Rothmund-Thomson Syndrome

Disease Overview

Rothmund-Thomson syndrome (RTS) is a rare genetic disorder that can affect many parts of the body. The disorder is characterized by distinctive abnormalities of the skin, sparse hair, eyelashes and/or eyebrows, small stature, skeletal and dental abnormalities and a predisposition to cancer. Patients typically begin having signs of RTS during infancy and the first feature to appear is a rash that starts on the cheeks and later spreads to other parts of the body. The rash gradually becomes chronic and persists for life. Other features may appear that involve other areas of the body such as the eyes, bones, teeth and hair, and patients may be small compared to their peers. Patients are at an increased risk for developing cancer, particularly certain types of skin and bone cancer (osteosarcoma). Lifespan is generally thought to be normal in patients who do not develop cancer, but follow-up data in the published literature are limited. RTS is inherited as an autosomal recessive genetic condition. Approximately two-thirds of patients have changes (variants or mutations) in one of two genes, the RECQL4 and ANAPC1 genes. For the remaining cases of RTS, the gene(s) involved has not yet been identified.

RTS was first described in 1868 by Dr. Auguste Rothmund, a German ophthalmologist who described the characteristic rash and juvenile cataracts in his patients. In 1921, Dr. Sydney Thomson, who was a British dermatologist, described a very similar rash along with bone findings in his patients. Later in 1957, Dr. William Taylor in the United States proposed that the disorders were the same and coined the eponym “Rothmund-Thomson syndrome”.

Since the original reporting of RTS, the characteristics associated with RTS have been widened. Specific gene variants have been found to be associated with certain characteristics (genotype-phenotype correlations). Currently, RTS is divided into two types: type 1 RTS, caused by variants in the ANAPC1 gene and characterized by bilateral juvenile cataracts and type 2 RTS, caused by variants in the RECQL4 gene, and characterized by bone abnormalities and increased risk for osteosarcoma.

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Synonyms

• poikiloderma atrophicans and cataract
• poikiloderma congenitale
• RTS

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Signs & Symptoms

Rothmund-Thomson syndrome is a rare genetic disorder that manifests in early infancy. The range and severity of symptoms may vary from person to person. RTS is typically characterized by skin rash, sparse hair, malformed bones, abnormal clouding of the lenses of the eyes (juvenile cataracts), small stature and other physical abnormalities. Intelligence is usually normal, but some affected individuals have been reported to have intellectual disability.

Skin and hair
Between the ages of approximately three to six months, infants with RTS typically develop redness (erythema) on the cheeks that may appear as patches or inflamed plaques and may resemble sunburn or even eczema. The redness may be accompanied by swelling (edema). In some children, the rash may be apparent earlier in life or may develop as late as two years old. The rash typically spreads to the arms and legs and may or may not involve the buttocks. The trunk and belly are generally spared. Over time and usually by early childhood, the inflammation tends to recede and the skin of affected areas develops into a more chronic pattern of rash known as poikiloderma, characterized by telangiectasis (prominent, small, spider-like blood vessels); small spots of atrophy (skin tissue degeneration or thinning); and areas of abnormal skin pigmentation alternating between increased pigment (hyperpigmentation) and decreased pigment (hypopigmentation), giving a lacy, web-like or mottled appearance.

Sensitivity of the skin to sun exposure (photosensitivity) has been reported in some patients, and the rash tends to affect areas that are more sun exposed. However, it is important to note that the rash is not always limited to sun-exposed areas (e.g., buttocks). Some affected individuals report a history of blistering (bullae) on the skin that may or may not be related to sun exposure. Blistering tends to diminish as patients reach late childhood.

One of the other skin manifestations of RTS that tends to be more prominent in adulthood is a condition called hyperkeratosis, where certain areas such as the palms and soles, knees and sometimes around the fingers or toes, become thickened and overgrown and develop a rough, wart-like (verrucous) texture. In severe cases, large, verrucous overgrowth of certain areas may cause significant discomfort or restriction of activities.

In addition, many patients with RTS have sparse scalp hair, and some may have complete baldness (alopecia). In many people, eyebrows, eyelashes and body hair may also be sparse or absent. In some patients, the nails may be malformed (dystrophic) and/or unusually small (hypoplastic).

