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Rothmund-Thomson Syndrome

, MD and , MD, PhD, FACMG.

Author Information

Initial Posting: ; Last Update: January 3, 2019.

Estimated reading time: 21 minutes

Summary

Clinical characteristics.

Rothmund-Thomson syndrome (RTS) is characterized by a rash that progresses to poikiloderma; sparse hair, eyelashes, and/or eyebrows; small size; 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 ages three and six months as erythema, swelling, and blistering on the face, subsequently spreading 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) and/or the identification of biallelic pathogenic variants in RECQL4 on molecular genetic testing.

Management.

Treatment of manifestations: Surgical removal of cataracts; standard treatment for cancer; pulsed dye laser to the telangiectatic component of the rash for cosmetic management. 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 exposure to heat or sunlight; growth hormone for those with short stature with normal growth hormone levels.

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, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis 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 ages 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 and/or biallelic pathogenic variants in RECQL4 identified on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Rothmund-Thomson syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical findings in whom the diagnosis of Rothmund-Thomson syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of Rothmund-Thomson syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of RECQL4 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis 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 thus far been identified as a cause of RTS.
  • A multigene panel that includes RECQL4 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of Rothmund-Thomson syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Rothmund-Thomson Syndrome (RTS)

Gene 1Test MethodProportion of Pathogenic Variants 2 Detectable by This Method
RECQL4Sequence analysis 3~60% 4
Gene-targeted deletion/duplication analysis 5Unknown 6
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.

Authors, unpublished data from the RTS Registry

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may 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.

In nearly 40% of individuals with the typical clinical findings of RTS, molecular genetic testing fails to identify a pathogenic variant in RECQL4, making the existence of one or more additional causative genes likely [Wang et al 2003; Authors, personal observation].

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) also varies.

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 (collectively referred to as poikiloderma) that 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 included 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.

In a study of metabolic bone disease in 29 individuals with a clinical diagnosis of RTS, a significant proportion were found to have decreased bone mineral density as well as history of fractures [Cao et al 2017]. Additionally, the presence of pathogenic variants in RECQL4 and low bone mineral density correlated with the history of increased risk of fractures [Cao et al 2017].

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 [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].
  • Skin cancer. 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.
  • Second malignancy. 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].
  • Chemotherapy effects. 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 individuals have reported increased toxicities after treatment with high-dose methotrexate, but side effect profiles vary significantly among individuals and appear to be specific to the individual.

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, life span 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

No genotype-phenotype correlations have been identified.

Wang et al [2003] found that individuals with RTS and one or two truncating pathogenic variants in RECQL4 were at increased risk of developing osteosarcoma.

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 Austria in 1868, fewer than 500 individuals have been described in the English-language literature.

RTS has been described in all ethnicities. 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 and carrier frequency of RTS are unknown [Larizza et al 2013].

Differential Diagnosis

The differential diagnosis of Rothmund-Thomson syndrome (RTS) includes the disorders summarized in Table 2, which can exhibit features of poikiloderma but are otherwise clinically distinct from RTS.

Table 2.

Disorders That Can Exhibit Features of Poikiloderma to Consider in the Differential Diagnosis of Rothmund-Thomson Syndrome (RTS)

DisorderGene(s)MOIOverlapping Clinical Features of This DisorderDistinguishing Clinical Features of This Disorder
Bloom syndrome 1BLMAR
  • Rash characterized by an erythematous, sun-sensitive lesion of the face; not true poikiloderma
  • Loss of lower eyelashes & blister & fissure formation of lower lip common
  • Café au lait macules or paired hypopigmented & hyperpigmented macules in some
  • Most common cause of death: cancer (occurring at younger-than-usual ages)
  • Severe pre- & postnatal growth deficiency w/↓ subcutaneous fat
  • Recurrent infections (otitis media & pneumonia)
  • Chronic pulmonary disease
  • Diabetes mellitus
Werner syndromeWRNAR
  • Initial findings (usually in 3rd decade): loss & graying of hair, alopecia, scleroderma-like skin changes
  • Skin ulcers (4th decade)
  • Cancer predisposition
  • Premature appearance of features associated w/normal aging
  • Normal development until end of 1st decade
  • 1st symptom: no growth spurt during early teen years
  • Initial signs: hoarseness followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, & osteoporosis in 4th decade
Ataxia-telangiectasiaATMAR
  • Increased risk for malignancy, particularly leukemia & lymphoma
  • Unusual sensitivity to ionizing radiation
  • Progressive cerebellar ataxia beginning ages 1-4 yrs
  • Oculomotor apraxia
  • Frequent infections
  • Choreoathetosis
  • Telangiectasias of the conjunctivae
  • Immunodeficiency
Fanconi anemia>20 genes 2AR
AD
XL
  • Abnormal skin pigmentation
  • Increased risk of malignancy
    • 10%-30% incidence of hematologic malignancies (primarily acute myeloid leukemia)
    • 25%-30% incidence of nonhematologic malignancies (solid tumors, particularly of head & neck, skin, GI tract, & genital tract)
  • Bone marrow failure in 1st decade; 90% estimated cumulative incidence of bone marrow failure by age 40-50 yrs
  • Physical abnormalities: short stature; malformations of thumbs, forearms, skeletal system, eye, kidneys & urinary tract, ear, heart, GI system, oral cavity, & CNS; hearing loss; hypogonadism; DD
Xeroderma pigmentosumDDB2
ERCC1
ERCC2
ERCC3
ERCC4
ERCC5
POLH
XPA
XPC
AR
  • Sun sensitivity (sunburn w/blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals, & severe, marked freckle-like pigmentation of face @ age <2 years)
  • Greatly ↑ risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma)
  • Xerosis (dry skin)
  • Poikiloderma
  • Loss of lashes
  • Median age of onset of non-melanoma skin cancer is <10 years.
  • Neurologic manifestations in ~25%
  • Photophobia
  • Keratitis
  • Atrophy of the skin of the lids
Kindler syndromeFERMT1AR
  • Acral bullae at birth & after minor trauma
  • Diffuse poikiloderma w/striate & reticulate atrophy
  • Widespread eczematoid dermatitis
  • Keratotic papules of hands, feet, elbows, knees
  • Marked photosensitivity
  • Esophageal & urethral strictures
  • Webbing of fingers & toes
  • No ↑ risk for cataract or malignancy
Dyskeratosis congenitaACD
CTC1
DKC1
NHP2
NOP10
PARN
RTEL1
TERC
TERT
TINF2
WRAP53
XL
AD
AR
  • Lacy reticular pigmentation of neck & upper chest
  • Nail dystrophy
  • Increased risk of leukemia & skin cancers
  • Bone marrow failure
  • Oral leukoplakia w/variable onset
  • Not associated w/radial ray defects or cataracts
Poikiloderma with neutropeniaUSB1AR
  • Rash
  • Less common finding: acute myeloid leukemia
  • Onset of rash differs from that seen in RTS: more eczematous, starting peripherally & spreading centrally
  • Rash affecting the trunk
  • Not associated w/radial ray abnormalities
  • Clinically significant neutropenia w/recurrent sinopulmonary infection
  • Less common finding: bone marrow failure
  • Paronychias common
Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosisFAM111BAD
  • Poikiloderma (typically beginning in 1st 6 mos & mainly facial)
  • Chronic erythematous & scaly skin lesions on extremities (distinct from chronic poikiloderma of extremities seen in RTS)
  • Sclerosis of digits
  • Mild palmoplantar keratoderma
  • Scalp hair, eyelashes, &/or eyebrows typically sparse
  • Nail dysplasia in some
  • Hypohidrosis w/heat intolerance
  • Mild lymphedema of extremities
  • Muscle contractures usually seen in childhood & can be present as early as age 2 yrs
  • In most: progressive weakness of proximal & distal muscles of all 4 limbs
  • In some adults: progressive interstitial pulmonary fibrosis that can be life-threatening w/in 3-4 yrs after respiratory symptoms appear

