RESUMEN
Hair shafts from three trichothiodystrophy (TTD) patients with mutations in the ERCC2 (XPD) gene were examined by transmission electron microscopy. TTD is a rare, recessive disorder with mutations in several genes in the DNA repair/transcription pathway, including ERCC2. Unlike previous studies, the hair shafts were examined after relaxation of their structure by partial disulphide bond reduction in the presence of sodium dodecyl sulphate, permitting improved visualization. Compared with hair shafts of normal phenotype, TTD cuticle cells displayed aberrant marginal bands and exocuticle layers. Clusters of cells stained differently (light versus dark) in the cortex of aberrant shafts, and the keratin macrofibrils appeared much shorter in the cytoplasm. Considerable heterogeneity in these properties was evident among samples and even along the length of single hair shafts. The results are consistent with not only a paucity of high sulphur components, such as keratin-associated proteins, but also a profound imbalance in protein content and organization.
Asunto(s)
Enfermedades del Cabello , Síndromes de Tricotiodistrofia , Reparación del ADN , Cabello/metabolismo , Enfermedades del Cabello/genética , Enfermedades del Cabello/metabolismo , Humanos , Síndromes de Tricotiodistrofia/genética , Síndromes de Tricotiodistrofia/metabolismo , Rayos Ultravioleta , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Proteína de la Xerodermia Pigmentosa del Grupo D/metabolismoRESUMEN
Trichothiodystrophy (TTD) is a rare, autosomal recessive, multisystem disorder of DNA repair and transcription with developmental delay and abnormalities in brain, eye, skin, nervous, and musculoskeletal systems. We followed a cohort of 37 patients with TTD at the National Institutes of Health (NIH) from 2001 to 2019 with a median age at last observation of 12 years (range 2-36). Some children with TTD developed rapidly debilitating hip degeneration (DHD): a distinctive pattern of hip pain, inability to walk, and avascular necrosis on imaging. Ten (27%) of the 37 patients had DHD at median age 8 years (range 5-12), followed by onset of imaging findings at median age 9 years (range 5-13). All 10 had mutations in the ERCC2/XPD gene. In 7 of the 10 affected patients, DHD rapidly became bilateral. DHD was associated with coxa valga, central osteosclerosis with peripheral osteopenia of the skeleton, and contractures/tightness of the lower limbs. Except for one patient, surgical interventions were generally not effective at preventing DHD. Four patients with DHD died at a median age of 11 years (range 9-15). TTD patients with ERCC2/XPD gene mutations have a high risk of musculoskeletal abnormalities and DHD leading to poor outcomes. Monitoring by history, physical examination, imaging, and by physical medicine and rehabilitation specialists may be warranted.
Asunto(s)
Enfermedades Óseas Metabólicas , Contractura , Coxa Valga , Osteonecrosis , Osteosclerosis , Síndromes de Tricotiodistrofia , Niño , Humanos , Preescolar , Adolescente , Adulto Joven , Adulto , Síndromes de Tricotiodistrofia/diagnóstico , Síndromes de Tricotiodistrofia/genética , Coxa Valga/complicaciones , Mutación , Contractura/genética , Contractura/complicaciones , Enfermedades Óseas Metabólicas/genética , Proteína de la Xerodermia Pigmentosa del Grupo D/genéticaRESUMEN
BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder with defective DNA nucleotide excision repair and associated with a high frequency of skin cancer. Approximately 25% of patients develop progressive neurological degeneration. Complementation groups XP-A and XP-D are most frequently associated with neurological disorders. DESIGN/METHODS: This is a retrospective review of patients with XP who were evaluated at NIH from 1986 to 2015 and had nerve conduction studies (NCS). In the complementation groups with peripheral neuropathy, further comparisons of the NCS were made with audiological, brain imaging, neuropsychological assessments that were also performed on most of the patients. Limited neuropathology of XP-A and XP-D patients were examined.. RESULTS: The 33 patients had NCS: XP-A (9 patients), XP-C (7 patients), XP-D (10 patients), XP-E (1 patient), XP-V (4 patients), and XP-unknown (2 patients). Peripheral neuropathy based on nerve conduction studies was documented only in two complementation groups: 78% (7/9) of XP-A patients had a sensorimotor neuropathy while 50% (5/10) of XP-D patients had a sensory neuropathy only. Analysis of sural sensory nerve amplitude in both complementation groups XP-A and XP-D correlated with sensorineural hearing loss (SNHL), MRI/CT severity, and Full-scale Intelligence Quotient (IQ). Analysis of fibular motor nerve amplitude in complementation XP-A correlated with SNHL and MRI/CT severity. Limited follow-up studies showed gradual loss of NCS responses compared to an earlier and more rapid progression of the hearing loss. CONCLUSIONS: Despite similar brain imaging and audiological findings patients, XP-A and XP-D complementation groups differ in the type of neuropathy, sensorimotor versus sensory alone. A few cases suggest that sensorineural hearing loss may precede abnormal NCS in XP and therefore serve as valuable clinical indicators of XP patients that will later develop peripheral neuropathy.
