Dyskeratosis congenita

This is part of Rare diseases.

Diagnosis: Dyskeratosis congenita

Synonyms: Hoyeraal-Hreidarsson syndrome


Date of publication: 2014-10-16
Version: 3.0



The disease

Dyskeratosis congenita (dys=abnormal, keratosis= overdevelopment of the horny, outermost layer of the skin, congenita=congenital) is an inherited disorder characterised among other things by skin pigmentation abnormalities, nail defects, lesions on the oral mucous membranes and bone marrow failure.

There are several variants of the disorder, each associated with a different pattern of inheritance. What all these disorders have in common is damage to the ends of chromosome strands, known as telomeres (from the Greek "telos" for end, and "meros" for part). The classic type was first described by the German dermatologist Ferdinand Zinsser in 1906, and some decades later by American dermatologists Martin Feeney Engman and Harold Newton Cole. The most severe type is often referred to as Hoyeraal-Hreidarsson syndrome after the Norwegian paediatrician Hans Martin Hoyeraal and the Icelandic physician Stefan Hreidarsson. In addition to other symptoms, children with this form of disease also experience many infections.


It is estimated that one person in every million has this disease. Just over 200 cases of dyskeratosis congenita have been described in international medical literature. More men than women are affected. Only a few cases in Sweden have been diagnosed.


Dyskeratosis congenita is caused by a defect in the maintenance of the regions at the ends of chromosomes (telomeres). The function of telomeres is to protect the ends of chromosome strands and they consist of short sequences of DNA which are duplicated hundreds or thousands of times. They have a particular construction, where the last piece of DNA does not consist of the usual two strands. Instead, the single-stranded end of a piece of DNA folds over the double-stranded part of the telomere. Every time a cell divides, the telomere becomes very slightly shorter. When it has shortened to a critical length the cell is prevented from dividing and dies.

An enzyme found in cells, named telomerase, enables these shortened telomeres to return to their former lengths. Telomerase consists of four proteins as well as RNA (ribonucleic acid) and together they make a ribonucleic complex. After birth, telomerase is active only in the sex cells (gametes) and in certain cells of the immune system. This means that shortened telomeres are not passed down to the next generation. Excessive telomerase activity protects abnormal cells and is considered to play an important role in the survival and spread of certain forms of cancer. Telomere shortening plays a role in the normal ageing process and has been shown to increase the risk of heart disease. Besides telomerase, cells also contain a specific complex of six proteins named shelterin, which protect the areas of duplicate DNA sequences. Dyskeratosis congenita is caused by mutations in one of the genes which codes for (controls the creation of) those proteins which build up telomerase and shelterin, as well as the RNA which is a part of telomerase. This means that normal telomere protection is impaired.

Gene Chromosome Protein Heredity
DKCI Xq28 dyskerin X
TERT 5p1 telomerase reverse transcriptase AD/AR
TINF2 14q12 TIN2 shelterin protein AD
NHP2 5q35.3 NHP2 AR
NOP10 15q14-15 NOP10 AR
WRAP53 17p13 WRAP53 AR
RTEL1 20q13 Regulator of telomere elongation helicase1 AD/AR

Table showing known genes causing dysteratosis congenita, the proteins affected and the different patterns of inheritance. X= X-linked recessive inheritance, AD= autosomal dominant, AR = autosomal recessive (See also under "Heredity.")

To date, mutations in six of the genes which control the production of telomerase and in one of the genes which controls the production of proteins included in the shelterin compound, have been identified. DKC1 codes for the protein dyskerin, TERC codes for ribonucleic acid TERC, NHP2 codes for the NHP2 protein, NOP10 codes for protein NOP10, TERT codes for telomerase reverse transcriptase and TINF2 codes for the shelterin protein TIN2. Mutations in DKC1 are the most common cause of dyskeratosis congenita and are found in approximately one third of all those with the disease. Apart from building up telomeres, dyskerin has other functions in cell division, abnormalities in which can account for many of the symptoms associated with dyskeratosis congenita. Mutations in TERC and TINF2 are found in approximately 10 per cent of those who have the disease, while other mutations are much rarer. In approximately 50 per cent of people with the disease, no mutation has been found which can explain why the disease has developed.

