Fig. 1. Skin and eye involvement in XP. (A) Patient XP6BE, 17 year old female with marked poikilodermatous changes of her face with areas of increased freckle-like pigmentation, areas of decreased pigment and atrophy. The lips show cheilitis and there is absence of eyelashes on both lower lids. She had multiple surgeries for removal of skin cancers including basal cell carcinoma and melanoma. (B) Back of patient XP5BE, age 26 years, sister of XP6BE. Her skin shows marked poikilodermatous changes with a sharp cutoff at her sun-protected buttocks. These sisters had XP neurological disease. They inherited a defect in the XPD (ERCC2) DNA repair gene. Detailed information is reported in Robbins et al. (1974). (C) Right calf of patient XP1BE at age 46 years. She had multiple large pigmented lesions. Lesion 15 was a large melanoma that measured 0.55 mm in depth when excised. (D) Right eye of patient XP1BE at age 29 years. There is clouding of the cornea, prominent vascular growth on the conjunctiva approaching the limbus and loss of lashes on the lower lid. She is wearing a contact lens. She subsequently had a corneal transplant and an ocular squamous cell carcinoma that required enucleation. This patient inherited a defect in the XPC DNA repair gene. Detailed information is reported in Robbins et al 1974 and Robbins et al 1993.

Fig. 2. Progressive cachexia in XP patient XP12BE. At age 4 years she had prominent pigmentary changes on the sun-exposed portions of her body (face, arms) with sparing of her chest. By age 17 years she had had many basal cell and squamous cell carcinomas excised. Her main neurological abnormalities were loss of deep tendon reflexes and bilateral sensorineural hearing loss. By age 37 years she had become cachectic, was unable to swallow her food and required assistance to walk. Details of her neurological status up to age 22 years are described in Robbins et al. (1991). This patient inherited a defect in the XPA DNA repair gene (Cleaver et al., 1999).

Fig. 3. Clinical appearance of TTD. (A, B) Three year old female with short, brittle hair which is sparse and broken off at different lengths. She rarely has haircuts except to trim uneven areas. (C) Tiger-tail appearance of hair with polarizing microscopy. (D) Irregular, undulating hair shaft with light microscopy. From Liang et al. (2005).

Fig. 4. Calcification of brain in CS. (A) Axial brain CT scan of a 3 year old girl showing bilateral and symmetric speckled calcifications of the putamen. Tomographic sections at higher levels (not shown) revealed mild enlargement of the lateral ventricles, decreased attenuation in the white matter due to leukodystrophy and thick skull. She had CS with skin sun sensitivity, short stature and progressive neurological degeneration. (B) Axial brain CT scan of a 16 year old girl showing extensive bilateral and symmetric calcifications in the putamen, the globus pallidus and the head of the caudate nucleus. Prominent calcifications are also identified in both cerebellar hemispheres. Less prominent calcifications were present at the gray–white matter junction of the frontal and the parietal lobes which were appreciated in higher tomographic sections. Furthermore in the higher sections there was evident leukodystrophy in the white matter of the cerebral hemispheres and increased skull thickness. She had skin sun sensitivity, short statue and progressive neurological degeneration. Modified from Kraemer (2003b).

Fig. 5. Patient XP20BE with XP/CS complex. (A) Patient at age 4 months after he developed severe sunburn in March, the first sign of illness. Note the sharp change in redness on his lower legs where his socks blocked some sunlight. (B) Normal fullness of the face at age 1 year. (C) Age 1.5 years. Characteristic skin lesions of XP: freckling and hypopigmented macules of skin and lips. A benign pedunculated lesion is circled. (D) Age 6 years. Typical appearance of CS with deep set eyes, prominent ears, and profound cachexia with posturing of the hand. (E) Age 6 years. Pigmentary changes and wrinkling of the dorsum of the hand showing signs of premature aging. (F) Age 6 years. Signs of advanced CS with profound weakness of dorsiflexion of the hand. Note small size in comparison to the mother who is holding him. (G) Profound wasting and contractures of the legs with distal cyanosis and permanently upgoing toes. From Lindenbaum et al. (2001).

Fig. 6. NER pathway. Transcription-coupled repair (TCR) removes damage from actively transcribing genes while global genome repair (GGR) removes damage from the remainder of the genome. In GGR damage such as ultraviolet induced cyclobutane pyrimidine dimers (CPD) or 6-4 photoproducts (6-4 PP) are recognized by proteins including the XPE (DDB2) and XPC gene products. In TCR, the lesion appears to block the progress of RNA polymerase II in a process involving the CSA and CSB gene products. Following initial damage recognition the pathways converge. The XPB (ERCC3) and XPD (ERCC2) helicases unwind the region surrounding the lesion along with the XPA and XPG (ERCC5) gene products, and replication protein A (RPA). The XPF and XPG (ERCC5) endonucleases perform incisions to remove the lesion in a fragment of about 30 nucleotides. The resulting gap is filled in by de novo DNA synthesis. This system is coordinated so that if one part of the pathway is mutated the entire pathway fails to function normally. Mutations in the genes in rectangles have been associated with clinical disease. This diagram is modified from Van Steeg and Kraemer (1999).

Fig. 7. DNA repair diseases; relationship of clinical disorders (red rectangles) to molecular defects (gray ovals) in DNA repair diseases. Eight clinical diseases are represented. One disease may be caused by mutations in several different genes. Conversely, different mutations in one gene may result in several different clinical diseases. Modified from Kraemer (2004). For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.

Comparison of features of XP, TTD and CS