RECQL4

Gene Summary

Gene:RECQL4; RecQ protein-like 4
Aliases: RECQ4
Location:8q24.3
Summary:The protein encoded by this gene is a DNA helicase that belongs to the RecQ helicase family. DNA helicases unwind double-stranded DNA into single-stranded DNAs and may modulate chromosome segregation. This gene is predominantly expressed in thymus and testis. Mutations in this gene are associated with Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. [provided by RefSeq, Jan 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:ATP-dependent DNA helicase Q4
HPRD
Source:NCBIAccessed: 08 August, 2015

Ontology:

What does this gene/protein do?
Show (12)

Cancer Overview

Some children with Rhmund-Thomson Syndrome (RTS) have germline mutations of the RECQL4 gene, which is associated with an increased risk of developing cancer, and in particular a predisposition to osteosarcoma and skin cancer.

Research Indicators

Publications Per Year (1990-2015)
Graph generated 08 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Tumor Markers
  • Chromosome 8
  • Skin Cancer
  • Young Adult
  • Laryngeal Cancer
  • RTPCR
  • DNA Mutational Analysis
  • p53 Protein
  • Smoking
  • DNA Repair
  • Base Sequence
  • Disease Progression
  • Genetic Recombination
  • Exodeoxyribonucleases
  • Adolescents
  • Case-Control Studies
  • Twist Transcription Factor
  • Self-Help Groups
  • Oligonucleotide Array Sequence Analysis
  • Adenosine Triphosphatases
  • Breast Cancer
  • Protein Tyrosine Phosphatases
  • Genetic Predisposition
  • Bone Cancer
  • Gene Expression Profiling
  • Genomic Instability
  • Childhood Cancer
  • Osteosarcoma
  • Chromosomes, Human
  • RECQL4
  • Cancer Gene Expression Regulation
  • Transcriptome
  • Risk Factors
  • Cervical Cancer
  • Neoplastic Cell Transformation
  • RecQ Helicases
  • DNA Helicases
  • Reproducibility of Results
  • DNA Sequence Analysis
  • Single Nucleotide Polymorphism
  • Mutation
  • Rothmund-Thomson Syndrome
Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Rothmund-Thomson SyndromeRECQL4 mutations in Rothmund-Thomson Syndrome / Cancer
Rhmund-Thomson Syndrome (RTS) is a rare autosomal recessive disorder. Symptoms include early photosensitivity and poikilodermatous skin changes, juvenile cataracts and skeletal dysplasias. RTS can be sub-divided according to whether the person has genetic mutations of the RECQL4 gene. Children with Type 2 RTS, who do have mutations in RECQL4, have an increased risk of developing cancer, and in particular a predisposition to osteosarcoma and skin cancer.
See: More details below...
View Publications123
OsteosarcomaRECQL4 - Rothmund-Thomson Syndrome and increased risk of Osteosarcoma
Patients with RTS have an increased risk of developing osteosarcoma compared with the general population (Wang et al, 2005). In a clinicopathologic study of 12 RTS patients with osteosarcoma (Hicks et al, 2007) found they develop osteosarcoma at a younger age but otherwise histopathology and clinical outcomes were no different to sporadic osteosarcoma.
View Publications41
Skin Cancer, NonmelanomaRECQL4 - Rothmund-Thomson Syndrome and increased risk of Skin Cancer
There is thought to be an increased risk of skin cancers (basal cell carcinoma and squamous cell carcinoma) with RTS (Borg, 1998) though this is not well characterised. There have been cases of skin cancer developing at an early age in RTS.
View Publications30
Laryngeal CancerRECQL4 and Laryngeal Cancer View Publications4
Breast CancerRECQL4 and Breast Cancer View Publications4
Cervical CancerRECQL4 and Cervical Cancer View Publications3

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

RECQL4 mutations in Rothmund-Thomson Syndrome / Cancer

Rhmund-Thomson Syndrome (RTS) is a rare autosomal recessive disorder. Symptoms include early photosensitivity and poikilodermatous skin changes, juvenile cataracts and skeletal dysplasias. RTS can be sub-divided according to whether the person has genetic mutations of the RECQL4 gene. Children with Type 2 RTS, who do have mutations in RECQL4, have an increased risk of developing cancer, and in particular a predisposition to osteosarcoma and skin cancer.

