Dyskeratosis Congenita

Dyskeratosis Congenita

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Dyskeratosis Congenita is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • DKC
  • DC
  • dysfunctional telomere maintenance
  • dyskeratosis congenita syndrome
  • short telomere disease

Disorder Subdivisions

  • dyskeratosis congenita, autosomal recessive
  • dyskeratosis congenita, autosomal dominant, Scoggins type
  • dyskeratosis congenita, X-linked, Zinsser-Cole-Engleman syndrome
  • Hoyeraal-Hreidarsson syndrome
  • Revesz syndrome

General Discussion

Dyskeratosis congenita is a rare genetic form of bone marrow failure, the inability of the marrow to produce sufficient blood cells. Dyskeratosis is Latin and means the irreversible degeneration of skin tissue, and congenita means inborn. First described in the medical literature in 1906, dyskeratosis congenita was originally thought to be a skin disease that also affects the nails and the mouth. Only later in the sixties was it realized that patients with these skin changes almost always develop bone marrow failure. Thus, for the last 40 years or so, the bone marrow failure syndrome dyskeratosis congenita was diagnosed when patients presented with the triad of abnormal skin, malformation (dystrophy) of the nails, and white, thickened patches on the mucous membranes of the mouth (oral leukoplakia). The skin changes may be present before the development of bone marrow failure. Bone marrow failure is usually diagnosed by the low number of circulating blood cells including red blood cells, white blood cells, and platelets. Additional findings in patients with dyskeratosis congenita may include short stature, eye and tooth abnormalities, thin and early graying of the hair, lung (pulmonary) disease, liver disease, gut abnormalities, bone thinning (osteoporosis), infertility, learning difficulties, and delays in reaching developmental milestones. An increased incidence of leukemia and cancer has also been documented.



Today, in addition to examining the skin, nails, and mouth for these classical changes, we also use other tests to diagnose dyskeratosis congenita including testing for the genetic abnormality responsible for the development of the disease. Using these more sensitive tests, we are beginning to realize, that only a minority of patients with the genetic abnormality actually develop the full clinical picture of dyskeratosis congenita as outlined above. We find that there are many more individuals with the genetic abnormality (mutation) who have only a mild form of the disease. Often these individuals may only show one or two of the clinical features and these only become obvious, late in life. Some never develop the classic skin abnormalities that coined the name of the disease. Whether the disease in these patients in the absence of skin manifestations should also be labeled with dyskeratosis congenita is controversial and often these individuals are referred to as having atypical dyskeratosis congenita. There are even individuals carrying the mutation who will never develop disease, however their children or grandchildren might. These individuals are often referred to as silent mutation carriers. This new knowledge is important for physicians and patients because much of what has previously been published about this disease may actually not apply anymore for all individuals newly diagnosed with dyskeratosis congenita. In addition to the many more mild manifestations of this disease we also realize that there are some rare but very severe forms of dyskeratosis congenita. These were previously known as the Hoyeraal-Hreidarsson syndrome and the Revesz syndrome but today we know that they have the same underlying abnormality and are caused at least in part by mutations in the same genes responsible for dyskeratosis congenita. These severe forms manifest early in life and are associated with additional clinical features that are usually not present in other forms of dyskeratosis congenita (see also below).



In the majority of cases dyskeratosis congenita is inherited. The pattern of inheritance may be X-linked (Zinsser-Cole-Engleman syndrome), autosomal dominant (dyskeratosis congenita, Scoggins type) or autosomal recessive. However, in a large proportion of patients dyskeratosis congenita occurs sporadically, meaning that the parents do not show disease. In some patients with sporadic DC the genetic abnormality may have newly arisen (de novo mutation) and therefore is not present in either parent.

