| Phenotype | Gene(s) | Clinical features |
COFS syndrome
(Pena-Shokeir syndrome, type II; OMIM PS214150) | ERCC2
ERCC5
ERCC6 | - Progressive neurologic disorder marked by microcephaly with intracranial calcifications and growth failure.
- Ocular findings of microcornea, cataracts, and optic atrophy are present along with congenital joint contractures.
- Photosensitivity may occur with a concurrent cellular phenotype of UV sensitivity.
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| CS | ERCC6
ERCC8 | - CS type I – Normal prenatal growth with onset of growth and developmental abnormalities in the first two years. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function lead to severe disability. Death typically occurs in the first or second decade.
- As in XP, cells from individuals with CS are hypersensitive to killing by UV; however, CS cells have normal post-UV unscheduled DNA synthesis (UDS). CS cells also have delayed recovery of RNA synthesis after UV exposure, reflecting their deficiency in TC-NER.
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| TTD (OMIM PS601675) | ERCC3
ERCC2
GTF2H5
MPLKIP
GTF2E2 | - Variable phenotype including photosensitivity, ichthyosis, brittle hair with "tiger tail" appearance under polarizing microscopy, intellectual impairment, short stature, microcephaly, dysmyelination of the brain, and the characteristic facial features of protruding ears and micrognathia.
- Twenty-fold increased risk of death before age 10 years, primarily from infections.
- Frequency of pregnancy complications and neonatal abnormalities is increased in TTD but not in mothers with XP who have different pathogenic variants in the same gene (ERCC2).
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| XP/CS complex | ERCC2
ERCC3
ERCC4
ERCC5 | - Facial freckling and early skin cancers typical of XP and some features of CS (eg, intellectual disability, spasticity, short stature, hypogonadism) but not skeletal dysplasia. In contrast to XP, in which neuronal degeneration predominates, dysmyelination typical of CS is observed in XP/CS.
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| COFS/TTD | ERCC2 | - Combined features of COFS and TTD
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| CS/TTD complex | ERCC2 | - Combined features of CS and TTD
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| UV-sensitive syndrome | ERCC6
ERCC8
UVSSA | - Mild photosensitivity without pigmentary abnormalities or apparent defects in the central nervous system. Cells from affected individuals have the same transcription defects as those in individuals with CS.
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| XP/TTD complex | ERCC2 | - Phenotypic features of TTD with the clinical and cellular phenotype of XP. Unlike most people with TTD, those with XP/TTD may experience increased frequency of skin cancers.
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