DISEASE CARD

Definition

UV-sensitive syndrome (UV^SS) is a rare autosomal recessive disorder first reported as a distinct clinical entity in 1994.¹ The patients affected by UV^SS exhibit photosensitivity and mild skin abnormalities in sunexposed areas of the skin, with freckling and telangiectasia, with no skin cancers.

UV^SS is genetically heterogeneous, in that it is linked to mutations in the CSA/ERCC8, CSB/ERCC6 or UVSSA/KIAA1530 gene.

Clinical Description

The cardinal clinical features of UV^SS are (mild) cutaneous photosensitivity and development of skin pigmentation with freckles primarily on the face and sun-exposed areas, as well as hypopigmented spots, telangiectasia, erythema and dry skin. The clinical phenotype closely resembles mild xeroderma pigmentosum. The action spectrum of photosensitivity is not known. No neurological abnormalities, cutaneous or internal cancers have been reported to date. Growth, mental development and life span are normal as well. However, only few UV^SS cases have been reported up to date, possibly because of mild symptoms that may be overlooked.^{2, 3}

Pathogenesis

Following exposure to ultraviolet (UV) light, cells from UV^SS patients show reduced survival and recovery of DNA and RNA synthesis but normal capability to perform DNA repair synthesis. Genetic analysis led to the definition of three distinct complementation groups, CS-A and CS-B and UVSS-A. Like cells from Cockayne syndrome (CS) patients, UV^SS cells fail to perform preferential repair of the transcribed strand of transcriptionally active genes at the rate seen in normal cells, but they are capable of removing damage from the non-transcribed part of the genome at the normal rate.⁴ All activities whose alteration results in UV^SS are involved in transcription-coupled repair, the nucleotide excision repair (NER) sub-pathway that specifically removes DNA damage blocking the progression of the transcription machinery in actively transcribed regions of DNA (TC-NER). Given the involvement of CSA and CSB not only in UVSS but also in CS, questions remain open for clinical pathology especially about the developmental and neurological impairment so evident in patients with CS but not in those with UV^SS. The only consistent correlation between defects in TC-NER in all these individuals is with skin photosensitivity. As reported in the specific card, the CS proteins have additional functions including the repair of oxidative damage in DNA. Interestingly, cells of UV^SS patients are UV-sensitive but they are not sensitive to oxidizing agents.^4-6

Diagnosis

The diagnosis of UV^SS is made clinically based on skin manifestations. Laboratory testing can be useful for confirming the suspected clinical diagnosis. The presence of repair defects in UV^SS can be conclusively diagnosed by analyzing patient’s cells for the appropriate DNA repair defect. Specific functional assays on in vitro cultured fibroblasts from the patients (obtained from small skin biopsies) are available to evaluate the cellular response to UV light and to define the gene responsible for the DNA repair defect. Identification of the molecular defect by sequencing of the relevant gene(s) allows genetic counselling of the families involved.

Treatment

The management largely involves prevention of UV exposure and cutaneous complications like photosensitivity and pigmentation. UV^SS patients should follow the general precautionary measures reported for xeroderma pigmentosum patients (see article Xeroderma pigmentosum).²

References

^{1. Itoh T, Ono T, Yamaizumi M. A new UV-sensitive syndrome not belonging to any complementation groups of xeroderma pigmentosum or Cockayne syndrome: siblings showing biochemical characteristics of Cockayne syndrome without typical clinical manifestations. Mutat Res. 1994;314(3):233-248.}

^{2. Yew YW, Giordano CN, Spivak G, Lim HW. Understanding photodermatoses associated with defective DNA repair: Photosensitive syndromes without associated cancer predisposition. J Am Acad Dermatol. 2016;75(5):873-882.}

^{3. Ferri D, Orioli D, Botta E. Heterogeneity and overlaps in nucleotide excision repair disorders. 2020;97(1):12-24.}

^{4. Spivak G, Itoh T, Matsunaga T, Nikaido O, Hanawalt P, Yamaizumi M. Ultraviolet-sensitive syndrome cells are defective in transcription-coupled repair of cyclobutane pyrimidine dimers. DNA repair. 2002;1(8):629-643.}

^{5. Ijaz A, Wolf S, Mandukhail SR, Basit S, Betz RC, Wali A. UV-sensitive syndrome: Whole exome sequencing identified a nonsense mutation in the gene UVSSA in two consanguineous pedigrees from Pakistan. J Dermatol Sci. 2019;95(3):113-118.}

^{6. Nakazawa Y, Sasaki K, Mitsutake N, et al. Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair. Nat Genet. 2012;44(5):586-592.}