Squamous Cell Carcinoma
Risk Factors for Squamous Cell Carcinoma
Other radiation exposure
Other environmental factors
Characteristics of the skin
Personal history of nonmelanoma skin cancer
Family history of squamous cell carcinoma or associated premalignant lesions
Syndromes and Genes Associated with a Predisposition for Squamous Cell Carcinoma
Multiple self-healing squamous epitheliomata (Ferguson-Smith syndrome)
Other albinism syndromes
Dystrophic epidermolysis bullosa
Junctional epidermolysis bullosa
Dyskeratosis congenita (Zinsser-Cole-Engman syndrome)
Prevention and treatment of skin cancers
Squamous cell carcinoma (SCC) is the second most common type of skin cancer and accounts for approximately 20% of cutaneous malignancies. Although most cancer registries do not include information on the incidence of nonmelanoma skin cancer, annual incidence estimates range from 1 million to 3.5 million cases in the United States.[1,2]
Mortality is rare from this cancer; however, the morbidity and costs associated with its treatment are considerable.Risk Factors for Squamous Cell Carcinoma
Sun exposure is the major known environmental factor associated with the development of skin cancer of all types; however, different patterns of sun exposure are associated with each major type of skin cancer. (Refer to the Sun exposure section in the Basal Cell Carcinoma section of this summary for more information.) This section focuses on sun exposure and increased risk of cutaneous SCC.
Unlike basal cell carcinoma (BCC), SCC is associated with chronic exposure, rather than intermittent intense exposure to ultraviolet (UV) radiation. Occupational exposure is the characteristic pattern of sun exposure linked with SCC. A case-control study in southern Europe showed increased risk of SCC when lifetime sun exposure exceeded 70,000 hours. People whose lifetime sun exposure equaled or exceeded 200,000 hours had an odds ratio (OR) 8 to 9 times that of the reference group. A Canadian case-control study did not find an association between cumulative lifetime sun exposure and SCC; however, sun exposure in the 10 years before diagnosis and occupational exposure were found to be risk factors.Other radiation exposure
In addition to environmental radiation, exposure to therapeutic radiation is another risk factor for SCC. Individuals with skin disorders treated with psoralen and ultraviolet-A radiation (PUVA) had a threefold to sixfold increase in SCC. This effect appears to be dose-dependent, as only 7% of individuals who underwent fewer than 200 treatments had SCC, compared with more than 50% of those who underwent more than 400 treatments. Therapeutic use of ultraviolet-B (UVB) radiation has also been shown to cause a mild increase in SCC (adjusted incidence rate ratio, 1.37). Devices such as tanning beds also emit UV radiation and have been associated with increased SCC risk, with a reported OR of 2.5 (95% confidence interval [CI], 1.7–3.8).
Investigation into the effect of ionizing radiation on SCC carcinogenesis has yielded conflicting results. One population-based case-control study found that patients who had undergone therapeutic radiation had an increased risk of SCC at the site of previous radiation (OR, 2.94) as compared with individuals who had not undergone radiation treatments. Cohort studies of radiology technicians, atomic-bomb survivors, and survivors of childhood cancers have not shown an increased risk of SCC, although the incidence of BCC was increased in all of these populations.[11-13] For those who develop SCC at previously radiated sites that are not sun-exposed, the latent period appears to be quite long; these cancers may be diagnosed years or even decades after the radiation exposure.
The effect of other types of radiation, such as cosmic radiation, is also controversial. Pilots and flight attendants have a reported incidence of SCC that ranges between 2.1 and 9.9 times what would be expected; however, the overall cancer incidence is not consistently elevated. Some attribute the high rate of nonmelanoma skin cancers in airline flight personnel to cosmic radiation, while others suspect lifestyle factors.[15-20]Other environmental factors
The influence of arsenic on the risk of nonmelanoma skin cancer is discussed in detail in the Other environmental factors section in the Basal Cell Carcinoma section of this summary. Like BCCs, SCCs appear to be associated with exposure to arsenic in drinking water and combustion products.[21,22] However, this association may hold true only for the highest levels of arsenic exposure. Individuals who had toenail concentrations of arsenic above the 97th percentile were found to have an approximately twofold increase in SCC risk. For arsenic, the latency period can be lengthy; invasive SCC has been found to develop at an average of 20 years after exposure.
Current or previous cigarette smoking has been associated with a 1.5-fold to 2-fold increase in SCC risk,[25-27] although one large study showed no change in risk. Available evidence suggests that the effect of smoking on cancer risk seems to be greater for SCC than for BCC.
Additional reports have suggested weak associations between SCC and exposure to insecticides, herbicides, or fungicides.Characteristics of the skin
Like melanoma and BCC, SCC occurs more frequently in individuals with lighter skin than in those with darker skin.[3,30] However, SCC can also occur in individuals with darker skin. An Asian registry based in Singapore reported an increase in skin cancer in that geographic area, with an incidence rate of 8.9 per 100,000 person-years. Incidence of SCC, however, was shown to be on the decline. SCC is the most common form of skin cancer in black individuals in the United States and in certain parts of Africa; the mortality rate for this disease is relatively high in these populations.[31,32] Epidemiologic characteristics of, and prevention strategies for, SCC in those individuals with darker skin remain areas of investigation.
Freckling of the skin and reaction of the skin to sun exposure have been identified as other risk factors for SCC. Individuals with heavy freckling on the forearm were found to have a 14-fold increase in SCC risk if freckling was present in adulthood, and an almost threefold risk if freckling was present in childhood.[33,34] The degree of SCC risk corresponded to the amount of freckling. In this study, the inability of the skin to tan and its propensity to burn were also significantly associated with risk of SCC (OR of 2.9 for severe burn and 3.5 for no tan).
The presence of scars on the skin can also increase the risk of SCC, although the process of carcinogenesis in this setting may take years or even decades. SCCs arising in chronic wounds are referred to as Marjolin’s ulcers. The mean time for development of carcinoma in these wounds is estimated at 26 years. One case report documents the occurrence of cancer in a wound that was incurred 59 years earlier.Immunosuppression
Immunosuppression also contributes to the formation of nonmelanoma skin cancers. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than that observed in the general population, although the risks vary with transplant type.[37-40] Nonmelanoma skin cancers in high-risk patients (solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age, are more common and more aggressive, and have a higher risk of recurrence and metastatic spread than these cancers do in the general population.[41,42] Additionally, there is a high risk of second SCCs.[43,44] In one study, over 65% of kidney transplant recipients developed subsequent SCCs after their first diagnosis. Among patients with an intact immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.
This increased risk has been linked to an interaction between the level of immunosuppression and UV radiation exposure. As the duration and dosage of immunosuppressive agents increase, so does the risk of cutaneous malignancy; this effect is reversed with decreasing the dosage of, or taking a break from, immunosuppressive agents. Heart transplant recipients, requiring the highest rates of immunosuppression, are at much higher risk of cutaneous malignancy than liver transplant recipients, in whom much lower levels of immunosuppression are needed to avoid rejection.[37,45,46] The risk appears to be highest in geographic areas with high UV exposure. When comparing Australian and Dutch organ transplant populations, the Australian patients carried a fourfold increased risk of developing SCC and a fivefold increased risk of developing BCC. This finding underlines the importance of rigorous sun avoidance, particularly among high-risk immunosuppressed individuals.
Certain immunosuppressive agents have been associated with increased risk of SCC. Kidney transplant patients who received cyclosporine in addition to azathioprine and prednisolone had a 2.8-fold increase in risk of SCC over those kidney transplant patients on azathioprine and prednisolone alone. In cardiac transplant patients, increased incidence of SCC was seen in individuals who had received OKT3 (muromonab-CD3), a murine monoclonal antibody against the CD3 receptor.Personal history of nonmelanoma skin cancer
A personal history of BCC or SCC is strongly associated with subsequent SCC. A study from Ireland showed that individuals with a history of BCC had a 14% higher incidence of subsequent SCC; for men with a history of BCC, the subsequent SCC risk was 27% higher. In the same report, individuals with melanoma were also 2.5 times more likely to report a subsequent SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these nonmelanoma skin cancers is the middle of the sixth decade of life.[26,50-54]Family history of squamous cell carcinoma or associated premalignant lesions
Although the literature is scant on this subject, a family history of SCC may increase the risk of SCC in first-degree relatives (FDRs). Review of the Swedish Family Center Database showed that individuals with at least one sibling or parent affected with SCC, in situ SCC (Bowen disease), or actinic keratosis had a twofold to threefold increased risk of invasive and in situ SCC relative to the general population.[55,56] Increased number of tumors in parents was associated with increased risk to the offspring. Of note, diagnosis of the proband at an earlier age was not consistently associated with a trend of increased incidence of SCC in the FDR, as would be expected in most hereditary syndromes because of germline mutations. Further analysis of the Swedish population-based data estimates genetic risk effects of 8% and familial shared-environmental effects of 18%. Thus, shared environmental and behavioral factors likely account for some of the observed familial clustering of SCC.Syndromes and Genes Associated with a Predisposition for Squamous Cell Carcinoma
Major genes have been defined elsewhere in this summary as genes that are necessary and sufficient for disease, with important mutations of the gene as causal. The disorders resulting from single-gene mutations within families lead to a very high risk of disease and are relatively rare. The influence of the environment on the development of disease in individuals with these single-gene disorders is often very difficult to determine because of the rarity of the genetic mutation.
Identification of a strong environmental risk factor—chronic exposure to UV radiation—makes it difficult to apply genetic causation for SCC of the skin. Although the risk of UV exposure is well known, quantifying its attributable risk to cancer development has proven challenging. In addition, ascertainment of cases of SCC of the skin is not always straightforward. Many registries and other epidemiologic studies do not fully assess the incidence of SCC of the skin owing to: (1) the common practice of treating lesions suspicious for SCC without a diagnostic biopsy, and (2) the relatively low potential for metastasis. Moreover, nonmelanoma skin cancer is routinely excluded from the major cancer registries such as the Surveillance, Epidemiology, and End Results registry.
With these considerations in mind, the discussion below will address genes associated with disorders that have an increased incidence of skin cancer.
