Rothmund-Thomson?s syndrome

Related Terms

Anhidrosis, ectodermal dysplasia, lung infections, poikiloderma atrophicans and cataract, poikiloderma congenitale, RECQL4 helicase gene, Rothmund-Thomson syndrome, RTS.

Background

Rothmund-Thomson syndrome (RTS) is a form of ectodermal dysplasia, one of a group of syndromes deriving from abnormalities of the ectodermal structures, which include the hair, teeth, nails, sweat glands, cranial-facial structure, and hands. These are genetic disorders that can be inherited in an autosomal dominant or recessive manner.
RTS is characterized by skin problems, sensitivity to the sun, short stature, hair defects, cataracts, a clouding of the lens of the eye, abnormalities of the head and face, tooth problems, digestive issues, and skeletal conditions. Rarely, people with RTS may have intellectual disabilities. People with RTS have an increased risk of developing cancer, specifically bone and skin cancers.
RTS is inherited, or passed down among family members, and is caused by a mutation or defect in the RECQL4 gene. The protein product of the RECQL4 gene is the RECQ protein, which appears to be involved in genome maintenance and may be related to a predisposition to cancer, increased chromosomal defects, and an increased sensitivity to DNA-damaging agents in individuals with this disease. RTS follows a recessive pattern of inheritance, meaning that two copies of the defective gene, one from each parent, are needed for the condition to appear.
RTS is very rare, with only about 300 known cases worldwide. The condition appears to affect males and females equally. Ectodermal dysplasias can occur in any race but are much more dominant in Caucasians than in any other group, particularly in fair-skinned Caucasians.
If an individual with RTS does not develop cancer, he or she can expect to live a long and healthy life.

Signs and symptoms

General: People with Rothmund-Thomson syndrome (RTS) typically develop redness on the cheeks between three and six months of age. Over time, the rash spreads to the arms and legs, causing patchy changes in skin coloring, areas of atrophy (skin tissue degeneration), and telangiectases (small clusters of enlarged blood vessels just under the skin). These skin problems persist throughout life and are collectively known as poikiloderma. Individuals with RTS also experience delayed growth and development. As a result, they are generally of short stature.
Bones: People with RTS may have small hands and feet, osteopenia (low bone density), absent or poorly developed bones in the forearms, and absent or poorly developed thumbs, which may lead to difficulty in performing everyday tasks.
Digestive: Infants with RTS may suffer from chronic diarrhea and vomiting. There have also been some reports of celiac disease, an autoimmune condition in which an individual's immune system attacks the tissue of one's own cells and tissues. Celiac disease affects the digestive tract and is triggered by gluten, the protein found in wheat and other grains. Upon exposure to the gluten protein, an enzyme modifies the protein and the immune system attacks the bowel tissue, resulting in inflammation. Individuals with celiac disease must exclude gluten from their diets in order to manage the condition. The connection between celiac disease and RTS is unclear.
Eyes: About 40-50% of patients with RTS develop cataracts, a clouding of the lens of the eye, between the ages of four and seven.
Face: Distinctive facial characteristics in RTS include a prominent forehead, a sunken bridge of the nose, and a small but protruding lower jaw.
Hair: As with many ectodermal dysplasias, the hair is affected in RTS. Patients may have sparse hair on the scalp, eyebrows, and eyelashes, early alopecia (loss of hair), or premature graying of the hair.
Nails: People with RTS may have poorly developed fingernails and toenails.
Skin: About 90% of people with RTS generally develop redness on the cheeks between three and six months of age. In rare cases, redness is apparent at birth, but it may also appear as late as two years of age. This redness, which appears as a patchy rash, gradually spreads to the arms and legs.
Other skin problems include photosensitivity (sensitivity to the sun), including skin rash and an increased chance of developing skin cancer, atrophy (breakdown of the skin) leading to a depression in the skin, and telangiectases (clusters of enlarged blood vessels under the skin). In some cases, people with RTS have hypohidrosis (decreased sweat glands) or anhidrosis (absent sweat glands). Skin on the elbows, knees, hands, and feet may become hyperkeratotic (thickened). Occasionally, people with RTS will also have increased or decreased pigment in certain areas of the skin. Many of these symptoms are present in other ectodermal dysplasias.
Skin problems in RTS continue throughout the life span of the patient.
Teeth: In patients with RTS, the teeth may be abnormally small or altogether absent.
Other: Other symptoms of RTS include edema, which is the collection of fluid between the layers of skin, and abnormalities of the reproductive system, including absence of secondary sex characteristics, underactive ovaries or testes, amenorrhea (absence of menstruation), and infertility. Although the connection between RTS and abnormalities of the reproductive system is unclear, it is possible that there is an association between these symptoms and the mutation in the RECQL4 gene.

