Dyskeratosis congenita

• Dyskeratosis congenita (DKC) is a rare condition marked by progressive failure of the bone marrow, the spongy tissue inside the bones that is essential for the production of new cells. The cells that are produced in the bone marrow can develop into red or white blood cells or platelets. People with DKC do not have adequate numbers of some cells, which causes a condition known as aplastic anemia.
• Other symptoms include skin discoloration, nail problems, and oral leukoplakia, a condition in which white or gray patches develop in the mouth as a result of irritation. Symptoms generally appear during the first 10 years of life. Changes in skin coloration and fingernails and toenails tend to be the first symptoms to appear.
• DKC is caused by a mutation or defect in any of the following
  genes: DKC1, TERT, TERC, and NOP10. All of the genes associated with this condition are involved with the protection of DNA (deoxyribonucleic acid), the genetic material contained in every cell in the body. DKC may occur as an X-linked recessive, autosomal dominant, or autosomal recessive condition. The severity and prognosis of DKC can be different based on how it is inherited.
• DKC is estimated to occur in one out of 1,000,000 people. It is more common among males than females, occurring in three males for every one female. The condition appears to affect all races and ethnicities in equal numbers.
• People with DKC have an average life span of 30 years, although most die in their teens. The cause of death is generally from complications caused by bone marrow failure, including infections and cancers.
• There is currently no known cure for DKC; treatments aim to reduce symptoms and provide comfort to the individual. Stem cell transplantation has been used with mixed results for the treatment of aplastic anemia in DKC.

• Because dyskeratosis congenita is inherited, the only known risk factor is a family history of the condition. DKC is estimated to occur in one out of 1,000,000 people. It is more common among males than females, occurring in three males for every one female. The condition appears to affect all races and ethnicities in equal numbers.

• Genetic mutations: Dyskeratosis congenita (DKC) is caused by mutations or defects in any of the following genes: DKC1, TERT, TERC, and NOP10. It is not clear what proportion of DKC cases is caused by each type of mutation. All of these genes are involved with the protection of DNA, the genetic material contained in every cell in the body. Analysis of individuals with the condition found that identified genes account for only about 65% of patient cases. This may mean that other genes are also responsible or that the disease can occur as the result of a spontaneous mutation in the sperm or egg cells or in the developing fetus. Wide variations among patients with DKC suggest there may also be environmental factors that contribute to the disease.
• X-linked recessive inheritance: The mutated dyskerin (DKC1) gene that causes DKC is inherited, or passed down, among family members as an X-linked recessive trait. Females have two copies of the X chromosome, while males have one X chromosome and one Y chromosome. Males inherit one X chromosome from the mother and one Y chromosome from the father. A male can inherit the DKC1 gene only from the mother. A female needs to inherit two mutated copies of the DKC1 gene to develop DKC (one from each parent), while a male needs to inherit only one mutated copy of the gene to develop the condition.
• Autosomal dominant inheritance: The mutated TERC or TERT genes that cause DKC are inherited, or passed down, among family members, as autosomal dominant traits. Each gene has two variations, called alleles. One allele is inherited from each parent. To inherit an autosomal dominant trait, just one copy of the mutated gene is needed. If one parent has DKC caused by mutations in the TERC or TERT genes, there is a 50% chance that his or her child will have the disorder. If both parents have DKC caused by these specific genetic mutations, there is a 75% chance that the child will inherit the disorder.
• Autosomal recessive inheritance: The mutated NOP10 gene that causes DKC is inherited, or passed down, among family members as an autosomal recessive trait. To inherit an autosomal recessive trait, a person must inherit two defective copies of the causative gene (one copy from each parent). People who inherit a mutation from only one parent are called "carriers" of the condition, and they may pass the mutation on to their children.
• If one parent is a carrier, or has only one copy of the defective gene, then each child has a 50% chance of inheriting one defective gene and also of being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two defective genes, a 50% chance of inheriting only one defective gene, and a 25% chance of inheriting neither defective gene. Therefore, if both parents are carriers, about one out of four children will have DKC.