Asunto(s)
Enfermedades del Sistema Nervioso Periférico , Xerodermia Pigmentosa , Reparación del ADN , Humanos , Conducción Nerviosa , Enfermedades del Sistema Nervioso Periférico/diagnóstico por imagen , Enfermedades del Sistema Nervioso Periférico/genética , Estudios Retrospectivos , Xerodermia Pigmentosa/complicaciones , Xerodermia Pigmentosa/genéticaRESUMEN
The availability of genomic sequencing for inherited diseases provides a more complete molecular basis for how an individual's genetic landscape influences clinical outcome. We describe a family where exome sequencing of a 3-year-old boy with clinical features of Cockayne syndrome (CS) confirmed the diagnosis of CS. He also had a mutation consistent with a pre-symptomatic second disease, multiple endocrine neoplasia type 1 (MEN1), each potentially affecting multiple organ systems, in addition to a poorly defined variant in fumarate hydratase (FH). Genomic sequencing may reveal coexisting pathogenic mutations and variants which complicate clinical interpretation.
Asunto(s)
Síndrome de Cockayne , Neoplasia Endocrina Múltiple Tipo 1 , Preescolar , Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/genética , Exoma/genética , Genómica , Humanos , Masculino , Neoplasia Endocrina Múltiple Tipo 1/genética , Mutación , Linaje , Secuenciación del ExomaRESUMEN
The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA polymerase II (RNA pol II) via direct interaction with the basal transcription/DNA repair factor IIH (TFIIH). TFIIH harbors mutations in two rare genetic disorders, the cancer-prone xeroderma pigmentosum (XP) and the cancer-free, multisystem developmental disorder trichothiodystrophy (TTD). The phenotypic complexity resulting from mutations affecting TFIIH has been attributed to the nucleotide excision repair (NER) defect as well as to impaired transcription. Here, we report two unrelated children showing clinical features typical of TTD who harbor different homozygous missense mutations in GTF2E2 (c.448G>C [p.Ala150Pro] and c.559G>T [p.Asp187Tyr]) encoding the beta subunit of transcription factor IIE (TFIIEß). Repair of ultraviolet-induced DNA damage was normal in the GTF2E2 mutated cells, indicating that TFIIE was not involved in NER. We found decreased protein levels of the two TFIIE subunits (TFIIEα and TFIIEß) as well as decreased phosphorylation of TFIIEα in cells from both children. Interestingly, decreased phosphorylation of TFIIEα was also seen in TTD cells with mutations in ERCC2, which encodes the XPD subunit of TFIIH, but not in XP cells with ERCC2 mutations. Our findings support the theory that TTD is caused by transcriptional impairments that are distinct from the NER disorder XP.
