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.
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.
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.
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.
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.