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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. The diagnosis of RTS is established by clinical findings — in particular, the characteristic rash. Routine cytogenetic studies of lymphocytes or skin fibroblasts may reveal mosaic abnormalities of chromosome 8, such as trisomy 8, partial 8q duplication, and tetrasomy 8q, which have been seen in individuals with RTS but are not diagnostic. Skin biopsy may show poikilodermatous changes, which are nonspecific but consistent with RTS. RECQL4 is the only gene associated with RTS to date; although evidence suggests genetic heterogeneity, no other locus for RTS has been identified. Molecular testing of RECQL4 is clinically available.
Management. Treatment of manifestations: pulsed dye laser to treat the telangiectatic component of the rash; surgical removal of cataracts; and standard treatment for cancer. Prevention of secondary complications: use of sunscreens with both UVA and UVB protection to prevent skin cancer. Surveillance: annual physical and eye examination, monitoring of skin for lesions with unusual color or texture, screening for osteosarcoma. Agents/circumstances to avoid: excessive sun exposure.
Genetic counseling. RTS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.
A diagnosis of Rothmund-Thomson syndrome (RTS) can be made in individuals in whom poikiloderma, the classic rash, shows the following pattern of onset, spread, and appearance:
Poikiloderma starts in infancy, usually between age three to six months, as erythema on the cheeks and face (acute phase), and spreads to involve the extensor surfaces of the extremities. The trunk and abdomen are usually spared; the buttocks may be involved. Gradually, over a period of months to years, the rash enters a more chronic phase with reticulated hyper- and hypopigmentation, telangiectases, and areas of punctate atrophy. These changes, described as poikiloderma, persist throughout life.
A diagnosis of probable RTS can be made if the rash is atypical (either in appearance, distribution, or pattern of onset and spread) and two other features of RTS are present:
Sparse scalp hair, eyelashes, and/or eyebrows
Small size, usually symmetrical for height and weight
Gastrointestinal disturbance as young children, usually consisting of chronic vomiting and diarrhea, sometimes requiring feeding tubes
Radial ray defects
Radiographic bone abnormalities that include dysplasias, absent or malformed bones, osteopenia, abnormal trabeculation
Dental abnormalities that include rudimentary or hypoplastic teeth, enamel defects, delayed tooth eruption
Nail abnormalities such as dysplastic or poorly formed nails
Hyperkeratosis particularly of the soles of the feet
Cataracts, usually juvenile, bilateral
Cancers including skin cancers (basal cell carcinoma and squamous cell carcinoma) and in particular bone cancer (osteosarcoma)
Cytogenetic testing. Routine cytogenetic testing of lymphocytes or skin fibroblasts may reveal abnormalities of chromosome 8 (e.g., trisomy 8, partial 8q duplication, tetrasomy 8q) caused by the presence of an isochromosome 8q [Miozzo et al 1998]. The percentage of cytogenetically abnormal cells can vary. Note: (1) Many individuals with RTS have normal cytogenetic studies. (2) Routine cytogenetic testing is not a useful adjunct to clinical diagnosis.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. RECQL4 is the only gene associated with RTS to date [Kitao et al 1999, Lindor et al 2000, Wang et al 2003a].
Other loci. Although evidence suggests genetic heterogeneity, no other locus for RTS has been identified.
Clinical testing
Sequence analysis. Sequence analysis of all coding regions and short introns detects mutations in approximately 66% of affected individuals [Wang et al 2003b].
Deletion/duplication analysis. Using methods such as quantitative real-time PCR, small deletions in RECQL4 may be detected. The sensitivity, specificity and accuracy of such testing for RTS are not known.
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|---|
| RECQL4 | Sequence analysis | Sequence variants | 66% | Clinical
 |
| Deletion/ duplication analysis 1 | Partial- or whole-gene deletions | Unknown |
1. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation dependent probe amplification (MLPA), or array CGH may be used.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Confirming the diagnosis in a proband. Sequence analysis typically does not identify a disease-causing mutation in approximately 34% of individuals with RTS that has been attributed to genetic heterogeneity.
Deletion testing for RECQL4 is clinically available; however, it is unknown whether a significant number of individuals with RTS harbor RECQL4 deletions. Deletion testing may be most helpful in people with RTS when only one RECQL4 mutation is identified by sequencing.
Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.
