Chromosomal instability in fibroblasts and mesenchymal tumors from 2 sibs with Rothmund-Thomson syndrome

Miozzo, Monica; Castorina, Pierangela; Riva, Paola; Dalprà, Leda; Conti, A. M. Fuhrman; Volpi, L.; Hoe, T S; Khoo, Alan Soo‐Beng; Wiegant, J.; Rosenberg, Carla; Larizza, Lidia

doi:10.1002/(sici)1097-0215(19980812)77:4<504::aid-ijc5>3.0.co;2-y

Cited by 61 publications

(27 citation statements)

References 18 publications

(19 reference statements)

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“…A multicentric osteosarcoma is synchronous if more than one lesion is found at presentation and metachronous if development of apparently new tumour(s) is detected at a new site [45]. Considering this, three additional cases in which second primary osteosarcoma lesions have been described, apparently without pulmonary metastasis, may also be included as OSMC [9,46-48], making a total of ten cases. It has been reported that the incidence of multicentric disease associated with sporadic osteosarcoma ranges between 0.4% and 10% of all cases of osteosarcoma [49].…”

Section: Clinical Descriptionmentioning

confidence: 99%

“…Independent of the method and target cell, chromosomal instability, whenever found, appears to be distinctive and is mainly represented by mosaic aneuploidies and isochromosomes [80]. Multiple evidence for in vivo mosaicism of trisomy 8 and/or 7 and/or 2 [13,19,30,46,98,99] has been found, even in the absence of increased spontaneous chromosomal instability [27]. Among structural chromosomal abnormalities, isochromosomes (mainly of the same chromosomes that were found to be trisomic, namely 8, 7 and 2) have been frequently observed and appear to be quite characteristic for this syndrome [13,19,30,99,100].…”

Section: Cytogenetic Studies and Chromosomal Instabilitymentioning

confidence: 99%

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Rothmund-Thomson syndrome

Larizza

Roversi

Volpi

2010

Orphanet J Rare Dis

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242

276

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Rothmund-Thomson syndrome (RTS) is a genodermatosis presenting with a characteristic facial rash (poikiloderma) associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging and a predisposition to cancer. The prevalence is unknown but around 300 cases have been reported in the literature so far. The diagnostic hallmark is facial erythema, which spreads to the extremities but spares the trunk, and which manifests itself within the first year and then develops into poikiloderma. Two clinical subforms of RTS have been defined: RTSI characterised by poikiloderma, ectodermal dysplasia and juvenile cataracts, and RTSII characterised by poikiloderma, congenital bone defects and an increased risk of osteosarcoma in childhood and skin cancer later in life. The skeletal abnormalities may be overt (frontal bossing, saddle nose and congenital radial ray defects), and/or subtle (visible only by radiographic analysis). Gastrointestinal, respiratory and haematological signs have been reported in a few patients. RTS is transmitted in an autosomal recessive manner and is genetically heterogeneous: RTSII is caused by homozygous or compound heterozygous mutations in the RECQL4 helicase gene (detected in 60-65% of RTS patients), whereas the aetiology in RTSI remains unknown. Diagnosis is based on clinical findings (primarily on the age of onset, spreading and appearance of the poikiloderma) and molecular analysis for RECQL4 mutations. Missense mutations are rare, while frameshift, nonsense mutations and splice-site mutations prevail. A fully informative test requires transcript analysis not to overlook intronic deletions causing missplicing. The diagnosis of RTS should be considered in all patients with osteosarcoma, particularly if associated with skin changes. The differential diagnosis should include other causes of childhood poikiloderma (including dyskeratosis congenita, Kindler syndrome and Poikiloderma with Neutropaenia), other rare genodermatoses with prominent telangiectasias (including Bloom syndrome, Werner syndrome and Ataxia-telangiectasia) and the allelic disorders, RAPADILINO syndrome and Baller-Gerold syndrome, which also share some clinical features. A few mutations recur in all three RECQL4 diseases. Genetic counselling should be provided for RTS patients and their families, together with a recommendation for cancer surveillance for all patients with RTSII. Patients should be managed by a multidisciplinary team and offered long term follow-up. Treatment includes the use of pulsed dye laser photocoagulation to improve the telangiectatic component of the rash, surgical removal of the cataracts and standard treatment for individuals who develop cancer. Although some clinical signs suggest precocious aging, life expectancy is not impaired in RTS patients if they do not develop cancer. Outcomes in patients with osteosarcoma are similar in RTS and non-RTS patients, with a five-year survival rate of 60-70%. The...