See also: Rothmund-Thomson Syndrome - Clinical and Research information

Web Resources (5)

Latest Publications

Lu L, Jin W, Liu H, Wang LL
RECQ DNA helicases and osteosarcoma.
Adv Exp Med Biol. 2014; 804:129-45 [PubMed] Related Publications
The RECQ family of DNA helicases is a conserved group of enzymes that are important for maintaining genomic integrity. In humans, there are five RECQ helicase genes, and mutations in three of them-BLM, WRN, and RECQL4-are associated with the genetic disorders Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome (RTS), respectively. Importantly all three diseases are cancer predisposition syndromes. Patients with RTS are highly and uniquely susceptible to developing osteosarcoma; thus, RTS provides a good model to study the pathogenesis of osteosarcoma. The "tumor suppressor" role of RECQL4 and the other RECQ helicases is an area of active investigation. This chapter reviews what is currently known about the cellular functions of RECQL4 and how these may relate to tumorigenesis, as well as ongoing efforts to understand RECQL4's functions in vivo using animal models. Understanding the RECQ pathways may provide insight into avenues for novel cancer therapies in the future.

Gupta S, De S, Srivastava V, et al.
RECQL4 and p53 potentiate the activity of polymerase γ and maintain the integrity of the human mitochondrial genome.
Carcinogenesis. 2014; 35(1):34-45 [PubMed] Related Publications
UNLABELLED: Germline mutations in RECQL4 and p53 lead to cancer predisposition syndromes, Rothmund-Thomson syndrome (RTS) and Li-Fraumeni syndrome (LFS), respectively. RECQL4 is essential for the transport of p53 to the mitochondria under unstressed conditions. Here, we show that both RECQL4 and p53 interact with mitochondrial polymerase (PolγA/B2) and regulate its binding to the mitochondrial DNA (mtDNA) control region (D-loop). Both RECQL4 and p53 bind to the exonuclease and polymerase domains of PolγA. Kinetic constants for interactions between PolγA-RECQL4, PolγA-p53 and PolγB-p53 indicate that RECQL4 and p53 are accessory factors for PolγA-PolγB and PolγA-DNA interactions. RECQL4 enhances the binding of PolγA to DNA, thereby potentiating the exonuclease and polymerization activities of PolγA/B2. To investigate whether lack of RECQL4 and p53 results in increased mitochondrial genome instability, resequencing of the entire mitochondrial genome was undertaken from multiple RTS and LFS patient fibroblasts. We found multiple somatic mutations and polymorphisms in both RTS and LFS patient cells. A significant number of mutations and polymorphisms were common between RTS and LFS patients. These changes are associated with either aging and/or cancer, thereby indicating that the phenotypes associated with these syndromes may be due to deregulation of mitochondrial genome stability caused by the lack of RECQL4 and p53.
SUMMARY: The biochemical mechanisms by which RECQL4 and p53 affect mtDNA replication have been elucidated. Resequencing of RTS and LFS patients' mitochondrial genome reveals common mutations indicating similar mechanisms of regulation by RECQL4 and p53.

Castori M, Morrone A, Kanitakis J, Grammatico P
Genetic skin diseases predisposing to basal cell carcinoma.
Eur J Dermatol. 2012 May-Jun; 22(3):299-309 [PubMed] Related Publications
Basal cell carcinoma (BCC) is the commonest cancer in humans. Predisposing factors reflect common genetic variations and environmental influences in most cases. However, an underlying Mendelian disorder should be suspected in a specific subset of patients, namely those with multiple, early onset lesions. Some specific conditions, including Gorlin, Bazex-Dupré-Christol and Rombo syndromes, and Xeroderma Pigmentosum, show BCC as a prominent feature. In addition, BCC may represent a relatively common, although less specific, finding in many other genodermatoses. These include disorders of DNA replication/repair functions (Bloom, Werner, Rothmund-Thomson and Muir-Torre syndromes), genodermatoses affecting the folliculo-sebaceus unit (Brooke-Spiegler, Schöpf-Schulz-Passarge and Cowden syndromes), immune response (cartilage-hair hypoplasia and epidermodysplasia verruciformis) and melanin biosynthesis (oculocutaneous albinism and Hermansky-Pudlak syndrome), and some epidermal nevus syndromes. Further conditions occasionally associated with BCCs exist, but the significance of the association remains to be proven.