Two other phenotypes are associated with mutations in RECQL4:
RAPADILINO, an autosomal recessive disorder described in the Finnish population, is characterized by irregular pigmentation with café au lait spots (but no poikiloderma), small stature, palate defects, radial ray defects, patellar hypoplasia, and GI abnormalities. Direct sequencing of the RECQL4 gene in the initial cohort of Siitonen and colleagues revealed that the majority of those with RAPADILINO were homozygous for IVS7+2delT (termed Fin-major mutation), which destroys the 5' splice site of intron 7 causing in-frame deletion of exon 7 [Siitonen et al 2003]. The other mutations found in compound-heterozygous individuals include inactivating mutations of the RECQL4 gene typical of RTS [Siitonen et al 2009]. Follow-up studies by this group of investigators revealed seven new RECQL4 mutations in patients with RAPADILINO, and importantly, the development of osteosarcomas and lymphomas in some of these patients.
Baller-Gerold syndrome (BGS) is characterized by radial ray defects, skeletal dysplasia, short stature, and craniosynostosis, a feature not usually associated with RTS. RECQL4 mutations have been reported in five individuals (three unrelated and two sibs) with BGS [Van Maldergem et al 2006, Siitonen et al 2009].
Individuals with Rothmund-Thomson syndrome (RTS) can exhibit few or many of the associated clinical features. The severity of the features (such as rash) can also vary.
Skin. Children with RTS typically develop a rash between age three and six months but occasionally as late as age two years. The skin changes begin as erythema, swelling, and occasionally blistering on the face, then spread to the buttocks and extremities. Gradually, over a period of months to years, the skin changes become chronic with reticulated hypo- and hyperpigmentation, telangiectases, and punctate atrophy, which persist throughout life.
Hyperkeratotic lesions occur in approximately one-third of individuals.
Uncommon but reported findings [Mak et al 2006] include:
Calcinosis, the formation of calcium deposits in the skin usually at the site of an injury. Note: Calcinosis cutis differs from osteoma cutis, which is true bone formation.
Porokeratosis, a sign of disordered keratinization. This has been reported in one person with RTS and, thus, may or may not be a related finding.
Teeth. Many individuals with RTS also have dental abnormalities, such as rudimentary or hypoplastic teeth, microdontia, delayed eruption, supernumerary and congenitally missing teeth, ectopic eruption, and increased incidence of caries [Kraus et al 1970, Haytaç et al 2002].
Hair. Children with RTS may have sparse scalp hair or even total alopecia. Eyelashes and/or eyebrows may also be sparse or absent.
Growth. Most individuals with RTS are the result of a full-term pregnancy but tend to have low birth weight and length for gestational age. They remain small throughout their lives, usually below the fifth percentile for both weight and height. Growth hormone levels appear to be normal.
Skeleton. A study of 28 individuals with RTS examined by skeletal survey found that 75% had at least one major skeletal abnormality [Mehollin-Ray et al 2008].
Findings can include generalized skeletal dysplasia (as visualized on x-ray) and can take the form of abnormal trabeculation with longitudinal metaphyseal striations, multiple transverse metaphyseal growth arrest lines, and dysplastic changes in the phalanges. They may have absent or malformed bones (e.g., aplastic radii, hypoplastic thumbs), delayed bone formation, osteopenia, and hypoplasia or absent patella [Green & Rickett 1998].
Gastrointestinal. Some infants or young children with RTS have feeding difficulties or other gastrointestinal problems, such as chronic emesis or diarrhea. Although feeding tubes are occasionally required, most of these problems resolve spontaneously during childhood [Wang et al 2001].
Hematologic. Benign and malignant hematologic abnormalities, including isolated anemia and neutropenia, myelodysplasia, aplastic anemia, and leukemia, have been reported in individuals with RTS [Knoell et al 1999, Porter et al 1999, Narayan et al 2001, Pianigiani et al 2001].
Cataract. The prevalence of juvenile cataracts has been reported in some series to be as high as 50%, with onset usually between age three and seven years. Earlier onset (as early as the first few months of life) and later onset (teens or adulthood) have also been reported. Most of the reports of early-onset, bilateral juvenile cataracts come from descriptions from Europe. More recently, in an international cohort of 41 individuals with RTS (age range nine months to 42 years), the prevalence of cataracts was found to be much lower (<10%), and no cases were bilateral [Wang et al 2001].
Cancer. The overall prevalence of cancers in adults with RTS is unknown.
Osteosarcoma is the most commonly reported malignancy [Green & Rickett 1998, Wang et al 2003b]. In a contemporary cohort of those with RTS, the prevalence of osteosarcoma was 30% [Wang et al 2001]. The median age at diagnosis, 11 years, was slightly younger than that seen in the general population. Families in which more than one sib had RTS and osteosarcoma have been identified [Lindor et al 2000, Wang et al 2001].