Eyes
Between the ages of approximately two to seven years of age, some children with RTS may also develop sudden clouding of the lenses of both eyes (bilateral juvenile cataracts). Such cataracts typically are opaque, semisolid, white dots appearing on one broad or narrow area of an otherwise clear lens (zonular or lamellar cataract). Development of such cataracts may result in severe visual impairment or loss within weeks, and prompt surgical intervention by an eye specialist (ophthalmologist) can usually restore vision.

Growth and development
A large percentage of individuals with RTS experience abnormally slow growth before and after birth (prenatal and postnatal growth delay), leading to mild to moderate small stature. This small stature is symmetrical for height and weight, and patients have proportional development of the upper and lower body.

Bones and teeth
A large percentage of patients have bone abnormalities that may or may not be visible clinically. One of the most obvious abnormalities is a radial ray defect which manifests as small, malformed or missing thumbs or shortened forearms. Other bones in the body, particularly those in the arms, hands and legs, can also be abnormally formed, shortened, or fused, and some of these bone findings can only be seen on x-rays. Some patients may also have characteristic abnormalities of the craniofacial area including a prominent forehead (frontal bossing) or a sunken nasal bridge (saddle nose). Patients may also have decreased bone density (osteopenia or osteoporosis) which in severe cases could lead to fractures. The teeth in patients with RTS may be small or malformed.

Gastrointestinal and feeding
Many infants and young children with RTS experience gastrointestinal disturbances including non-specific vomiting and diarrhea that are often attributed to intolerance of milk or formula. Some patients require feeding tubes to maintain nutritional intake. However, in virtually all patients, these issues resolve by later childhood.

Cancer
Individuals with RTS have an increased risk of developing cancer, particularly osteosarcoma and non-melanoma skin cancers (squamous and basal cell carcinomas). While these are the most frequent cancers encountered in RTS, there have been a few patients reported who developed squamous cell carcinoma of the head and neck region and hematologic malignancies such as leukemia.

Fertility
Some individuals with RTS have hypogonadism, a condition characterized by deficient activity of the gonads (i.e., ovaries in females or testes in males). As a result, affected females may experience irregular menstruation, while both affected males and females may have delayed sexual development. In individuals with hypogonadism, fertility may be reduced; however, some patients (both male and female) have had children.

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Causes

Rothmund-Thompson syndrome is a genetic disorder that is inherited in an autosomal recessive pattern. Approximately 2/3 of individuals with RTS are found to have an abnormality (variant or mutation) in the RECQL4 gene (type 2 RTS) or the ANAPC1 gene (type 1 RTS). The RECQL4 gene is responsible for production of a protein that is involved in the replication and repair of DNA, the genetic material in the cells of the body. ANAPC1 encodes a protein, APC1, which is important for cell cycle progression and also plays a role in DNA replication and repair. Since about 1/3 of affected individuals do not have detectable variants in these genes, other as yet undiscovered genes are probably also associated with RTS.

Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

RTS has been diagnosed in people of all races and has been described in multiple nationalities; therefore, it does not appear that there is any particular population at increased risk for developing the disease.

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Disorders with Similar Symptoms

The following disorders share some overlapping clinical features with those of RTS. RAPADILINO and Baller-Gerold syndromes are related to RTS because they can also be caused in some cases by variants in the RECQL4 gene. Bloom and Werner syndromes are related to RTS because they are caused by variants in the BLM and WRN genes, respectively, which both belong to the same gene family as RECQL4.

RAPADILINO syndrome is an autosomal recessive genetic condition that is characterized by abnormal skin pigmentation (but not poikiloderma), small size, radial ray defects of the bone, abnormal palate, absent or poorly developed kneecaps and gastrointestinal abnormalities. These patients are prone to developing lymphomas as well as osteosarcomas.

Baller-Gerold syndrome is characterized by small size, radial ray defects and other bone abnormalities, including premature closure of the bones of the skull (craniosynostosis).

Bloom syndrome is a rare genetic disorder characterized by short stature; increased sensitivity to light (photosensitivity); multiple small, dilated blood vessels on the face (facial telangiectasia), often resembling a butterfly in shape; immune deficiency leading to increased susceptibility to infections; and, perhaps most importantly, a markedly increased susceptibility to cancer of any organ, but especially to leukemia and lymphoma. Variants in the BLM gene are causative. Bloom syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Bloom” as your search term in the Rare Disease Database.)

