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

Abstract

Several genetic disorders caused by defective nucleotide excision repair that affect the skin and the nervous system have been described, including Xeroderma Pigmentosum (XP), De Sanctis-Cacchione syndrome (DSC), Cockayne syndrome, and Trichothiodystrophy. Cutaneous photosensitivity with an increased risk of skin malignancy is a common feature of these disorders, but clinical manifestations commonly overlap these syndromes. Several genes have been found to be altered in these pathologies, but we lack more genotype-phenotype correlations in order to make an accurate diagnosis. Very few cases of DSC syndrome have been reported in the literature. We present a case of a 12-year-old Colombian male, with multiple skin lesions in sun-exposed areas from the age of 3 months and a history of 15 skin cancers. He also displayed severe neurologic abnormalities (intellectual disability, ataxia, altered speech, and hyperreflexia), short stature, and microcephaly, which are features associated with DSC. Genetic testing revealed a novel germline mutation in the XP-C gene (c.547A>T). This is the first case of an XP-C mutation causing De Sanctis-Cacchione syndrome. Multigene panel testing is becoming more widely available and accessible in the clinical setting and will help rapidly unveil the molecular etiology of these rare genetic disorders.

Figure 1

Nucleotide excision repair (NER) pathway. Transcription coupled repair (TCR) removes DNA damage from actively transcribed genes and global genome repair (GGR) from the rest of the genome [13]. TCR starts when RNA polymerase stops at the damaged DNA, which acts as a signal for CSA and CSB binding. In GGR, the XPE protein and the XPC-HR23B complex recognize the DNA damage. Upon initial recognition of the DNA lesion, both pathways converge. The XP-B and XP-D DNA helicases unwind the region surrounding the damaged site, along with the XP-A, XP-G, and replication protein A (RPA) [14]. The XPF-ERCC1 nuclease complex and XP-G endonuclease excise the damaged DNA. The resulting gap is replaced by de novo DNA synthesis.

Figure 2

(a) Pedigree chart of the patient. The arrow indicates the index patient. Filled squares indicate affected individuals. (b) Photographs of the patient showing alopecia, freckle-like skin lesions, and actinic keratosis in sun-exposed areas. (c) Cerebral MRI showing parenchymal volume loss, cerebellar atrophy, and white matter gliosis.