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.

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).

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 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 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].

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.

Treatment of Manifestations

Surveillance

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 with 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 EU Clinical Trials Register 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 with normal GH levels. For individuals with documented GH deficiency, routine treatment with growth hormone is appropriate.

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 ANAPC1 or RECQL4 are obligate heterozygotes (i.e., presumed to be carriers of one ANAPC1 or RECQL4 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for an ANAPC1 or RECQL4 pathogenic variant and allow reliable recurrence risk assessment. (Although a de novo pathogenic variant has not been reported in RTS to date, de novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• 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 ANAPC1 or 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 in ANAPC1 may be present (e.g., in 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 ANAPC1 or RECQL4 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the RECQL4 or ANAPC1 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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

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

Molecular Pathogenesis

Rothmund-Thomson syndrome (RTS) is caused by pathogenic variants in ANAPC1 or RECQL4; it is often classified as a disorder of DNA repair and replication.

ANAPC1 encodes the APC1 protein, which is the largest subunit of the anaphase-promoting complex/cyclosome (APC/C). APC/C is an E3 ubiquitin ligase that targets specific proteins for degradation. It helps to control cellular transition at distinct phases of the cell cycle. The phenotypes seen in individuals with type 1 RTS may thus be the result of defective cell cycling [Ajeawung et al 2019]. The APC/C has also been shown to play a role in DNA replication and repair, senescence, and cell differentiation.

RECQL4 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. 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].

Pathogenic variants in ANAPC1 have been found in a proportion of individuals with type 1 RTS and pathogenic variants in RECQL4 has been found in individuals with type 2 RTS (see Clinical Description). How ANAPC1 and RECQL4 may potentially interact is currently unknown.

Mechanism of disease causation. RTS occurs via a loss-of-function mechanism.

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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

• 4 June 2020 (ha) Revision: added ANAPC1 as a cause of RTS; edits to Diagnosis, Management, Genetic Counseling, and Molecular Genetics
• 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