Hoyeraal-Hreidarsson syndrome is associated with mutations in genes TINF2, DKC1, TERT and RTELI. The reason why some mutations result in more severe symptoms, such as microcephalus and immunodeficiency, is not as yet known.

Mutations in genes which control the formation of the telomerase complex can be found in other diseases, including certain forms of aplastic anaemia with lung fibrosis.


Three inheritance patterns are known to be associated with dyskeratosis congenita.

The most common is X-linked recessive inheritance caused by a mutated gene, DKC1, which is located on the X chromosome, one of the chromosomes which determines sex. Men have one X chromosome and one Y chromosome, while women have two X chromosomes. Inherited X-linked recessive disorders usually occur only in men, being passed down via a healthy female carrier who has one normal and one mutated gene. Sons of female carriers of a mutated gene run a 50 per cent risk of inheriting the disease and daughters run the same risk of being healthy carriers of a mutated gene. A man with an inherited X-linked recessive disease cannot pass it on to his sons, but all his daughters will be carriers of the mutated gene.

Figure: X-linked recessive inheritance  via a healthy female carrier

The inheritance pattern of dyskeratosis congenita can also be autosomal dominant. This occurs in mutations in TERC and TINF and sometimes in TERT and RTETI, and means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it on.

Figure: Autosomal dominant inheritance

Autosomal recessive inheritance of dyskeratosis congenita occurs in mutations in NOP10 and NHP2 and sometimes in TERT. This means that both parents are healthy carriers of a mutated gene. In each pregnancy with the same parents there is a 25 per cent risk that the child will inherit double copies of the mutated gene (one from each parent). In this case the child will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.


Different forms of dyskeratosis congenita have varying degrees of severity. The condition is associated with premature ageing, abnormalities in the mucous membranes of the oral cavity (leukoplakia), skin pigmentation abnormalities, nail dystrophy and bone marrow failure (aplastic anaemia) along with haemorrhages, anaemia and infections. Symptoms may also be associated with many other organs.

The first symptoms of dyskeratosis congenita usually develop in childhood, but onset can occur later. Early signs often include skin and nail changes, which are usually evident before the age of ten. Bone marrow failure usually develops between the ages of 20 and 30, but in some cases onset occurs earlier and is the first sign of the disorder. Sometimes the skin and mucous membrane changes are so subtle that they may not be noticed until more severe symptoms develop.

The pattern of inheritance seems to affect the severity of the disease. The X-linked recessive form and the variant characterised by defective shelterin are often more severe than the dominant forms. Variation in the severity of the autosomal recessive form is often considerable.

Skin and hair

Most patients have net-like or mottled patterns on the skin. They usually appear in areas of skin exposed to sunlight, such as the chest, throat and face.

Hair on the scalp is thin and grows poorly. Eyebrows and lashes may also be affected. Other symptoms include premature greying of the hair, reduced perspiration, and thickened horny layers of skin on the palms of the hands and soles of the feet. Some people with the condition lack the ridges which form a unique pattern on the fingertips (fingerprints).


Nail dystrophy often begins with ridges and vertical splitting. The nails become thinner and grow poorly, which may result in underdeveloped or absent nails. Fingernails are affected before toenails.

Mucous membranes

Symptoms usually include white patches or plaques (leukoplakia) which develop on the oral mucous membranes. These lesions sometimes become ulcerous and wart-like, and may be pre-cancerous. There is also an increased risk of developing periodontal disease and caries.

Other mucous tissues may be affected, for example those in the oesophagus, the tear ducts, the urinary tract and the genitalia. Constriction can occur at these sites, causing swallowing difficulties, excessive tear production (epiphora), problems emptying the bladder and dry, fragile, genital mucous membranes.

Bone marrow

Most individuals with the disorder develop bone marrow failure, leading to deficiencies in red and white blood cells (erythrocytes and leukocytes) and blood platelets (thrombocytes). Impaired bone marrow function increases proneness to bleeding, infection, fever and fatigue. A low thrombocyte count is the first sign of impaired blood production, which results in skin bleeding (bruises or tiny spots resembling pin-pricks) as well as bleeding from the gum, nose and urinary tract. A year or so later the white blood cell count also drops, causing symptoms including recurrent throat, ear and pulmonary infections. An excessively low red blood count causes fatigue. Untreated, bone marrow failure leads to premature death.


