Rothmund-Thomson Syndrome
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; juvenile cataracts; and an increased risk for cancer, especially osteosarcoma. A variety of benign and malignant hematologic abnormalities have been reported in affected individuals. The rash of RTS typically develops between ages three and six months (occasionally as late as age two years) 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, telangiectasias, and punctate atrophy (collectively known as poikiloderma) that persist throughout life. Hyperkeratotic lesions occur in approximately one third of individuals. Skeletal abnormalities can 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 ANAPC1 or RECQL4 on molecular genetic testing.
Management.
Treatment of manifestations: Pulsed dye laser to the telangiectatic component of the rash for cosmetic management; surgical removal of cataracts; standard treatment for cancer and/or hematologic concerns.
Surveillance: Annual general physical, dermatologic, and eye examination; monitoring of health and growth, skin for lesions with unusual color or texture, for cataracts. Prompt skeletal radiographic examination when clinical suspicion of osteosarcoma is present (bone pain, swelling or enlarging lesion on a limb); however, surveillance screening for osteosarcoma is not routinely recommended.
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 testing are possible if the ANAPC1 or 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 of the following additional 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
- 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
- Skeletal abnormalities including radial ray defects, ulnar defects, absent or hypoplastic patella, osteopenia, abnormal trabeculation
- Cancers including skin cancers (basal cell carcinoma and squamous cell carcinoma) and in particular 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 ANAPC1 or RECQL4 identified on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, single-gene testing,) 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 findings suggest the diagnosis of Rothmund-Thomson syndrome, molecular genetic testing approaches can include use of a multigene panel or single gene testing.
A multigene panel that includes ANAPC1 and 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.
Note: As ANAPC1 has only recently been identified as a gene associated with RTS [Ajeawung et al 2019], the ordering clinician may need to contact the laboratory to request testing of this gene.
Single-gene testing. If a multigene panel is not available, single-gene testing could be performed:
- If the individual presents with skeletal abnormalities or osteosarcoma, recommend starting with RECQL4 testing.
- For individuals with early-onset juvenile cataracts without skeletal defects or osteosarcoma, recommend starting with ANAPC1 testing.
Sequence analysis of either gene can detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no pathogenic variant is detected in either gene by the sequencing method used, gene-targeted deletion/duplication analysis may be considered; however, no exon or whole-gene deletions/duplications have thus far been identified as a cause of RTS.
Option 2
When the diagnosis of Rothmund-Thomson syndrome is unclear 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 1, 2 | Proportion of RTS Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detectable by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| ANAPC1 | 10% | 14/14 6, 7 | Unknown 8 |
| RECQL4 | 60% | >99% 6, 9 | Unknown 8 |
| Unknown 10 | 30% | NA | |
- 1.
Genes are listed in alphabetic order.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on allelic variants detected in these genes.
- 4.
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.
- 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.
Data derived from the subscription-based professional view of the Human Gene Mutation Database [Stenson et al 2017]
- 7.
The most frequently detected pathogenic variant, c.2705-198C>T [Ajeawung et al 2019], is deep intronic and may not be detected by routine analysis.
- 8.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
- 9.
Some pathogenic variants are in short introns of RECQL4; therefore, sequencing should encompass these intronic regions [Wang et al 2002].
- 10.
In nearly 40% of individuals with the typical clinical findings of RTS, molecular genetic testing fails to identify a pathogenic variant in RECQL4. These individuals have been designated as having type 1 RTS. A proportion of probands with type 1 RTS will have pathogenic variants in ANAPC1 (7 of 9 families tested by Ajeawung et al [2019]). The existence of one or more additional causative genes is likely [Wang et al 2003, Ajeawung et al 2019].
Clinical Characteristics
Clinical Description
Rothmund-Thomson syndrome (RTS) is a genetic disorder associated with a characteristic skin rash in combination with certain other findings detailed in this section. One subset of affected individuals defined by the lack of RECQL4 pathogenic variants (historically referred to as type 1 RTS) is predisposed to developing juvenile cataracts but not osteosarcoma when followed over time. The other, larger subset of individuals with RTS and RECQL4 pathogenic variants (historically referred to as type 2 RTS) is at increased risk of developing osteosarcoma and other cancers, and these individuals are also more likely to have skeletal abnormalities [Wang et al 2003]. It is important to keep in mind that there are phenotypic overlaps between types 1 and 2, and some individuals have not had any abnormality found on molecular genetic testing thus far.
Variability. Individuals with 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 injuryNote: 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 are usually 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. These skeletal findings are more often seen in individuals with type 2 RTS, caused by pathogenic variants in RECQL4.
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. 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%) [Wang et al 2001]. 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; these individuals are more likely to represent type 1 RTS, caused by pathogenic variants in ANAPC1 [Ajeawung et al 2019]
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]. Osteosarcoma is associated with type 2 RTS.
- 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. Skin cancer occurs in individuals with both type 1 and type 2 RTS.
- 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.
Phenotype Correlations by Gene
Osteosarcoma and skeletal defects are more often found in individuals with RTS associated with RECQL4 pathogenic variants (type 2 RTS) [Wang et al 2001, Wang et al 2003, Mehollin-Ray et al 2008], while bilateral juvenile cataracts are more often associated with ANAPC1 pathogenic variants (type 1 RTS) [Ajeawung et al 2019].
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
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)
| Disorder | Gene(s) | MOI | Overlapping Clinical Features of Disorder | Distinguishing Clinical Features of Disorder |
|---|---|---|---|---|
| Bloom syndrome 1 | BLM | AR |
|
|
| Werner syndrome | WRN | AR |
|
|
| Ataxia-telangiectasia | ATM | AR |
|
|
| Fanconi anemia | >20 genes 2 | AR AD XL |
|
|
| Xeroderma pigmentosum | DDB2 ERCC1 ERCC2 ERCC3 ERCC4 ERCC5 POLH XPA XPC | AR |
|
|
| Kindler syndrome | FERMT1 | AR |
|
|
| Dyskeratosis congenita | ACD CTC1 DKC1 NHP2 NOP10 PARN RTEL1 TERC TERT TINF2 WRAP53 | XL AD AR |
|
|
| Poikiloderma with neutropenia | USB1 | AR |
|
|
| Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis | FAM111B | AD |
|
|
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 in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with RTS
| System/Concern | Evaluation | Comment |
|---|---|---|
| Skin | Dermatologic eval | |
| Skeletal | Baseline skeletal radiographic exam by age 5 yrs to identify underlying skeletal abnormalities; baseline DEXA scan to assess bone mineral density if indicated | Obtain DEXA if osteopenia is seen on skeletal survey or there is a history of fractures. |
| Hematologic | Baseline complete blood count (CBC) w/differential | Individuals w/clinical evidence of anemia or cytopenias should be evaluated by CBC & bone marrow biopsy if clinically indicated. |
| Vision | Ophthalmologic exam to evaluate for cataracts | |
| Other | Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with RTS
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Skin rash | Pulsed dye laser has been used for cosmetic management of the telangiectatic component of rash. | |
| Hematologic concerns | Individuals w/hematologic abnormalities should be treated in standard manner by hematologist familiar w/RTS. | |
| Cataract | Visually significant cataracts require surgical removal. | |
| Cancer | Affected individuals who develop cancer should be treated per standard chemotherapy &/or radiation regimens. | Doses should be modified only if individual experiences significantly ↑ toxicities. |
Surveillance
Table 5.
Recommended Surveillance for Individuals with RTS
| System |
|---|