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Rothmund-Thomson Syndrome

, MD and , MD, PhD, FACMG.

Author Information

Initial Posting: ; Last Revision: August 11, 2016.

Summary

Clinical characteristics.

Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma; sparse hair, eyelashes, and/or eyebrows; small stature; skeletal and dental abnormalities; cataracts; and an increased risk for cancer, especially osteosarcoma. The skin is typically normal at birth; the rash of RTS develops between age three and six months as erythema, swelling, and blistering on the face and subsequently spreads to the buttocks and extremities. The rash evolves over months to years into the chronic pattern of reticulated hypo- and hyperpigmentation, punctate atrophy, and telangiectasias, collectively known as poikiloderma. Hyperkeratotic lesions occur in approximately one third of individuals. Skeletal abnormalities include radial ray defects, ulnar defects, absent or hypoplastic patella, and osteopenia.

Diagnosis/testing.

The diagnosis of RTS is established by clinical findings – in particular, the characteristic rash. Identification of biallelic pathogenic variants in RECQL4 on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

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; calcium and vitamin D supplements may be warranted in individuals with osteopenia or a history of fractures.

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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the RECQL4 pathogenic variants in the family are known.

Diagnosis

Suggestive Findings

Rothmund-Thomson syndrome (RTS) should be suspected in individuals with the classic rash of RTS:

  • Acute phase:
    • Starts in infancy, usually between age three and six months
    • Erythema on the cheeks and face
    • Spreads to involve the extensor surfaces of the extremities
    • Typically, sparing of the trunk and abdomen; possible involvement of the buttocks
  • Chronic phase:
    • Gradually develops over a period of months to years
    • Reticulated hyper- and hypopigmentation, telangiectasias, and areas of punctate atrophy (i.e., poikiloderma)
    • Persists throughout life

If the rash is atypical (either in appearance, distribution, or pattern of onset and spread), a diagnosis of probable RTS can be made if two other features of RTS are present:

  • Sparse scalp hair, eyelashes, and/or eyebrows
  • Small size, usually symmetric for height and weight
  • Gastrointestinal disturbance as young children, usually consisting of chronic vomiting and diarrhea, sometimes requiring feeding tubes
  • Skeletal abnormalities including radial ray defects, ulnar defects, absent or hypoplastic patella, 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)

Establishing the Diagnosis

The diagnosis of RTS is established in a proband with the classic rash of RTS with onset, spread, and appearance described above. Identification of biallelic pathogenic variants in RECQL4 on molecular genetic testing (see Table 1) establishes the diagnosis if clinical features are inconclusive.

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of RECQL4 is performed first. For this gene, optimal sequence analysis would include not only the coding and splice junction regions but also the exceptionally short introns, where a small deletion may be pathogenic because it renders the intron too short for proper splicing [Wang et al 2002] (see Molecular Genetics). Gene-targeted deletion/duplication analysis may be considered if only one or no pathogenic variant is found; however, no exon or whole-gene deletions/duplications have been identified as a cause of RTS.
  • A multigene panel that includes RECQL4 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost.
    For more information on multigene panels click here.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes RECQL4) fails to confirm a diagnosis in an individual with features of RTS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation). For more information on comprehensive genomic testing click here.

Table 1.

Molecular Genetic Testing Used in Rothmund-Thomson Syndrome

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
RECQL4Sequence analysis 366% 4
Gene-targeted deletion/duplication analysis 5Unknown 6 (i.e., no data on gene-targeted del/dup analysis are available)
Unknown 7NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

7.

None published to date

Test characteristics. See Clinical Utility Gene Card [Larizza et al 2013] for information on test characteristics including sensitivity and specificity.

Clinical Characteristics

Clinical Description

Individuals with Rothmund-Thomson syndrome (RTS) can exhibit few or many of the associated clinical features. The severity of the features (e.g., rash) can also vary.

Skin. Children with RTS typically develop a rash between ages 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, telangiectasias, 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 the following:

  • 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 including rudimentary or hypoplastic teeth, microdontia, delayed eruption, supernumerary and congenitally missing teeth, ectopic eruption, and increased incidence of caries [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 abnormal trabeculation with longitudinal and transverse metaphyseal striations, dysplastic changes in the phalanges, absent or malformed bones (e.g., aplastic radii, malformed ulnae, hypoplastic thumbs), fused bones, osteopenia, and hypoplastic or absent patella [Green & Rickett 1998].