Carlson AM, Lindor NM, Litzow MR
Therapy-related myelodysplasia in a patient with Rothmund-Thomson syndrome.
Eur J Haematol. 2011; 86(6):536-40 [PubMed] Related Publications
Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder of which approximately 300 cases have been reported in the literature. Patients with RTS often present early in life with skeletal and dental abnormalities, short stature, juvenile cataracts, and a characteristic poikilodermal rash. They are at increased risk for the development of osteosarcoma that usually presents by the second decade of life. The genetic defects underlying RTS are truncating mutations in RECQL4, a gene involved with chromosomal stability. Several cases of primary hematological malignancies have been reported in RTS, but it is unclear whether patients with RTS are at higher risk to develop either primary or secondary hematological malignancies. We report a patient with RTS who presented to our clinic at the age of 7, subsequently developed multifocal and recurrent osteosarcoma that was followed by the development of a myelodysplastic syndrome with subsequent progression to acute myeloid leukemia.

Monnat RJ
Human RECQ helicases: roles in DNA metabolism, mutagenesis and cancer biology.
Semin Cancer Biol. 2010; 20(5):329-39 [PubMed] Free Access to Full Article Related Publications
Helicases use the energy of ATP hydrolysis to separate double-stranded nucleic acids to facilitate essential processes such as replication, recombination, transcription and repair. This article focuses on the human RECQ helicase gene and protein family. Loss of function of three different members has been shown to cause Bloom syndrome (BS), Werner syndrome (WS) and Rothmund-Thomson syndrome (RTS). This article outlines clinical and cellular features of these cancer predisposition syndromes, and discusses their pathogenesis in light of our understanding of RECQ helicase biochemical activities and in vivo functions. I also discuss the emerging role for RECQ helicases as predictors of disease risk and the response to therapy.

Simon T, Kohlhase J, Wilhelm C, et al.
Multiple malignant diseases in a patient with Rothmund-Thomson syndrome with RECQL4 mutations: Case report and literature review.
Am J Med Genet A. 2010; 152A(6):1575-9 [PubMed] Related Publications
RECQL4 mutations cause genetic instability and increase the risk of malignant disease. We report on a patient with compound heterozygosity for two novel RECQL4 mutations: mutation c.1919_1924delTCACAG, p.L640_A642delinsP in exon 12 of the RECQL4 gene and mutation c.1704+1G>A in intron 10 of the RECQL4 gene. He subsequently developed large cell anaplastic T cell lymphoma at the age of 9 years, diffuse large cell B lymphoma and osteosarcoma when he was 14 years old, and finally acute lymphatic leukemia when he was 21 years old. The most remarkable clinical features are young age, spontaneous remission of diffuse large cell lymphoma, and severe CNS and skin toxicity of cytotoxic treatment.

Kamenisch Y, Berneburg M
Progeroid syndromes and UV-induced oxidative DNA damage.
J Investig Dermatol Symp Proc. 2009; 14(1):8-14 [PubMed] Related Publications
Progeroid syndromes are a group of diseases characterized by signs of premature aging. These syndromes comprise diseases such as Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Hutchinson-Gilford syndrome, Fanconi anemia, and ataxia-telangiectasia, as well as xeroderma pigmentosum, trichothiodystrophy, and Cockayne syndrome. Clinical symptoms of premature aging are skin atrophy with loss of cutaneous elasticity, dysfunction of cutaneous appendices, degeneration of the central nervous system and an increased susceptibility for malignant tumors. Genetic defects in the repair of DNA damage can lead to progeroid syndromes, and it is becoming increasingly evident that direct DNA damage and indirect damage by highly reactive oxygen species play central roles in aging. The clinical signs of progeroid syndromes and the molecular aspects of UV (ultraviolet radiation)-induced oxidative stress in aging are discussed.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 8-14; doi:10.1038/jidsymp.2009.6.