Children with RTS are also at increased risk of developing skin cancer, including basal cell carcinoma and squamous cell carcinoma [Borg et al 1998], and more recently melanoma [Howell & Bray 2008]. The prevalence of skin cancers in individuals with RTS is estimated from the literature to be 5%. Skin cancer can occur at any age, although it often occurs earlier than in the general population. Piquero-Casals et al [2002] report on a consanguineous Brazilian family with classic features of RTS including poikiloderma and bilateral cataracts. All three affected sibs developed cutaneous squamous cell carcinoma in adulthood (age 35-48 years). The cancers occurred on non-sun-exposed surfaces.
Two individuals with RTS have been reported to have a second malignancy. One developed non-Hodgkin lymphoma nine years after chemotherapy for osteosarcoma [Spurney et al 1998] and the other developed Hodgkin lymphoma eight years after therapy for osteosarcoma [Wang et al 2001]. In general, follow-up time for individuals with RTS and osteosarcoma has been too short to draw conclusions about the risk of secondary malignancy.
Because RTS is felt to be a chromosome instability syndrome, those treated for malignancy may, in theory, be more sensitive to the effects of chemotherapy and have a higher risk for second malignancy. However, from the limited number of cases reported, it appears that most individuals with RTS and cancer treated with chemotherapy have not had significantly increased toxicities, although some individuals may experience increased mucositis with doxorubicin treatment [Hicks et al 2007].
Other. Infertility has been described in affected males and females; however, a few affected females have had normal pregnancies, and a few males have produced offspring.
Immunologic function appears to be intact. One individual with combined immunodeficiency underwent successful hematopoietic stem cell transplantation (HSCT) [Broom et al 2006].
Most individuals with RTS appear to have normal intelligence.
Life span, in the absence of malignancy, is probably normal, although follow-up data in the published literature are limited. Death from metastatic osteosarcoma has been reported in a number of children and adults with RTS.
The correlation between presence of mutations in RECQL4 and presence of osteosarcoma in RTS has been evaluated [Wang et al 2003b]. Thirty-three individuals with RTS were screened for mutations in RECQL4. Twenty-three of these individuals were found to have at least one truncating mutation. All 11 of those with osteosarcoma had truncating mutations. Using Kaplan-Meier analysis, it was found that those with truncating mutations were at increased risk for developing osteosarcoma. The incidence of osteosarcoma was 0.05 per year in subjects with one or two truncating mutations (230 person-years of observation) and 0.00 per year in individuals with no RECQL4 mutations (100 person-years of observation) (p<0.04).
"Poikiloderma congenitale," the name given by M. Sidney Thomson to the disorder he described in 1923, has been used in the literature to describe RTS in the past.
RTS is a rare disorder. Since its original description by Auguste Rothmund in the Bavarian Alps in Austria in 1868, a total of approximately 300 individuals have been reported in the English-language literature.
RTS has been described in all races and many nationalities. No population appears to be at higher or lower risk for the disorder. However, specific mutations may exist within certain ethnic groups.
Carrier frequency for RTS is unknown.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
The differential diagnosis of Rothmund-Thomson syndrome (RTS) includes the following disorders that can exhibit features of poikiloderma but are otherwise clinically distinct from RTS.
Bloom syndrome is characterized by severe pre- and postnatal growth retardation. The rash in Bloom syndrome is characterized by neonatal blistering, distinctive facial erythema, and telangiectases and develops in sun-exposed areas of the skin; it is not a true poikiloderma. Individuals with Bloom syndrome may also have café au lait spots or paired hypopigmented and hyperpigmented spots. Recurrent infections (otitis media and pneumonia), chronic pulmonary disease, and diabetes mellitus are common. Many have learning disabilities. The most common cause of death is cancer (epithelial, hematopoietic, lymphoid, connective tissue, germ cell, nervous system, or kidney), which occurs at younger-than-usual ages. A greatly increased frequency of sister chromatid exchanges (SCEs) in cells exposed to bromodeoxyuridine (BrdU) is diagnostic. Bloom syndrome is the only disorder in which such evidence of hyper-recombination is known to occur. Mutations in BLM are causative. Inheritance is autosomal recessive.
Werner syndrome is characterized by the premature appearance of features associated with normal aging and by cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first symptom is the lack of a growth spurt during the early teen years. Initial findings (usually observed in the 20s) include loss and graying of hair, alopecia, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Myocardial infarction and cancer are the most common causes of death, typically at approximately age 48 years. Mutations in WRN are causative. Inheritance is autosomal recessive.
Ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between age one and four years, oculomotor apraxia, frequent infections, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation. Mutations in the ATM gene are causative. Inheritance is autosomal recessive.
Fanconi anemia (FA) is characterized by a range of physical abnormalities, bone marrow failure in the first decade, and myelodysplasia (~5%) or acute myelogenous leukemia (~10%). Physical abnormalities include short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eye, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity, and central nervous system; hearing loss; hypogonadism; and developmental delay. Individuals with FA are also at increased risk of developing solid tumors, particularly of the head and neck, skin, GI tract, and genital tract. Mutations in at least 13 genes are causative. Inheritance is autosomal recessive.
Xeroderma pigmentosum (XP) is characterized by sun sensitivity, ocular involvement, and greater than 1000-fold increased risk of cutaneous and ocular neoplasms. Half of affected individuals demonstrate acute sun sensitivity (severe sunburn with blistering or persistent erythema on minimal sun exposure) from early infancy. Marked freckling of the face of a child under age two years is typical of XP and rarely seen in normal children. Most individuals with XP develop xerosis (dry skin) and poikiloderma (the constellation of hyper- and hypopigmentation, atrophy, and telangiectasia). Ophthalmologic abnormalities include keratitis, loss of lashes, and atrophy of the skin of the lids. The median age of onset of non-melanoma skin cancer is before ten years. Approximately 30% have neurologic manifestations. Xeroderma pigmentosum is known to be associated with mutations in XPA, ERCC3 (XPB), XPC, ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG), ERCC1 (XPH), and POLH. Inheritance is autosomal recessive.
Kindler syndrome. Individuals with Kindler syndrome have acral bullae at birth and after minor trauma, diffuse poikiloderma with striate and reticulate atrophy, widespread eczematoid dermatitis, keratotic papules of the hands, feet, elbows, and knees, marked photosensitivity, esophageal and urethral strictures, webbing of fingers and toes, and no increased risk for cataract or malignancy. Mutations in FERMT1 (KIND1) are causative; both autosomal dominant and autosomal recessive inheritance are reported.
Dyskeratosis congenita. The onset of poikiloderma and nail dystrophy occurs in late childhood. Individuals with dyskeratosis congenita do not have skeletal abnormalities or cataracts. They are at risk for aplastic anemia and skin cancers. Mutations in six genes are causative and associated with different modes of inheritance: DKC1 (X-linked recessive); NHP2 and NOP10 (autosomal recessive; and TERC (autosomal dominant), TERT (autosomal recessive or dominant), and TINF2 (autosomal dominant or sporadic) [Walne & Dokal 2009].
Poikiloderma with neutropenia (PN, Navajo poikiloderma) was first described in Navajo individuals and has now been described in a few European kindreds as well. The onset of rash in individuals with PN differs from that seen in RTS in that it tends to be more eczematous and to start peripherally and spread centrally. The rash does not spare the trunk. Radial ray abnormalities and hair abnormalities are not seen. Individuals with PN have clinically significant neutropenia with recurrent sinopulmonary infections. Paronychias are commonly seen. Mutations in RECQL4 have not been identified in individuals with PN [Erickson 1999, Wang et al 2003a]. The causative gene(s) are not known. Inheritance is autosomal recessive.
To establish the extent of disease in an individual diagnosed with Rothmund-Thomson syndrome (RTS), the following evaluations are recommended:
Baseline skeletal radiographs by age five years to define underlying skeletal dysplasias
Ophthalmologic examination because of increased incidence of cataracts
Baseline complete blood count
Dermatologic. Pulsed dye laser has been used to treat the telangiectatic component of the rash [Potozkin & Geronemus 1991].
Cataract. Visually significant cataracts require surgical removal.
Hematologic. Individuals with clinical evidence of anemia or cytopenias should be evaluated by CBC and bone marrow biopsy if clinically indicated.
Cancer. Affected individuals who develop cancer should be treated according to standard chemotherapy and/or radiation regimens. Doses should be modified only if the patient experiences significantly increased toxicities.
Avoidance of excessive sun exposure and use of sunscreens with both UVA and UVB protection are recommended to prevent skin cancer.