AD = autosomal dominant; AR = autosomal recessive; CNS = central nervouse system; DD = developmental delay; GI = gastrointestinal; MOI = mode of inheritance; XL = X-linked

1.

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.

2.

See Phenotypic Series: Fanconi Anemia for a list of genes associated with this phenotype in OMIM.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Rothmund-Thomson syndrome (RTS), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

  • Dermatologic evaluation
  • Baseline skeletal radiographic examination by age five years to identify underlying skeletal abnormalities
  • Baseline complete blood count with differential
    Individuals with clinical evidence of anemia or cytopenias should be evaluated by CBC and bone marrow biopsy if clinically indicated.
  • Ophthalmologic examination to evaluate for cataracts
  • 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].

Skeletal. Calcium and vitamin D supplements may be warranted in individuals with osteopenia or a history of fractures [Cao et al 2017].

Hematologic. Individuals with hematologic abnormalities should be treated in the standard manner by a hematologist familiar with RTS.

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.

Surveillance

The following are appropriate:

  • Annual evaluation by a physician familiar with RTS for overall health maintenance and monitoring of growth
  • Evaluation by a dermatologist annually or more frequently if indicated and otherwise close monitoring of the skin for lesions with unusual color or texture, as individuals with RTS are at increased risk for skin cancers
  • 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

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.

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, standard treatment with growth hormone is appropriate.

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 in the US and www.ClinicalTrialsRegister.eu in Europe 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 a proband with confirmed biallelic pathogenic variants in RECQL4 are obligate heterozygotes (i.e., carriers of one RECQL4 pathogenic variant).
  • Heterozygotes (carriers) are apparently asymptomatic, 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 apparently 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 in 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

RECQL4, pathogenic variants of which cause RTS, encodes ATP-dependent DNA helicase Q4, a member of the RecQ DNA helicase family, categorized by a 3'-5' polarity of unwinding double-stranded DNA and RNA-DNA hybrids to produce single-stranded DNA templates. At least five RecQ human paralogs with distinct but partially overlapping roles are known: RECQL, BLM, WRN, RECQL4, and RECQL5. Pathogenic variants in BLM are associated with Bloom syndrome; pathogenic variants in WRN are associated with Werner syndrome; both are autosomal recessive chromosome instability conditions characterized by predisposition to cancer and/or premature aging. These features are shared by RECQL4-associated autosomal recessive RTS and by the phenotypically overlapping RAPADILINO and BGS, characterized by genetic instability, growth deficiency, and cancer predisposition. To date, no human disease has been associated with RECQL or RECQL5.

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 at various stages of DNA processing (replication, recombination, repair, telomere maintenance) but also in translation, RNA processing, mtDNA maintenance, and chromosome segregation [Croteau et al 2014, Lu et al 2014]. Since they act in virtually all aspects of DNA metabolism, perturbation of their expression and biochemical activity leads to genomic instability, resulting in disease and cancer predisposition [Bochman 2014].

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 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 belongs to the family of proteins known as RecQ helicases. RecQ helicases 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.

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 be loss-of-function variants [Kitao et al 1999, Siitonen et al 2009].

References

Literature Cited

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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

  • 3 January 2019 (ha) Comprehensive update posted live
  • 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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