Asunto(s)
Quinasas Ciclina-Dependientes/genética , Reparación del ADN , Factores de Transcripción TFII/genética , Síndromes de Tricotiodistrofia/genética , Secuencia de Aminoácidos , Quinasas Ciclina-Dependientes/metabolismo , Daño del ADN , ADN Helicasas/genética , ADN Helicasas/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Silenciador del Gen , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Mutación Missense , Linaje , Fosforilación , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Factor de Transcripción TFIIH/genética , Factor de Transcripción TFIIH/metabolismo , Factores de Transcripción TFII/metabolismo , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Proteína de la Xerodermia Pigmentosa del Grupo D/metabolismo , Quinasa Activadora de Quinasas Ciclina-DependientesRESUMEN
About 12% of human genetic disorders involve premature termination codons (PTCs). Aminoglycoside antibiotics have been proposed for restoring full-length proteins by readthrough of PTC. To assess the efficiency of readthrough, we selected homozygous and compound heterozygous skin fibroblasts from xeroderma pigmentosum (XP) patients with different PTCs in the XPC DNA repair gene. XP patients have a nucleotide excision repair defect and a 10,000-fold increased risk of UV-induced skin cancer. In six of eight PTC-containing XP-C cells, treatment with Geneticin and gentamicin resulted in (i) stabilized XPC-mRNA, which would have been degraded by nonsense-mediated decay; (ii) increased expression of XPC protein that localized to UV-damaged sites; (iii) recruitment of XPB and XPD proteins to UV DNA damage sites; and (iv) increased repair of 6-4 photoproducts and cyclobutane pyrimidine dimers. Expression of PTC in a transfected vector revealed that readthrough depends on the PTC sequence and its location within the gene. This sensitive DNA repair assay system demonstrates the complexity of response to PTC readthrough inducers. The efficiency of aminoglycoside-mediated readthrough depends on the type and copy number of PTC, the downstream 4+ nucleotide, and the location within the exon. Treatment with small-molecule nonaminoglycoside compounds (PTC124, BZ16, or RTC14) resulted in similarly increased XPC mRNA expression and photoproduct removal with less toxicity than with the aminoglycosides. Characterizing PTC structure and parameters governing effective PTC readthrough may provide a unique prophylactic therapy for skin cancer prevention in XP-C patients.
Asunto(s)
Reparación del ADN/genética , Gentamicinas/farmacología , Estabilidad del ARN/efectos de los fármacos , Neoplasias Cutáneas/prevención & control , Xerodermia Pigmentosa/tratamiento farmacológico , Xerodermia Pigmentosa/genética , Codón sin Sentido/genética , Cartilla de ADN/genética , Reparación del ADN/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Fibroblastos/efectos de los fármacos , Técnica del Anticuerpo Fluorescente , Humanos , Immunoblotting , Luciferasas , Oxadiazoles , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Readthrough of premature termination (stop) codons (PTC) is a new approach to treatment of genetic diseases. We recently reported that readthrough of PTC in cells from some xeroderma pigmentosum complementation group C (XP-C) patients could be achieved with the aminoglycosides geneticin or gentamicin. We found that the response depended on several factors including the PTC sequence, its location within the gene and the aminoglycoside used. Here, we extended these studies to investigate the effects of other aminoglycosides that are already on the market. We reasoned that topical treatment could deliver much higher concentrations of drug to the skin, the therapeutic target, and thus increase the therapeutic effect while reducing renal or ototoxicity in comparison with systemic treatment. Our prior clinical studies indicated that only a few percent of normal XPC expression was associated with mild clinical disease. We found minimal cell toxicity in the XP-C cells with several aminoglycosides. We found increased XPC mRNA expression in PTC-containing XP-C cells with G418, paromomycin, neomycin and kanamycin and increased XPC protein expression with G418. We conclude that in selected patients with XP, topical PTC therapy can be investigated as a method of personalized medicine to alleviate their cutaneous symptoms.