Symptoms

The symptoms and onset of symptoms in patients with dyskeratosis congenita varies greatly depending on the gene mutated, the nature of the mutation, for how many generations the mutation has been inherited, and possibly other genetic and environmental factors. However, even among members of the same family the symptoms and onset may vary to some degree. In some families disease seems to become more severe and manifests earlier in life with subsequent generations. One of the characteristics is that, with the exception of the very severe forms (Hoyeraal-Hreidarsson and to some extent the Revesz syndrome), clinical symptoms are not present at birth, but develop during childhood, adolescence, and in some cases only late in life. In general, the earlier the disease becomes apparent, the more likely it is that the disease is severe and rapidly progressing. Likewise, the later in life clinical symptoms appear, the milder the form of disease and the slower the progression of disease. The exception to this is the risk of cancer and leukemia, which increases with age and is more common in patients with moderate to mild forms of disease. Patients with the classic form of dyskeratosis congenita are those who present with the originally described skin, nail and mouth abnormalities. In these patients the skin and nail abnormalities usually appear before 10 years of age and bone marrow failure by 20 years of age. In approximately 80-90 percent of patients with classic dyskeratosis congenita bone marrow failure occurs by age 30. In some cases, bone marrow failure appears before skin, nail or mucous membrane symptoms. Patients with the mild form of dyskeratosis congenita may have no apparent symptoms (asymptomatic) into their 30s or 40s and often present only with one of the clinical features associated with dyskeratosis congenita such as bone marrow failure, pulmonary fibrosis, liver fibrosis, or osteoporosis. Skin and nail changes, might be so mild that they are overlooked, or not noticed.



The X-linked form and some of the sporadic forms often present as classic dyskeratosis congenita, whereas individuals with the autosomal dominant form of dyskeratosis congenita often tend to have fewer abnormalities and later onset of symptoms. The skin and mucous membranes abnormalities are usually milder in the autosomal dominant form. The autosomal recessive form can vary dramatically with some individuals experiencing bone marrow failure early during childhood, while others have no blood abnormalities into their 40s. Although these findings are typical of many cases, individual cases may turn out differently.



Skin, nail, and mouth changes

The skin abnormalities associated with dyskeratosis congenita include abnormal dark discoloration of the skin with a distribution pattern that resembles a net (reticulate hyperpigmentation). Affected areas may appear as grayish, flat spots (macules) on a degenerated (atrophic) or light colored patch of skin. The face, neck and shoulders are most often affected.



Nail abnormalities usually affect the fingernails before the toenails and are characterized by fissures, underdevelopment (hypoplasia) and eventually degeneration and distortion of the affected nails. Some individuals may ultimately lose the affected nails.



The development of white, thickened patches on mucous membranes of the mouth (oral leukoplakia) usually develops slowly appearing anywhere during the second, third or fourth decade. Although the mouth is predominantly affected, the mucous membranes of the anus and the urethra may become involved in rare cases.



Bone marrow failure

Most individuals with dyskeratosis congenita eventually develop bone marrow failure marked by deficiency of all three of the main types of blood cells (i.e., red cells, white cells, and platelets) a condition called pancytopenia. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (erythrocytes), white blood cells (leukocytes), and platelets. The cells are released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections, and platelets allow the body to form clots to stop bleeding. The degree of bone marrow failure can greatly vary from very mild with only one type of blood cell affected to very severe with low counts in all blood cell lineages. Bone marrow examination shows a reduced number of blood cell producing progenitor cells (hyopcelular or empty bone marrow). Sometimes it is not only the blood counts that are abnormal but the blood cells themselves can show abnormalities, such as chromosomal (karyotypic) differences. These findings are usually described as myelodysplasia or myelodysplastic syndrome (MDS). Patients with MDS are at a higher risk of developing leukemia particularly if they are associated with certain karyotypic abnormities such as only one chromosome 7 (monosomy 7) over a long period of time. In rare cases MDS or leukemia may be the first manifestation of disease.



Pancytopenia (low blood cell count of all blood cell lineages) may result in a variety of symptoms. Bruising, small red spots on the skin (petechiae), paleness of the skin (pallor) and frequent infections may be the first signs of bone marrow failure. The specific symptoms and progression of the disorder vary from case to case. Some individuals may have mild symptoms that remain stable for many years; others may have serious symptoms that can progress to life-threatening complications. Bone marrow failure may develop during childhood or not become severe until well into adulthood.



Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing (dyspnea), and cardiac symptoms. Individuals with low white blood cell counts (leukopenia) have an increased risk of contracting bacterial and fungal infections. Individuals with low platelet counts (thrombocytopenia) are more susceptible to excessive bruising following minimal injury and to spontaneous bleeding from the mucous membranes, especially those of the gums and nose.