Gastrointestinal. Some infants or young children with RTS have feeding difficulties or other gastrointestinal problems including 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 ages 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. In an international cohort of 41 individuals with RTS (age range 9 months to 42 years), the prevalence of cataracts was found to be much lower (<10%), and none of the individuals had bilateral cataracts [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 2003]. In a 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].

Individuals with RTS are also at increased risk of developing skin cancer, including basal cell carcinoma and squamous cell carcinoma [Borg et al 1998] and 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. The mean age for epithelial tumors has been estimated at 34.4 years [Stinco et al 2008]. 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.

A few 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 another 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.

Multiple primary cancers have also been reported in individuals with RTS. For example, one affected individual developed anaplastic large-cell lymphoma at age nine years, diffuse large cell B lymphoma and osteosarcoma at age 14 years, and acute lymphoblastic leukemia at age 21 years. Whether the latter cancers represent secondary malignancies is not known [Simon et al 2010].

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 at a higher risk for second malignancy. However, from the limited number of individuals 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, Simon et al 2010].

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. However, there are several isolated reports of individuals with RTS who have concomitant immune dysfunction. These include an individual who had humoral immune deficiency associated with granulomatous skin lesions [De Somer et al 2010], an affected individual with IgG4 deficiency and recurrent sinopulmonary infections [Kubota et al 1993], and another affected individual with low serum immunoglobulin (IgG and IgA) levels who presented with herpes encephalitis [Ito et al 1999]. One individual with RTS and severe combined immunodeficiency (T-B+NK- phenotype with agammaglobulinemia) underwent successful hematopoietic stem cell transplantation [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 and other cancers has been reported in a number of children and adults with RTS.

Genotype-Phenotype Correlations

The correlation between presence of pathogenic variants in RECQL4 and presence of osteosarcoma in RTS has been evaluated [Wang et al 2003]. Thirty-three individuals with RTS were screened for pathogenic variants in RECQL4. Twenty-three of these individuals were found to have at least one truncating variant. All 11 of those with osteosarcoma had truncating variants. Using Kaplan-Meier analysis, it was found that those with truncating variants were at increased risk for developing osteosarcoma. The incidence of osteosarcoma was 0.05 per year in subjects with one or two truncating variants (230 person-years of observation) and 0.00 per year in individuals with no RECQL4 pathogenic variants (100 person-years of observation) (p<0.04).

The correlation between presence of pathogenic variants in RECQL4 and the presence of skeletal abnormalities has also been evaluated in 28 individuals with RTS [Mehollin-Ray et al 2008]. Genotype-phenotype analysis using Fisher’s exact test showed a significant positive correlation between those individuals with confirmed RECQL4 pathogenic variants and the presence of skeletal abnormalities (p < 0.0001).

Nomenclature

"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.

Prevalence

RTS is a rare disorder. Since its original description by Auguste Rothmund in the Bavarian Alps in Austria in 1868, fewer than 400 individuals have been described 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 pathogenic variants may exist within certain ethnic groups.

The population prevalence of RTS and carrier frequency are unknown [Larizza et al 2013].

Differential Diagnosis

The differential diagnosis of Rothmund-Thomson syndrome (RTS) includes the following disorders, which can exhibit features of poikiloderma but are otherwise clinically distinct from RTS.

Bloom syndrome is characterized by severe pre- and postnatal growth deficiency with decreased subcutaneous fat. The rash in Bloom syndrome is characterized by an erythematous, sun-sensitive lesion of the face; it is not a true poikiloderma. Loss of the lower eyelashes and blister and fissure formation of the lower lip are common. Individuals with Bloom syndrome may also have café au lait macules or paired hypopigmented and hyperpigmented macules. Recurrent infections (otitis media and pneumonia), chronic pulmonary disease, and diabetes mellitus are common. The most common cause of death is cancer, 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. Pathogenic variants 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; the mean age of death in individuals with Werner syndrome is 54 years. Pathogenic variants in WRN are causative. Inheritance is autosomal recessive.

Ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages 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. Pathogenic variants in ATM 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 increased risk of malignancy. 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. By age 40-50 years, the estimated cumulative incidence of bone marrow failure is 90%; the incidence of hematologic malignancies (primarily acute myeloid leukemia) 10%-30%; and of nonhematologic malignancies (solid tumors, particularly of the head and neck, skin, GI tract, and genital tract) 25%-30%. Pathogenic variants in one of at least 15 genes are causative. Inheritance is autosomal recessive except for FANCB-related FA, which is X-linked.