Asunto(s)
Aminoglicósidos/farmacología , Codón sin Sentido , Proteínas de Unión al ADN/genética , Xerodermia Pigmentosa/tratamiento farmacológico , Xerodermia Pigmentosa/genética , Administración Tópica , Aminoglicósidos/administración & dosificación , Células Cultivadas , Codón sin Sentido/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Expresión Génica/efectos de los fármacos , Gentamicinas/farmacología , Humanos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Medicina de Precisión , ARN Mensajero/genética , ARN Mensajero/metabolismo , Xerodermia Pigmentosa/metabolismoAsunto(s)
Agammaglobulinemia/mortalidad , Neutropenia/mortalidad , Síndromes de Tricotiodistrofia/mortalidad , Adolescente , Adulto , Agammaglobulinemia/inmunología , Niño , Preescolar , Femenino , Humanos , Inmunoglobulinas/deficiencia , Masculino , Neutropenia/inmunología , Neutropenia/patología , Neutrófilos/inmunología , Estudios Retrospectivos , Análisis de Supervivencia , Síndromes de Tricotiodistrofia/inmunología , Síndromes de Tricotiodistrofia/patología , Adulto JovenRESUMEN
To assess the role of DNA repair in maintenance of hearing function and neurological integrity, we examined hearing status, neurological function, DNA repair complementation group and history of acute burning on minimal sun exposure in all patients with xeroderma pigmentosum, who had at least one complete audiogram, examined at the National Institutes of Health from 1971 to 2012. Seventy-nine patients, aged 1-61 years, were diagnosed with xeroderma pigmentosum (n = 77) or xeroderma pigmentosum/Cockayne syndrome (n = 2). A total of 178 audiograms were included. Clinically significant hearing loss (>20 dB) was present in 23 (29%) of 79 patients. Of the 17 patients with xeroderma pigmentosum-type neurological degeneration, 13 (76%) developed hearing loss, and all 17 were in complementation groups xeroderma pigmentosum type A or type D and reported acute burning on minimal sun exposure. Acute burning on minimal sun exposure without xeroderma pigmentosum-type neurological degeneration was present in 18% of the patients (10/55). Temporal bone histology in a patient with severe xeroderma pigmentosum-type neurological degeneration revealed marked atrophy of the cochlear sensory epithelium and neurons. The 19-year mean age of detection of clinically significant hearing loss in the patients with xeroderma pigmentosum with xeroderma pigmentosum-type neurological degeneration was 54 years younger than that predicted by international norms. The four frequency (0.5/1/2/4 kHz) pure-tone average correlated with degree of neurodegeneration (P < 0.001). In patients with xeroderma pigmentosum, aged 4-30 years, a four-frequency pure-tone average ≥10 dB hearing loss was associated with a 39-fold increased risk (P = 0.002) of having xeroderma pigmentosum-type neurological degeneration. Severity of hearing loss parallels neurological decline in patients with xeroderma pigmentosum-type neurological degeneration. Audiometric findings, complementation group, acute burning on minimal sun exposure and age were important predictors of xeroderma pigmentosum-type neurological degeneration. These results provide evidence that DNA repair is critical in maintaining neurological integrity of the auditory system.
Asunto(s)
Encéfalo/patología , Reparación del ADN , Pérdida Auditiva Sensorineural/fisiopatología , Audición/fisiología , Degeneración Nerviosa/fisiopatología , Quemadura Solar/fisiopatología , Xerodermia Pigmentosa/fisiopatología , Estimulación Acústica , Adolescente , Adulto , Atrofia , Audiometría , Encéfalo/fisiopatología , Niño , Preescolar , Síndrome de Cockayne/complicaciones , Síndrome de Cockayne/genética , Síndrome de Cockayne/patología , Síndrome de Cockayne/fisiopatología , Femenino , Estudios de Seguimiento , Pérdida Auditiva Sensorineural/complicaciones , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Estudios Retrospectivos , Quemadura Solar/complicaciones , Quemadura Solar/genética , Xerodermia Pigmentosa/complicaciones , Xerodermia Pigmentosa/genética , Xerodermia Pigmentosa/patologíaRESUMEN
Xeroderma pigmentosum (XP) is a rare autosomal recessive disease of deoxyribonucleic acid (DNA) repair with ultraviolet (UV) radiation sensitivity and a 10 000-fold increased risk of skin cancer. Symptoms include: freckle-like pigmentation in sun-exposed skin before age 2 years, severe burns after minimal sun exposure (50% of patients) and damage to exposed surfaces of the eyes with loss of vision and ocular cancer. About 25% of patients develop a progressive neurodegeneration. The combination of an inherited inability to repair UV-induced DNA damage and environmental exposure to UV must occur for cutaneous and ocular symptoms to develop. There is no cure for XP, but many of its manifestations may be reduced or prevented through consistent UV protection; thus XP serves as a model for sun protection of patients with marked photosenstivity. Sun protective clothing including hats, sunglasses and face shields, sun screen lotions and avoidance of environmental sources of UV are cornerstones of prevention of skin and eye damage and cancer. Although XP is a serious disease with the potential for limitation of life expectancy, XP patients can live active lives while at the same time avoiding UV.