Characteristics of the major hereditary syndromes associated with a predisposition to SCC are described in Table 3 below.Table 3. Hereditary Syndromes Associated with Squamous Cell Carcinoma of the Skin
|Condition||Gene(s)||Clinical Testing Availabilitya||Pathway|
|aFor more information on genetic testing laboratories, refer to the NIH Genetic Testing Registry.|
|Xeroderma pigmentosum (complementation group A [OMIM], group B [OMIM], group C [OMIM], group D [OMIM], group E [OMIM], group F [OMIM], and group G [OMIM])||XPA (OMIM), XPB/ERCC3 (OMIM), XPC (OMIM), XPD/ERCC2 (OMIM), XPE/DDB2 (OMIM), XPF/ERCC4 (OMIM), XPG/ERCC5 (OMIM)||XPA, XPC||Nucleotide excision repair|
|Xeroderma pigmentosum variant (OMIM)||POLH/XPV (OMIM)||No||Error-prone polymerase|
|Multiple self-healing squamous epithelioma (Ferguson-Smith syndrome) (OMIM)||TGFBR1 (OMIM)||No||Growth factor signaling|
|Oculocutaneous albinism (type IA [OMIM], type IB [OMIM],type II [OMIM], type III [OMIM], and type IV [OMIM])||TYR (OMIM), OCA2 (OMIM), SLC45A2/MATP/OCA4 (OMIM), TYRP1 (OMIM)||TYR, OCA2, TYRP1||Melanin synthesis|
|Hermansky-Pudlak syndrome (OMIM)||HPS1 (OMIM), HPS3 (OMIM), HPS4 (OMIM), HPS5 (OMIM), HPS6 (OMIM), HPS7/DTNBP1 (OMIM), HPS8/BLOC1S3 (OMIM)||HPS1, HPS3, HPS4, HPS7||Melanosomal and lysosomal storage|
|Hermansky-Pudlak syndrome, Type 2 (OMIM)||AP3B1 (OMIM)||No||Melanosomal and lysosomal storage|
|Chediak-Higashi syndrome (OMIM)||LYST (OMIM)||LYST||Lysosomal transport regulation|
|Griscelli syndrome (type 1 [OMIM], type 2 [OMIM], and type 3 [OMIM])||MYO5A (OMIM), RAB27A (OMIM), MLPH (OMIM)||RAB27A||Pigment granule transport|
|Elejalde disease (OMIM)||MYO5A (OMIM)||No||Pigment granule transport|
|Dystrophic epidermolysis bullosa (dominant [OMIM] and autosomal recessive [OMIM] subtypes)||COL7A1 (OMIM)||COL7A1||Collagen anchor of basement membrane to dermis|
|Junctional epidermolysis bullosa (OMIM)||LAMA3 (OMIM), LAMB3 (OMIM), LAMC2 (OMIM), COL17A1 (OMIM)||LAMA3, LAMB3, LAMC2, COL17A1||Connective tissue|
|Epidermodysplasia verruciformis (OMIM)||EVER1 (OMIM), EVER2 (OMIM)||No||Signal transduction in endoplasmic reticulum|
|Fanconi anemia (OMIM)||FANCA ( OMIM), FANCB (OMIM), FANCC (OMIM), FANCD1/BRCA2 (OMIM), FANCD2 (OMIM), FANCE (OMIM), FANCF (OMIM), FANCG/XRCC9 (OMIM), FANCI (OMIM), FANCJ/BRIP1 (OMIM), FANCL (OMIM), FANCM (OMIM), FANCN/PALB2 (OMIM)||Chromosomal breakage testing; BRIP1, FANCA, FANCC, FANCE, FANCF, FANCG, PALB2||DNA repair|
|Dyskeratosis congenita (OMIM)||DKC1 (OMIM), TERC (OMIM), TINF2 (OMIM), NHP2/NOLA2 (OMIM), NOP10/NOLA3 (OMIM), TERT (OMIM), WRAP53 (OMIM), C16orf57 (OMIM), RTEL1 (OMIM)||DKC1, TERC, TINF2, NHP2, NOP10, TERT||Telomere maintenance and trafficking|
|Rothmund-Thomson syndrome (OMIM)||RECQL4 (OMIM), C16orf57 (OMIM)||RECQL4||Chromosomal stability|
|Bloom syndrome (OMIM)||BLM/RECQL3 (OMIM)||Sister chromatid exchange, BLM||Chromosomal stability|
|Werner syndrome (OMIM)||WRN/RECQL2 (OMIM)||No||Chromosomal stability|
Xeroderma pigmentosum (XP) is a hereditary disorder of nucleotide excision repair that results in cutaneous malignancies in the first decade of life. Affected individuals have an increased sensitivity to sunlight, resulting in a markedly increased risk of SCCs, BCCs, and melanomas. One report found that nonmelanoma skin cancer was increased 150-fold in individuals with XP; for those younger than 20 years, the prevalence was almost 5,000 times what would be expected in the general population.
The natural history of this disease begins in the first year of life, when sun sensitivity becomes apparent, and xerosis and pigmentary changes may occur in the skin. About half of XP patients have a history of severe burning on minimal sun exposure. Other XP patients do not have this reaction but develop freckle-like pigmentation before age 2 years on sun-exposed sites. These manifestations progress to skin atrophy and formation of telangiectasias. Approximately one-half of people with this disorder will develop nonmelanoma skin cancers, and approximately one-quarter of these individuals will develop melanoma. In the absence of sun avoidance, the median age of diagnosis for any skin cancer is 8 to 9 years.[58-60] On average, nonmelanoma skin cancer occurs at a younger age than melanoma in the XP population.
Noncutaneous manifestations of XP include ophthalmologic and neurologic abnormalities. Disorders of the cornea and eyelids associated with this disorder are also linked to exposure to UV radiation and include keratitis, corneal opacification, ectropion or entropion, hyperpigmentation of the eyelids, and loss of eyelashes. About 25% of the XP patients examined at the National Institutes of Health (NIH) between 1971 and 2009 had progressive neurological degeneration. Features included microcephaly, progressive sensorineural hearing loss, diminished deep tendon reflexes, seizures, and cognitive impairment. Neurological degeneration, which is most commonly observed in individuals with complementation groups XPA and XPC, was associated with a shorter lifespan (median age of death was 29 years in individuals with neurological degeneration and 37 years in individuals without neurological degeneration). De Sanctis-Cacchione syndrome is found in a subgroup of XP patients, who exhibit severe neurologic manifestations, dwarfism, and delayed sexual development. A variety of noncutaneous neoplasms, most notably SCC of the tip of the tongue, central nervous system cancers, and lung cancer in smokers, have been reported in people who have XP.[58,61] The relative risk for these cancers is estimated to be about 50-fold higher than in the general population.
The inheritance for XP is autosomal recessive. Seven complementation groups have been associated with this disorder. About 40% of the XP cases seen at the NIH were XPC. ERCC2 (XPD) mutations were present in about 20%. Complementation group A, due to mutation in XPA, accounts for approximately 10% of cases. Other mutated genes in this disorder include ERCC3 (XPB), ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), and ERCC5 (XPG). An XPH group had been described but is now considered to be a subgroup of the XPD group. Heterozygotes for mutations in XP genes are generally asymptomatic. Founder mutations in XPA (R228A) and XPC (V548A fs X572) have been identified in North African populations, and a founder mutation in XPC resulting in a splice alteration (IVS 12-1G>C) has been found in an East African (Mahori) population. It has been proposed that direct screening for these mutations would be appropriate in these populations.[64-67]
The function of the XP genes is to recognize and repair photoproducts from UV radiation. The main photoproducts are formed at adjacent pyrimidines and consist of cyclobutane dimers and pyrimidine-pyrimidone (6-4) photoproducts. The product of XPC is involved in the initial identification of DNA damage; it binds to the lesion to act as a marker for further repair. The DDB2 (XPE) protein is also part of this process and works with XPC. The XPA gene product maintains single-strand regions during repair and works with the TFIIH transcription factor complex. The TFIIH complex includes the gene products of both ERCC3 (XPB) and ERCC2 (XPD), which function as DNA helicases in the unwinding of the DNA. The ERCC4 (XPF) and ERCC5 (XPG) proteins act as DNA endonucleases to create single-strand nicks in the 5’ and 3’ sides of the damaged DNA with resulting excision of about 28 to 30 nucleotides, including the photoproduct. DNA polymerases replace the lesion with the correct sequence, and a DNA ligase completes the repair.[68,69]
An XP variant that is associated with mutations in POLH (XPV) is responsible for approximately 10% of reported cases. This gene encodes for the error-prone bypass polymerase (polymerase eta) which, unlike other genes associated with XP, is not involved in nucleotide excision repair. People with polymerase eta mutations have the same cutaneous and ocular findings as other XP patients but do not have progressive neurologic degeneration.
Work on genotype-phenotype correlations among the XP complementation groups continues. The main distinguishing features appear to be the presence or absence of burning on minimal sun exposure, skin cancer, and progressive neurologic abnormalities. All complementation groups are characterized by the presence of cutaneous neoplasia. There is clinical variation within each complementation group. Mild to severe neurologic impairment has been described in individuals with XPA mutations. Individuals with XPA mutations in the DNA binding region (amino acids 98–219) may have a more severe presentation that includes neurological findings. A very small number of people in the XPB, XPD, and XPG complementation groups have been identified as having xeroderma pigmentosum-Cockayne syndrome (XP-CS) complex. These individuals have characteristics of both disorders, including an increased predisposition to cutaneous neoplasms and developmental delay, visual and hearing impairment, and central and peripheral nervous system dysfunction. It should be noted that people with Cockayne syndrome without XP do not appear to have an increased cancer risk. Similarly, trichothiodystrophy (TTD) is another genetic disorder that can occur in combination with XP. Individuals affected solely with TTD do not appear to have an increased cancer incidence, but some affected with XP/TTD have an increased risk of cutaneous neoplasia. The complementation groups connected with XP/TTD (XPD and XPB) and XP-CS (XPB, XPD, and XPG) are associated with defects in both transcription-coupled nucleotide excision repair and global genomic nucleotide excision repair. In contrast, XP complementation groups C and E have defects only in global genomic nucleotide excision repair. In addition, individuals in the XPA, XPD and XPG groups may exhibit severe neurologic abnormalities without symptoms of Cockayne syndrome or TTD. Cerebro-oculo-facio-skeletal syndrome, which has been described with some ERCC2 (XPD) or XP-CS mutations, does not appear to confer an increased risk of skin cancer.[75-78]
The diagnosis of XP is made on the basis of clinical findings and family history. Functional assays to assess DNA repair capabilities after exposure to radiation have been developed, but these tests are currently not clinically available in the United States. Sequence analysis testing may be done to confirm mutations in XPA and XPC previously identified in an affected family; however, molecular testing for mutations associated with other complementation groups is currently done only in research laboratories.Multiple self-healing squamous epitheliomata (Ferguson-Smith syndrome)
Multiple self-healing squamous epitheliomata (MSSE), or Ferguson-Smith syndrome, first described in 1934, is characterized by invasive skin tumors that are histologically identical to sporadic cutaneous SCC, but they resolve spontaneously without intervention. Linkage analysis of affected families showed association with the long arm of chromosome 9, and haplotype analysis localized the gene to 9q22.3 between D9S197 and D9S1809. Transforming growth factor beta-receptor 1 (TGFBR1) was identified through next-generation sequencing as the gene responsible for MSSE. Loss-of-function mutations in TGFBR1 have been identified in 18 of 22 affected families. Gain-of-function mutations in TGFBR1 are associated with unrelated Marfan-like syndromes, such as Loeys-Dietz syndrome, which have no described increase in skin cancer risk.
Somatic loss of heterozygosity in Ferguson-Smith–related SCC has been demonstrated at this genomic location, suggesting that TGFBR1 can act as a tumor suppressor gene. The long arm of chromosome 9 has also been a site of interest in sporadic SCC. Up to 65% of sporadic SCCs have been found to have loss of heterozygosity at 9q22.3 between D9S162 and D9S165.Oculocutaneous albinism
SCC occurring at extremely early ages is a hallmark of oculocutaneous albinism. Albinism is a major risk factor for skin cancer in individuals of African ancestry.[32,82] One report describing a cohort of 350 albinos in Tanzania found 104 cutaneous cancers; of these, 100 were SCCs, three were BCCs, and one was melanoma. The median age for this population was 10 years. Similar proportions of skin cancer diagnoses were observed in a Nigerian population, with 62% of dermatological malignancies diagnosed as SCC, 16% as malignant melanoma, and 8% as BCC.
Two types of oculocutaneous albinism are known to be associated with increased risk of SCC of the skin. Oculocutaneous albinism type 1, or tyrosinase-related albinism, is caused by mutations in the tyrosinase gene, TYR, located on the long arm of chromosome 11. This type of albinism accounts for about one-half of cases in individuals of Caucasian ancestry. The OCA2 gene, also known as the P gene, is mutated in oculocutaneous albinism type 2, or tyrosinase-positive albinism. Both disorders are autosomal recessive, with frequent compound heterozygosity.
Tyrosinase acts as the critical enzyme in the synthesis of melanin in melanocytes. Mutation in this gene in oculocutaneous albinism type 1 produces proteins with minimal to no activity, corresponding to the OCA1B and OCA1A phenotypes, respectively. Individuals with OCA1B have light skin, hair, and eye coloring at birth but develop some pigment during their lifetimes, while the coloring of those with OCA1A does not darken with age.
The gene product of OCA2 is a protein found in the membrane of melanosomes. Its function is unknown, but it may play a role in maintaining the structure or pH of this environment. Murine models with mutations in this gene had significantly decreased melanin production compared with normal controls.