Xeroderma pigmentosum (XP) is characterized by sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals, and marked freckle-like pigmentation of the face before age 2 years in most affected individuals); ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); and greatly increased risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Most individuals with XP develop xerosis (dry skin) and poikiloderma. 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 25% have neurologic manifestations. XP is known to be associated with pathogenic variants in XPA, ERCC1, ERCC3 (XP-B), XPC, ERCC2 (XP-D), DDB2 (XP-E), ERCC4 (XP-F), ERCC5 (XP-G), 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. Pathogenic variants in FERMT1 (KIND1) are causative; both autosomal dominant and autosomal recessive inheritance are reported.

Dyskeratosis congenita. Individuals with dyskeratosis congenita have a lacy reticular pigmentation of the neck and upper chest, nail dystrophy, and oral leukoplakia with variable onset. Individuals with dyskeratosis congenita do not have radial ray defects or cataracts. They are at risk for bone marrow failure, leukemia, and skin cancers. Pathogenic variants in one of ten genes are causative and associated with different modes of inheritance: DKC1 (X-linked), TERC and TINF2 (autosomal dominant), TERT and RTEL1 (autosomal dominant or autosomal recessive), CTC1, WRAP53, NHP2, NOP10, and PARN (autosomal recessive).

Poikiloderma with neutropenia. The onset of rash in individuals with poikiloderma with neutropenia 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 are not seen. Individuals have clinically significant neutropenia with recurrent sinopulmonary infections. Paronychias are commonly seen. Less common findings include bone marrow failure and acute myeloid leukemia. Pathogenic variants in USB1 are causative. Inheritance is autosomal recessive.

Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is characterized by the skin findings of poikiloderma (typically beginning in the first six months and mainly localized to the face), hypohidrosis with heat intolerance, mild lymphedema of the extremities, chronic erythematous and scaly skin lesions on the extremities (distinct from the chronic poikiloderma of extremities seen in individuals with RTS), sclerosis of the digits, and mild palmoplantar keratoderma. Scalp hair, eyelashes, and/or eyebrows are typically sparse; nail dysplasia may be associated. Muscle contractures are usually seen in childhood and can be present as early as age two years. The majority of affected individuals develop progressive weakness of the proximal and distal muscles of all four limbs. Some adults develop progressive interstitial pulmonary fibrosis which can be life-threatening within three to four years after respiratory symptoms appear. Pathogenic variants in FAM111B are causative. Inheritance is autosomal dominant.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Rothmund-Thomson syndrome (RTS), the following evaluations are recommended:

  • Baseline skeletal radiographic examination by age five years to identify underlying skeletal abnormalities
  • Baseline complete blood count with differential
  • Ophthalmologic examination to evaluate for cataracts
  • Dermatologic evaluation
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Dermatologic. Pulsed dye laser has been used for cosmetic management of the telangiectatic component of the rash [Potozkin & Geronemus 1991].

Hematologic. Individuals with clinical evidence of anemia or cytopenias should be evaluated by CBC and bone marrow biopsy if clinically indicated.

Cataract. Visually significant cataracts require surgical removal.

Cancer. Affected individuals who develop cancer should be treated according to standard chemotherapy and/or radiation regimens. Doses should be modified only if the individual experiences significantly increased toxicities.

Prevention of Secondary Complications

Avoidance of excessive sun exposure and use of sunscreens with both UVA and UVB protection are recommended to prevent skin cancer. Calcium and vitamin D supplements may also be warranted in individuals with osteopenia or a history of fractures.

Surveillance

The following are appropriate:

  • Annual evaluation by a physician familiar with RTS
  • Monitoring of growth
  • For individuals without cataracts, yearly eye examinations for screening purposes
  • Prompt skeletal radiographic examination when clinical suspicion of osteosarcoma is present (including bone pain, swelling, or an enlarging lesion on a limb) due to the high risk for this potentially lethal malignancy, particularly for those individuals with pathogenic deleterious variants in RECQL4
  • Frequent monitoring for any evidence of malignancy in affected family members of individuals with RTS and osteosarcoma (because of reports of more than one sib with RTS also developing osteosarcoma)
  • Close monitoring of the skin for lesions with unusual color or texture, as individuals with RTS are at increased risk for skin cancers

Agents/Circumstances to Avoid

Exposure to heat or sunlight may exacerbate the rash in some individuals.