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Ceguera/prevención & control , Daño del ADN , Neoplasias del Ojo/prevención & control , Neoplasias Cutáneas/prevención & control , Pigmentación de la Piel , Protectores Solares/uso terapéutico , Xerodermia Pigmentosa , Animales , Humanos , Pigmentación de la Piel/efectos de los fármacos , Pigmentación de la Piel/efectos de la radiaciónRESUMEN
Melanoma is the most deadly form of skin cancer and DiGeorge syndrome (DGS) is the most frequent interstitial deletion syndrome. We characterized a novel balanced t(9;22)(p21;q11.2) translocation in a patient with melanoma, DNA repair deficiency, and features of DGS including deafness and malformed inner ears. Using chromosome sorting, we located the 9p21 breakpoint in CDKN2A intron 1. This resulted in underexpression of the tumor suppressor p14 alternate reading frame (p14ARF); the reduced DNA repair was corrected by transfection with p14ARF. Ultraviolet radiation-type p14ARF mutations in his melanoma implicated p14ARF in its pathogenesis. The 22q11.2 breakpoint was located in a palindromic AT-rich repeat (PATRR22). We identified a new gene, FAM230A, that contains PATRR22 within an intron. The 22q11.2 breakpoint was located 800 kb centromeric to TBX1, which is required for inner ear development. TBX1 expression was greatly reduced. The translocation resulted in a chimeric transcript encoding portions of p14ARF and FAM230A. Inhibition of chimeric p14ARF-FAM230A expression increased p14ARF and TBX1 expression and improved DNA repair. Expression of the chimera in normal cells produced dominant negative inhibition of p14ARF. Similar chimeric mRNAs may mediate haploinsufficiency in DGS or dominant negative inhibition of other genes such as those involved in melanoma.
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Trastornos por Deficiencias en la Reparación del ADN/genética , Sordera/genética , Fusión Génica , Melanoma/genética , Proteínas de Dominio T Box/genética , Translocación Genética , Proteína p14ARF Supresora de Tumor/genética , Secuencia de Bases , Proteínas Portadoras , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 9 , Trastornos por Deficiencias en la Reparación del ADN/metabolismo , Sordera/metabolismo , Genes p16 , Humanos , Masculino , Melanoma/metabolismo , Datos de Secuencia Molecular , ARN Largo no Codificante , Análisis de Secuencia de ADN , Proteínas de Dominio T Box/metabolismo , Proteína p14ARF Supresora de Tumor/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations in DNA repair genes. Clinical manifestations of XP include mild to extreme sensitivity to ultraviolet radiation resulting in inflammation and neoplasia in sun-exposed areas of the skin, mucous membranes, and ocular surfaces. This report describes the ocular manifestations of XP in patients systematically evaluated in the Clinical Center at the National Institutes of Health. DESIGN: Retrospective observational case series. PARTICIPANTS: Eighty-seven participants, aged 1.3 to 63.4 years, referred to the National Eye Institute (NEI) for examination from 1964 to 2011. Eighty-three patients had XP, 3 patients had XP/Cockayne syndrome complex, and 1 patient had XP/trichothiodystrophy complex. METHODS: Complete age- and developmental stage-appropriate ophthalmic examination. MAIN OUTCOME MEASURES: Visual acuity; eyelid, ocular surface, and lens pathology; tear film and tear production measures; and cytologic analysis of conjunctival surface swabs. RESULTS: Of the 87 patients, 91% had at least 1 ocular abnormality. The most common abnormalities were conjunctivitis (51%), corneal neovascularization (44%), dry eye (38%), corneal scarring (26%), ectropion (25%), blepharitis (23%), conjunctival melanosis (20%), and cataracts (14%). Thirteen percent of patients had some degree of visual axis impingement, and 5% of patients had no light perception in 1 or both eyes. Ocular surface cancer or a history of ocular surface cancer was present in 10% of patients. Patients with an acute sunburning skin phenotype were less likely to develop conjunctival melanosis and ectropion but more likely to develop neoplastic ocular surface lesions than nonburning patients. Some patients also showed signs of limbal stem cell deficiency. CONCLUSIONS: Our longitudinal study reports the ocular status of the largest group of patients with XP systematically examined at 1 facility over an extended period of time. Structural eyelid abnormalities, neoplasms of the ocular surface and eyelids, tear film and tear production abnormalities, ocular surface disease and inflammation, and corneal abnormalities were present in this population. Burning and nonburning patients with XP exhibit different rates of important ophthalmologic findings, including neoplasia. In addition, ophthalmic characteristics can help refine diagnoses in the case of XP complex phenotypes. DNA repair plays a major role in protection of the eye from sunlight-induced damage.
