Gene Summary

Gene:RECQL4; RecQ like helicase 4
Aliases: RECQ4
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, HGNC, Ensembl, GeneCard, Gene
Protein:ATP-dependent DNA helicase Q4
Source:NCBIAccessed: 31 August, 2019


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 (1994-2019)
Graph generated 31 August 2019 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.

Tag cloud generated 31 August, 2019 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 Publications136
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 Publications52
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 Publications33
Breast CancerRECQL4 and Breast Cancer View Publications10
Laryngeal CancerRECQL4 and Laryngeal 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

Salih A, Inoue S, Onwuzurike N
Rothmund-Thomson syndrome (RTS) with osteosarcoma due to
BMJ Case Rep. 2018; 2018 [PubMed] Related Publications
Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder with clinical features consisting of poikiloderma, skeletal abnormalities, sparse hair, absent or scanty eyelashes and eyebrows and short stature. Patients with RTS due to genetic mutations of

Mo D, Zhao Y, Balajee AS
Human RecQL4 helicase plays multifaceted roles in the genomic stability of normal and cancer cells.
Cancer Lett. 2018; 413:1-10 [PubMed] Related Publications
Human RecQ helicases that share homology with E. coli RecQ helicase play critical roles in diverse biological activities such as DNA replication, transcription, recombination and repair. Mutations in three of the five human RecQ helicases (RecQ1, WRN, BLM, RecQL4 and RecQ5) result in autosomal recessive syndromes characterized by accelerated aging symptoms and cancer incidence. Mutational inactivation of Werner (WRN) and Bloom (BLM) genes results in Werner syndrome (WS) and Bloom syndrome (BS) respectively. However, mutations in RecQL4 result in three human disorders: (I) Rothmund-Thomson syndrome (RTS), (II) RAPADILINO and (III) Baller-Gerold syndrome (BGS). Cells from WS, BS and RTS are characterized by a unique chromosomal anomaly indicating that each of the RecQ helicases performs specialized function(s) in a non-redundant manner. Elucidating the biological functions of RecQ helicases will enable us to understand not only the aging process but also to determine the cause for age-associated human diseases. Recent biochemical and molecular studies have given new insights into the multifaceted roles of RecQL4 that range from genomic stability to carcinogenesis and beyond. This review summarizes some of the existing and emerging knowledge on diverse biological functions of RecQL4 and its significance as a potential molecular target for cancer therapy.

Gnoli M, Ponti F, Sangiorgi L
Tumor Syndromes That Include Bone Tumors: An Update.
Surg Pathol Clin. 2017; 10(3):749-764 [PubMed] Related Publications
Tumor syndromes, including bone neoplasias, are genetic predisposing conditions characterized by the development of a pattern of malignancies within a family at an early age of onset. Occurrence of bilateral, multifocal, or metachronous neoplasias and specific histopathologic findings suggest a genetic predisposition syndrome. Additional clinical features not related to the neoplasia can be a hallmark of specific genetic syndromes. Mostly, those diseases have an autosomal dominant pattern of inheritance with variable percentage of penetrance. Some syndromic disorders with an increased tumor risk may show an autosomal recessive transmission or are related to somatic mosaicism. Many genetic tumor syndromes are known. This update is specifically focused on syndromes predisposing to osteosarcoma and chondrosarcoma.

van Rij MC, Grijsen ML, Appelman-Dijkstra NM, et al.
Rothmund-Thomson syndrome and osteoma cutis in a patient previously diagnosed as COPS syndrome.
Eur J Pediatr. 2017; 176(2):279-283 [PubMed] Free Access to Full Article Related Publications
We present a patient with poikiloderma, severe osteoporosis and a mild intellectual disability. At the age of 9 years, this patient was proposed to suffer from a novel disease entity designated as calcinosis cutis, osteoma cutis, poikiloderma and skeletal abnormalities (COPS) syndrome. At the age of 35, he was diagnosed with Hodgkin's lymphoma. Recently, biallelic pathogenic variants in the RECQL4 gene were detected (c.1048_1049delAG and c.1391-1G>A), confirming a diagnosis of Rothmund-Thomson syndrome (RTS). In the brother of this patient, who had a milder phenotype, a similar diagnosis was made.
CONCLUSION: We conclude that COPS syndrome never existed as a separate syndrome entity. Instead, osteoma cutis may be regarded as a novel feature of RTS, whereas mild intellectual disability and lymphoma may be underreported parts of the phenotype. What is new: • Osteoma cutis was not a known feature in Rothmund-Thomson patients. • Intellectual disability may be considered a rare feature in RTS; more study is needed. What is known: • RTS is a well-described syndrome caused by mutations in the RECQL4 gene. • Patients with RTS frequently show chromosomal abnormalities like, e.g. mosaic trisomy 8.