Debeljak M, Zver A, Jazbec J
A patient with Baller-Gerold syndrome and midline NK/T lymphoma.
Am J Med Genet A. 2009; 149A(4):755-9 [PubMed] Related Publications
Three autosomal recessive disorders are associated with mutations in the RECQL4 gene: Rothmund-Thomson syndrome (RTS), Baller-Gerold syndrome (BGS), and RAPADILINO syndrome. BGS is characterized by two major clinical abnormalities: craniosynostosis and preaxial limb anomalies but not cancer development. We performed RECQL4 mutation detection in a patient with BGS and several clinical signs of RTS who developed a midline NK/T-cell lymphoma. Sequencing was used to identify RECQL4 mutations, and RNA analysis was used to examine expression of mRNA in leukocytes. The patient was found to be compound heterozygous for two mutations in exon 15, namely c.[2492_2493delAT] + c.[2506_2518del13bp]. We found that only the allele with 13 bp deletion was expressed in blood leukocytes. Our patient showed severe phenotypic abnormalities, with clinical signs of both BGS and RTS. She developed an extranodal NK/T-cell lymphoma, which is extremely rare in children of her age and is the first described case of BGS with development of a cancer. This case of a RECQL4-related disorder highlights the significant phenotypic overlap between the classically delineated RECQL4-associated syndromes and questions the need to redefine or combine these clinical entities.

Morihara K, Katoh N, Takenaka H, et al.
Granulomatous mycosis fungoides presenting as poikiloderma.
Clin Exp Dermatol. 2009; 34(6):718-20 [PubMed] Related Publications
Granulomatous mycosis fungoides (MF) is a rare subtype of MF, characterized by the histological presence of a granulomatous reaction, but distinct clinical characteristics are not present. A 41-year-old healthy man presented with poikiloderma, ichthyosis and erythematous scaly plaque. Histological examination of a biopsy taken from poikilodermic skin showed a granulomatous reaction to epidermotropic atypical lymphocytes. However, in other areas there were only findings of conventional MF without granuloma. Granulomatous MF may be associated with poikiloderma.

Siitonen HA, Sotkasiira J, Biervliet M, et al.
The mutation spectrum in RECQL4 diseases.
Eur J Hum Genet. 2009; 17(2):151-8 [PubMed] Free Access to Full Article Related Publications
Mutations in the RECQL4 gene can lead to three clinical phenotypes with overlapping features. All these syndromes, Rothmund-Thomson (RTS), RAPADILINO and Baller-Gerold (BGS), are characterized by growth retardation and radial defects, but RAPADILINO syndrome lacks the main dermal manifestation, poikiloderma that is a hallmark feature in both RTS and BGS. It has been previously shown that RTS patients with RECQL4 mutations are at increased risk of osteosarcoma, but the precise incidence of cancer in RAPADILINO and BGS has not been determined. Here, we report that RAPADILINO patients identified as carriers of the c.1390+2delT mutation (p.Ala420_Ala463del) are at increased risk to develop lymphoma or osteosarcoma (6 out of 15 patients). We also summarize all the published RECQL4 mutations and their associated cancer cases and provide an update of 14 novel RECQL4 mutations with accompanying clinical data.

Stinco G, Governatori G, Mattighello P, Patrone P
Multiple cutaneous neoplasms in a patient with Rothmund-Thomson syndrome: case report and published work review.
J Dermatol. 2008; 35(3):154-61 [PubMed] Related Publications
Rothmund-Thomson syndrome (RTS) is a rare genodermatosis characterized by early poikilodermatous skin lesions, often combined with juvenile cataracts, photosensitivity and bone defects. Data in the published work indicate that there is an increased risk of RTS patients developing malignant tumors. Herein, we report the multiple skin carcinomas observed in a case of RTS and review the published work on the occurrence of malignant tumors in these patients. We report the case of a 63-year-old male with RTS who developed multiple cutaneous neoplasms (three basal cell carcinomas, three squamous cell carcinomas and Bowen's disease) over the previous 15 years. A published work review confirmed that RTS is a genetic condition that predisposes subjects to the development of bone tumors, especially at an early age, and skin tumors at an adult age. Therefore, alongside careful osteoarticular monitoring to identify a bone tumor quickly, during the life of a patient suffering from the syndrome, it is just as important to take appropriate preventive action and monitor the possible onset of skin tumors.

Holman JD, Dyer JA
Genodermatoses with malignant potential.
Curr Opin Pediatr. 2007; 19(4):446-54 [PubMed] Related Publications
PURPOSE OF REVIEW: The delineation of syndromes carrying a predisposition to malignancy has led to great insights into the molecular biology of malignancy. Many such syndromes have cutaneous findings which can precede the development of neoplasia. Early recognition of the cutaneous stigmata of the genodermatoses with malignant potential can lead to early diagnosis and initiation of proper screening and treatment when indicated.
RECENT FINDINGS: This article reviews 'classic' genodermatoses with malignant potential and highlights recent recommendations for screening and treatment. Additionally more recently delineated syndromes and their cutaneous findings are discussed.
SUMMARY: Certain inherited syndromes with a risk of neoplasia exhibit characteristic cutaneous findings. Recognition of these findings by the astute practitioner can lead to early intervention which can impact the course of these rare diseases.