Werner syndrome is a rare progressive disorder that is characterized by early onset of features associated with aging as well as increased risk of cancer. The first symptom is usually the lack of a growth spurt during the early teen years. Myocardial infarction and cancer are the most common causes of death, typically about age 48 years. Variants in the WRN gene are causative. Werner syndrome is inherited in an autosomal recessive pattern. As a result, affected individuals have unusually short stature and low weight even relative to height. Initial findings usually observed in the 20s include loss and graying of hair, hoarseness, and scleroderma-like skin changes. As the disease progresses, additional abnormalities include loss of the layer of fat beneath the skin; severe wasting (atrophy) of muscle tissue in certain areas of the body; and degenerative skin changes. Due to degenerative changes affecting the facial area, individuals with Werner syndrome may have unusually prominent eyes, a beaked or pinched nose and/or other characteristic facial abnormalities.

Werner syndrome may also be characterized by development of a distinctive high-pitched voice, eye abnormalities, including premature clouding of the lenses of the eyes due to aging (bilateral senile cataracts) and certain endocrine defects, such as hypogonadism and diabetes mellitus. In addition, individuals with Werner syndrome can develop age-associated heart disease such as atherosclerosis. Patients are also at risk for developing cancers, particularly thyroid cancer and sarcomas (cancers of the supporting, connective or soft tissues). Progressive heart disease, diabetes, or malignancy may result in potentially life-threatening complications by approximately the fourth or fifth decade of life. (For further information, choose “Werner” as your search term in the Rare Disease Database.)

Other diseases that have some clinical features in common with RTS include:

Poikiloderma with neutropenia (PN, Navajo poikiloderma), which was first described in Navajo individuals but has now been described in other ethnicities as well. These patients also have poikiloderma, but the onset and pattern of spread of rash in individuals with PN differs from that seen in RTS. Individuals with PN have clinically significant neutropenia (low white blood counts) and can develop recurrent lung infections. They also have abnormally thickened nails. Radial ray defects and hair abnormalities are not generally seen. PN is caused by variants in the USB1 gene.

Dyskeratosis congenita (DC) is a genetically and clinically heterogeneous disorder. Patients have overlapping features with RTS including abnormal skin pigmentation, nail dystrophy, sparse hair, dental and bone abnormalities and small stature. In addition, patients can have oral leukoplakia, pulmonary fibrosis and other findings, and they have an increased risk of developing cancer (leukemia, head and neck and anogenital cancers) and bone marrow failure (aplastic anemia, myelodysplastic syndrome). DC is caused by many different mutations in genes involved in telomere maintenance.

Individuals with Kindler syndrome also display poikiloderma. They usually present with blisters at birth and after minor trauma and their skin is markedly photosensitive. They can also develop thickened plaques on the hands, feet, elbows and knees. Other features include esophageal and urethral strictures, and webbing of fingers and toes.
Fanconi anemia (FA) is an autosomal recessive condition that is characterized by a range of physical abnormalities. Among those that are shared with RTS include radial ray defects, small stature, abnormal skin pigmentation, hypogonadism and increased risk for cancer, most often hematologic malignancies and solid tumors of the head and neck, skin, GI tract, and genital tract. Variants in multiple different genes can result in FA.

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Diagnosis

Rothmund-Thompson syndrome is diagnosed based on the onset, appearance and progression of the poikilodermatous rash. A diagnosis of RTS may be suspected if the rash is present but atypical and other physical characteristics associated with RTS are present. Molecular genetic testing for the RECQL4 gene is available to confirm the diagnosis, although in one-third of cases of RTS this test can be negative. Thus, a negative test does not rule out the diagnosis of RTS, but a positive test confirms the diagnosis.

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Standard Therapies

The treatment of Rothmund-Thomson syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who specialize in the diagnosis and treatment of disorders of the skin (dermatologists), doctors who specialize in genetic disorders (geneticists), eye specialists (ophthalmologists), specialists who diagnose and treat bone disorders (orthopedists), dental specialists and/or other health care professionals may need to plan an affected child’s management systematically and comprehensively.

Specific therapies for the treatment of RTS are symptomatic and supportive. Special measures may be recommended to protect affected individuals from sun exposure (e.g., use of topical sunscreens, sunglasses, etc.). Because patients are prone to developing skin cancer (e.g., squamous, or basal cell carcinomas), physicians may closely monitor affected skin areas to ensure prompt detection and treatment of skin malignancies.

