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

1. Xeroderma pigmentosum (XP),
2. Cockayne syndrome (CS),
3. Trichothiodystrophy (TTD) and
4. 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 soon proceed to more severe changes that include development of multiple and various skin cancers.

Many patients are extremely sensitive to sun exposure, they don’t like to look at sunlight and have abnormalities in the sun-exposed portions of their eyes. About 20-30% of cases also have neurological problems with a variable age of onset, and tendency to become worse over time.  In previous times, many patients died at an early age (<10 years of life) from skin cancers. However, as the skin abnormalities including the skin cancers are provoked by exposure to sunlight, avoidance strategy may lead to a normal lifespan. 

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's 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 lies in a different gene, not involved in nucleotide excision repair, called DNA polymerase eta. This DNA polymerase is specifically designed to copy damaged DNA , however, 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, gloves long-sleeved clothing and wide-brimmed hats and should use the highest factor sunscreens, both in UVA and UVB range. Homes, schools, cars and workplaces should have their windows coated with a film that does not allow the passage of UV light. Modern protective filter exist that filter > 90% of UV radiation without darkening normal daylight. The skin should be regularly examined for suspicious lesions.

Cockayne Syndrome (CS)

Patients with CS show a broad clinical variance. An important clinical feature of CS is growth failure either prenatal or typically after 1 or 2 years of life. This is followed by progressive neurological degeneration and a loss of subcoutaneous fatty tissue leading to a wizened appearance. Therefore this disease belongs to the group of pre-aging syndromes. The head is small with a bird-like nose, deep-lying eyes 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. In particular the combination of mental retardation and growth retardation should make one think of a possible CS. 

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 subtype 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.

Therapy involves UV protection and supportive therapy of symptoms.

A combination of XP and CS is possible, usually characterized by a severe clinical course. 

Trichothiodystrophy (TTD)

The main diagnostic features of TTD are brittle hair, mental and growth retardation, characteristic face (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 defects 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 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 where the repair defect in the affected member(s) has been already characterized.

In patients with the non-photosensitive (NER-proficient) form, sequencing of the XPB/ERCC3, XPD/ERCC2 and TTDA/GTF2H5 genes might be informative. Prenatal testing may be available for families in which disease-causing mutations have been identified in the affected family member(s).

UV-sensitive syndrome (UV^SS)

This condition is extremely rare and currently only a few individuals have been described. 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.

UV^SS patients show the same altered cellular response to UV observed in CS. The genes associated with UV^SS are CSA/ERCC8, CSB/ERCC6 or UVSSA.

The clinical diagnosis is based on sun sensitivity with easy sun burning, erythema and presence of freckles.  UV^SS 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.