) also observed late-onset xeroderma pigmentosum in an individual heterozygous for a missense variant (p.Thr738Ala) and a frameshift variant (p.Leu763Cysfs * 4). These data suggest that hypomorphic alleles can lead to an atypical late-onset presentation of XP, group C.…”

“…Although c.1709T > G has not been descried in the literature or population databases, other missense variants in XPC have been reported in individuals with similar clinical features, including late-onset XP manifestations (Chavanne et al 2000;Bernardes de Jesus et al 2008;Meneses et al 2015;Fassihi et al 2016). Fassihi et al describe a patient with a homozygous missense variant (p.Tyr585Cys) in XPC who did not develop their first melanoma until age 28, and who displayed almost no pigmentary changes.…”