Avoidance of excessive sun exposure decreases the risk for skin cancer.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

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.

Other

Given the theoretic 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.

Genetic Counseling

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. —ED.

Mode of Inheritance

Rothmund-Thomson syndrome (RTS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual with confirmed biallelic pathogenic variants in RECQL4 are obligate heterozygotes (i.e., carriers of one RECQL4 pathogenic variant).
  • 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.
  • 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) for a pathogenic variant in RECQL4.
  • 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 variant may be present (e.g., western Austria, where Rothmund originally described RTS) and the Mennonite population.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an RECQL4 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the RECQL4 pathogenic variants in the family.

Related Genetic Counseling Issues

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the RECQL4 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for RTS are possible.

Ultrasound examination. Ultrasound examination at 16 to 18 weeks' gestation may detect forearm reduction defects; 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.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Rothmund-Thomson Syndrome Foundation
    RTS Foundation
    4307 Woodward Court
    Chantilly VA 20151
    Email: rtssupport@rtsplace.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Rothmund-Thomson Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
RECQL48q24​.3ATP-dependent DNA helicase Q4RECQL4 databaseRECQL4RECQL4

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Rothmund-Thomson Syndrome (View All in OMIM)

268400ROTHMUND-THOMSON SYNDROME; RTS
603780RECQ PROTEIN-LIKE 4; RECQL4

Gene structure. RECQL4 has 21 exons. The gene has a coding sequence consisting of 3,627 bases based on the open reading frame of the NM_004260.3 cDNA. While most human genes have large introns, RECQL4 has 13 introns that are fewer than 100 bp in length, which is near the minimum intron length for efficient splicing estimated in model organisms [Wang et al 2002 and references therein]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Approximately 50 different pathogenic variants spanning exons 5 through 21 and introns 1 through 17 have been published [Siitonen et al 2009]. Interestingly, small deletions that occur in the short introns are pathogenic because they render the intron too short for efficient splicing [Wang et al 2002, Wang et al 2003, Jin et al 2008]. See Clinical Utility Gene Card and Table A, Genes and Databases.

Normal gene product. RECQL4 encodes ATP-dependent DNA helicase Q4, a protein [Kitao et al 1998] of 1,208 amino acids (NP_004251.3) that bears homology to a family of proteins known as RecQ helicases. RecQ helicases are DNA helicases (enzymes that promote DNA unwinding, allowing many basic cellular processes to occur) that play a role in maintaining chromosome 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 including worms, bacteria, and yeast. In humans, five RecQ helicases have been identified; three are associated with genetic conditions: Bloom syndrome, Werner syndrome, and RTS.

The exact role of ATP-dependent DNA helicase Q4 is not known; several lines of work show that it likely has diverse biologic functions [Larizza et al 2010]. These include roles in DNA replication [Sangrithi et al 2005, Matsuno et al 2006, Wu et al 2008], DNA repair [Kumata et al 2007, Schurman et al 2009, Singh et al 2010], and telomere maintenance [Ghosh et al 2012]. Recql4 has been shown in mouse models to play a role in normal skeletal development as well as in hematopoiesis [Smeets et al 2014, Lu et al 2015, Ng et al 2015].

Abnormal gene product. The majority of pathogenic variants 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].

References

Literature Cited

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Suggested Reading

  • Beghini A, Larizza L. Rothmund-Thomson syndrome (RTS). Atlas of Genetics and Cytogenetics Oncology and Haematology. 2002. Available online. Accessed 10-25-17.

Chapter Notes

Author Notes

Dr. Wang is a pediatric oncologist at Texas Children's Cancer Center with particular interest in treating children with solid tumors, including osteosarcoma.

Dr. Wang’s web page

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.

Dr. Plon’s web page

Revision History

  • 11 August 2016 (bp) Revision: POIKTMP added to Differential Diagnosis
  • 3 December 2015 (me) Comprehensive update posted live
  • 6 June 2013 (me) Comprehensive update posted live
  • 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 live
  • 5 January 2005 (sp) Revision: Genetically Related Disorders
  • 9 June 2004 (me) Comprehensive update posted live
  • 19 April 2004 (cd) Revision: clinical testing availability
  • 31 May 2002 (me) Comprehensive update posted live
  • 6 October 1999 (me) Review posted live
  • 1 July 1999 (sp) Original submission
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