Diagnosis

General: Rothmund-Thomson syndrome (RTS) is diagnosed based on observation of the characteristic physical features of the condition, in particular those associated with the skin (e.g., a distinctive rash) but may also be diagnosed based on other features such as short stature, hair defects, cataracts (clouding of the lenses of the eye), abnormalities of the head and face, and tooth problems.
Imaging: X-rays may be taken to assess the degree of skeletal defects, such as missing or malformed bones in the hands, feet, forearms, and other parts of the body.
Genetic testing: If RTS is suspected, DNA sequencing can be performed to determine whether the individual carries a mutated RECQL4 gene. A sample of the patient's blood is taken and analyzed in a laboratory for the defect in the RECQL4 gene. If this is detected, a positive diagnosis is made. Relying only on genetic diagnosis may result in a number of false negatives, because one-third of people with RTS do not have the genetic mutation. Therefore, a negative result does not always mean that the patient does not have RTS.
Prenatal DNA testing: If there is a family history of RTS, prenatal testing may be performed to determine whether the fetus has the disorder. Amniocentesis and chorionic villus sampling (CVS) can diagnose RTS. However, because there are serious risks associated with these tests, patients should discuss the potential health benefits and risks with a medical professional.
During amniocentesis, a long, thin needle is inserted through the abdominal wall and into the uterus, and a small amount of amniotic fluid is removed from the sac surrounding the fetus. Cells in the fluid are then analyzed for normal and abnormal chromosomes. This test is performed after 15 weeks of pregnancy. The risk of miscarriage is about one in 200-400 patients. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.
During chorionic villus sampling (CVS), a small piece of tissue (chorionic villi) is removed from the placenta between the ninth and 14th weeks of pregnancy. CVS may be performed through the cervix or through the abdomen. The cells in the tissue sample are then analyzed for a mutation in the RECQL4 gene. Miscarriage occurs in about 0.5-1% of women who undergo this procedure.

Complications

Cancer: Individuals with Rothmund-Thomson syndrome (RTS) are at increased risk for certain types of cancer, specifically bone and skin cancers.
The type of bone cancer seen in patients with RTS is known as osteosarcoma and is marked by the growth of tumors most commonly found in certain bones of the leg, such as the tibia and fibula. Osteosarcoma is malignant and occurs in about 30% of patients with RTS. This is a deadly form of cancer if allowed to progress.
Skin cancers that may develop in patients with RTS include nonmelanoma skin cancers. Examples include Bowen's disease, a localized, or nonspreading, skin growth that does not usually cause much harm, and squamous-cell carcinoma, a malignant tumor of the layer of skin that shows growth of squamous cells. Left untreated, squamous-cell carcinoma can lead to the loss of the affected area; it has also been reported to spread to the lymph nodes, which may result in death.
Dental problems: People with RTS may develop dental problems, including loose teeth, tooth discoloration, and cavities.
Feeding difficulties: People with RTS tend to have a small jaw and small or missing teeth, all of which may make eating difficult. In addition, they may have gastrointestinal problems, including chronic diarrhea; vomiting; and celiac disease, an autoimmune disease triggered by a protein found in wheat. In celiac disease, upon exposure to the gluten protein, an enzyme modifies the protein and the immune system attacks the bowel tissue, resulting in inflammation and causing diarrhea and fatigue.
Reduced sweat glands: Individuals with RTS may have a decreased ability to sweat, caused by a reduced number of sweat glands.
Vision problems: If a patient with RTS develops cataracts, a clouding of the lens of the eye, his or her vision might be affected. The degree of vision loss depends on the severity of the cataract.