Scheibye-Knudsen M
Neurodegeneration in accelerated aging.
Dan Med J. 2016; 63(11) [PubMed] Related Publications
The growing proportion of elderly people represents an increasing economic burden, not least because of age-associated diseases that pose a significant cost to the health service. Finding possible interventions to age-associated disorders therefore have wide ranging implications. A number of genetically defined accelerated aging diseases have been characterized that can aid in our understanding of aging. Interestingly, all these diseases are associated with defects in the maintenance of our genome. A subset of these disorders, Cockayne syndrome, Xeroderma pigmentosum group A and ataxia-telangiectasia, show neurological involvement reminiscent of what is seen in primary human mitochondrial diseases. Mitochondria are the power plants of the cells converting energy stored in oxygen, sugar, fat, and protein into ATP, the energetic currency of our body. Emerging evidence has linked this organelle to aging and finding mitochondrial dysfunction in accelerated aging disorders thereby strengthens the mitochondrial theory of aging. This theory states that an accumulation of damage to the mitochondria may underlie the process of aging. Indeed, it appears that some accelerated aging disorders that show neurodegeneration also have mitochondrial dysfunction. The mitochondrial alterations may be secondary to defects in nuclear DNA repair. Indeed, nuclear DNA damage may lead to increased energy consumption, alterations in mitochondrial ATP production and defects in mitochondrial recycling, a term called mitophagy. These changes may be caused by activation of poly-ADP-ribose-polymerase 1 (PARP1), an enzyme that responds to DNA damage. Upon activation PARP1 utilizes key metabolites that attenuate pathways that are normally protective for the cell. Notably, pharmacological inhibition of PARP1 or reconstitution of the metabolites rescues the changes caused by PARP1 hyperactivation and in many cases reverse the phenotypes associated with accelerated aging. This implies that modulation of PARP1 or the downstream metabolites may be a therapeutic strategy for treating accelerated aging disorders and potentially age-associated neurological decline seen in the normal population.

Giordano CN, Yew YW, Spivak G, Lim HW
Understanding photodermatoses associated with defective DNA repair: Syndromes with cancer predisposition.
J Am Acad Dermatol. 2016; 75(5):855-870 [PubMed] Related Publications
Hereditary photodermatoses are a spectrum of rare photosensitive disorders that are often caused by genetic deficiency or malfunction of various components of the DNA repair pathway. This results clinically in extreme photosensitivity, with many syndromes exhibiting an increased risk of cutaneous malignancies. This review will focus specifically on the syndromes with malignant potential, including xeroderma pigmentosum, Bloom syndrome, and Rothmund-Thomson syndrome. The typical phenotypic findings of each disorder will be examined and contrasted, including noncutaneous identifiers to aid in diagnosis. The management of these patients will also be discussed. At this time, the mainstay of therapy remains strict photoprotection; however, genetic therapies are under investigation.

Kumari J, Hussain M, De S, et al.
Mitochondrial functions of RECQL4 are required for the prevention of aerobic glycolysis-dependent cell invasion.
J Cell Sci. 2016; 129(7):1312-8 [PubMed] Related Publications
Germline mutations in RECQL4 helicase are associated with Rothmund-Thomson syndrome, which is characterized by a predisposition to cancer. RECQL4 localizes to the mitochondria, where it acts as an accessory factor during mitochondrial DNA replication. To understand the specific mitochondrial functions of RECQL4, we created isogenic cell lines, in which the mitochondrial localization of the helicase was either retained or abolished. The mitochondrial integrity was affected due to the absence of RECQL4 in mitochondria, leading to a decrease in F1F0-ATP synthase activity. In cells where RECQL4 does not localize to mitochondria, the membrane potential was decreased, whereas ROS levels increased due to the presence of high levels of catalytically inactive SOD2. Inactive SOD2 accumulated owing to diminished SIRT3 activity. Lack of the mitochondrial functions of RECQL4 led to aerobic glycolysis that, in turn, led to an increased invasive capability within these cells. Together, this study demonstrates for the first time that, owing to its mitochondrial functions, the accessory mitochondrial replication helicase RECQL4 prevents the invasive step in the neoplastic transformation process.