Mutations in the genes SLC45A2 (MATP/OCA4) and TYRP1 (tyrosinase-related protein 1) are associated with less common types of oculocutaneous albinism. A study of 61 albinism patients found 22 novel mutations, including 14 in TYR, 5 in OCA2, 2 in SLC45A2, and 1 in TYRP1. SLC45A2 is found in 24% of oculocutaneous albinism cases in Japan, making it the most common type of albinism among Japanese individuals with identifiable mutations. A study of 22 individuals of Italian ancestry without mutations in TYR, OCA2, or TYRP1 found 5 individuals with biallelic mutations in SLC45A2, 4 of whom met clinical criteria for a diagnosis of oculocutaneous albinism. The increased risk of SCC of the skin in people with these mutations has not been quantified. It is generally assumed to be similar to other types of albinism.Other albinism syndromes
A subgroup of albinism includes people who exhibit a triad of albinism, prolonged bleeding time, and deposition of a ceroid substance in organs such as the lungs and gastrointestinal tract. This syndrome, known as Hermansky-Pudlak syndrome, is inherited in an autosomal recessive manner but may have a pseudodominant inheritance in Puerto Rican families, owing to the high prevalence in this population. The underlying cause is believed to be a defect in melanosome and lysosome transport. A number of mutations at disparate loci have been associated with this syndrome, including HPS1, HPS3, HPS4, HPS5, HPS6, HPS7 (DTNBP1), HPS8 (BLOC1S3), and HPS9 (PLDN).[91-98] Pigmentation characteristics can vary significantly in this disorder, particularly among those with HPS1 mutations, and patients report darkening of the skin and hair as they age. In a small cohort of individuals with HPS1 mutations, 3 out of 40 developed cutaneous SCCs, and an additional 3 had BCCs. Hermansky-Pudlak syndrome type 2, which includes increased susceptibility to infection resulting from congenital neutropenia, has been attributed to defects in AP3B1.
Two additional syndromes are associated with decreased pigmentation of the skin and eyes. The autosomal recessive Chediak-Higashi syndrome is characterized by eosinophilic, peroxidase-positive inclusion bodies in early leukocyte precursors, hemophagocytosis, increased susceptibility to infection, and increased incidence of an accelerated phase lymphohistiocytosis. Mutations in the LYST gene underlie this syndrome, which is often fatal in the first decade of life.[101-103]
Griscelli syndrome, also inherited in an autosomal recessive manner, was originally described as decreased cutaneous pigmentation with hypomelanosis and neurologic deficits, but its clinical presentation is quite variable. This combination of symptoms is now designated Griscelli syndrome type 1 or Elejalde disease. It has been attributed to mutations in the MYO5A gene, which affects melanosome transport. Individuals with Griscelli syndrome type 2 have decreased cutaneous pigmentation and immunodeficiency but lack neurological deficits. They also may have hemophagocytosis or lymphohistiocytosis that is often fatal, like that seen in Chediak-Higashi syndrome. Griscelli syndrome type 2 is caused by mutations in RAB27A, which is part of the same melanosome transport pathway as MYO5A. Griscelli syndrome type 3 presents with hypomelanosis and does not include neurologic or immunologic disorders. Mutations in the melanophilin (MLPH) gene and MYO5A have been associated with this variant.Dystrophic epidermolysis bullosa
Approximately 95% of individuals with the heritable disorder dystrophic epidermolysis bullosa (DEB) have a detectable germline mutation in the gene COL7A1. This gene, which is located at 3p21.3, is expressed in the basal keratinocytes of the epidermis and encodes for type VII collagen. This collagen forms a part of the fibrils that anchor the basement membrane to the dermis, thereby providing structural stability and resistance to mild skin trauma. The lack of type VII collagen results in generalized blistering, often starting from birth, and is associated with skin atrophy and scarring. A registry of DEB mutations, The International DEB Patient Registry, is accessible on the Internet.
There are two recessively inherited subtypes of DEB: severe-generalized (HDEB-sev gen; previously named Hallopeau-Siemens type) and generalized-other (HDEB-O; previously named non–Hallopeau-Siemens type); and a dominantly inherited form, dominant dystrophic epidermolysis bullosa (DDEB). The clinical manifestations demonstrate a continuum of severity that complicates definitive diagnosis, especially early in life. The severe generalized subtype, associated with formation of pseudosyndactyly (a mitten-like deformity secondary to fusion of interdigital webbing) in early childhood, carries a SCC risk of up to 85% by age 45 years.[109,110] These cancers arise in nonhealing wounds and usually metastasize to cause death within 5 years of the diagnosis of SCC. In one case series, SCC was the leading cause of death for the 15 patients with the severe generalized subtype. Early mortality also has been observed in this disorder, with a mortality rate of up to 40% by age 30 years. Extracutaneous manifestations of HDEB-severe generalized include short stature, anemia, strictures of the gastrointestinal and genitourinary tracts, and corneal scarring that may result in blindness.
Diagnosis of epidermolysis bullosa may be accomplished by immunofluorescence or electron microscopy. A list of recommended diagnostic antibodies and their suppliers is available on the Dystrophic EB Research Association Web site. Mutation testing is generally used for prenatal diagnosis rather than for the primary diagnosis of epidermolysis bullosa.[114,115]
The rate of de novo mutation for DDEB is approximately 30%; maternal germline mosaicism has also been reported.[116,117] Glycine substitutions in exons 73 to 75 are the most common mutations in DDEB. G2034R and G2043R account for half of these mutations. Less frequently, splice junction mutations and substitutions of glycine and other amino acids may cause the dominant form of dystrophic epidermolysis bullosa. In contrast, more than 400 mutations have been described for the two types of recessive epidermolysis bullosa. The recessive form of the disease is caused primarily by null mutations, although amino acid substitutions, splice junction mutations, and missense mutations have also been reported. In-frame exon skipping may generate a partially functional protein in recessive disease. A founder mutation, c.6527insC (p.R525X), has been observed in 27 of 49 Spanish individuals with recessive DEB. Genotype-phenotype correlations suggest an inverse correlation between the amount of functional protein and severity.
Mutations in COL7A1 result in abnormal triple helical coiling and decreased function, which causes increased skin fragility and blistering. In studies of Ras-driven carcinogenesis in HDEB-severe generalized keratinocytes, retention of the amino-terminal NC1, the first noncollagenous fragment of type VII collagen, is tumorigenic in mice. This retained sequence may mediate tumor-stroma interactions that promote carcinogenesis.Junctional epidermolysis bullosa
Junctional epidermolysis bullosa (JEB) is an autosomal recessive type of epidermolysis bullosa. JEB results in considerable mortality with approximately 50% of cases dying within the first year of life. Mutations in any of the genes encoding the three basic subunits of laminin 332, previously known as laminin 5 (LAMA3, LAMB3, LAMC2), or mutations in COL17A1 can result in this syndrome.[121-123] Individuals with the Herlitz type (a severe clinical form) of JEB are at increased risk of SCC, with a cumulative risk of 18% by age 25 years. A mutational study of COL17A1 in individuals with a milder subtype of JEB, called JEB-other, identified mutations in 85 of 86 alleles from 43 individuals. Total loss of COL17A1 protein staining correlated with a more severe phenotype.Epidermodysplasia verruciformis
Mutations in either of two adjacent genes on chromosome 17q25 can cause epidermodysplasia verruciformis, a rare heritable disorder associated with increased susceptibility to human papillomavirus (HPV). Infection with certain HPV subtypes can lead to development of generalized nonresolving verrucous lesions, which develop into in situ and invasive SCCs in 30% to 60% of patients. Malignant transformation is thought to occur in about half of these lesions. Approximately 90% of these lesions are attributed to HPV types 5 and 8, although types 14, 17, 20, and 47 have occasionally been implicated. The association between HPV infection and increased risk of SCC has also been demonstrated in people without epidermodysplasia verruciformis; one case-control study found that HPV antibodies were found more frequently in the plasma of individuals with SCC (OR, 1.6; 95% CI, 1.2–2.3) than in plasma from cancer-free individuals.
The genes associated with this disorder, EVER1 and EVER2, were identified in 2002. The inheritance pattern of these genes appears to be autosomal recessive; however, autosomal dominant inheritance has also been reported.[130-132] Both of these gene products are transmembrane proteins localized to the endoplasmic reticulum, and they likely function in signal transduction. This effect may be through regulation of zinc balance; it has been shown that these proteins form a complex with the zinc transporter 1 (ZnT-1), which is, in turn, blocked by certain HPV proteins.
A recent case-control study examined the effect of a specific EVER2 polymorphism (rs7208422) on the risk of cutaneous SCC in 239 individuals with prior SCC and 432 controls. This polymorphism is a (A > T) coding single nucleotide polymorphism in exon 8, codon 306 of the EVER2 gene. The frequency of the T allele among controls was 0.45. Homozygosity for the polymorphism caused a modest increase in SCC risk, with an adjusted OR of 1.7 (95% CI, 1.1–2.7) relative to wild-type homozygotes. In this study, those with one or more of the T alleles were also found to have increased seropositivity for any HPV and for HPV types 5 and 8, as compared with the wild type.
Some evidence suggests nonallelic heterogeneity in epidermodysplasia verruciformis. An individual born to consanguineous parents with epidermodysplasia verruciformis and additional bacterial and fungal infections was found to have homozygous R115X mutations in the MST1 gene. Another susceptibility locus associated with this disorder has been identified at chromosome regions 2p21-p24 through linkage analysis of an affected consanguineous family. Unlike those with mutations in the EVER1 and EVER2 genes, affected individuals linked to this genomic region were infected with HPV 20 rather than the usual HPV subtypes associated with this disorder, and this family did not have a history of cutaneous SCC.Fanconi anemia
Fanconi anemia is a complex disorder that is characterized by increased incidence of hematologic and solid tumors, including SCC of the skin. Fanconi anemia is inherited as an autosomal recessive disease. It is a relatively rare syndrome with an estimated carrier frequency of one in 181 individuals in the United States (range: 1 in 156 to 1 in 209) and a carrier frequency of up to one in 100 individuals of Ashkenazi Jewish ancestry. Leukemia is the most commonly reported cancer in this population, but increased rates of gastrointestinal, head and neck, and gynecologic cancers have also been seen. By age 40 years, individuals affected with Fanconi anemia have an 8% risk per year of developing a solid tumor; the median age of diagnosis for solid tumors is 26 years. Multiple cases of cancers of the brain, breast, lung, and kidney (Wilms tumor) have been reported in this population. Data on the incidence of nonmelanoma skin cancers in this population are sparse; however, review of the literature suggests that the age of diagnosis is between the mid-20s and early 30s and that women seem to be affected more often than men.[139-143]
Individuals with this disease have increased susceptibility to DNA cross-linking agents (e.g., mitomycin-C or diepoxybutane) and ionizing and UV radiation. Cells from individuals with Fanconi anemia have shown decreased ability to excise pyrimidine dimers. The diagnosis of this disease is made by observing increased chromosomal breakage, rearrangements, or exchanges in cells after exposure to carcinogens such as diepoxybutane.