• General: Changes in the skin and nails are generally the first symptoms to appear and are often the reason individuals seek medical care. Females who are carriers of dyskeratosis congenita (DKC) may experience very mild symptoms that affect the skin, nails, and mouth.
• Bone marrow failure: In some cases, the first symptom of DKC is bone marrow failure. Eventually, 90% of patients with DKC develop bone marrow failure. The bone marrow is the spongy tissue inside the bones that is essential for the production of new cells. The cells that are produced in the bone marrow can develop into red or white blood cells or platelets. People with DKC do not have adequate numbers of some cells, which causes a condition known as aplastic anemia.
• Eyes: People with DKC may have inflammation of the lining of the eyes (conjunctivitis), inflammation of the eyelids (blepharitides), growths in the eye, and excessive tearing.
• Gastrointestinal: Patients with DKC may have an enlarged spleen and a serious liver disease known as cirrhosis.
• Lungs: About 20% of patients with DKC develop lung conditions, including the growth of fibrous tissue and problems with the veins that carry blood from the lungs back to the heart.
• Mouth: Oral leukoplakia, grayish white patches that form on the gums, tongue, throat, and inside of the cheeks, is seen in about 80% of patients with DKC. Patients may also be at increased risk for gum disease.
• Nails: About 90% of patients with DKC also have nail symptoms, including ridged, split, thin, or absent nails.
• Skeletal: Patients with DKC may have underdeveloped jaw bones, scoliosis (curvature of the spine), and osteoporosis (thin, brittle bones).
• Skin: One of the main findings in DKC is changes in skin discoloration, which is seen in about 90% of patients. Patches of skin may be tan or gray and may form a net-like pattern. Patients with DKC may also experience hair loss from the head, eyebrows, and eyelashes; early graying of hair; increased sweating; thickening of the skin on the palms of the hands and soles of the feet; and loss of the ridges on the fingers and toes.
• Other: Symptoms similar to those in the mouth may develop in the esophagus, urethra, penis, tear ducts, lining of the eye, vagina, and anus. Males and females with DKC may have urinary or reproductive problems. Individuals with DKC may have developmental delays or intellectual disabilities.

• General: Diagnosis of dyskeratosis congenita (DKC) generally begins with a detailed family history and complete physical exam. Because skin discoloration and nail changes become apparent between ages five and 15, this is usually done by a pediatrician. Diagnosis should aim to distinguish DKC from similar or seemingly similar conditions, including Fanconi syndrome. Clinicians should screen for skin and mucosal changes, nail problems, bone marrow failure, lung disease, enlarged spleen, liver disease, scoliosis, osteoporosis, and the development of cancer.
• Blood tests: A complete blood count (CBC) can measure the numbers of red and white blood cells and platelets.
• Fecal occult blood test (FOBT): A fecal occult blood test determines whether blood is present in the stool, which may indicate gastrointestinal bleeding. In people with DKC, this can be caused by low numbers of platelets, the cells that help with clotting.
• Imaging: Imaging studies, such as magnetic resonance imaging (MRI), can be used to assess the health status of the spleen and liver. A chest radiograph can be used to screen for lung problems.
• Pulmonary function tests: Pulmonary function tests assess how efficiently the lungs are working and sending oxygen to other parts of the body.
• Genetic (DNA) testing: DNA tests may be performed to confirm the presence of the mutated genes (DKC1, TERC, TERT, and NOP10) that cause DKC and to confirm the results from other testing methods.
• Amniotic fluid (prenatal) genetic testing: Genetic tests may be performed on blood from a developing fetus or on amniotic fluid, which is the fluid contained in the sac that surrounds and cushions the fetus. Because taking a blood sample may cause harm to a fetus, taking samples of amniotic fluid is generally preferred. It is important to note that any prenatal test carries a risk of miscarriage.
• Chorionic villus sampling (CVS): Chorionic villus sampling (CVS) is another type of prenatal diagnosis that can detect genetic problems in a fetus. Samples are taken from the chorionic villus, or placental tissue. As with any prenatal test, this procedure carries a risk of miscarriage.
• Pre-implantation genetic diagnosis (PGD): A new procedure called pre-implantation genetic diagnosis (PGD) may be performed on embryos produced by in vitro (artificial) fertilization. This test allows parents to implant and carry to term only the embryos that do not have the mutated genes that cause DKC.

• Aplastic anemia: In some cases, the first symptom of dyskeratosis congenita (DKC) is bone marrow failure. Eventually, 90% of patients with DKC develop bone marrow failure. When the bone marrow fails, not enough blood cells are produced, and the individual becomes anemic. The condition that results from bone marrow failure is known as aplastic anemia. A common complication of aplastic anemia is frequent infections, which may be fatal in some cases.
• Cancer: Because of the genetic mutations associated with DKC, people with this condition are at an increased risk of various cancers, including squamous cell carcinoma of the mucus membranes, such as the mouth, throat, esophagus, rectum, vagina, or cervix. Skin cancer, Hodgkin's lymphoma, adenocarcinoma of the digestive tract, and lung cancer may also develop. Cancer tends to develop in individuals with DKC during their 20s.
• Gastrointestinal: Patients with DKC may have an enlarged spleen and a serious liver disease known as cirrhosis.
• Skeletal: Patients with DKC may have underdeveloped jaw bones, scoliosis (curvature of the spine), and osteoporosis (thin, brittle bones).