Asunto(s)
Reparación del ADN/fisiología , ADN/efectos de la radiación , Oftalmopatías/diagnóstico , Traumatismos por Radiación/diagnóstico , Luz Solar/efectos adversos , Xerodermia Pigmentosa/diagnóstico , Adolescente , Adulto , Niño , Preescolar , Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/etiología , Síndrome de Cockayne/prevención & control , Oftalmopatías/etiología , Oftalmopatías/prevención & control , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Traumatismos por Radiación/etiología , Traumatismos por Radiación/prevención & control , Estudios Retrospectivos , Síndromes de Tricotiodistrofia/diagnóstico , Síndromes de Tricotiodistrofia/etiología , Síndromes de Tricotiodistrofia/prevención & control , Rayos Ultravioleta/efectos adversos , Agudeza Visual/fisiología , Xerodermia Pigmentosa/etiología , Xerodermia Pigmentosa/prevención & control , Adulto JovenRESUMEN
Background: Xeroderma pigmentosum (XP), a rare disease with defects in DNA repair genes, has >1,000-fold increased risk of ultraviolet-induced skin cancers. Immune checkpoint inhibitors (ICIs) are used for treating cancers with large numbers of mutations but may also promote adverse events (AEs). Deficient DNA repair in XP patients may lead to increased numbers of mutations, leading to enhanced efficacy of cancer response or, alternatively, to increased AE in response to ICI. We sought to compare the efficacy and AE of ICI in XP patients with metastatic or unresectable cancers to that of ICI-treated patients in the general population. Methods: In this retrospective study, we reviewed medical records of XP patients treated in the United States and in London (UK). We also reviewed published reports of ICI-treated XP patients and patients in the general population. Results: Metastatic or unresectable cancers in all 22 (100%) XP patients showed regression or remission in response to ICI. The types and frequencies of AE in XP patients were similar to those reported among ICI-treated patients in the general population. However, two XP patients had concurrent additional cancers that did not respond to ICI, two XP patients had cancer recurrence or progression after initial response, and eight XP patients developed new skin cancers during or after ICI treatment. Conclusion: In this retrospective study with small sample size, XP patients demonstrated positive responses to ICI and the treatment was well tolerated but some patients developed new skin cancers while being treated. ICIs can be considered in treating metastatic or unresectable cancers in XP patients.
RESUMEN
We describe an unusual xeroderma pigmentosum (XP) patient with a mutation in XP complementation group G, representing only the third reported Japanese XP-G patient. A 40-year-old men (XP3HM), born from consanguineous parents experienced sun sensitivity and pigmentary changes of sun-exposed skin since childhood. He developed a squamous cell carcinoma on his lower lip at the age of 40. He has neither neurological abnormalities nor Cockayne syndrome. The primary fibroblasts of the patient were hypersensitive to killing by UV (D(0) = 0.6 J/m(2)) and the post-UV unscheduled DNA synthesis was 8% of normal. Host cell reactivation complementation analysis implicated XP complementation group G. We identified a novel homozygous mutation (c.194T>C) in a conserved portion of the XPG(ERCC5) gene, resulting in a predicted amino acid change; p.L65P. We confirmed that this genetic change reduced DNA repair thus linking this mutation to increased skin cancer.