Treatment

There is no cure for Rothmund-Thomson syndrome (RTS). Instead, treatment aims to reduce symptoms and prevent or treat complications.
Cancer: Individuals with RTS are predisposed to developing certain kinds of cancer, including bone and skin cancers. Cancer is usually treated with a combination of surgery, chemotherapy, and radiotherapy.
Dental care: Patients with RTS must practice good preventive dental care, including regular flossing, teeth brushing, and visits to the dentist. Dentures may be appropriate for patients with RTS who are missing teeth. Dental surgery may be needed to correct structural problems.
Diet: Infants with RTS may suffer from chronic diarrhea and vomiting. There have also been some reports of celiac disease, an autoimmune condition in which an individual's own immune system attacks the tissue of one's own cells and tissues. Celiac disease affects the digestive tract and is triggered by gluten, the protein found in wheat and other grains. Upon exposure to the gluten protein, an enzyme modifies the protein and the immune system attacks the bowel tissue, resulting in inflammation. Individuals with celiac disease must exclude gluten from their diets in order to manage the condition.
Skin care: Patients with RTS should use a broad-spectrum sunscreen regularly to protect against skin damage from the sun, including skin cancer. Keratolytics (skin softeners such as salicylic acid) and retinoids (vitamin A-related compounds used to treat skin problems) can be used on problem skin areas such as the elbows, knees, palms of the hands, and soles of the feet. However, it should be noted that retinoids have been associated with toxicity and birth defects and should be used with caution.
Surgery: Laser surgery may be an option for the removal of telangiectases (collections of enlarged blood vessels under the skin) and cataracts.
Other: People with RTS should regularly see an ophthalmologist, dentist, orthopedist, endocrinologist, and oncologist to be screened for related disorders and disease complications.
Patients with RTS and their families should be educated about the potential danger of hyperthermia, or increased body temperature. Because of their reduced or absent ability to sweat, patients with RTS may not be able to regulate body temperature correctly. Precautions should be taken during exercise or during exposure to extreme heat.