Thirteen complementation groups have been identified for Fanconi anemia; details regarding the genes associated with these groups are listed in Table 4 below.Table 4. Genes Associated with Fanconi Anemia (FA)
|Gene||Locus||Approximate Incidence Among FA Patients (%)||Pattern of Disease Transmission|
|AR = autosomal recessive; XLR = X-linked recessive.|
|FANCD1 (BRCA2) (OMIM)||13q12.3||Rare||AR|
|FANCG (XRCC9) (OMIM)||9p13||~10||AR|
|FANCI (KIAA1794) (OMIM)||15q25-26||Rare||AR|
|FANCJ (BACH1/BRIP1) (OMIM)||17q22.3||Rare||AR|
|FANCL (PHF9/POG) (OMIM)||2p16.1||Rare||AR|
|FANCM (Hef) (OMIM)||14q21.3||Rare||AR|
|FANCN (PALB2) (OMIM)||16p12.1||Rare||AR|
The proteins involved with DNA crosslink repairs have been termed the FANC pathway because of their involvement with Fanconi anemia. They interact with several other proteins associated with hereditary cancer risk, including those for Bloom syndrome and ataxia-telangiectasia. Further investigation has revealed that FANCD1 is the same gene as BRCA2, a gene that causes predisposition to breast and ovarian cancer. Other Fanconi anemia genes, FANCJ (BRIP1) and FANCN (PALB2), have also been identified as rare breast cancer susceptibility genes. (Refer to the PDQ summary on Genetics of Breast and Ovarian Cancer for more information about BRCA2, BRIP1, PALB2, and RAD51.) Individuals who are heterozygous carriers of other Fanconi anemia–associated mutations do not appear to have an increased risk of cancer, with the possible exception of a twofold increase in breast cancer incidence in FANCC mutation carriers.Dyskeratosis congenita (Zinsser-Cole-Engman syndrome)
Dyskeratosis congenita, like Werner syndrome, results in premature aging and is considered a progeroid disease. The classic clinical triad for diagnosis includes dysplastic nails, reticular pigmentation of the chest and neck, and oral leukoplakia. In addition, individuals with this disorder are at markedly increased risk of myelodysplastic syndrome, acute leukemia, and bone marrow failure. Ocular, dental, neurologic, gastrointestinal, pulmonary, and skeletal abnormalities have also been described in conjunction with this disease, but clinical expressivity is variable. Developmental delay may also be present in variants of dyskeratosis congenita, such as Hoyeraal-Hreidarsson syndrome (HHS) and Revesz syndrome.
Approximately 10% of individuals with dyskeratosis congenita will develop nonhematologic tumors, often before the third decade of life.[151,152] Solid tumors may be the first manifestation of this disorder. Head and neck cancers were the most commonly reported, accounting for nearly half of the cancers observed. Cutaneous SCC occurred in about 1.5% of the subjects, and the median age at diagnosis was 21 years. These cancers are generally managed as any other SCC of the skin.
Several genes associated with telomere function (DKC1, TERC, TINF2, NHP2, NOP10, RTEL1 and TERT) have been implicated in dyskeratosis congenita; approximately one-half of the individuals with a clinical diagnosis of this disease have an identified mutation in one of these seven genes.[153-160] TERC and TINF2 are inherited in an autosomal dominant manner, whereas NHP2 (NOLA2) and NOP10 (NOLA3) show autosomal recessive inheritance, and RTEL1 and TERT can be either autosomal dominant or autosomal recessive. Recessive mutations in RTEL1 can also be associated with HHS. DKC1 shows an X-linked recessive pattern. Alterations in these genes result in shortening of telomeres, which in turn leads to defects in proliferation and spontaneous chromosomal rearrangements. Levels of TERC, the RNA component of the telomerase complex, are reduced in all dyskeratosis congenita patients. Missense mutations in WRAP53, a gene with a protein product that facilitates trafficking of telomerase, have also been associated with an autosomal recessive form of dyskeratosis congenita. Mutations in C16orf57 were identified in 6 of 132 families who did not have a mutation detected in other known genes. C16orf57 mutations are also associated with poikiloderma with neutropenia. (Refer to the Rothmund-Thomson syndrome section of this summary for more information about poikiloderma congenitale.)
The recommended approach for diagnosis begins with a six-cell panel assay for leukocyte telomere length testing. If telomere length is in the lowest 1% for three or more cell types, molecular genetic testing is indicated. Testing of DKC1 may be performed first in male probands, as mutations in this gene account for up to 36% of those identified in dyskeratosis congenita to date. Mutations in TINF2 and TERT are responsible for 11% to 24% and 6% to 10% of cases, respectively.[150,157,158,168,169] Clinical testing is available for six of the seven genes.Rothmund-Thomson syndrome
Rothmund-Thomson syndrome, also known as poikiloderma congenitale, is a heritable disorder characterized by chromosomal instability. The cutaneous presentation of this condition is an erythematous, blistering rash appearing on the face, buttocks, and extremities in early infancy. Other characteristics of this syndrome include telangiectasias, skeletal abnormalities, short stature, cataracts, and increased risk of osteosarcoma. Areas of hyperpigmentation and hypopigmentation of the skin develop later in life, and nonmelanoma skin cancers can develop at an early age. Reports of multiple SCCs in situ have been reported in individuals as young as 16 years. The precise increased risk of skin cancer is not well characterized, but the point prevalence of nonmelanoma skin cancer, including both BCC and SCC, is 2% to 5% in young individuals affected by this syndrome. This prevalence is clearly greater than that found in individuals in the same age group in the general population. Although increased UV sensitivity has been described, SCCs are also found in areas of the skin that are not exposed to the sun.
A detectable mutation in the gene RECQL4 is present in 66% of clinically affected individuals. This gene is located at 8q24.3, and inheritance is believed to be autosomal recessive. RECQL4 encodes the ATP-dependent DNA helicase Q4, which promotes DNA unwinding to allow for cellular processes such as replication, transcription, and repair. A role for this protein in repair of DNA double-strand breaks has also been suggested. Mutations in similar DNA helicases lead to the inherited disorders of Bloom syndrome and Werner syndrome.
At least 19 different truncating mutations in this gene have been identified as deleterious. These mutations cause severe down-regulation of RECQL4 transcripts in this subset of individuals with Rothmund-Thomson syndrome. Cells deficient in RECQL4 have been found to be hypersensitive to oxidative stress, resulting in decreased DNA synthesis. Deficiencies in the RecQ helicases permit hyper-recombination, thereby leading to loss of heterozygosity. Loss of heterozygosity associated with deficiencies of this protein suggests that the helicases are caretaker-type tumor suppressor proteins.
Three of six families with Rothmund-Thomson syndrome were found to have homozygous mutations in the C16orf57 gene. Mutations in this gene have also been identified in individuals with dyskeratosis congenita and poikiloderma with neutropenia, suggesting that these syndromes are related;[165,166] however, skin cancer risk in these conditions is not well characterized. (Refer to the Dyskeratosis congenita (Zinsser-Cole-Engman syndrome) section of this summary for more information.)Bloom syndrome
Loss of genomic stability is also the major cause of Bloom syndrome. This disorder shows increased chromosomal breakage and is diagnosed by increased sister chromatid exchanges on chromosomal analysis. Clinical manifestations of Bloom syndrome include severe growth retardation, recurrent infections, diabetes, chronic pulmonary disease, and an increased susceptibility to cancers of many types. The typical skin lesion seen in this disorder is a photosensitive erythematous telangiectatic rash that occurs in the first or second year of life. Although it is most commonly found on the face, it can also be present on the dorsa of hands or forearms. SCC of the skin is the third most common malignancy associated with this disorder. Skin cancer accounts for approximately 14% of tumors in the Bloom Syndrome Registry. Skin cancers occur at an earlier age in this population, with a mean age of 31.8 years at the time of diagnosis.
The BLM gene, located on the short arm of chromosome 15, is the only gene known to be mutated in Bloom syndrome. This gene encodes a 1,417-amino acid protein that is regulated by the cell cycle and demonstrates DNA-dependent ATPase and DNA duplex-unwinding activities. Its helicase domain shows considerable similarity to the RecQ subfamily of DNA helicases. Absence of this gene product is thought to destabilize other enzymes that participate in DNA replication and repair.[181,182]
This rare chromosomal breakage syndrome is inherited in an autosomal recessive manner and is characterized by loss of genomic stability. Sixty-four deleterious mutations described in the BLM gene include nucleotide insertions and deletions (41%), nonsense mutations (30%), mutations resulting in mis-splicing (14%), and missense mutations (16%).[183,184] A specific mutation identified in the Ashkenazi Jewish population is a 6-bp deletion/7-bp insertion at nucleotide 2,281, designated as BLMASH. Many of these mutations result in truncation of the C-terminus, which prevents normal localization of this protein to the nucleus. Absence of functional BLM protein can cause increased rates of mutation and recombination. This somatic hypermutability can thereby lead to an increased risk of cancer at an early age in virtually every organ, including the skin.
Cells from people with Bloom syndrome have been found to have abnormal responses to UV radiation. Normal nuclear accumulation of TP53 after UV radiation was absent in 2 of 11 primary cultures from individuals with Bloom syndrome; in contrast, responses in cultures from people who have XP and ataxia-telangiectasia were normal. The gene product of the BLM gene has also been found to complex with Fanconi proteins, raising the possibility of connections between the BLM and Fanconi anemia pathways for DNA stability.Werner syndrome
Like Bloom syndrome, Werner syndrome is characterized by spontaneous chromosomal instability, resulting in increased susceptibility to cancer and premature aging. Diagnostic criteria, often in the setting of consanguinity, include cataracts, short stature, premature graying or thinning of hair, and a positive 24-hour urinary hyaluronic acid test. Cardinal cutaneous manifestations of this disorder consist of sclerodermatous skin changes, ulcerations, atrophy, and pigmentation changes. Individuals with this syndrome have an average life expectancy of fewer than 50 years. Cancers have an early onset and occur in up to 43% of these patients. The spectrum of tumors associated with this disorder has primarily been described in the Japanese population and includes an increased incidence of sarcoma, thyroid cancers, and skin cancers. Approximately 20% of the cancers reported in this syndrome are cutaneous, with melanoma and SCC of the skin accounting for 14% and 5%, respectively. A study of 189 individuals with Werner syndrome estimated melanoma risk to be elevated 53-fold in these individuals. SCC was less frequently diagnosed. Acral lentiginous melanomas are overrepresented, and SCCs may exhibit more aggressive behavior, with metastasis to lymph nodes and internal organs.[190,193]
Mutations in the WRN gene on chromosome 8p12-p11.2 have been identified in approximately 90% of individuals with this syndrome; no other genes are known to be associated with Werner syndrome.[189,194-197] Inheritance of this gene is believed to be autosomal recessive. The product of the WRN gene is a multifunctional protein including a DNA exonuclease and an ATP-dependent DNA helicase belonging to the RecQ subfamily. This protein may play a role in processes such as DNA repair, recombination, replication, transcription, and combined DNA functions.[198-206] Telomere dysfunction has been associated with premature aging and cancer susceptibility. Other helicases with similar function are altered in other chromosomal instability syndromes, such as BLM in Bloom syndrome and RecQL4 in Rothmund-Thomson syndrome.
Deleterious mutations described in the WRN gene include all types of mutations; however, the 1136C→T mutation is the most common and is found in 20% to 25% of the Japanese and white populations.[208,209] In the Japanese population, a founder mutation (IVS 25-1G→C) is present in 60% of affected individuals.
Mutation in the WRN gene causes loss of nuclear localization of the gene product. Intracellular levels of the mRNA and protein associated with the mutated gene are also markedly decreased, compared with those of the wild-type. Half-lives of the mRNA and protein associated with the mutated gene are also shorter than those associated with the wild-type mRNA and protein.[209,211]Interventions
Prevention and treatment of skin cancers
Because many of the syndromes described above are rare, few clinical trials have been conducted in these specific populations. However, valuable information has been developed from the clinical management experience related to skin cancer risk and treatment in the XP population. Strict sun avoidance beginning in infancy, use of protective clothing, and close clinical monitoring of the skin are key components to management of XP. Full-body photography of the skin, conjunctivae, and eyelids is recommended to aid in follow-up. Although few studies on treatment of SCC in the XP population have been done, in most cases treatment is similar to what would be recommended for the general population. Actinic keratoses are treated with topical therapies such as 5-fluorouracil (5-FU), cryotherapy with liquid nitrogen, or dermabrasion, whereas cutaneous cancers are generally managed surgically.
Oral isotretinoin has been used as chemoprevention in XP patients with promising results. A small study of daily use of isotretinoin (13-cis retinoic acid; given as 2 mg/kg/day) reduced nonmelanoma skin cancer incidence by 63% in a small number of people with XP. Toxicities associated with this treatment included mucocutaneous symptoms, abnormalities in liver function tests and triglyceride levels, and musculoskeletal symptoms such as arthralgias, calcifications of tendons and ligaments, and osteoporosis.[213,214] Dose reduction to 0.5 mg/kg/day reduced toxicity and decreased skin cancer frequency in three of seven subjects (43%); increasing the dose to 1 mg/kg/day resulted in decreased skin cancer frequency in three of the four subjects who did not respond at the lower dose. Oral isotretinoin use may be useful as a chemopreventive agent in other hereditary skin cancer syndromes, including basal cell nevus syndrome (BCNS), Rombo syndrome, and epidermodysplasia verruciformis.