Asunto(s)
Proteínas de Unión al ADN/genética , Endonucleasas/genética , Mutación Missense , Proteínas Nucleares/genética , Factores de Transcripción/genética , Xerodermia Pigmentosa/genética , Adulto , Sustitución de Aminoácidos , Carcinoma de Células Escamosas/genética , Análisis Mutacional de ADN , Homocigoto , Humanos , Neoplasias de los Labios/genética , Masculino , Xerodermia Pigmentosa/clasificación , Xerodermia Pigmentosa/patología , Xerodermia Pigmentosa/fisiopatologíaRESUMEN
BACKGROUND: The frequency of cancer, neurologic degeneration and mortality in xeroderma pigmentosum (XP) patients with defective DNA repair was determined in a four decade natural history study. METHODS: All 106 XP patients admitted to the National Institutes of Health from 1971 to 2009 were evaluated from clinical records and follow-up. RESULTS: In the 65 per cent (n=69) of patients with skin cancer, non-melanoma skin cancer (NMSC) was increased 10,000-fold and melanoma was increased 2000-fold in patients under age 20. The 9 year median age at diagnosis of first non-melanoma skin cancer (NMSC) (n=64) was significantly younger than the 22 year median age at diagnosis of first melanoma (n=38)-a relative age reversal from the general population suggesting different mechanisms of carcinogenesis between NMSC and melanoma. XP patients with pronounced burning on minimal sun exposure (n=65) were less likely to develop skin cancer than those who did not. This may be related to the extreme sun protection they receive from an earlier age, decreasing their total ultraviolet exposure. Progressive neurologic degeneration was present in 24% (n=25) with 16/25 in complementation group XP-D. The most common causes of death were skin cancer (34%, n=10), neurologic degeneration (31%, n=9), and internal cancer (17%, n=5). The median age at death (29 years) in XP patients with neurodegeneration was significantly younger than those XP patients without neurodegeneration (37 years) (p=0.02). CONCLUSION: This 39 year follow-up study of XP patients indicates a major role of DNA repair genes in the aetiology of skin cancer and neurologic degeneration.
Asunto(s)
Reparación del ADN , Melanoma/genética , Enfermedades Neurodegenerativas/genética , Neoplasias Cutáneas/genética , Xerodermia Pigmentosa/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Melanoma/complicaciones , Persona de Mediana Edad , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/mortalidad , Receptor de Melanocortina Tipo 1/genética , Estudios Retrospectivos , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/mortalidad , Xerodermia Pigmentosa/complicaciones , Adulto JovenRESUMEN
To look for a direct role of ultraviolet radiation (UV) exposure in cutaneous melanoma induction, we studied xeroderma pigmentosum (XP) patients who have defective DNA repair resulting in a 1000-fold increase in melanoma risk. These XP melanomas have the same anatomic distribution as melanomas in the general population. We analyzed laser capture microdissection samples of skin melanomas from XP patients studied at the National Institutes of Health. The tumor suppressor gene PTEN was sequenced and analyzed for UV-induced mutations. Samples from 59 melanomas (47 melanomas in situ and 12 invasive melanomas) from 8 XP patients showed mutations in the PTEN tumor suppressor gene in 56% of the melanomas. Further, 91% of the melanomas with mutations had 1 to 4 UV type base substitution mutations (occurring at adjacent pyrimidines) (P < 0.0001 compared to random mutations). We found a high frequency of amino-acid-altering mutations in the melanomas and demonstrated that these mutations impaired PTEN function; UV damage plays a direct role in induction of mutations and in inactivation of the PTEN gene in XP melanomas including in situ, the earliest stage of melanoma. This gene is known to be a key regulator of carcinogenesis and therefore these data provide solid mechanistic support for UV protection for prevention of melanoma.
Asunto(s)
Melanoma/genética , Rayos Ultravioleta , Xerodermia Pigmentosa/genética , Secuencia de Aminoácidos , Secuencia de Bases , Células Cultivadas , Humanos , Melanoma/metabolismo , Melanoma/patología , Mutación/genética , Fosfohidrolasa PTEN/química , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Xerodermia Pigmentosa/metabolismo , Xerodermia Pigmentosa/patologíaRESUMEN
OBJECTIVE: Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and multisystem abnormalities. Many TTD patients have a defect in known DNA repair genes. This report systematically evaluates the ocular manifestations of the largest-to-date cohort of TTD patients and xeroderma pigmentosum (XP)/TTD patients. DESIGN: Case series. PARTICIPANTS: Thirty-two participants, ages 1 to 30 years, referred to the National Eye Institute for examination from 2001 to 2010; 25 had TTD and 7 had XP/TTD. METHODS: Complete, age- and developmental stage-appropriate ophthalmic examination. MAIN OUTCOME MEASURES: Visual acuity (VA), best-corrected VA, ocular motility, state of the ocular surface and corneal endothelial cell density, corneal diameter, and lens assessment. RESULTS: Developmental abnormalities included microcornea (44% TTD), microphthalmia (8% TTD, 14% XP/TTD), nystagmus (40% TTD), and infantile cataracts (56% TTD, 86% XP/TTD). Corrective lenses were required by 65% of the participants, and decreased best-corrected VA was present in 28% of TTD patients and 71% of XP/TTD patients. Degenerative changes included dry eye (32% TTD, 57% XP/TTD) and ocular surface disease identified by ocular surface staining with fluorescein (32% TTD) that usually are exhibited by much older patients in the general population. The 2 oldest TTD patients exhibited clinical signs of retinal/macular degeneration. Four XP/TTD patients presented with corneal neovascularization. CONCLUSIONS: These TTD and XP/TTD study participants had a wide variety of ocular findings including refractive error, infantile cataracts, microcornea, nystagmus, and dry eye/ocular surface disease. Although many of these can be ascribed to abnormal development--likely owing to abnormalities in basal transcription of critical genes--patients may also have a degenerative course. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosures may be found after the references.