Some patients with the same genetic abnormality responsible for dyskeratosis congenita may present with bone marrow failure only. The severity of bone marrow failure in these patients can vary greatly, from affecting only one or two blood values in peripheral blood, to the full picture with low blood counts in all blood cell lineages, a condition termed aplastic anemia. Features of the skin or other symptoms associated with dyskeratosis congenita may not be present or be so mild that they are not appreciated. These patients are often initially misdiagnosed as having idiopathic aplastic anemia (see also below). Whether patients with the genetic abnormality for dyskeratosis congenita but only showing bone marrow failure should be classified as having dyskeratosis congenita is controversial, alternative classifications used are atypical dyskeratosis congenita, or aplastic anemia with short telomeres. It is important that in these individuals the treatment plan, response to treatment, disease surveillance, and prognosis differs from patients with idiopathic aplastic anemia. In addition because of the inherited nature of the disease, members of the family of the affected individual may also be at risk.



Leukemia and cancer

Individuals with dyskeratosis congenita also have a predisposition to develop leukemia and cancer (malignancy) especially squamous cell carcinoma of the head and neck, and especially at the site of leukoplakia. If cancer occurs, it usually does not develop until the age of about 30. Thus, leukemia and cancer are more common in individuals who have a moderate or milder form of dyskeratosis congenita. Individuals who underwent a stem cell or bone marrow transplant for the treatment of their bone marrow failure are also at risk of developing cancer later in life. In rare cases leukemia or cancer may be the first manifestation of disease.



Lung disease

The development of lung disease (pulmonary fibrosis) is often found in patients with dyskeratosis congenita. It usually develops later than the skin abnormalities and bone marrow failure, however in some patients with mild disease pulmonary fibrosis may be the first or only obvious manifestation. In these patients disease usually manifest at the age of 50 to 60 years of age. The cause of pulmonary fibrosis in patients with dyskeratosis congenita is not fully understood. Breathing difficulties and a decreased lung function may be signs of lung disease. Smoking seems to accelerate the progression of pulmonary disease.



Other symptoms

A variety of additional symptoms have been reported in individuals with dyskeratosis congenita. These symptoms occur with much less frequency than the abovementioned symptoms. These less common symptoms include excessively watery eyes due to obstruction of the tear ducts (epiphora), excessive sweating (hyperhidrosis) of the palms of the hands and the soles of the feet, cavities and tooth loss, narrowing of the esophagus (esophageal stricture), urinary tract anomalies, especially hypospadism, early graying and premature hair loss, lung disease and short stature, liver disease, underdeveloped testes (hypogonadism), failure of the testes to descend into the scrotum, and skeletal abnormalities.



Some affected children may experience delays in attaining developmental milestones and learning disabilities. Additional symptoms have been reported that occur in less than 10 percent of cases including deafness, or abnormalities of the eye retina.



Hoyeraal-Hreidarsson syndrome

Once considered a separate disorder, Hoyeraal-Hreidarsson syndrome is now identified as a severe variant of dyskeratosis congenita. Symptoms usually occur during the first year of life and include severe growth retardation that occurs before birth (intrauterine growth retardation), bone marrow failure, immune system deficiencies, underdevelopment of the cerebellum (cerebellar hypoplasia), clumsiness caused by the inability to coordinate voluntary movements (ataxia), and microcephaly, a condition that indicates that head circumference is smaller than would be expected for an infant's age and sex. Abnormalities of the gut varying from malabsorbtion to severe inflammation with ulcers may be present in these children. Bone marrow failure and immune system deficiency may result in life-threatening complications. Because of the complexity and because multiple organs are severely impaired the prognosis of children diagnosed with Hoyeraal-Hreidarsson syndrome is usually poor. These children often die before they develop the characteristic nail and skin abnormalities.



Revesz syndrome

Revesz syndrome is another severe form of dyskeratosis congenita that may present similar to the Hoyeraal-Hreidarsson syndrome but in addition is associated with abnormalities of the eye (bilateral exudative retinopathy, Coats retinopathy).

Causes

To date six genes when mutated have been shown to be responsible for dyskeratosis congenita. However, mutations in these genes only account for about one half of patients with classical clinical manifestations of dyskeratosis congenita, suggesting that there are additional genes that when mutated cause dyskeratosis congenita.



X-linked dyskeratosis congenita

The first gene to be identified was DKC1. Mutations in DKC1 are responsible for the X-linked form and for about 20-25% of sporadic cases. Male patients with DKC1 gene mutations, almost always present with the classic form of dyskeratosis congenita (high disease penetrance). Mutations in DKC1 have also been found in patients with Hoyeraal-Hreidarsson syndrome.