Hicks MJ, Roth JR, Kozinetz CA, Wang LL
Clinicopathologic features of osteosarcoma in patients with Rothmund-Thomson syndrome.
J Clin Oncol. 2007; 25(4):370-5 [PubMed] Related Publications
PURPOSE: Patients with Rothmund-Thomson syndrome (RTS) and RECQL4 gene mutations have an increased risk of developing osteosarcoma (OS). Because RTS is considered a genomic instability syndrome, patients may experience increased toxicity with chemotherapy. The purpose of this study was to summarize the clinical features and response to therapy of OS in patients with RTS. The results of this analysis will help to define treatment guidelines for this complex and rare condition.
PATIENTS AND METHODS: An international cohort of patients with RTS and OS was enrolled in an institutional review board-approved study at Baylor College of Medicine (Houston, TX). Medical records were reviewed, and the following information was extracted: clinical features, treatment, pathologic findings, and clinical outcome.
RESULTS: The median age at diagnosis of OS for the 12 patients was 10 years. The most common primary tumor sites were the long bones (femur, tibia); the most frequent histologic subtype was conventional OS. Histologic response to chemotherapy and outcome were similar to other published large series of sporadic OS. Eight patients are alive and disease free; four died as a result of cancer. Five patients required chemotherapy dose modifications, most commonly due to mucositis from doxorubicin.
CONCLUSION: Our results indicate that patients with RTS and OS are younger, but that their clinical behavior is similar to patients with sporadic OS. Our report suggests that these patients should initially be treated with conventional doses of chemotherapy as prescribed by current protocols; however, cautious and careful clinical observation is warranted to monitor for enhanced doxorubicin sensitivity in patients with RTS.

Kansara M, Thomas DM
Molecular pathogenesis of osteosarcoma.
DNA Cell Biol. 2007; 26(1):1-18 [PubMed] Related Publications
Osteosarcoma is a devastating but rare disease, whose study has illuminated both the basic biology and clinical management of cancer over the past 30 years. These contributions have included insight into the roles of key cancer genes such as the retinoblastoma tumor suppressor gene and TP53, the identification of familial cancer syndromes implicating DNA helicases, and dramatic improvements in survival by the use of adjuvant chemotherapy. This review provides a synoptic overview of our current understanding of the molecular causes of osteosarcoma, and suggests future directions for study.

Werner SR, Prahalad AK, Yang J, Hock JM
RECQL4-deficient cells are hypersensitive to oxidative stress/damage: Insights for osteosarcoma prevalence and heterogeneity in Rothmund-Thomson syndrome.
Biochem Biophys Res Commun. 2006; 345(1):403-9 [PubMed] Related Publications
Rothmund-Thomson syndrome (RTS) is a heterogeneous disease, associated with increased prevalence of osteosarcoma in very young patients with a mutated RECQL4 gene. In this study, we tested the ability of RECQL4 deficient fibroblasts, derived from a RTS patient to recover from hydrogen peroxide (H(2)O(2))-induced oxidative stress/damage. Immunoperoxidase staining for 8-oxo-deoxyguanosine (8-oxo-dG) formation in RTS and normal human fibroblasts were compared to assess DNA damage. We determined DNA synthesis, cell growth, cell cycle distribution, and viability in RTS and normal human fibroblasts before and after H(2)O(2) treatment. H(2)O(2) induces 8-oxo-dG formation in both RTS and normal fibroblasts. In normal human fibroblasts, RECQL4 was predominantly localized to cytoplasm; nuclear translocation and foci formation occurred in response to oxidant stimulation. After recovery from oxidant exposure, viable RTS fibroblasts showed irreversible growth arrest compared to normal fibroblasts. DNA synthesis decreased significantly in treated RTS cells, with concomitant reduction of cells in the S-phase. These results suggest that enhanced oxidant sensitivity in RECQL4 deficient fibroblasts derived from RTS patients could be attributed to abnormal DNA metabolism and proliferation failure. The ramifications of these findings on osteosarcoma prevalence and heterogeneity in RTS are discussed.