• General: There is currently no known cure for dyskeratosis congenita (DKC), but treatment may help relieve symptoms and prevent complications. Patients with DKC should avoid substances that may worsen their condition. These include drugs that cause lung toxicity, such as busulfan. Patients should also limit their exposure to radiation, such as unnecessary X-rays.
• Anabolic steroids: Anabolic steroids such as oxymetholone (Anadrol®) are drugs derived from the male hormone testosterone that help to promote the growth and repair of tissues. Anabolic steroids may be used as a short-term treatment for bone marrow failure in DKC.
• Colony-stimulating factors: Colony-stimulating factors (CSFs) are substances that stimulate the production of blood cells. CSFs include erythropoietin (Epogen®, Procrit®) and filgrastim (Neupogen®).
• Stem cell transplantation: Human stem cell transplantation has been used in patients with aplastic anemia. To do a stem cell transplant, a suitable donor must be identified. To increase the chances of a successful procedure, the patient is pretreated with chemotherapy or radiation. This is done to suppress the immune system so it does not attack the donated cells. The success rate of this treatment currently remains unknown.

Note
: Currently there is insufficient evidence available on the safety and effectiveness of integrative therapies for the prevention or treatment of dyskeratosis congenita (DKC). The therapies listed below have been studied for related conditions, should be used only under the supervision of a qualified healthcare provider, and should not be used in replacement of other proven therapies or preventive measures.

A

Strong scientific evidence

• Calcium
  : Osteoporosis is a disorder of the skeleton in which bone strength is reduced, resulting in an increased risk of fracture. Calcium is the nutrient consistently found to be the most important for attaining peak bone mass and preventing osteoporosis. Adequate vitamin D intake is required for optimal calcium absorption. Adequate calcium and vitamin D are deemed essential for the prevention of osteoporosis in general, including postmenopausal osteoporosis. Although calcium and vitamin D alone are not recommended as the sole treatment for osteoporosis, they are necessary additions to pharmaceutical treatments. The vast majority of clinical trials investigating the efficacy of pharmaceutical treatments for osteoporosis have investigated these agents in combination with calcium and vitamin D.
• Avoid if allergic or hypersensitive to calcium or lactose. High doses taken by mouth may cause kidney stones. Avoid with high levels of calcium in the blood, high levels of calcium in the urine, high levels of parathyroid hormone, bone tumors, digitalis toxicity, ventricular fibrillation (the ventricles of the heart contracting in an unsynchronized rhythm), kidney stones, kidney disease, or sarcoidosis (the inflammation of lymph nodes and various other tissues). Calcium supplements made from dolomite, oyster shells, or bone meal may contain unacceptable levels of lead. Use cautiously with achlorhydria (the absence of hydrochloric acid in gastric juices) or irregular heartbeat. Calcium appears to be safe in pregnant or breastfeeding women. It is advised to consult with a healthcare provider to determine appropriate dosing during pregnancy and breastfeeding.

B

Good scientific evidence

• Vitamin D
  : Without sufficient vitamin D, calcium absorption cannot be maximized and the resulting elevation in parathyroid hormone (PTH) secretion by the parathyroid glands results in increased bone resorption, which may weaken bones and increase the risk of fracture. Vitamin D supplementation has been demonstrated to slow bone loss and reduce fractures, particularly when taken with calcium.
• Avoid if allergic or hypersensitive to vitamin D or any of its components. Vitamin D is generally well-tolerated in recommended doses. Doses higher than recommended may cause toxic effects. Individuals with an overactive thyroid, kidney disease, sarcoidosis, tuberculosis, or histoplasmosis are at a higher risk of experiencing toxic effects. Vitamin D is generally considered safe for pregnant women. It may be necessary to give infants vitamin D supplements along with breast milk. The recommended intake of vitamin D for normal infants, children, and adolescents is 200 IU daily.