X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off" and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder or only very mild ones, because it is usually the X chromosome with the abnormal gene that is "turned off". A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy of having a carrier daughter like themselves, a 25% chance of having a non-carrier daughter, a 25% chance of having a son affected with the disease, and a 25% chance of having an unaffected son.



Investigators have shown that in the majority of families with an X-linked inheritance pattern of dyskeratosis congenita the disease results from changes or disruptions (mutations) of the DKC1 gene located on the end (distal) portion of the long arm of the X chromosome (Xq28). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome Xq28" refers to band 28 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.



The DKC1 gene contains instructions for the synthesis of a protein known as dyskerin. Dyskerin plays a role in the creation (biogenesis) of certain small structures found within cells that assemble proteins (ribosomes) and in the maintenance of telomeres, structures found at the end of chromosomes that are essential in the replication and stability of chromosomes.



Autosomal dominant dyskeratosis congenita

Dominant genetic disorders occur when only one of the two copies of a gene needs to be mutated for the disease to occur. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.



Investigators have found mutations in three different genes can account for some cases of the dominant form of dyskeratosis congenita. These include the telomerase RNA gene TERC located on the long arm (q) of the chromosome 3 (3q26), the gene encoding the enzymatically active component of telomerase TERT, located on the short arm of chromosome 5 (5p15.33) and the TINF2 gene encoding the telomere-associated protein TIN2 located on the long arm of chromosome 14 (14q12). Patients how carry a TERC or TERT gene mutation have often milder form of the disease compared to the X-linked form and some mutation carrier may not show disease, or only very late in life (low disease penetrance). However in rare cases TERT gene mutations have been identified to be responsible for severe forms of the disease including in patients with Hoyeraal-Hreidarsson syndrome. Patients who have inherited two mutations (homozygous or compound heterozygous), one from each parent, have usually an earlier onset and more severe disease. Patients with certain TINF2 gene mutations, have usually an early onset and severe disease. Mutations in TINF2 have also been found in patients with Revesz syndrome.



Autosomal recessive dyskeratosis congenita

Three genes have been associated with the recessive form of dyskeratosis congenita; these are the NOP10 (NOLA3) gene, located on the long arm of chromosome 15 (15q14-q15) the NHP2 (NOLA2) gene, located on the long arm of chromosome 5 (5q35.3), and the TERT gene on chromosome 5 (5p15.33). Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females. In some cases the parents, who each have a mutation in one copy of the gene may show mild disease, whereas the affected child, who has a mutation in both gene copies, will have more severe disease. In this scenario the effects of the mutations are additive and the mutations are expressed co-dominantly.



Sporadic dyskeratosis congenita

In a significant proportion of patients with moderate or severe disease the mutation is not inherited but has newly arisen either in the germ cells of the parents or shortly after conception (de novo mutation). De novo mutations in DKC1 and TINF2 have been found to be responsible for spontaneous dyskeratosis congenita, whereas spontaneous mutations in TERT causing disease in the first generation are very rare. Spontaneous mutations in TERC with disease in the first generation have not been described. Patients with de novo mutation usually have moderate to severe and progressive disease.



A significant proportion of individuals thought to have sporadic dyskeratosis congenita actually have inherited the mutation from their parents, but their parents do not show disease. Similarly their siblings may also not show disease despite having inherited the mutation. This is due to fact that the manifestation of disease may vary (variable penetrance) and that the symptoms of disease manifestation may vary (variable expressivity).



Disease anticipation

In some families with autosomal dominant dyskeratosis congenita the disease seems to get more severe and to occur earlier in life with subsequent generations. This is known as disease anticipation. Disease anticipation in autosomal dominant dyskeratosis congenita is thought to be due to the fact that not only the mutation, but also the short telomeres are inherited, and that these get shorter with every generation.



Common pathway of the genes mutated

All six genes that have been found to be mutated in patients with dyskeratosis congenita are involved in the elongation and maintenance of telomeres. Telomeres are the ends of chromosomes. Telomeres can be thought of as being like the plastic tips on shoelaces because they prevent chromosomes from sticking together, becoming frayed or damaged and protect the vital genetic information on a chromosome.



Premature accelerated telomere shortening is thought to be the underlying mechanism of disease. It has been proposed that the time point when telomeres become critically short greatly determines the clinical picture of disease. According to this model, in the severe forms of dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome and the Revesz syndrome the telomeres become critically short early in life, in classic dyskeratosis congenita telomeres are getting critically short during childhood and adolescence, and in atypical dyskeratosis congenita, telomeres become critically short in adults.