Kaviarasan PK, Prasad PV, Shradda, Viswanathan P
Kindler syndrome.
Indian J Dermatol Venereol Leprol. 2005 Sep-Oct; 71(5):348-50 [PubMed] Related Publications
Kindler syndrome is a rare autosomal recessive disorder associated with skin fragility. It is characterized by blistering in infancy, photosensitivity and progressive poikiloderma. The syndrome involves the skin and mucous membrane with radiological changes. The genetic defect has been identified on the short arm of chromosome 20. This report describes an 18-year-old patient with classical features like blistering and photosensitivity in childhood and the subsequent development of poikiloderma. The differential diagnosis of Kindler syndrome includes diseases like Bloom syndrome, Cockayne syndrome, dyskeratosis congenita, epidermolysis bullosa, Rothmund-Thomson syndrome and xeroderma pigmentosum. Our patient had classical cutaneous features of Kindler syndrome with phimosis as a complication.

Mann MB, Hodges CA, Barnes E, et al.
Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome.
Hum Mol Genet. 2005; 14(6):813-25 [PubMed] Related Publications
Type II Rothmund-Thomson syndrome (Type II RTS) is a rare autosomal recessive genetic disorder characterized by a congenital skin rash, birth defects of the skeleton, genomic instability and cancer predisposition. It is caused by mutations in the RECQL4 gene and thus represents one of the three cancer-prone genetic diseases that are caused by mutations in a RecQ helicase-encoding gene. Genomic instability has been suspected as a major underlying cause of this disease, and analyses of Type II RTS patient-derived cells demonstrate unusually high frequencies of chromosomal aberrations, suggesting the involvement of chromosomal instability. However, the nature of the instability induced by RECQL4 mutations has not been clearly defined. We created a viable Recql4 mutant mouse model. These mice exhibit a distinctive skin abnormality, birth defects of the skeletal system, genomic instability and increased cancer susceptibility in a sensitized genetic background. Thus, they provide a useful model for studying Type II RTS. In addition, we demonstrate that cells from these mutant mice have high frequencies of premature centromere separation and aneuploidy. Thus, our observations provide evidence for a previously unsuspected role for Recql4 in sister-chromatid cohesion, and suggest that the chromosomal instability may be the underlying cause of cancer predisposition and birth defects in these mutant mice.

Dahele MR, Benton EC, Hennessy A, et al.
A patient with Rothmund-Thomson syndrome and tongue cancer--experience of radiation toxicity.
Clin Oncol (R Coll Radiol). 2004; 16(5):371-2 [PubMed] Related Publications
We describe a male patient with Rothmund-Thomson syndrome (RTS) given postoperative radiotherapy for squamous carcinoma of the tongue. This was well tolerated. This is only the second reported case of oral cancer and radiotherapy in RTS.

Gelaw B, Ali S, Becker J
Rothmund-Thomson syndrome, Klippel-Feil syndrome, and osteosarcoma.
Skeletal Radiol. 2004; 33(10):613-5 [PubMed] Related Publications
We report on a 33 year old woman with Rothmund-Thompson syndrome, Klippel-Feil syndrome and osteosarcoma. We briefly discuss the relationship of these diseases and suggest that the cause for mental retardation is cerebral atrophy as shown on imaging.

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. 2003; 95(9):669-74 [PubMed] Related Publications
BACKGROUND: Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder associated with an increased predisposition to osteosarcoma. Children with RTS typically present with a characteristic skin rash (poikiloderma), small stature, and skeletal dysplasias. Mutations in the RECQL4 gene, which encodes a RecQ DNA helicase, have been reported in a few RTS patients. We examined whether a predisposition to developing osteosarcoma among an international cohort of RTS patients was associated with a distinctive pattern of mutations in the RECQL4 gene.
METHODS: We obtained clinical information about and biologic samples from 33 RTS patients (age range = 1-30 years). Eleven patients were diagnosed with osteosarcoma. All 21 exons and 13 short introns of the RECQL4 gene were sequenced from the genomic DNA of all subjects. Kaplan-Meier survival analysis was used to estimate the incidence of osteosarcoma among patients with and without mutations predicted to produce a truncated RECQL4 protein.
RESULTS: Twenty-three RTS patients, including all 11 osteosarcoma patients, carried at least one of 19 truncating mutations in their RECQL4 genes. The incidence of osteosarcoma was 0.00 per year in truncating mutation-negative patients (100 person-years of observation) and 0.05 per year in truncating mutation-positive patients (230 person-years of observation) (P =.037; two-sided log-rank test).
CONCLUSIONS: Mutations predicted to result in the loss of RECQL4 protein function occurred in approximately two-thirds of RTS patients and are associated with risk of osteosarcoma. Molecular diagnosis has the potential to identify those children with RTS who are at high risk of this cancer.