In addition, because some individuals with RTS are more prone to developing certain non-skin related malignancies (e.g., osteosarcoma) than the general population, physicians may closely monitor affected individuals to ensure early detection and prompt, appropriate treatment. Baseline skeletal surveys are recommended since these patients often have underlying skeletal defects that need to be distinguished from any new pathologic lesions. Effective therapies for osteosarcoma and other cancers are currently available, and it appears that some patients with RTS can tolerate these therapies similar to cancer patients in the general population. Other patients may require dose reductions based on individual tolerance to specific chemotherapy agents.

RTS patients may be at risk for osteoporosis and bone fractures. Monitoring with DXA scans may be warranted and some patients may benefit from bone supplements.

Because serious visual impairment or loss may result from cataracts, infants and children with RTS should be closely monitored by pediatricians and ophthalmologists to ensure immediate detection of cataracts and prompt, appropriate treatment. Surgical removal of opacified lenses can be performed to prevent serious visual impairment or loss.

Dental abnormalities potentially occurring in association with RTS may be treated through surgery, use of dentures and other artificial devices (prosthetics), and/or other supportive techniques.

Pulsed dye laser has been used for the cosmetic management of the telangiectatic component of the rash.

Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
Explore Clinical Trials & Research for Rare Disease Patients (rarediseases.org)

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Researchers at Texas Children’s Hospital and Texas Children’s Cancer Center at Baylor College of Medicine are studying the genetics and biology of Rothmund-Thomson Syndrome (RTS) and they have enrolled an international group of RTS patients in these studies. For information contact:

Dr. Lisa L. Wang
(832) 824-4822
llwang@bcm.edu
1102 Bates Avenue, Suite 1200, Houston, Texas, 77030

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References

JOURNAL ARTICLES
Ajeawung NF, Nguyen TM, Lu L, Kucharski TJ, Rousseau J, Molidperee S, Atienza J, Gamache I, Jin W, Plon SE, Lee BH, Teodoro JG, Wang LL*, Campeau PM* (*co-senior authors). Mutations in ANAPC1, encoding a scaffold subunit of the anaphase promoting complex, cause Rothmund-Thomson syndrome Type 1. Am J Hum Genet. 2019 Sep 5;105(3):625-630. doi: 10.1016/j.ajhg.2019.06.011. Epub 2019 Jul 11. PMID: 31303264

Cao F, Lu L, Abrams SA, Hawthorne KM, Tam A, Jin W, Dawson B, Shypailo R, Liu H, Lee B, Nagamani SCS, Wang LL. Generalized metabolic bone disease and fracture risk in Rothmund-Thomson syndrome. Hum Mol Genet. 2017 Aug 15;26(16):3046-3055. doi: 10.1093/hmg/ddx178.

Lu L, Jin W, Wang LL. Aging in Rothmund-Thomson syndrome and related RECQL4 genetic disorders. Ageing Res Rev. 2017 Jan;33:30-35. doi: 10.1016/j.arr.2016.06.002. Epub 2016 Jun 7.

Lu H, Shamanna RA, Keijzers G, Anand R, Rasmussen LJ, Cejka P, Croteau DL, Bohr VA. RECQL4 Promotes DNA End Resection in Repair of DNA Double-Strand Breaks. Cell Rep. 2016 Jun 28;16(1):161-173. doi: 10.1016/j.celrep.2016.05.079. Epub 2016 Jun 16.

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Singh DK, Karmakar P, Aamann M, Schurman SH, May A, Croteau DL, Burks L, Plon SE, Bohr VA. The involvement of human RECQL4 in DNA double-strand break repair. Aging Cell. 2010 Jun;9(3):358-71.

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Van Maldergem L, Siitonen HA, Jalkh N, et al. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. J Med Genet. 2006; 43: 148-52.

Wang LL, Gannavarapu A, Kozinetz CA, et al. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst. 2003; 95: 669-74.

Siitonen HA, Kopra O, Kaariainen H, et al. Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases. Hum Mol Genet. 2003; 12: 2837-44.

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Anbari KK, et al. Two primary osteosarcomas in a patient with Rothmund-Thomson syndrome. Clin Orthop. 2000;378:213-23.

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INTERNET
Wang LL, Plon SE. Rothmund-Thomson Syndrome. 1999 Oct 6 [Updated 2020 Jun 4]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1237/ Accessed August 14, 2023.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Rothmund-Thomson Syndrome; RTS. Entry No: 268400. Last Edited 11/22/2021. Available at: https://omim.org/entry/268400 Accessed August 14, 2023.

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