Asunto(s)
Anomalías Múltiples/etiología , Anomalías del Ojo/etiología , Síndromes de Tricotiodistrofia/complicaciones , Anomalías Múltiples/diagnóstico , Adolescente , Adulto , Catarata/congénito , Recuento de Células , Niño , Preescolar , Córnea/anomalías , Endotelio Corneal/patología , Anomalías del Ojo/diagnóstico , Femenino , Humanos , Lactante , Degeneración Macular/congénito , Masculino , Microftalmía , Nistagmo Congénito , Trastornos de la Visión/congénito , Agudeza Visual/fisiología , Xerodermia Pigmentosa/complicaciones , Adulto JovenRESUMEN
OBJECTIVE: To identify the frequency of pregnancy and neonatal complications in pregnancies carrying fetuses affected with trichothiodystrophy (TTD). METHODS: We identified pregnancy and neonatal complications and serum screening results from mothers of TTD patients in a DNA repair diseases study from 2001 to 2011. RESULTS: Pregnancy reports of 27 TTD patients and their 23 mothers were evaluated and 81% of the pregnancies had complications: 56% had preterm delivery, 30% had preeclampsia, 19% had placental abnormalities, 11% had HELLP syndrome, and 4% had an emergency c-section for fetal distress, while 44% had two or more complications. Only 19% of the pregnancies delivered at term without complications. Eight of the ten pregnancies tested had abnormal multiple marker results including elevated levels of human chorionic gonadotrophin. Eighty-five percent of the neonates had complications: 70% were low birth weight (<2500 g), 35% had birth weight < 10 centile for gestational age, 70% had NICU admission, 67% had a collodion membrane, and 31% of the 16 males had cryptorchidism. Cataracts were present in 54% of the TTD patients examined. CONCLUSION: TTD is a multisystem disease that predisposes mothers of affected patients to substantial risks for pregnancy complications and TTD neonates have a high incidence of multiple abnormalities.
Asunto(s)
Reparación del ADN/genética , Desarrollo Fetal/genética , Complicaciones del Embarazo/genética , Embarazo de Alto Riesgo/genética , Transcripción Genética , Síndromes de Tricotiodistrofia/genética , Adulto , Femenino , Síndrome HELLP/sangre , Síndrome HELLP/diagnóstico , Síndrome HELLP/genética , Humanos , Recién Nacido , Masculino , Preeclampsia/sangre , Preeclampsia/diagnóstico , Preeclampsia/genética , Embarazo , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/diagnóstico , Embarazo de Alto Riesgo/sangre , Síndromes de Tricotiodistrofia/sangre , Síndromes de Tricotiodistrofia/diagnóstico , Adulto JovenRESUMEN
A teenage girl had the rare combined phenotype of xeroderma pigmentosum and trichothiodystrophy, resulting from mutations in the XPD (ERCC2) gene involved in nucleotide excision repair (NER). After treatment with antibiotics, including metronidazole for recurrent infections, she showed signs of acute and severe hepatotoxicity, which gradually resolved after withdrawal of the treatment. Cultured skin fibroblasts from the patient revealed cellular sensitivity to killing by metronidazole compared with cells from a range of other donors. This reveals that the metronidazole sensitivity was an intrinsic property of her cells. It is well recognized that patients with Cockayne syndrome, another NER disorder, are at high risk of metronidazole-induced hepatotoxicity, but this had not been reported in individuals with other NER disorders. We would urge extreme caution in the use of metronidazole in the management of individuals with the xeroderma pigmentosum and trichothiodystrophy overlap or trichothiodystrophy phenotypes.