Topical T4N5 liposome lotion, containing the bacterial enzyme T4 endonuclease V, was also investigated as a chemopreventive agent in a randomized, placebo-controlled trial of 30 XP patients. Although no effect was seen on incidence of SCC, 17.7 fewer actinic keratoses per year were seen in the treatment group. Additionally, 1.6 fewer BCCs per year were observed in patients being treated with this therapy. Both of these results were statistically significant. The risk of BCC was reduced by 47%, which was of borderline statistical significance. No significant adverse effects of this agent were reported. To date, this agent has not been approved for use by the U.S. Food and Drug Administration.
For patients with XP and unresectable SCC, therapy with 5-FU has been investigated. Several treatment methods were used in this prospective study, including topical therapy to the lesions, short systemic infusion with folic acid, and continuous systemic infusion in combination with cisplatin. Topical 5-FU demonstrated some efficacy, but in some cases viable tumor remained in the deeper dermis. The systemic chemotherapy resulted in one complete response and three partial responses in a total of five patients, suggesting that this therapy may be an option for treatment of extensive lesions. A dose reduction of 30% to 50% has been recommended for systemic chemotherapeutic agents in this population because of the increased sensitivity of XP cells.
For people who have genetic disorders other than XP, data are lacking, but general sun-safety measures remain important. Careful protection of the skin and eyes is the mainstay of prevention in all patients with increased susceptibility to skin cancer. Key points include avoidance of sun exposure at peak hours, protective clothing and lenses, and vigilant use of sunscreen. Avoidance of x-ray therapy has also been advocated for some groups with hereditary skin cancer syndromes, such as those with epidermodysplasia verruciformis. However, XP patients with nonresectable skin cancers or internal cancers, such as spinal cord astrocytoma or glioblastomas of the brain, have been treated successfully with standard therapeutic doses of x-ray radiation. Some experts recommend dermatologic evaluation every 6 months and ophthalmologic evaluation at least annually in these high-risk populations.
For individuals with dystrophic epidermolysis bullosa, wound care is paramount. Use of silver sulfadiazine cream, medical grade honey, and soft silicone dressings can be helpful in these settings. Attention to nutritional status, which may be compromised because of esophageal strictures, iron-deficiency anemia, infection, and inflammation, is another critical consideration for wound healing for these patients. Multivitamin supplementation, often at higher doses than those routinely recommended for the general population, may be warranted. Bone marrow transplantation has been explored in patients with dystrophic epidermolysis bullosa, but there is no evidence for a reduction of skin cancer with this intervention.References
- Rogers HW, Weinstock MA, Harris AR, et al.: Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 146 (3): 283-7, 2010. [PUBMED Abstract]
- American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed May 21, 2014.
- Armstrong BK, Kricker A: The epidemiology of UV induced skin cancer. J Photochem Photobiol B 63 (1-3): 8-18, 2001. [PUBMED Abstract]
- Rosso S, Zanetti R, Martinez C, et al.: The multicentre south European study 'Helios'. II: Different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin. Br J Cancer 73 (11): 1447-54, 1996. [PUBMED Abstract]
- Gallagher RP, Hill GB, Bajdik CD, et al.: Sunlight exposure, pigmentation factors, and risk of nonmelanocytic skin cancer. II. Squamous cell carcinoma. Arch Dermatol 131 (2): 164-9, 1995. [PUBMED Abstract]
- Lindelöf B, Sigurgeirsson B, Tegner E, et al.: PUVA and cancer risk: the Swedish follow-up study. Br J Dermatol 141 (1): 108-12, 1999. [PUBMED Abstract]
- Nijsten TE, Stern RS: The increased risk of skin cancer is persistent after discontinuation of psoralen+ultraviolet A: a cohort study. J Invest Dermatol 121 (2): 252-8, 2003. [PUBMED Abstract]
- Lim JL, Stern RS: High levels of ultraviolet B exposure increase the risk of non-melanoma skin cancer in psoralen and ultraviolet A-treated patients. J Invest Dermatol 124 (3): 505-13, 2005. [PUBMED Abstract]
- Karagas MR, Stannard VA, Mott LA, et al.: Use of tanning devices and risk of basal cell and squamous cell skin cancers. J Natl Cancer Inst 94 (3): 224-6, 2002. [PUBMED Abstract]
- Lichter MD, Karagas MR, Mott LA, et al.: Therapeutic ionizing radiation and the incidence of basal cell carcinoma and squamous cell carcinoma. The New Hampshire Skin Cancer Study Group. Arch Dermatol 136 (8): 1007-11, 2000. [PUBMED Abstract]
- Yoshinaga S, Hauptmann M, Sigurdson AJ, et al.: Nonmelanoma skin cancer in relation to ionizing radiation exposure among U.S. radiologic technologists. Int J Cancer 115 (5): 828-34, 2005. [PUBMED Abstract]
- Ron E, Preston DL, Kishikawa M, et al.: Skin tumor risk among atomic-bomb survivors in Japan. Cancer Causes Control 9 (4): 393-401, 1998. [PUBMED Abstract]
- Levi F, Moeckli R, Randimbison L, et al.: Skin cancer in survivors of childhood and adolescent cancer. Eur J Cancer 42 (5): 656-9, 2006. [PUBMED Abstract]
- Foti C, Filotico R, Bonamonte D, et al.: Long-term toxic effects of radiations: sarcomatoid carcinoma and multiple basal cell carcinoma of the limbs in chronic radiodermatitis. Immunopharmacol Immunotoxicol 27 (1): 177-84, 2005. [PUBMED Abstract]
- Haldorsen T, Reitan JB, Tveten U: Cancer incidence among Norwegian airline cabin attendants. Int J Epidemiol 30 (4): 825-30, 2001. [PUBMED Abstract]
- Gundestrup M, Storm HH: Radiation-induced acute myeloid leukaemia and other cancers in commercial jet cockpit crew: a population-based cohort study. Lancet 354 (9195): 2029-31, 1999. [PUBMED Abstract]
- Rafnsson V, Hrafnkelsson J, Tulinius H: Incidence of cancer among commercial airline pilots. Occup Environ Med 57 (3): 175-9, 2000. [PUBMED Abstract]
- Linnersjö A, Hammar N, Dammström BG, et al.: Cancer incidence in airline cabin crew: experience from Sweden. Occup Environ Med 60 (11): 810-4, 2003. [PUBMED Abstract]
- Hammar N, Linnersjö A, Alfredsson L, et al.: Cancer incidence in airline and military pilots in Sweden 1961-1996. Aviat Space Environ Med 73 (1): 2-7, 2002. [PUBMED Abstract]
- Pukkala E, Aspholm R, Auvinen A, et al.: Incidence of cancer among Nordic airline pilots over five decades: occupational cohort study. BMJ 325 (7364): 567, 2002. [PUBMED Abstract]
- Guo X, Fujino Y, Ye X, et al.: Association between multi-level inorganic arsenic exposure from drinking water and skin lesions in China. Int J Environ Res Public Health 3 (3): 262-7, 2006. [PUBMED Abstract]
- Chen Y, Hall M, Graziano JH, et al.: A prospective study of blood selenium levels and the risk of arsenic-related premalignant skin lesions. Cancer Epidemiol Biomarkers Prev 16 (2): 207-13, 2007. [PUBMED Abstract]
- Karagas MR, Stukel TA, Morris JS, et al.: Skin cancer risk in relation to toenail arsenic concentrations in a US population-based case-control study. Am J Epidemiol 153 (6): 559-65, 2001. [PUBMED Abstract]
- Schwartz RA: Arsenic and the skin. Int J Dermatol 36 (4): 241-50, 1997. [PUBMED Abstract]
- Grodstein F, Speizer FE, Hunter DJ: A prospective study of incident squamous cell carcinoma of the skin in the nurses' health study. J Natl Cancer Inst 87 (14): 1061-6, 1995. [PUBMED Abstract]
- Karagas MR, Stukel TA, Greenberg ER, et al.: Risk of subsequent basal cell carcinoma and squamous cell carcinoma of the skin among patients with prior skin cancer. Skin Cancer Prevention Study Group. JAMA 267 (24): 3305-10, 1992. [PUBMED Abstract]
- De Hertog SA, Wensveen CA, Bastiaens MT, et al.: Relation between smoking and skin cancer. J Clin Oncol 19 (1): 231-8, 2001. [PUBMED Abstract]
- Odenbro A, Bellocco R, Boffetta P, et al.: Tobacco smoking, snuff dipping and the risk of cutaneous squamous cell carcinoma: a nationwide cohort study in Sweden. Br J Cancer 92 (7): 1326-8, 2005. [PUBMED Abstract]
- Gallagher RP, Bajdik CD, Fincham S, et al.: Chemical exposures, medical history, and risk of squamous and basal cell carcinoma of the skin. Cancer Epidemiol Biomarkers Prev 5 (6): 419-24, 1996. [PUBMED Abstract]
- Koh D, Wang H, Lee J, et al.: Basal cell carcinoma, squamous cell carcinoma and melanoma of the skin: analysis of the Singapore Cancer Registry data 1968-97. Br J Dermatol 148 (6): 1161-6, 2003. [PUBMED Abstract]
- Halder RM, Bang KM: Skin cancer in blacks in the United States. Dermatol Clin 6 (3): 397-405, 1988. [PUBMED Abstract]
- Asuquo ME, Ebughe G: Major dermatological malignancies encountered in the University of Calabar Teaching Hospital, Calabar, southern Nigeria. Int J Dermatol 51 (Suppl 1): 32-6, 36-40, 2012. [PUBMED Abstract]
- English DR, Armstrong BK, Kricker A, et al.: Demographic characteristics, pigmentary and cutaneous risk factors for squamous cell carcinoma of the skin: a case-control study. Int J Cancer 76 (5): 628-34, 1998. [PUBMED Abstract]
- Kricker A, Armstrong BK, English DR, et al.: Pigmentary and cutaneous risk factors for non-melanocytic skin cancer--a case-control study. Int J Cancer 48 (5): 650-62, 1991. [PUBMED Abstract]
- Akgüner M, Barutçu A, Yilmaz M, et al.: Marjolin's ulcer and chronic burn scarring. J Wound Care 7 (3): 121-2, 1998. [PUBMED Abstract]
- Friedman R, Hanson S, Goldberg LH: Squamous cell carcinoma arising in a Leishmania scar. Dermatol Surg 29 (11): 1148-9, 2003. [PUBMED Abstract]
- Jensen P, Hansen S, Møller B, et al.: Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 40 (2 Pt 1): 177-86, 1999. [PUBMED Abstract]
- Hartevelt MM, Bavinck JN, Kootte AM, et al.: Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation 49 (3): 506-9, 1990. [PUBMED Abstract]
- Lindelöf B, Sigurgeirsson B, Gäbel H, et al.: Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol 143 (3): 513-9, 2000. [PUBMED Abstract]
- Krynitz B, Edgren G, Lindelöf B, et al.: Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008--a Swedish population-based study. Int J Cancer 132 (6): 1429-38, 2013. [PUBMED Abstract]
- Glover MT, Niranjan N, Kwan JT, et al.: Non-melanoma skin cancer in renal transplant recipients: the extent of the problem and a strategy for management. Br J Plast Surg 47 (2): 86-9, 1994. [PUBMED Abstract]
- Kaplan AL, Cook JL: Cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia. Skinmed 4 (5): 300-4, 2005 Sep-Oct. [PUBMED Abstract]
- Euvrard S, Kanitakis J, Decullier E, et al.: Subsequent skin cancers in kidney and heart transplant recipients after the first squamous cell carcinoma. Transplantation 81 (8): 1093-100, 2006. [PUBMED Abstract]
- Herrero JI, España A, D'Avola D, et al.: Subsequent nonmelanoma skin cancer after liver transplantation. Transplant Proc 44 (6): 1568-70, 2012 Jul-Aug. [PUBMED Abstract]
- Frezza EE, Fung JJ, van Thiel DH: Non-lymphoid cancer after liver transplantation. Hepatogastroenterology 44 (16): 1172-81, 1997 Jul-Aug. [PUBMED Abstract]
- Alam M, Brown RN, Silber DH, et al.: Increased incidence and mortality associated with skin cancers after cardiac transplant. Am J Transplant 11 (7): 1488-97, 2011. [PUBMED Abstract]