The following are appropriate:
Annual evaluation by a physician familiar with RTS
For individuals without cataracts, yearly eye examinations for screening purposes
For parents of an affected individual at the time of initial diagnosis, counseling with regard to risk for associated medical problems (e.g., cancer, cataract) and development of a surveillance plan
Close monitoring of the skin for lesions with unusual color or texture, as individuals with RTS are at risk for skin cancers
Skeletal radiographs when clinical suspicion of osteosarcoma is present
Currently, no specific guidelines exist with regard to screening for osteosarcoma. However, the high risk for this potentially lethal malignancy, particularly for those individuals with deleterious mutations in the RECQL4 gene, argues for prompt evaluation of any symptoms or signs (including bone pain, swelling, or an enlarging lesion on a limb) suggestive of osteosarcoma.
Because of reports of more than one sib with osteosarcoma, particularly close attention for any evidence of malignancy should be paid to family members of an individual with RTS and osteosarcoma or individuals with documented RECQL4 mutations.
Exposure to heat or sunlight may exacerbate the rash in some individuals.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Given the theoretical potential for tumorigenesis, growth hormone (GH) therapy is not recommended for individuals who have normal GH levels. For individuals with documented GH deficiency, routine treatment with growth hormone is appropriate.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Rothmund-Thomson syndrome (RTS) is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected individual are obligate heterozygotes and thus carry a mutation in the disease-causing gene.
No abnormalities have been reported in parents of individuals with RTS, although this issue has not been carefully studied.
Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic, although this issue has not been carefully studied.
Offspring of a proband
The offspring of an individual with RTS are obligate heterozygotes (carriers).
The carrier frequency for RTS is unknown; however, given the rarity of the disorder, the likelihood that an affected individual will have children with a carrier is very low. Exceptions include areas in which a founder mutation may be present (e.g., Western Austria, where Rothmund originally described RTS) and the Mennonite population.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known.
Family planning
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.
Ultrasound examination. Ultrasound examination at 16-18 weeks' gestation may detect aplastic radii; however, given the variability of clinical findings, the absence of skeletal abnormalities on ultrasound examination in a fetus at risk does not exclude the possibility of RTS.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | HGMD |
|---|---|---|---|
| RECQL4 | 8q24.3 | ATP-dependent DNA helicase Q4 | RECQL4 |
Normal allelic variants. RECQL4 has 21 exons. The gene has a coding sequence consisting of 3,627 bases based on the open reading frame of the initial cDNA clone. Sequencing has identified normal allelic variants.
Pathologic allelic variants. Approximately 50 different mutations spanning exons 5 through 21 and introns 1 through 17 have been published [Siitonen et al 2009].
Normal gene product. The normal gene encodes ATP-dependent DNA helicase Q4, a protein [Kitao et al 1998] of 1,208 amino acids that bears homology to a family of proteins known as RecQ helicases. RecQ helicases are DNA helicases — or enzymes that promote DNA unwinding, allowing many basic cellular processes to occur — that probably play a role in maintaining chromosomal integrity [Chakraverty & Hickson 1999, van Brabant et al 2000, Mohaghegh & Hickson 2001]. They all share a conserved 350-amino acid helicase region consisting of seven consensus motifs, with 42%-44% identity in this region; they all have ATP- and Mg-binding sites. RecQ helicases are found in many species, from worms to bacteria to yeast. In humans, five RecQ helicases have been identified; three are associated with diseases: Bloom syndrome, Werner syndrome, and RTS.
The exact role of ATP-dependent DNA helicase Q4 is not known, but recent work has shown that it may play a role in the initiation of DNA replication [Sangrithi et al 2005].
Abnormal gene product. The majority of mutated alleles identified thus far in individuals with RECQL4-related disorders are predicted to encode absent or truncated proteins [Kitao et al 1999, Siitonen et al 2009].
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page
No specific guidelines regarding genetic testing for this disorder have been developed.
Dr. Wang is a pediatric oncologist at Texas Children's Cancer Center with particular interest in treating children with solid tumors, including osteosarcoma.
Dr. Plon is a board-certified geneticist with expertise in cancer genetics and the control of genomic stability. She directs the Baylor Cancer Genetics Clinic at Texas Children's Hospital/Baylor College of Medicine and is actively involved in genetic evaluation and counseling for families at increased risk for cancer.
7 April 2009 (me) Comprehensive update posted live
2 October 2006 (cd) Revision: deletion/duplication analysis clinically available
26 September 2006 (me) Comprehensive update posted to live Web site
5 January 2005 (sp) Revision: Genetically Related Disorders
9 June 2004 (me) Comprehensive update posted to live Web site
19 April 2004 (cd) Revision: clinical testing availability
31 May 2002 (me) Comprehensive update posted to live Web site
6 October 1999 (me) Review posted to live Web site
1 July 1999 (sp) Original submission