C

Unclear or conflicting scientific evidence

• Beta-carotene
  : Taking beta-carotene orally seems to induce remission in patients with oral leukoplakia. Further research is needed to confirm these results. Avoid if sensitive to beta-carotene, vitamin A, or any other ingredients in beta-carotene products.
• Black tea
  : Early studies report that black tea may lead to clinical improvement in oral leukoplakia and therefore prevent oral carcinoma. Further research is needed to confirm these results.
• Avoid if allergic or hypersensitive to caffeine or tannins. Skin rash and hives have been reported with caffeine ingestion. Use caution with diabetes. Use cautiously if pregnant. Heavy caffeine intake during pregnancy may increase the risk of SIDS (sudden infant death syndrome). Very high doses of caffeine have been linked to birth defects. Caffeine is transferred into breast milk. Caffeine ingestion by infants can lead to sleep disturbances and insomnia. Infants nursing from mothers consuming greater than 500 milligrams of caffeine daily have been reported to experience tremors and heart rhythm abnormalities. Tea consumption by infants has been linked to anemia, decreased iron metabolism, and irritability.
• Rehmannia
  : Rehmannia is frequently recommended to mitigate duration and severity of aplastic anemia. Although preliminary results appear promising, additional study is needed to make a firm recommendation.
• Avoid if allergic or hypersensitive to rehmannia, any of its constituents or any members of the Scrophulariaceae family. Use cautiously if taking anticoagulants, blood pressure medications, diuretics, or thyroid medications. Use cautiously with diabetes. Use cautiously in children younger than two years of age. Avoid if taking therapeutic immunosuppressants. Avoid with diarrhea and lack of appetite. Avoid if pregnant or breastfeeding.
• Rhubarb
  : A combination mixture containing rhubarb has been shown to alleviate aplastic anemia. However, the role of rhubarb in the treatment of this condition is still to be determined, and additional study is needed in this area.
• Avoid if allergic or hypersensitive to rhubarb, its constituents, or related plants from the Polygonaceae family. Avoid using rhubarb for more than two consecutive weeks because it may induce tolerance in the colon, melanosis coli, laxative dependence, pathological alterations to the colonic smooth muscles, and substantial loss of electrolytes. Avoid with atony, colitis, Crohn's disease, dehydration with electrolyte depletion, diarrhea, hemorrhoids, insufficient liver function, intestinal obstruction or ileus, irritable bowel syndrome, menstruation, pre-eclampsia, renal disorders, ulcerative colitis, or urinary problems. Avoid handling rhubarb leaves, as they may cause contact dermatitis. Avoid rhubarb in children younger than age 12 because of possible water depletion. Use cautiously with bleeding disorders, cardiac conditions, coagulation therapy, constipation, history of kidney stones, or thin or brittle bones. Use cautiously if taking anti-psychotic drugs or oral drugs, herbs or supplements, including calcium, iron, and zinc. Avoid if pregnant or breastfeeding.
• Spirulina
  : Early research has not clearly shown benefits of spirulina in the treatment of oral leukoplakia. Additional research is needed in this area. Avoid if allergic or hypersensitive to spirulina or blue-green algae. Avoid with phenylketonuria. Avoid if pregnant or breastfeeding.
• Turmeric
  : Turmeric (Curcuma longa) is a perennial plant native to India and Indonesia, and it is often used as a spice in cooking. The root of turmeric has long been used in traditional Asian medicine. Based on available research, it is unclear whether turmeric is an effective treatment for oral leukoplakia.
• Avoid if allergic to turmeric (curcumin), yellow food colorings, or plants belonging to the Curcuma and Zingiberaceae (ginger) families. Use cautiously with a history of bleeding disorders, immune system deficiencies, liver disease, or gallstones. Use cautiously if taking blood thinners, such as warfarin (Coumadin®). Historically turmeric has been considered safe when used as a spice in foods during pregnancy and breastfeeding. However, turmeric has been found to cause uterine stimulation and to stimulate menstrual flow, so caution is warranted during pregnancy.

• General: Because dyskeratosis congenita (DKC) is an inherited condition, there is currently no known way to prevent the disease. However, a number of options are available for patients with family histories of DKC.
• Genetic testing and counseling: Individuals who have DKC may meet with a genetic counselor to discuss the risks of having children with the disease. Individuals from high-risk populations, or those with family histories of DKC, may meet with a genetic counselor to determine whether they carry any of the genes for DKC. Carrier status can be determined through detailed family histories or genetic testing.
• Known carriers of DKC may undergo genetic counseling before they conceive a child. Genetic counselors can explain the options and the associated risks of various tests, including pre-implantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS).
• Pre-implantation genetic diagnosis (PGD) may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for the genes that cause DKC, and only the embryos that are free of those mutations are selected for implantation. Because DKC can be detected in a fetus, prospective parents may choose whether to continue the pregnancy. Genetic counselors may assist parents with these difficult decisions.
• Secondary infections: Patients can help reduce their risk of infections by avoiding or minimizing exposure to disease-causing pathogens, such as bacteria or viruses. Individuals should regularly wash their hands with soap and water and avoid close contact with individuals who have contagious infections or diseases.