Integrative therapies

Note: Currently there is a lack of scientific evidence on the use of integrative therapies for the treatment or prevention of Rothmund-Thomson syndrome (RTS). The therapies listed below have been studied for related conditions, such as sun sensitivity and skin cancer, should be used only under the supervision of a qualified healthcare provider, and should not be used in replacement of other proven therapies.
Unclear or conflicting scientific evidence:
Chlorella: Early studies suggest a potential effect of chlorella on skin cancer. Avoid with known allergy or hypersensitivity to chlorella, its constituents, or members of the Oocystaceae family. Children have been found to be allergic to chlorella. Chlorella has a high vitamin K content and may decrease the effectiveness of anticoagulants (blood thinners) such as warfarin. Long-term consumption of chlorella may cause manganese-induced parkinsonism. Other adverse effects include photosensitivity, occupational asthma, and fatigue.
Green tea: There is limited animal and human research on green tea as a protective agent from ultraviolet light injury to the skin. Some studies have found conflicting results. Comparisons have not been made with well-established forms of sun protection such as ultraviolet-protective sunscreen. The effects of green tea on skin damage caused by the sun remain unclear. Avoid if allergic or hypersensitive to caffeine or tannin. Use cautiously with diabetes or liver disease.
Lutein: Numerous laboratory studies have shown the antioxidant effect of lutein. More research is required on the use of lutein for sunburn prevention before a firm conclusion can be made. Avoid if allergic or hypersensitive to lutein or zeaxanthin. Use cautiously if at risk for cardiovascular disease or cancer. Avoid if pregnant or breastfeeding.
Lycopene: Lycopene, in combination with other carotenoids, such as beta-carotene, vitamins C and E, selenium, and proanthocyanidins, may help in reducing sunburn. Selected protective effects from ultraviolet (UV) rays have been observed in small, short-term studies. More research is needed before a firm conclusion can be drawn. Avoid if allergic to tomatoes or to lycopene. Avoid if pregnant or breastfeeding.
Para-aminobenzoic acid (PABA): PABA is best known for its topical use as a component of sunscreen products. Although PABA and related compounds have frequently been used as topical sunscreen agents, only a few studies in the literature have demonstrated its effectiveness for this specific purpose. Further studies are needed to better understand the protective properties of PABA. Its use as a component of sunscreens has diminished recently because of reports of frequent allergic reactions and cross-sensitivity with other medications.
Pycnogenol?: Pycnogenol? taken by mouth may reduce redness of the skin caused by solar ultraviolet light. Further research is needed before a recommendation can be made. Avoid if allergic or hypersensitive to Pycnogenol?, its components, or members of the Pinaceae family. Use cautiously with diabetes, hypoglycemia, and bleeding disorders. Use cautiously if taking medications that reduce blood cholesterol levels, may increase the risk of bleeding, lower blood pressure, or affect the immune system. Avoid if pregnant or breastfeeding.
Selenium: Protection from UV damage was initially observed in early research using selenium and other antioxidant supplementation, although there is some evidence that selenium does not prevent light-induced skin redness. Avoid if allergic or sensitive to products containing selenium. Avoid with history of nonmelanoma skin cancer. Selenium is generally regarded as safe for pregnant or breastfeeding women. However, there are reports from animal research that large doses of selenium may lead to birth defects.
Vitamin A: It is unclear whether vitamin A or beta-carotene, taken by mouth or used on the skin with sunscreen, is beneficial in the prevention or treatment of skin cancers or wrinkles. Avoid if allergic or hypersensitive to vitamin A. Vitamin A toxicity can occur if taken at high dosages. Use cautiously with liver disease or alcoholism. Smokers who consume alcohol and beta-carotene may be at increased risk for lung cancer or heart disease. Vitamin A appears safe in pregnant women if taken at recommended doses. However, excess or inadequate vitamin A has been associated with birth defects. Excessive doses of vitamin A have been associated with central nervous system problems. Use cautiously if breastfeeding, because the benefits or dangers to nursing infants have not been clearly established.
Fair negative scientific evidence:
Selenium: Results from the Nutritional Prevention of Cancer (NPC) trial, conducted among 1,312 Americans over a 13-year period, suggest that selenium supplementation given to individuals at high risk of nonmelanoma skin cancer is ineffective in the prevention of basal cell carcinoma and actually increases the risk of squamous cell carcinoma and total nonmelanoma skin cancer. Therefore, selenium supplementation should be avoided in individuals at risk for or with a history of nonmelanoma skin cancer. Avoid if allergic or sensitive to products containing selenium. Avoid with a history of nonmelanoma skin cancer. Selenium is generally regarded as safe for pregnant or breastfeeding women. However, animal research reports that large doses of selenium may lead to birth defects.

Prevention

General: Because Rothmund-Thomson syndrome (RTS) is an inherited condition, there is currently no known way to prevent the disease. However, a number of options are available for prospective parents with a family history of RTS.
Genetic testing and counseling: Individuals who have RTS may meet with genetic counselors to discuss the risks of having children with the disease. Individuals with a family history of RTS may meet with a genetic counselor to determine whether they carry the defective RECQL4 gene. Carriers can be determined through detailed family histories or genetic testing.
Genetic counselors can explain the options and the associated risks of various tests, including preimplantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS).
Preimplantation genetic diagnosis (PGD) may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for the defective RECQL4 gene, and only the embryos that are not affected may be selected for implantation. Because RTS can be detected in a fetus, parents may choose whether to continue the pregnancy. Genetic counselors may assist parents with these difficult decisions.