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Section: Clinical Descriptionmentioning

confidence: 99%

Section: Cytogenetic Studies and Chromosomal Instabilitymentioning

confidence: 99%

Rothmund-Thomson syndrome

Larizza

Roversi

Volpi

2010

Orphanet J Rare Dis

Self Cite

242

276

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“…RTS is the best characterized of the RECQ4 diseases and these patients also have skeletal abnormalities, skin disorders, light sensitivity, and age prematurely (75, 120, 127). Rothmund-Thomson patients are especially susceptible to forming bone and skin cancer and their cells display increased chromosomal rearrangements like translocations and deletions (95). …”

Section: Introductionmentioning

confidence: 99%

The RecQ DNA Helicases in DNA Repair

2010

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The RecQ helicases are conserved from bacteria to humans and play a critical role in genome stability. In humans, loss of RecQ gene function is associated with cancer predisposition and/or premature aging. Recent data have shown that the RecQ helicases function during two distinct steps during DNA repair; DNA end resection and resolution of double Holliday junctions (dHJs). RecQ functions in these different processing steps has important implications for its role in repair of double-strand breaks (DSBs) that occur during DNA replication, meiosis and at specific genomic loci such as telomeres.

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“…Other clinical features include growth retardation, skeletal abnormalities, hair loss, gastrointestinal disturbances, juvenile cataracts, and a high incidence of malignancy, particularly osteosarcoma (OS) (Larizza et al 2006;Wang et al 2003). Cytogenetic analyses of cells from RTS patients demonstrate mosaic chromosomal abnormalities and genomic instability (Lindor et al 2000;Miozzo et al 1998;Wang et al 2001). In 1999, Kitao and coworkers linked a subset of RTS cases to mutations in the human RECQ protein-like 4 gene, RECQL4 (Kitao et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Sensitivity of RECQL4-deficient fibroblasts from Rothmund–Thomson syndrome patients to genotoxic agents

et al. 2008

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RECQ helicase protein-like 4 (RECQL4) is a member of the human RECQ family of DNA helicases. Two-thirds of patients with Rothmund-Thomson syndrome (RTS) carry biallelic inactivating mutations in the RECQL4 gene. RTS is an autosomal recessive disorder characterized by poikiloderma, sparse hair, small stature, skeletal abnormalities, cataracts, and an increased risk of cancer. Mutations in two other RECQ helicases, BLM and WRN, are responsible for the cancer predisposition conditions Bloom and Werner syndromes, respectively. Previous studies have shown that BLM and WRN-deficient cells demonstrate increased sensitivity to hydroxyurea (HU), camptothecin (CPT), and 4-nitroquinoline 1-oxide (4NQO). Little is known about the sensitivity of RECQL4-deficient cells to these and other genotoxic agents. The purpose of this study was to determine if RTS cells display any distinct cellular phenotypes in response to DNA damaging agents or replication blocks that could provide insight into the molecular function of the RECQL4 protein. Our results show that primary fibroblasts from RTS patients carrying two deleterious RECQL4 mutations, compared to wild type (WT) fibroblasts, have increased sensitivity to HU, CPT, and doxorubicin (DOX), modest sensitivity to other DNA damaging agents including ultraviolet (UV) irradiation, ionizing radiation (IR), and cisplatin (CDDP), and relative resistance to 4NQO. The RECQ family of DNA helicases has been implicated in the regulation of DNA replication, recombination, and repair. Because HU, CPT, and DOX exert their effects primarily during S phase, these results support a greater role for the RECQL4 protein in DNA replication as opposed to repair of exogenous damage.

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Chromosomal instability in fibroblasts and mesenchymal tumors from 2 sibs with Rothmund-Thomson syndrome

Cited by 61 publications

References 18 publications

Rothmund-Thomson syndrome

Rothmund-Thomson syndrome

The RecQ DNA Helicases in DNA Repair

Sensitivity of RECQL4-deficient fibroblasts from Rothmund–Thomson syndrome patients to genotoxic agents

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