- Bouwes Bavinck JN, Hardie DR, Green A, et al.: The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study. Transplantation 61 (5): 715-21, 1996. [PUBMED Abstract]
- Lampros TD, Cobanoglu A, Parker F, et al.: Squamous and basal cell carcinoma in heart transplant recipients. J Heart Lung Transplant 17 (6): 586-91, 1998. [PUBMED Abstract]
- Cantwell MM, Murray LJ, Catney D, et al.: Second primary cancers in patients with skin cancer: a population-based study in Northern Ireland. Br J Cancer 100 (1): 174-7, 2009. [PUBMED Abstract]
- Epstein E: Value of follow-up after treatment of basal cell carcinoma. Arch Dermatol 108 (6): 798-800, 1973. [PUBMED Abstract]
- Møller R, Nielsen A, Reymann F: Multiple basal cell carcinoma and internal malignant tumors. Arch Dermatol 111 (5): 584-5, 1975. [PUBMED Abstract]
- Bergstresser PR, Halprin KM: Multiple sequential skin cancers. The risk of skin cancer in patients with previous skin cancer. Arch Dermatol 111 (8): 995-6, 1975. [PUBMED Abstract]
- Robinson JK: Risk of developing another basal cell carcinoma. A 5-year prospective study. Cancer 60 (1): 118-20, 1987. [PUBMED Abstract]
- Greenberg ER, Baron JA, Stukel TA, et al.: A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin. The Skin Cancer Prevention Study Group. N Engl J Med 323 (12): 789-95, 1990. [PUBMED Abstract]
- Hussain SK, Sundquist J, Hemminki K: The effect of having an affected parent or sibling on invasive and in situ skin cancer risk in Sweden. J Invest Dermatol 129 (9): 2142-7, 2009. [PUBMED Abstract]
- Hemminki K, Zhang H, Czene K: Familial invasive and in situ squamous cell carcinoma of the skin. Br J Cancer 88 (9): 1375-80, 2003. [PUBMED Abstract]
- Lindström LS, Yip B, Lichtenstein P, et al.: Etiology of familial aggregation in melanoma and squamous cell carcinoma of the skin. Cancer Epidemiol Biomarkers Prev 16 (8): 1639-43, 2007. [PUBMED Abstract]
- Kraemer KH, Lee MM, Andrews AD, et al.: The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm. Arch Dermatol 130 (8): 1018-21, 1994. [PUBMED Abstract]
- Moussaid L, Benchikhi H, Boukind EH, et al.: [Cutaneous tumors during xeroderma pigmentosum in Morocco: study of 120 patients] Ann Dermatol Venereol 131 (1 Pt 1): 29-33, 2004. [PUBMED Abstract]
- Bradford PT, Goldstein AM, Tamura D, et al.: Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair. J Med Genet 48 (3): 168-76, 2011. [PUBMED Abstract]
- DiGiovanna JJ, Patronas N, Katz D, et al.: Xeroderma pigmentosum: spinal cord astrocytoma with 9-year survival after radiation and isotretinoin therapy. J Cutan Med Surg 2 (3): 153-8, 1998. [PUBMED Abstract]
- Robbins JH: Xeroderma pigmentosum complementation group H is withdrawn and reassigned to group D. Hum Genet 88 (2): 242, 1991. [PUBMED Abstract]
- Khan SG, Oh KS, Shahlavi T, et al.: Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients. Carcinogenesis 27 (1): 84-94, 2006. [PUBMED Abstract]
- Messaoud O, Ben Rekaya M, Cherif W, et al.: Genetic homogeneity of mutational spectrum of group-A xeroderma pigmentosum in Tunisian patients. Int J Dermatol 49 (5): 544-8, 2010. [PUBMED Abstract]
- Ben Rekaya M, Messaoud O, Talmoudi F, et al.: High frequency of the V548A fs X572 XPC mutation in Tunisia: implication for molecular diagnosis. J Hum Genet 54 (7): 426-9, 2009. [PUBMED Abstract]
- Cartault F, Nava C, Malbrunot AC, et al.: A new XPC gene splicing mutation has lead to the highest worldwide prevalence of xeroderma pigmentosum in black Mahori patients. DNA Repair (Amst) 10 (6): 577-85, 2011. [PUBMED Abstract]
- Doubaj Y, Laarabi FZ, Elalaoui SC, et al.: Carrier frequency of the recurrent mutation c.1643_1644delTG in the XPC gene and birth prevalence of the xeroderma pigmentosum in Morocco. J Dermatol 39 (4): 382-4, 2012. [PUBMED Abstract]
- Vogelstein B, Knizler K: Nucleotide excision repair syndromes: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. In: Vogelstein B, Kinzler KW, eds.: The Genetic Basis of Human Cancer. 2nd ed. New York, NY: McGraw-Hill, 2002, pp 211-37.
- van Steeg H, Kraemer KH: Xeroderma pigmentosum and the role of UV-induced DNA damage in skin cancer. Mol Med Today 5 (2): 86-94, 1999. [PUBMED Abstract]
- Kraemer KH, Slor H: Xeroderma pigmentosum. Clin Dermatol 3 (1): 33-69, 1985 Jan-Mar. [PUBMED Abstract]
- Moriwaki S, Kraemer KH: Xeroderma pigmentosum--bridging a gap between clinic and laboratory. Photodermatol Photoimmunol Photomed 17 (2): 47-54, 2001. [PUBMED Abstract]
- Amr K, Messaoud O, El Darouti M, et al.: Mutational spectrum of Xeroderma pigmentosum group A in Egyptian patients. Gene 533 (1): 52-6, 2014. [PUBMED Abstract]
- Schriver C, Cleaver J, et al., eds.: Xeroderma pigmentosum and cockayne syndrome. In: Cleaver J, Kraemer K, eds.: The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill Book Co, 1995, pp 4397.
- Lambert WC, Gagna CE, Lambert MW: Xeroderma pigmentosum: its overlap with trichothiodystrophy, Cockayne syndrome and other progeroid syndromes. Adv Exp Med Biol 637: 128-37, 2008. [PUBMED Abstract]
- Robbins JH, Kraemer KH, Lutzner MA, et al.: Xeroderma pigmentosum. An inherited diseases with sun sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair. Ann Intern Med 80 (2): 221-48, 1974. [PUBMED Abstract]
- Weeda G, Eveno E, Donker I, et al.: A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy. Am J Hum Genet 60 (2): 320-9, 1997. [PUBMED Abstract]
- Lehmann AR: The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev 15 (1): 15-23, 2001. [PUBMED Abstract]
- Broughton BC, Berneburg M, Fawcett H, et al.: Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations in the XPD gene. Hum Mol Genet 10 (22): 2539-47, 2001. [PUBMED Abstract]
- Goudie DR, Yuille MA, Leversha MA, et al.: Multiple self-healing squamous epitheliomata (ESS1) mapped to chromosome 9q22-q31 in families with common ancestry. Nat Genet 3 (2): 165-9, 1993. [PUBMED Abstract]
- Goudie DR, D'Alessandro M, Merriman B, et al.: Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1. Nat Genet 43 (4): 365-9, 2011. [PUBMED Abstract]
- Bose S, Morgan LJ, Booth DR, et al.: The elusive multiple self-healing squamous epithelioma (MSSE) gene: further mapping, analysis of candidates, and loss of heterozygosity. Oncogene 25 (5): 806-12, 2006. [PUBMED Abstract]
- Mabula JB, Chalya PL, Mchembe MD, et al.: Skin cancers among Albinos at a University teaching hospital in Northwestern Tanzania: a retrospective review of 64 cases. BMC Dermatol 12: 5, 2012. [PUBMED Abstract]
- Luande J, Henschke CI, Mohammed N: The Tanzanian human albino skin. Natural history. Cancer 55 (8): 1823-8, 1985. [PUBMED Abstract]
- Hutton SM, Spritz RA: A comprehensive genetic study of autosomal recessive ocular albinism in Caucasian patients. Invest Ophthalmol Vis Sci 49 (3): 868-72, 2008. [PUBMED Abstract]
- Brilliant MH: The mouse p (pink-eyed dilution) and human P genes, oculocutaneous albinism type 2 (OCA2), and melanosomal pH. Pigment Cell Res 14 (2): 86-93, 2001. [PUBMED Abstract]
- Sviderskaya EV, Bennett DC, Ho L, et al.: Complementation of hypopigmentation in p-mutant (pink-eyed dilution) mouse melanocytes by normal human P cDNA, and defective complementation by OCA2 mutant sequences. J Invest Dermatol 108 (1): 30-4, 1997. [PUBMED Abstract]
- Simeonov DR, Wang X, Wang C, et al.: DNA variations in oculocutaneous albinism: an updated mutation list and current outstanding issues in molecular diagnostics. Hum Mutat 34 (6): 827-35, 2013. [PUBMED Abstract]
- Inagaki K, Suzuki T, Shimizu H, et al.: Oculocutaneous albinism type 4 is one of the most common types of albinism in Japan. Am J Hum Genet 74 (3): 466-71, 2004. [PUBMED Abstract]
- Mauri L, Barone L, Al Oum M, et al.: SLC45A2 mutation frequency in Oculocutaneous Albinism Italian patients doesn't differ from other European studies. Gene 533 (1): 398-402, 2014. [PUBMED Abstract]
- Perry PK, Silverberg NB: Cutaneous malignancy in albinism. Cutis 67 (5): 427-30, 2001. [PUBMED Abstract]
- Fukai K, Oh J, Frenk E, et al.: Linkage disequilibrium mapping of the gene for Hermansky-Pudlak syndrome to chromosome 10q23.1-q23.3. Hum Mol Genet 4 (9): 1665-9, 1995. [PUBMED Abstract]
- Wildenberg SC, Oetting WS, Almodóvar C, et al.: A gene causing Hermansky-Pudlak syndrome in a Puerto Rican population maps to chromosome 10q2. Am J Hum Genet 57 (4): 755-65, 1995. [PUBMED Abstract]
- Anikster Y, Huizing M, White J, et al.: Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico. Nat Genet 28 (4): 376-80, 2001. [PUBMED Abstract]
- Suzuki T, Li W, Zhang Q, et al.: Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene. Nat Genet 30 (3): 321-4, 2002. [PUBMED Abstract]
- Zhang Q, Zhao B, Li W, et al.: Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6. Nat Genet 33 (2): 145-53, 2003. [PUBMED Abstract]
- Li W, Zhang Q, Oiso N, et al.: Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Nat Genet 35 (1): 84-9, 2003. [PUBMED Abstract]
- Morgan NV, Pasha S, Johnson CA, et al.: A germline mutation in BLOC1S3/reduced pigmentation causes a novel variant of Hermansky-Pudlak syndrome (HPS8). Am J Hum Genet 78 (1): 160-6, 2006. [PUBMED Abstract]
- Cullinane AR, Curry JA, Carmona-Rivera C, et al.: A BLOC-1 mutation screen reveals that PLDN is mutated in Hermansky-Pudlak Syndrome type 9. Am J Hum Genet 88 (6): 778-87, 2011. [PUBMED Abstract]
- Toro J, Turner M, Gahl WA: Dermatologic manifestations of Hermansky-Pudlak syndrome in patients with and without a 16-base pair duplication in the HPS1 gene. Arch Dermatol 135 (7): 774-80, 1999. [PUBMED Abstract]
- Dell'Angelica EC, Shotelersuk V, Aguilar RC, et al.: Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell 3 (1): 11-21, 1999. [PUBMED Abstract]
- Nagle DL, Karim MA, Woolf EA, et al.: Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nat Genet 14 (3): 307-11, 1996. [PUBMED Abstract]
- Perou CM, Moore KJ, Nagle DL, et al.: Identification of the murine beige gene by YAC complementation and positional cloning. Nat Genet 13 (3): 303-8, 1996. [PUBMED Abstract]
- Barbosa MD, Nguyen QA, Tchernev VT, et al.: Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature 382 (6588): 262-5, 1996. [PUBMED Abstract]
- Engle LJ, Kennett RH: Cloning, analysis, and chromosomal localization of myoxin (MYH12), the human homologue to the mouse dilute gene. Genomics 19 (3): 407-16, 1994. [PUBMED Abstract]
- Ménasché G, Pastural E, Feldmann J, et al.: Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet 25 (2): 173-6, 2000. [PUBMED Abstract]
- Ménasché G, Ho CH, Sanal O, et al.: Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1). J Clin Invest 112 (3): 450-6, 2003. [PUBMED Abstract]
- Bruckner-Tuderman L: Hereditary skin diseases of anchoring fibrils. J Dermatol Sci 20 (2): 122-33, 1999. [PUBMED Abstract]
- van den Akker PC, Jonkman MF, Rengaw T, et al.: The international dystrophic epidermolysis bullosa patient registry: an online database of dystrophic epidermolysis bullosa patients and their COL7A1 mutations. Hum Mutat 32 (10): 1100-7, 2011. [PUBMED Abstract]
- Fine J, Johnson L, Suchindran C, et al.: Cancer and inherited epidermolysis bullosa. In: Fine J, Bauer E, McGuire J, et al., eds.: Epidermolysis Bullosa; Clinical, Epidemiologic, and Laboratory Advances and the Findings of the National Epidermolysis Bullosa Registry. Baltimore, Md: The Johns Hopkins University Press, 1999, pp 175-92.