Further References

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. 2003; 95(9):669-74 [PubMed] Related Publications
BACKGROUND: Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder associated with an increased predisposition to osteosarcoma. Children with RTS typically present with a characteristic skin rash (poikiloderma), small stature, and skeletal dysplasias. Mutations in the RECQL4 gene, which encodes a RecQ DNA helicase, have been reported in a few RTS patients. We examined whether a predisposition to developing osteosarcoma among an international cohort of RTS patients was associated with a distinctive pattern of mutations in the RECQL4 gene.
METHODS: We obtained clinical information about and biologic samples from 33 RTS patients (age range = 1-30 years). Eleven patients were diagnosed with osteosarcoma. All 21 exons and 13 short introns of the RECQL4 gene were sequenced from the genomic DNA of all subjects. Kaplan-Meier survival analysis was used to estimate the incidence of osteosarcoma among patients with and without mutations predicted to produce a truncated RECQL4 protein.
RESULTS: Twenty-three RTS patients, including all 11 osteosarcoma patients, carried at least one of 19 truncating mutations in their RECQL4 genes. The incidence of osteosarcoma was 0.00 per year in truncating mutation-negative patients (100 person-years of observation) and 0.05 per year in truncating mutation-positive patients (230 person-years of observation) (P =.037; two-sided log-rank test).
CONCLUSIONS: Mutations predicted to result in the loss of RECQL4 protein function occurred in approximately two-thirds of RTS patients and are associated with risk of osteosarcoma. Molecular diagnosis has the potential to identify those children with RTS who are at high risk of this cancer.

Hicks MJ, Roth JR, Kozinetz CA, Wang LL
Clinicopathologic features of osteosarcoma in patients with Rothmund-Thomson syndrome.
J Clin Oncol. 2007; 25(4):370-5 [PubMed] Related Publications
PURPOSE: Patients with Rothmund-Thomson syndrome (RTS) and RECQL4 gene mutations have an increased risk of developing osteosarcoma (OS). Because RTS is considered a genomic instability syndrome, patients may experience increased toxicity with chemotherapy. The purpose of this study was to summarize the clinical features and response to therapy of OS in patients with RTS. The results of this analysis will help to define treatment guidelines for this complex and rare condition.
PATIENTS AND METHODS: An international cohort of patients with RTS and OS was enrolled in an institutional review board-approved study at Baylor College of Medicine (Houston, TX). Medical records were reviewed, and the following information was extracted: clinical features, treatment, pathologic findings, and clinical outcome.
RESULTS: The median age at diagnosis of OS for the 12 patients was 10 years. The most common primary tumor sites were the long bones (femur, tibia); the most frequent histologic subtype was conventional OS. Histologic response to chemotherapy and outcome were similar to other published large series of sporadic OS. Eight patients are alive and disease free; four died as a result of cancer. Five patients required chemotherapy dose modifications, most commonly due to mucositis from doxorubicin.
CONCLUSION: Our results indicate that patients with RTS and OS are younger, but that their clinical behavior is similar to patients with sporadic OS. Our report suggests that these patients should initially be treated with conventional doses of chemotherapy as prescribed by current protocols; however, cautious and careful clinical observation is warranted to monitor for enhanced doxorubicin sensitivity in patients with RTS.

Borg MF, Olver IN, Hill MP
Rothmund-Thomson syndrome and tolerance of chemoradiotherapy.
Australas Radiol. 1998; 42(3):216-8 [PubMed] Related Publications
Rothmund-Thomson syndrome (RTS) is a rare disorder with a predisposition for cutaneous and non-cutaneous malignancy. It is speculated that ultraviolet (UV) sensitivity and deficient DNA repair may account for this predisposition and influence the tolerance of chemoradiotherapeutic management. A case is reported of the management of an RTS patient with squamous cell carcinoma of the tongue who demonstrated increased radiosensitivity and tissue intolerance to chemotherapy.

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