Author information

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography

Broom MA, Wang LL, Otta SK, et al. Successful umbilical cord blood stem cell transplantation in a patient with Rothmund-Thomson syndrome and combined immunodeficiency. Clin Genet. 2006;69(4):337-43.
Dechenne C, Chantraine JM, Davin JC. A Rothmund-Thomson case with hypertension. Clin Genet. 1983;24: 266-72.
Drouin CA, Mongrain E, Sasseville D, et al. Rothmund-Thomson syndrome with osteosarcoma. J Am Acad Derm. 1993;28: 301-5.
Genetics Home Reference. .
Geronemus RG. Treatment of the cutaneous vascular component of the Rothmund-Thomson syndrome. Pediatr Dermatol. 1996;13(2):175.
Hall JC, Pagon RA, Wilson KM. Rothmund-Thomson syndrome with severe dwarfism. Am J Dis Child. 1980;134: 165-9.
Hilhorst-Hofstee Y, Shah N, Atherton D, et al. Radial aplasia, poikiloderma and auto-immune enterocolitis--new syndrome or severe form of Rothmund-Thomson syndrome? Clin Dysmorph. 2000;9: 79-85.
Leonard A, Craft AW, Moss C, et al. Osteogenic sarcoma in the Rothmund-Thomson syndrome. Med Pediatr Oncol. 1996;26(4):249-53.
Natural Standard: The Authority on Integrative Medicine. .
Piquero-Casals J, Okubo AY, Nico MM. Rothmund-thomson syndrome in three siblings and development of cutaneous squamous cell carcinoma. Pediatr Dermatol. 2002;19(4):312-6.
Pujol LA, Erickson RP, Heidenreich RA, et al. Variable presentation of Rothmund-Thomson syndrome. Am J Med Genet. 2000;95: 204-7.
Starr DG, McClure JP, Connor JM. Non-dermatological complications and genetic aspects of the Rothmund-Thomson syndrome. Clin Genet. 1985;27: 102-4.
Vennos EM, Collins M, James WD. Rothmund-Thomson syndrome: review of the world literature. J Am Acad Dermatol. 1992;27(5 Pt 1):750-62.
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(9):669-74.
Wang LL, Levy ML, Lewis RA, et al. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am J Med Genet. 2001;102(1):11-7.

Causes

Inheritance: Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder. About two-thirds of cases of RTS are caused by a mutation in the RECQL4 gene. The function of this gene is not well understood, but it may play a role in maintaining the integrity of DNA. In about one-third of individuals with Rothmund-Thomson syndrome, no mutation in the RECQL4 gene has been found. The cause of the condition in these individuals is unknown. However, researchers suspect that these cases may result from mutations in a gene related to RECQL4.
RTS is an autosomal recessive disorder, meaning that an individual must inherit two copies of the mutated gene, one from each parent, in order for the condition to appear. Individuals who inherit only one copy of the mutation may not have symptoms of the disorder but are considered carriers, because they can pass on the mutation to their children.
If one parent carries the defective RECQL4 gene, then each child has a 50% chance of inheriting one mutated gene and also being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two mutated genes, a 50% chance of inheriting only one mutation, and a 25% chance of inheriting neither mutation. Thus, if both parents are carriers, about one out of every four children will have RTS.
If one parent has RTS and the other does not carry the defective gene, then all of the children will be carriers. If one parent has RTS and the other parent is a carrier, then each child has a 50% chance of having RTS and a 50% chance of being a carrier. If both parents have RTS, then all of their children will also have RTS.
Random occurrence: It is not known whether RTS can result from a spontaneous mutation in the sperm, egg, or embryo.
Other: In about one-third of cases of RTS, the genetic mutation in the RECQL4 gene is not present. The cause of RTS in these cases is unknown, but researchers believe it is likely caused by a mutation in a related gene.

Risk factors

The only known risk factor for Rothmund-Thomson syndrome (RTS) is a family history of the disease. RTS is caused by a mutation or defect in the RECQL4 gene. RTS is usually inherited, or passed down among family members, as a recessive trait, meaning that two copies of the defective gene, one from each parent, must be inherited for the condition to appear.