Jen M, Nallasamy S
Ocular manifestations of genetic skin disorders.
Clin Dermatol. 2016 Mar-Apr; 34(2):242-75 [PubMed] Related Publications
Genetic skin diseases, or genodermatoses, often have extracutaneous manifestations. Ocular manifestations in particular can have significant clinical implications, like blindness. Other manifestations, such as the corneal opacities that occur in X-linked ichthyosis, are asymptomatic but characteristic of a particular genodermatosis. Ophthalmologic examination can aid in diagnosis when characteristic findings are seen. The genodermatoses with ocular manifestations will be reviewed, but neurocutaneous, syndromes, genetic pigmentary disorders, and genetic metabolic diseases are not included because they are covered elsewhere in this issue.

Zils K, Klingebiel T, Behnisch W, et al.
Osteosarcoma in patients with Rothmund-Thomson syndrome.
Pediatr Hematol Oncol. 2015; 32(1):32-40 [PubMed] Related Publications
BACKGROUND: Rothmund-Thomson syndrome (RTS) is associated with an increased risk of osteosarcoma, but information about affected patients is limited.
PROCEDURE: Seven patients with osteosarcoma, treated in the Cooperative Osteosarcoma Study Group-trials, had a diagnosis of RTS. Their patient-, tumor- and treatment-related variables and outcome were reviewed retrospectively.
RESULTS: Median age at diagnosis of osteosarcoma was 13 years (range 7-16), five were female, two male. Tumor involved proximal tibia (n = 4), distal tibia (n = 1), distal fibula (n = 1) and proximal ulna (n = 1). Three patients had metastatic disease at diagnosis. All patients received surgery and chemotherapy. Four of seven patients required dose modifications and three of them terminated treatment prematurely. Complete resection of the primary tumor was achieved in all individuals. Two of three affected patients failed to achieve surgical clearance of their primary metastases and died. The third patient relapsed with multiple metastases and died. Two of four patients with localized disease were alive in first complete remission, a third patient in second complete remission after recurrence and a fourth patient died of acute leukemia, while still in first complete remission of osteosarcoma.
CONCLUSIONS: Patients with RTS and osteosarcoma may be cured of their cancer with appropriate multimodal therapy. They should be treated like other osteosarcoma patients but preexisting disorders, needs for special support and development of toxicities have to be considered.

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.

Suhasini AN, Brosh RM
DNA helicases associated with genetic instability, cancer, and aging.
Adv Exp Med Biol. 2013; 767:123-44 [PubMed] Free Access to Full Article Related Publications
DNA helicases have essential roles in the maintenance of genomic -stability. They have achieved even greater prominence with the discovery that mutations in human helicase genes are responsible for a variety of genetic disorders and are associated with tumorigenesis. A number of missense mutations in human helicase genes are linked to chromosomal instability diseases characterized by age-related disease or associated with cancer, providing incentive for the characterization of molecular defects underlying aberrant cellular phenotypes. In this chapter, we discuss some examples of clinically relevant missense mutations in various human DNA helicases, particularly those of the Iron-Sulfur cluster and RecQ families. Clinically relevant mutations in the XPD helicase can lead to Xeroderma pigmentosum, Cockayne's syndrome, Trichothiodystrophy, or COFS syndrome. FANCJ mutations are associated with Fanconi anemia or breast cancer. Mutations of the Fe-S helicase ChlR1 (DDX11) are linked to Warsaw Breakage syndrome. Mutations in the RecQ helicases BLM and WRN are linked to the cancer-prone disorder Bloom's syndrome and premature aging condition Werner syndrome, respectively. RECQL4 mutations can lead to Rothmund-Thomson syndrome, Baller-Gerold syndrome, or RAPADILINO. Mutations in the Twinkle mitochondrial helicase are responsible for several neuromuscular degenerative disorders. We will discuss some insights gained from biochemical and genetic studies of helicase variants, and highlight some hot areas of helicase research based on recent developments.

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.

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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