When normal cells divide, the telomeres become shorter. When telomeres become too short, the cell stops growing or dies. The enzyme telomerase adds length to the telomeres so that they do not become too short too fast. The genes that are mutated in dyskeratosis congenita are all in one way or the other important for the telomerase enzyme to do its job or for the telomere end to be available for the enzyme. Mutations in these genes jeopardize the activity of the enzyme at the end of telomeres. Thus, the telomeres become shorter more rapidly until they are so short that the cell stops growing or dies. This occurs in all tissues, but fast dividing tissues such as the bone marrow, skin, and gut cells are affected the most.



Indeed, when bone marrow failure becomes apparent, patients with dyskeratosis congenita have much shorter telomeres then normal individuals. The measurement of telomere length in circulating blood cells is therefore being increasingly used to identify patients who have bone marrow failure due to dyskeratosis congenita. Amongst patients with bone marrow failure, the detection of very short telomeres is a very sensitive way to identify patients with dyskeratosis congenita. In the absence of bone marrow failure telomere length does not predict the presence or absence of a disease causing mutation. Thus, telomere length in individuals who do not have bone marrow failure has to be interpreted with great caution.

Affected Populations

The prevalence or incidence of dyskeratosis congenita is difficult to assess. In a population of patients with bone marrow failure about 2-5% of patients have bone marrow failure due to dyskeratosis congenita. In patients with pulmonary fibrosis similarly 2-5% are thought to be due to mutations in TERC or TERT. In families with an increased frequency of bone marrow failure and/or lung disease, dyskeratosis congenita should be excluded as a possible cause of their disease.

Standard Therapies

Diagnosis

A diagnosis of dyskeratosis congenita may be suspected based upon a thorough clinical evaluation, detailed patient history, and identification of characteristic findings especially changes in the skin or mouth. In individuals who develop aplastic anemia as the first sign of the disorder or pulmonary fibrosis diagnosis is more difficult.



Very short telomeres in peripheral blood cells may support the diagnosis of dyskeratosis in patients who present with bone marrow failure.



Molecular genetic tests to determine mutations in the DKC1, TERC, TERT, TINF2 NHP2, or NOP10 gene can confirm a diagnosis of dyskeratosis congenita. However, clinical genetic testing is expensive and for some genes only available on a research basis. Furthermore, genetic testing usually does not test for large gene deletions, thus patients with disease due to a large gene deletion are usually missed. Difficult may also be the proof that the identified sequence variant is in fact responsible for disease might be difficult. Not all the mutations described in the literature are in fact responsible for disease (rare polymorphisms) or cause disease in all individuals (variable penetrance). In about 50% of patients no mutation is identified, despite the presence of classic clinical manifestations.



Treatments

There is no consensus about how to treat patients with dyskeratosis congenita. The literature is biased toward treatment and treatment outcome of patients who present with the classical form of disease. Little is still known about the treatment and disease monitoring of individuals with atypical or silent disease.



The treatment of dyskeratosis congenita is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, adult internists and hematologist, dermatologists, dental specialists, medical geneticist, cancer specialists (oncologists) and other healthcare professionals may need to systematically and comprehensively plan an affected individual's treatment.



General treatment recommendations for individuals with dyskeratosis congenita include avoiding smoking and alcohol to preserve the lungs and liver and the use of moisturizing creams to prevent damage to the skin. Good dental hygiene may help to prevent early tooth loss and delay the development of malignancy of the tongue. In certain patients marrow failure and immunodeficiency transiently respond to androgens and hematopoietic growth hormones.



Androgens (e.g., oxymetholone), which are artificial male hormones, may increase red blood cell and, less often, platelet production in some individuals. Androgen therapy may be supplemented with corticosteroid (e.g., prednisone) therapy, which may delay growth acceleration potentially associated with androgen therapy and reduce bleeding associated with thrombocytopenia.



A class of drugs known as hematopoietic growth factors has been used to treat individuals with dyskeratosis congenita, specifically granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). These growth factors may transiently increase the production of certain white blood cells (neutrophils). In rare cases, treatment with these drugs also increases red blood cell and platelet levels.



In most cases, the benefits of androgens and growth factors are only temporary. The specific amount of time these treatments improve bone marrow function varies in each individual case.



