DNA Repair Disorders
Four genetic disorders of the skin are caused by the inability of cells to remove damage caused by sunlight to DNA, the genetic material. These disorders are xeroderma pigmentosum (XP), Cockayne syndrome (CS), trichothiodystrophy (TTD) and UV-sensitive syndrome (UVSS). They all result from an inability to handle damage generated in cellular DNA by ultraviolet (UV) light from the sun. As a consequence, patients with any one of these disorders share hypersensitivity to sunlight, but may be distinguished by the constellation of additional features.
Xeroderma Pigmentosum (XP)
XP patients show a wide variety of pigmentation changes in sun-exposed areas of the skin. These start off as freckles, but then proceed to more severe changes in skin pigment and later still to multiple skin cancers. Many patients are very sensitive to sun exposure, they don’t like to look at sunlight and have abnormalities in the sun-exposed portions of their eyes. About 30% of cases also have neurological problems. These can have a variable age of onset, but they get progressively worse. In previous times, many patients died at an early age from skin cancers. However, the skin abnormalities including the skin cancers are all caused by exposure to sunlight. So, if a person is diagnosed early, does not present severe neurological symptoms, and takes all the precautionary measures to avoid exposure to sunlight, can have a normal lifespan with minimal skin problems.
Most XP cases have a mutation (genetic error) in one of seven genes (XPA to XPG). These genes contain the code to make proteins, whose job is to carry out a process called nucleotide excision repair (NER). This process is the cell way of getting rid of dangerous damage produced in the genetic material by the ultraviolet rays of the sun. It doesn’t function properly in the majority of XP patients. In about 20% of cases, the so-called XP variant form, the defect is in an eighth gene that is not involved in nucleotide excision repair. All cells have to be able to copy their DNA in order to proliferate and survive. Enzymes that do this are called DNA polymerases. These enzymes are very efficient, but they can’t copy DNA that has been damaged. A special DNA polymerase, called DNA polymerase eta, is specifically designed to copy damaged DNA. It is this enzyme that is faulty in XP variant patients.
The diagnosis of XP is made clinically based on skin, eye, and neurological symptoms and can be conclusively confirmed by analyzing patient’s cells for the DNA repair defect. Prenatal diagnosis is available for at risk pregnancies in families in which the repair defect in the affected member(s) has been already identified in the cellular test.
Once diagnosed, patients should be completely protected from exposure to sunlight. Ideally when outdoors, they should wear a UV-resistant face mask and gloves and should use the highest factor sunscreens. Homes and schools should have their windows coated with film that does not allow the passage of UV light. The skin should be regularly examined for lesions.
Cockayne Syndrome (CS)
The clinical features of CS are growth failure either prenatal or typically after 1 or 2 years of life. There follows progressive neurological degeneration with a loss of fatty tissue leading to a wizened appearance. The head is small and patients are mentally retarded. Other clinical features include difficulties in standing and walking, problems with the eyes and deafness. Patients are very sensitive to sunlight but they don’t have pigmentation changes and they don’t get skin cancer. There is a wide range in type, severity, age at onset and progression of symptoms.
About 50% of CS patients show an altered cellular response to UV resulting from mutations in the CSA/ERCC8 or CSB/ERCC6 genes. These genes code for proteins that are involved in repairing a special fraction of the DNA that is in active use by the cell.
The diagnosis of CS is made clinically based on growth failure, neurological abnormalities and eye problems. The photosensitive form may be conclusively confirmed by analyzing patient’s cells for the appropriate DNA repair defect. Prenatal diagnosis is available for at risk pregnancies in families in which the repair defect in the affected member(s) has been already detected in the cellular test.
The main diagnostic features of TTD are brittle hair, mental and growth retardation, peculiar face, characterized by receding chin, small nose, large ears and a small head, abnormalities of the nails, and a scaly skin, referred to as ichthyosis. Approximately half of the patients are defective in nucleotide excision repair (NER) as XP. This defect can result from faults in one of three genes, XPB/ERCC3, XPD/ERCC2 and TTDA/GTF2H5. Curiously, unlike XP, NER-defective TTD patients do not show skin pigmentation changes and skin cancers.
The NER-proficient form of TTD is still largely unsolved. The three genes so far identified as associated with this form of the disease, namely TTDN1/MPLKIP, RNF113A and GTF2E2, together account for only about 20% of the patients. The products of the TTDN1/MPLKIP and RNF113A genes have unknown function whereas the product of GTF2E2 is involved in transcription, the first step in the essential cellular process of gene expression.
The diagnosis of TTD is made clinically based on hair abnormalities, together with growth retardation, peculiar face, skin, eye and neurological problems.
The photosensitive (NER-defective) form of TTD can be conclusively confirmed by analyzing patient’s cells for the appropriate DNA repair defect, and prenatal diagnosis is available for at risk pregnancies in families in which the repair defect in the affected member(s) has been already characterized at the cellular level.
In patients with the non-photosensitive (NER-proficient) form, sequencing of the TTDN1/MPLKIP, RNF113A and GTF2E2 genes might be informative. Prenatal testing may be available for families in which disease-causing mutations in TTDN1/MPLKIP, RNF113A or GTF2E2 have been identified in the affected family member(s).
UV-sensitive syndrome (UVSS)
This condition is extremely rare and currently includes only seven individuals. The patients exhibit photosensitivity and mild skin abnormalities; their growth, mental development and life span are normal. No skin or internal cancers have been reported to date.
UVSS patients show the same altered cellular response to UV observed in CS. The genes associated with UVSS are CSA/ERCC8, CSB/ERCC6 or UVSSA.
The clinical diagnosis is based on sun sensitivity with easy sun burning, erythema and presence of freckles. UVSS diagnosis can be conclusively confirmed by analyzing patient’s cells for the appropriate DNA repair defect. Prenatal diagnosis is available for at risk pregnancies in families in which the repair defect in the affected member(s) has been already detected in the cellular test.