Cutaneous diseases related do DNA repair disorders
Xeroderma pigmentosum (XP)
Xeroderma pigmentosum (XP) is a rare genodermatosis characterized by extreme sensitivity to ultraviolet (UV)-induced changes in the skin and eyes, and multiple skin cancers. It is subdivided into 8 complementation groups, according to the affected gene: classical XP (XPA to XPG) and XP variant (XPV).
The severity of the clinical manifestations and the age of onset are extremely variable and are in part dependent on exposure to sunlight and the complementation group. Approximately 50% of affected individuals have acute sun sensitivity from the first few months of life, presenting with severe sunburn and/or persistent erythema which takes weeks to resolve. Others do not show any sunburn reaction and gradually develop marked freckling at sun exposed sites. Individuals have dry skin and hypo- or hyperpigmented lesions. There is a greater than 10,000-fold increased risk of non-melanoma skin cancers, and a 2,000 fold increased risk of melanoma under the age of 20 when compared to the general population. Patients with classical XP develop skin cancer generally before the age of 20, while patients with XP variant start to develop skin cancer at about 20-30 years of age. Ocular abnormalities include keratitis resulting in corneal opacification and vascularization. Photophobia is common. Ocular squamous cell carcinoma and melanoma are common. Neurologic abnormalities of varying severity have been reported in about 30% of cases. These include acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, spasticity, ataxia, seizures and progressive cognitive impairment. De Sanctis-Cacchione syndrome is a term that was originally attributed to XP cases with severe neurological abnormalities but it is no longer in general use.
It has an estimated prevalence of 1/1,000,000 in the USA and Europe, with higher figures in other countries (e.g. Japan, North Africa and Pakistan), particularly in communities with a high degree of consanguinity.
Trichothiodystrophy or TTD is a heterogeneous group disorders characterised by short, brittle hair with low-sulphur content (due to an abnormal synthesis of the sulphur containing keratins). Within the spectrum of the TTD syndromes are numerous syndromes affecting mainly organs derived from the neuroectoderm. The clinical appearance is always characterised by brittle and fragile hair, often combined with growth retardation and intellectual deficit, congenital ichthyosis and nail abnormalities, among other symptoms. The abnormalities are usually obvious at birth, with variable clinical expression. The variants of TTD, depending on their different associations, are: BIDS syndrome (or TTD type D or Amish Brittle Hair syndrome), IBIDS syndrome (or Tay syndrome or TTD typeE), PIBIDS syndrome (or TTD type F), Sabinas syndrome (TTD type B), SIBIDS syndrome, ONMRS (Itin syndrome) and Pollitt syndrome (TTD type C). The exact prevalence of TTD is unknown, but it appears to be rather uncommon.
Cockayne syndrome (CS)
Cockayne syndrome (CS) is a multisystem condition characterized by short stature, a characteristic facial appearance, premature aging, photosensitivity, progressive neurological dysfunction, and intellectual deficit. Disease severity and the age of onset are variable. In classical type I CS, the first symptoms usually appear during the first year of life. Early-onset cases with more severe symptoms (type II) and late-onset cases with milder symptoms (type III) have also been described. Common signs of the disease include progressive growth failure, intellectual deficit, cerebellar ataxia, spasticity, peripheral demyelinating neuropathy, pigmentary retinopathy, sensorineural hearing loss and dental anomalies (presence of caries). The typical facial appearance includes microcephaly, large ears, a thin nose, and enophthalmia. Cataracts and cutaneous photosensitivity are observed in some patients. Subcutaneous lipoatrophy is present and can lead to signs of premature aging of the skin. COFS syndrome (see this term) is the extreme prenatal form of the CS clinical spectrum characterized by congenital microphthalmia and arthrogryposis.
The annual incidence of CS is close to 1/200,000 in European countries.
Werner syndrome (WS)
Werner syndrome (WS) is a rare inherited syndrome characterized by premature aging with onset in the third decade of life and with cardinal clinical features including bilateral cataracts, short stature, graying and thinning of scalp hair, characteristic skin disorders and premature onset of additional age-related disorders. WS patients are normal at birth and during childhood, apart from the absence of a pubertal growth spurt. WS presents between the ages of 20 and 30 with major symptoms of early onset bilateral cataracts, thinning and graying of the hair, short stature and skin changes (ankle ulceration, hyperkeratosis, tight skin, age spots, ”bird-like” facies and subcutaneous atrophy). In most cases, additional age-related disorders are seen and include osteoporosis, diabetes mellitus, mesenchymal neoplasms and atherosclerosis. Voice changes are frequent and flat feet are sometimes present. Patients with WS have a high risk of developing cancer, in particular sarcomas of mesenchymal origin and melanomas that are not due to sun exposure. Death is usually due to malignancies or myocardial infarction caused by extensive atherosclerosis. The prevalence among Japanese and Sardinian populations is estimated to be 1/50,000 due to the presence of founder mutations. Prevalence in other populations is unknown, but may be around 1/200,000.
Bloom syndrome (BSyn)
Bloom syndrome (BSyn) is a rare chromosomal breakage syndrome characterized by a marked genetic instability associated with pre- and postnatal growth retardation, facial sun-sensitive telangiectatic erythema, increased susceptibility to infections, and predisposition to cancer.
Individuals with BSyn show proportionate growth retardation of prenatal onset and have a short stature (average adult height of 150 cm). Respiratory and gastrointestinal tract infections of variable severity (e.g. otitis, pneumonia) occur frequently throughout childhood and are associated with variable immunodeficiency. Gastroesophageal reflux with tracheal aspiration, common during infancy, may contribute to respiratory infections. Telangiectatic erythema appears during the first 1-2 years of life on the face (in particular the cheek) and dorsum of the hands. One major feature of Bsyn is a greatly increased predisposition to cancers in a distribution corresponding to the general population but occurring at a much younger age. The most common malignancies are leukemias and lymphoma during childhood and adolescence, and various types of adenocarcinomas during adulthood (e.g. colon, esophagus, breast). Rare tumors such as Wilms tumor and osteosarcoma may occur during childhood. Several individuals have had more than one primary tumor. Other usual features are poor feeding during infancy, and an exceptionally sparse subcutaneous adipose tissue giving a wasted appearance. Dolichocephaly, narrow face, prominent nose and ears, and malar and mandibular hypoplasia can be observed. Additional features include blistering and bleeding from the lips, patchy areas of hyper- and hypopigmentation, male infertility, and premature menopause. Decreased attention span and reduced memory function result in lack of interest in learning, but intellectual disability is not present. Ocular anomalies (e.g. conjunctivitis, bilateral optic nerve hypoplasia) have been reported.
Overall prevalence is unknown, but in the Ashkenazi Jewish population it is estimated at approximately 1/ 48,000 births.