If a compatible donor can be located, hematopoietic stem cell transplantation can potentially cure the blood abnormalities associated with dyskeratosis congenita. Hematopoietic stem cell transplantation should be considered in patients who present with mainly bone marrow failure. Hematopoietic stem cell transplant does not improve tissues affected by dyskeratosis cogenita. Patients with dyskeratosis congenita have an increased sensitivity towards radiation and certain chemotherapy drugs. An alternative conditioning regiment is without irradiation or certain chemotherapy drugs such as busulfan or melphalan should be avoided. Pulmonary complications after hematopoietic stem cell transplantation are not uncommon and may be fatal.



The hypersensitivity of individuals with dyskeratosis congenita to radiation and chemotherapy encumbers the treatment of cancer in these individuals. Surgical resection of the cancer is probably the first line of treatment.



Affected individuals should be monitored for the development of lung disease and cancer. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

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 further information, consultation, and participation in research in dyskeratosis congenita and disorders caused by short telomeres see http://bmf.im.wustl.edu or email: mbessler@im.wustl.edu



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



Toll free: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



Please contact the following independent physicans for more information on clinical trials and studies at their facility:



Monica Bessler, Philip J. Mason, and David B. Wilson.

Correspondence: Monica Bessler, MD, PhD, Department of Internal Medicine, Washington University School of Medicine, 660 S Euclid Avenue, St. Louis MO 63110. E-mail:mbessler@im.wustl.edu Tel: 314-362-8807 Fax: 314-362-8826 web: http://bmf.im.wustl.edu

References

TEXTBOOKS

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Jones KL., ed. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Co; 1997:538-39.



Buyse ML. ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, For: Center for Birth Defects Information Services Inc; 1990:567-68.



Bessler M, Mason PJ, Link DC, Wilson DB. Inherited Bone Marrow Failure Syndromes. In: Orkin, SH Ginsburg, D, Nathan DG, Look, AT, Fisher, DE, Lux, SE, eds. Nathan's and Oski's Hematology of Infancy and Childhood. Vol. in press. Philadelphia: W.B. Saunders Co; 2008.



JOURNAL ARTICLES

Vulliamy TJ, Marrone A, Knight SW, et al., Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. Blood. 2006;107:2680-5.



Shimamura A. Inherited bone marrow failure syndromes: molecular features. Hematology Am Soc Hematol Educ Program. 2006;63-71.



Armanios M, Chen JL, Chang YPC, et al., Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci. 2005;102:15960-4.



Bagby GC, Lipton JM, Sloand EM, Schiffer CA. Marrow failure. Hematology. 2004;



Bessler M, Wilson DB, Mason PJ. Dyskeratosis congenita and telomerase. Curr Opin Pediatr. 2004;16:23-8.



Sznajer Y, Baumann C, David A, et al., Further delineation of the congenital form of X-linked dyskeratosis congenita (Hoyeraal-Hreidarsson syndrome). Eur J Pediatr. 2003;162:863-7.



Goldman F, Bouharich R, Kulkarni S, Freeman S, Du HY, Harrington L, Mason JP, Londono-Vallejo A, Bessler M. The effect of TERC haploinsufficiency on the inheritance of telomere length. PNAS. 2005; 102(47):17119-24.



Marciniak RA, Johnson FB, Guarente L. Dyskeratosis congenita, telomeres and human ageing. Trends Genet. 2000;16:193-195.



Bessler M, Du HY, Gu B, Mason PJ. Dysfunctional telomeres and dyskeratosis congenita. Haematologica 2007. 92;1009-1012.



FROM THE INTERENT

Robles DT. Dyskeratosis Congenita. Emedicine Journal, June 14 2006. Available at: http://www.emedicine.com/derm/topic111.htm Accessed on: May 17, 2007.



Dokal I, Vulliamy T. Dyskeratosis congenita. Orphanet encyclopedia, September 2003. Available at: http://www.orpha.net/data/patho/Pro/en/DyskeratosisCongenita-FRenPro477.pdf Accessed on: May 17, 2007.



McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:127550; Last Update:05/03/2004. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=127550 Accessed on: May 17, 2007.



McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:305000; Last Update:05/04/2007. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=305000 Accessed on: May 17, 2007.



McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:224230; Last Update:03/15/1999. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=224230 Accessed on: May 17, 2007.

Resources

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Internet: http://www.madisonsfoundation.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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