- Fine JD, Johnson LB, Weiner M, et al.: Chemoprevention of squamous cell carcinoma in recessive dystrophic epidermolysis bullosa: results of a phase 1 trial of systemic isotretinoin. J Am Acad Dermatol 50 (4): 563-71, 2004. [PUBMED Abstract]
- Fine JD, Johnson LB, Weiner M, et al.: Cause-specific risks of childhood death in inherited epidermolysis bullosa. J Pediatr 152 (2): 276-80, 2008. [PUBMED Abstract]
- van den Akker PC, van Essen AJ, Kraak MM, et al.: Long-term follow-up of patients with recessive dystrophic epidermolysis bullosa in the Netherlands: expansion of the mutation database and unusual phenotype-genotype correlations. J Dermatol Sci 56 (1): 9-18, 2009. [PUBMED Abstract]
- Farhi D: Surgical management of epidermolysis bullosa: the importance of a multidisciplinary management. Int J Dermatol 46 (8): 815-6, 2007. [PUBMED Abstract]
- Fine JD, Eady RA, Bauer EA, et al.: The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol 58 (6): 931-50, 2008. [PUBMED Abstract]
- Sawamura D, Nakano H, Matsuzaki Y: Overview of epidermolysis bullosa. J Dermatol 37 (3): 214-9, 2010. [PUBMED Abstract]
- Wessagowit V, Ashton GH, Mohammedi R, et al.: Three cases of de novo dominant dystrophic epidermolysis bullosa associated with the mutation G2043R in COL7A1. Clin Exp Dermatol 26 (1): 97-9, 2001. [PUBMED Abstract]
- Cserhalmi-Friedman PB, Garzon MC, Guzman E, et al.: Maternal germline mosaicism in dominant dystrophic epidermolysis bullosa. J Invest Dermatol 117 (5): 1327-8, 2001. [PUBMED Abstract]
- Cuadrado-Corrales N, Sánchez-Jimeno C, García M, et al.: A prevalent mutation with founder effect in Spanish Recessive Dystrophic Epidermolysis Bullosa families. BMC Med Genet 11: 139, 2010. [PUBMED Abstract]
- Ortiz-Urda S, Garcia J, Green CL, et al.: Type VII collagen is required for Ras-driven human epidermal tumorigenesis. Science 307 (5716): 1773-6, 2005. [PUBMED Abstract]
- Fine JD: Inherited epidermolysis bullosa. Orphanet J Rare Dis 5: 12, 2010. [PUBMED Abstract]
- Aumailley M, Bruckner-Tuderman L, Carter WG, et al.: A simplified laminin nomenclature. Matrix Biol 24 (5): 326-32, 2005. [PUBMED Abstract]
- Nakano A, Chao SC, Pulkkinen L, et al.: Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs. non-Herlitz phenotypes. Hum Genet 110 (1): 41-51, 2002. [PUBMED Abstract]
- Schumann H, Hammami-Hauasli N, Pulkkinen L, et al.: Three novel homozygous point mutations and a new polymorphism in the COL17A1 gene: relation to biological and clinical phenotypes of junctional epidermolysis bullosa. Am J Hum Genet 60 (6): 1344-53, 1997. [PUBMED Abstract]
- Fine JD, Mellerio JE: Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated tissues. J Am Acad Dermatol 61 (3): 367-84; quiz 385-6, 2009. [PUBMED Abstract]
- Kiritsi D, Kern JS, Schumann H, et al.: Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa. J Med Genet 48 (7): 450-7, 2011. [PUBMED Abstract]
- Majewski S, Jabłońska S: Epidermodysplasia verruciformis as a model of human papillomavirus-induced genetic cancer of the skin. Arch Dermatol 131 (11): 1312-8, 1995. [PUBMED Abstract]
- Sterling JC: Human papillomaviruses and skin cancer. J Clin Virol 32 (Suppl 1): S67-71, 2005. [PUBMED Abstract]
- Karagas MR, Nelson HH, Sehr P, et al.: Human papillomavirus infection and incidence of squamous cell and basal cell carcinomas of the skin. J Natl Cancer Inst 98 (6): 389-95, 2006. [PUBMED Abstract]
- Ramoz N, Rueda LA, Bouadjar B, et al.: Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat Genet 32 (4): 579-81, 2002. [PUBMED Abstract]
- Mulvihill J, Miller R, Fraumeni J, eds.: Nosology among the neoplastic genedermatoses. In: Mulvihill J, Miller R, Fraumeni J, eds.: Genetics of Human Cancer. New York, NY: Raven Press, 1977, pp 145-67.
- Jabłońska S, Orth G, Jarzabek-Chorzelska M, et al.: Twenty-one years of follow-up studies of familial epidermodysplasia verruciformis. Dermatologica 158 (5): 309-27, 1979. [PUBMED Abstract]
- McDermott DF, Gammon B, Snijders PJ, et al.: Autosomal dominant epidermodysplasia verruciformis lacking a known EVER1 or EVER2 mutation. Pediatr Dermatol 26 (3): 306-10, 2009 May-Jun. [PUBMED Abstract]
- Lazarczyk M, Pons C, Mendoza JA, et al.: Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses. J Exp Med 205 (1): 35-42, 2008. [PUBMED Abstract]
- Patel AS, Karagas MR, Pawlita M, et al.: Cutaneous human papillomavirus infection, the EVER2 gene and incidence of squamous cell carcinoma: a case-control study. Int J Cancer 122 (10): 2377-9, 2008. [PUBMED Abstract]
- Crequer A, Picard C, Patin E, et al.: Inherited MST1 deficiency underlies susceptibility to EV-HPV infections. PLoS One 7 (8): e44010, 2012. [PUBMED Abstract]
- Ramoz N, Taïeb A, Rueda LA, et al.: Evidence for a nonallelic heterogeneity of epidermodysplasia verruciformis with two susceptibility loci mapped to chromosome regions 2p21-p24 and 17q25. J Invest Dermatol 114 (6): 1148-53, 2000. [PUBMED Abstract]
- Rosenberg PS, Tamary H, Alter BP: How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi Anemia in the United States and Israel. Am J Med Genet A 155A (8): 1877-83, 2011. [PUBMED Abstract]
- Rosenberg PS, Greene MH, Alter BP: Cancer incidence in persons with Fanconi anemia. Blood 101 (3): 822-6, 2003. [PUBMED Abstract]
- Alter BP: Cancer in Fanconi anemia, 1927-2001. Cancer 97 (2): 425-40, 2003. [PUBMED Abstract]
- Puligandla B, Stass SA, Schumacher HR, et al.: Terminal deoxynucleotidyl transferase in Fanconi's anaemia. Lancet 2 (8102): 1263, 1978. [PUBMED Abstract]
- Alter BP, Frissora CL, Halpérin DS, et al.: Fanconi's anaemia and pregnancy. Br J Haematol 77 (3): 410-8, 1991. [PUBMED Abstract]
- Berger R, Le Coniat M, Schaison G: Chromosome abnormalities in bone marrow of Fanconi anemia patients. Cancer Genet Cytogenet 65 (1): 47-50, 1993. [PUBMED Abstract]
- Lebbé C, Pinquier L, Rybojad M, et al.: Fanconi's anaemia associated with multicentric Bowen's disease and decreased NK cytotoxicity. Br J Dermatol 129 (5): 615-8, 1993. [PUBMED Abstract]
- Poon PK, O'Brien RL, Parker JW: Defective DNA repair in Fanconi's anaemia. Nature 250 (463): 223-5, 1974. [PUBMED Abstract]
- Bagby GC, Alter BP: Fanconi anemia. Semin Hematol 43 (3): 147-56, 2006. [PUBMED Abstract]
- Wang W: Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet 8 (10): 735-48, 2007. [PUBMED Abstract]
- Howlett NG, Taniguchi T, Olson S, et al.: Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297 (5581): 606-9, 2002. [PUBMED Abstract]
- Seal S, Thompson D, Renwick A, et al.: Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38 (11): 1239-41, 2006. [PUBMED Abstract]
- Berwick M, Satagopan JM, Ben-Porat L, et al.: Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer. Cancer Res 67 (19): 9591-6, 2007. [PUBMED Abstract]
- Walne AJ, Vulliamy T, Beswick R, et al.: TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes. Blood 112 (9): 3594-600, 2008. [PUBMED Abstract]
- Alter BP, Giri N, Savage SA, et al.: Cancer in dyskeratosis congenita. Blood 113 (26): 6549-57, 2009. [PUBMED Abstract]
- Vulliamy T, Dokal I: Dyskeratosis congenita. Semin Hematol 43 (3): 157-66, 2006. [PUBMED Abstract]
- Knight SW, Heiss NS, Vulliamy TJ, et al.: X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene. Am J Hum Genet 65 (1): 50-8, 1999. [PUBMED Abstract]
- Vulliamy T, Marrone A, Szydlo R, et al.: Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet 36 (5): 447-9, 2004. [PUBMED Abstract]
- Vulliamy TJ, Walne A, Baskaradas A, et al.: Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol Dis 34 (3): 257-63, 2005 May-Jun. [PUBMED Abstract]
- Vulliamy T, Beswick R, Kirwan M, et al.: Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci U S A 105 (23): 8073-8, 2008. [PUBMED Abstract]
- Walne AJ, Vulliamy T, Marrone A, et al.: Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum Mol Genet 16 (13): 1619-29, 2007. [PUBMED Abstract]
- Savage SA, Giri N, Baerlocher GM, et al.: TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet 82 (2): 501-9, 2008. [PUBMED Abstract]
- Marrone A, Walne A, Tamary H, et al.: Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Blood 110 (13): 4198-205, 2007. [PUBMED Abstract]
- Ballew BJ, Yeager M, Jacobs K, et al.: Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita. Hum Genet 132 (4): 473-80, 2013. [PUBMED Abstract]
- Walne AJ, Vulliamy T, Kirwan M, et al.: Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. Am J Hum Genet 92 (3): 448-53, 2013. [PUBMED Abstract]
- Batista LF, Pech MF, Zhong FL, et al.: Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. Nature 474 (7351): 399-402, 2011. [PUBMED Abstract]
- Neveling K, Bechtold A, Hoehn H: Genetic instability syndromes with progeroid features. Z Gerontol Geriatr 40 (5): 339-48, 2007. [PUBMED Abstract]
- Zhong F, Savage SA, Shkreli M, et al.: Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev 25 (1): 11-6, 2011. [PUBMED Abstract]
- Walne AJ, Vulliamy T, Beswick R, et al.: Mutations in C16orf57 and normal-length telomeres unify a subset of patients with dyskeratosis congenita, poikiloderma with neutropenia and Rothmund-Thomson syndrome. Hum Mol Genet 19 (22): 4453-61, 2010. [PUBMED Abstract]
- Colombo EA, Bazan JF, Negri G, et al.: Novel C16orf57 mutations in patients with Poikiloderma with Neutropenia: bioinformatic analysis of the protein and predicted effects of all reported mutations. Orphanet J Rare Dis 7: 7, 2012. [PUBMED Abstract]
- Alter BP, Baerlocher GM, Savage SA, et al.: Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood 110 (5): 1439-47, 2007. [PUBMED Abstract]
- Vulliamy TJ, Marrone A, Knight SW, et al.: Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. Blood 107 (7): 2680-5, 2006. [PUBMED Abstract]
- Vulliamy TJ, Dokal I: Dyskeratosis congenita: the diverse clinical presentation of mutations in the telomerase complex. Biochimie 90 (1): 122-30, 2008. [PUBMED Abstract]
- Savage SA; Savage SA: Dyskeratosis Congenita. In: Pagon RA, Adam MP, Bird TD, et al., eds.: GeneReviews. Seattle, WA: University of Washington, 2013, pp. Available online. Last accessed October 16, 2013.
- Borg MF, Olver IN, Hill MP: Rothmund-Thomson syndrome and tolerance of chemoradiotherapy. Australas Radiol 42 (3): 216-8, 1998. [PUBMED Abstract]
- Haneke E, Gutschmidt E: Premature multiple Bowen's disease in poikiloderma congenitale with warty hyperkeratoses. Dermatologica 158 (5): 384-8, 1979. [PUBMED Abstract]
- Wang LL, Levy ML, Lewis RA, et al.: Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am J Med Genet 102 (1): 11-7, 2001. [PUBMED Abstract]
- Piquero-Casals J, Okubo AY, Nico MM: Rothmund-thomson syndrome in three siblings and development of cutaneous squamous cell carcinoma. Pediatr Dermatol 19 (4): 312-6, 2002 Jul-Aug. [PUBMED Abstract]
- Petkovic M, Dietschy T, Freire R, et al.: The human Rothmund-Thomson syndrome gene product, RECQL4, localizes to distinct nuclear foci that coincide with proteins involved in the maintenance of genome stability. J Cell Sci 118 (Pt 18): 4261-9, 2005. [PUBMED Abstract]
- Wang LL, Gannavarapu A, Kozinetz CA, et al.: Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst 95 (9): 669-74, 2003. [PUBMED Abstract]
- Kitao S, Lindor NM, Shiratori M, et al.: Rothmund-thomson syndrome responsible gene, RECQL4: genomic structure and products. Genomics 61 (3): 268-76, 1999. [PUBMED Abstract]
- Werner SR, Prahalad AK, Yang J, et al.: RECQL4-deficient cells are hypersensitive to oxidative stress/damage: Insights for osteosarcoma prevalence and heterogeneity in Rothmund-Thomson syndrome. Biochem Biophys Res Commun 345 (1): 403-9, 2006. [PUBMED Abstract]
- Nakayama H: RecQ family helicases: roles as tumor suppressor proteins. Oncogene 21 (58): 9008-21, 2002. [PUBMED Abstract]
- German J: Bloom's syndrome. XX. The first 100 cancers. Cancer Genet Cytogenet 93 (1): 100-6, 1997. [PUBMED Abstract]
- Ellis NA, Groden J, Ye TZ, et al.: The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 83 (4): 655-66, 1995. [PUBMED Abstract]
- Bugreev DV, Yu X, Egelman EH, et al.: Novel pro- and anti-recombination activities of the Bloom's syndrome helicase. Genes Dev 21 (23): 3085-94, 2007. [PUBMED Abstract]
- German J, Ellis N: Bloom syndrome. In: Vogelstein B, Kinzler KW, eds.: The Genetic Basis of Human Cancer. 2nd ed. New York, NY: McGraw-Hill, 2002, pp 267-88.
- German J, Sanz MM, Ciocci S, et al.: Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry. Hum Mutat 28 (8): 743-53, 2007. [PUBMED Abstract]
- Ellis NA, Ciocci S, Proytcheva M, et al.: The Ashkenazic Jewish Bloom syndrome mutation blmAsh is present in non-Jewish Americans of Spanish ancestry. Am J Hum Genet 63 (6): 1685-93, 1998. [PUBMED Abstract]
- Lu X, Lane DP: Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes? Cell 75 (4): 765-78, 1993. [PUBMED Abstract]
- Meetei AR, Sechi S, Wallisch M, et al.: A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Mol Cell Biol 23 (10): 3417-26, 2003. [PUBMED Abstract]
- Yamamoto K, Imakiire A, Miyagawa N, et al.: A report of two cases of Werner's syndrome and review of the literature. J Orthop Surg (Hong Kong) 11 (2): 224-33, 2003. [PUBMED Abstract]
- Huang S, Lee L, Hanson NB, et al.: The spectrum of WRN mutations in Werner syndrome patients. Hum Mutat 27 (6): 558-67, 2006. [PUBMED Abstract]
- Goto M, Miller RW, Ishikawa Y, et al.: Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomarkers Prev 5 (4): 239-46, 1996. [PUBMED Abstract]
- Tsuchiya H, Tomita K, Ohno M, et al.: Werner's syndrome combined with quintuplicate malignant tumors: a case report and review of literature data. Jpn J Clin Oncol 21 (2): 135-42, 1991. [PUBMED Abstract]
- Lauper JM, Krause A, Vaughan TL, et al.: Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One 8 (4): e59709, 2013. [PUBMED Abstract]
- Machino H, Miki Y, Teramoto T, et al.: Cytogenetic studies in a patient with porokeratosis of Mibelli, multiple cancers and a forme fruste of Werner's syndrome. Br J Dermatol 111 (5): 579-86, 1984. [PUBMED Abstract]
- Goto M, Imamura O, Kuromitsu J, et al.: Analysis of helicase gene mutations in Japanese Werner's syndrome patients. Hum Genet 99 (2): 191-3, 1997. [PUBMED Abstract]
- Oshima J, Yu CE, Piussan C, et al.: Homozygous and compound heterozygous mutations at the Werner syndrome locus. Hum Mol Genet 5 (12): 1909-13, 1996. [PUBMED Abstract]
- Uhrhammer NA, Lafarge L, Dos Santos L, et al.: Werner syndrome and mutations of the WRN and LMNA genes in France. Hum Mutat 27 (7): 718-9, 2006. [PUBMED Abstract]
- Yu CE, Oshima J, Wijsman EM, et al.: Mutations in the consensus helicase domains of the Werner syndrome gene. Werner's Syndrome Collaborative Group. Am J Hum Genet 60 (2): 330-41, 1997. [PUBMED Abstract]
- Shen JC, Loeb LA: The Werner syndrome gene: the molecular basis of RecQ helicase-deficiency diseases. Trends Genet 16 (5): 213-20, 2000. [PUBMED Abstract]
- Shen J, Loeb LA: Unwinding the molecular basis of the Werner syndrome. Mech Ageing Dev 122 (9): 921-44, 2001. [PUBMED Abstract]
- Brosh RM Jr, Bohr VA: Roles of the Werner syndrome protein in pathways required for maintenance of genome stability. Exp Gerontol 37 (4): 491-506, 2002. [PUBMED Abstract]
- Furuichi Y: Premature aging and predisposition to cancers caused by mutations in RecQ family helicases. Ann N Y Acad Sci 928: 121-31, 2001. [PUBMED Abstract]
- Lebel M: Werner syndrome: genetic and molecular basis of a premature aging disorder. Cell Mol Life Sci 58 (7): 857-67, 2001. [PUBMED Abstract]
- Bohr VA, Brosh RM Jr, von Kobbe C, et al.: Pathways defective in the human premature aging disease Werner syndrome. Biogerontology 3 (1-2): 89-94, 2002. [PUBMED Abstract]
- Chen L, Oshima J: Werner Syndrome. J Biomed Biotechnol 2 (2): 46-54, 2002. [PUBMED Abstract]
- Opresko PL, Cheng WH, von Kobbe C, et al.: Werner syndrome and the function of the Werner protein; what they can teach us about the molecular aging process. Carcinogenesis 24 (5): 791-802, 2003. [PUBMED Abstract]
- Pirzio LM, Pichierri P, Bignami M, et al.: Werner syndrome helicase activity is essential in maintaining fragile site stability. J Cell Biol 180 (2): 305-14, 2008. [PUBMED Abstract]
- Crabbe L, Jauch A, Naeger CM, et al.: Telomere dysfunction as a cause of genomic instability in Werner syndrome. Proc Natl Acad Sci U S A 104 (7): 2205-10, 2007. [PUBMED Abstract]
- Friedrich K, Lee L, Leistritz DF, et al.: WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations. Hum Genet 128 (1): 103-11, 2010. [PUBMED Abstract]
- Moser MJ, Oshima J, Monnat RJ Jr: WRN mutations in Werner syndrome. Hum Mutat 13 (4): 271-9, 1999. [PUBMED Abstract]
- Satoh M, Imai M, Sugimoto M, et al.: Prevalence of Werner's syndrome heterozygotes in Japan. Lancet 353 (9166): 1766, 1999. [PUBMED Abstract]
- Goto M, Yamabe Y, Shiratori M, et al.: Immunological diagnosis of Werner syndrome by down-regulated and truncated gene products. Hum Genet 105 (4): 301-7, 1999. [PUBMED Abstract]
- Tamura D, DiGiovanna JJ, Kraemer KH: Xeroderma pigmentosum. In: Lebwohl MG, Birth-Jones J, Heymann WR, et al., eds.: Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 3rd ed. London, England: Saunders Elsevier, 2010, pp 789-92.
- Kraemer KH, DiGiovanna JJ, Moshell AN, et al.: Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 318 (25): 1633-7, 1988. [PUBMED Abstract]
- DiGiovanna JJ: Retinoid chemoprevention in the high-risk patient. J Am Acad Dermatol 39 (2 Pt 3): S82-5, 1998. [PUBMED Abstract]
- DiGiovanna J: Oral isotretinoin chemoprevention of skin cancer in xeroderma pigmentosum. J Eur Acad Derm Venereol 5 (Suppl 1): 27, 1995.
- Otley CC, Stasko T, Tope WD, et al.: Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg 32 (4): 562-8, 2006. [PUBMED Abstract]
- Yarosh D, Klein J, O'Connor A, et al.: Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Xeroderma Pigmentosum Study Group. Lancet 357 (9260): 926-9, 2001. [PUBMED Abstract]
- Boussen H, Zwik J, Mili-Boussen I, et al.: [Therapeutic results of 5-fluorouracil in multiple and unresectable facial carcinoma secondary to xeroderma pigmentosum] Therapie 56 (6): 751-4, 2001 Nov-Dec. [PUBMED Abstract]
- Sarasin A: Progress and prospects of xeroderma pigmentosum therapy. Adv Exp Med Biol 637: 144-51, 2008. [PUBMED Abstract]
- Mellerio JE, Weiner M, Denyer JE, et al.: Medical management of epidermolysis bullosa: Proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile, 2005. Int J Dermatol 46 (8): 795-800, 2007. [PUBMED Abstract]
- Wagner JE, Ishida-Yamamoto A, McGrath JA, et al.: Bone marrow transplantation for recessive dystrophic epidermolysis bullosa. N Engl J Med 363 (7): 629-39, 2010. [PUBMED Abstract]