Pulmonary complications are common in dyskeratosis congenita. They are caused by the gradual replacement of lung tissue with fibrous tissue (fibrosis) or by impaired blood supply to the lungs, and can result in respiratory failure.

Other features

The illness can result in a failure to grow, both before and after birth, so the individual's stature remains short. Scoliosis (abnormal curvature of the spine) and osteoporosis (decreased bone density) are other common symptoms.

The liver and spleen may be enlarged, and some individuals develop liver cirrhosis. The genitals are sometimes underdeveloped and in boys the testicles may fail to descend into the scrotum (retentio testis).

Some children with the disease also have a mild mental disability.

Hoyeraal-Hreidarsson syndrome

Growth in children with the disease is impaired and they are born with smaller than average heads (microcephaly) and brain abnormalities. They also have severe abnormalities affecting their mucous membranes, a high number of severe infections and progressive bone marrow failure, often leading to death in early childhood.


It is not possible to make a diagnosis based solely on symptoms from the skin or mucous membranes. If the disease is suspected, telomere length is analysed. Shorter lengths confirm a diagnosis of dyskeratosis congenita.

Only DNA-based diagnostic techniques make it possible to make a confident diagnosis. At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD) in association with IVF (in vitro fertilization), are available to families where the mutation has been identified.

When the diagnosis is confirmed, an immunological analysis should be carried out testing the functioning of certain white blood cells (T, B and NK cells). This will establish whether the child has the severe variant of the disease known as Hoyeraal-Hreidarsson syndrome.


As several organs are affected, different specialists are involved in treatment. They need to collaborate to ensure that infections are detected early and that bone marrow function is checked regularly. Physicians specialising in immunology and haematology should be included in the team. To prevent severe infections it is important to identify and treat new symptoms as early as possible. Bone marrow failure is the most common cause of death in dyskeratosis congenita patients.

The white blood cell count can be increased by administering granulocyte-colony stimulating factor (G-CSF), a natural growth factor that encourages the production of neutrophil granulocytes.

Antibiotics are often prescribed as prophylactics to help prevent infection. If this preventive measure is not taken, antibiotics should be administered immediately on suspicion of bacterial infection.

The risk of lung tissue being gradually replaced by fibrous tissue (pulmonary fibrosis) means that lung function should be regularly checked. It is important that people with this condition do not smoke.

Anaemia can be treated with iron or blood transfusions. In very rare cases of severe thrombocytopenia complicated by a tendency to excessive bleeding, thrombocytes (platelets) may be administered in a transfusion. As a transfusion of thrombocytes has very short-term effects, it should be given only in cases of severe bleeding or before a surgical procedure.

A dentist should check the mucous membranes of the mouth. Children should have early contact with the dental services, preferably with a paediatric dental specialist (pedodontist), for an assessment, as well as help with preventive care and information on oral hygiene.

The psychological repercussions of living with skin and nail abnormalities, poor hair growth and running eyes should be noted. For this reason psychological and social support are important, both for the person affected and for the family. It is important to provide people in contact with the child, including personnel at day care and school, with clear information in order to increase their understanding of the condition.

Haematopoietic stem cell transplantation

Stem cell transplantation (or haematopoietic stem cell transplantation, commonly called bone marrow transplant) is used to treat dyskeratosis congenita. The outcome of the operation depends on the severity of the damage to organs prior to the transplant. Individuals with this disorder are particularly sensitive to medication administered before the procedure. For this reason they must be given lower doses to avoid subsequent serious complications.

Bone marrow is found in the body's bone cavities. All blood cells are produced from blood stem cells in the bone marrow. Stem cells can develop into red blood cells (erythrocytes), different kinds of white blood cells (leukocytes) and blood platelets (thrombocytes). Stem cell transplantation provides the opportunity to replace a sick person's bone marrow with that of a healthy person.

To optimise the chances of successful transplantation, the recipient of the marrow should be as free from infection and in as good physical condition as possible. For this reason, it is important to carry out the transplantation at an early stage of the disease. The intervention itself is fairly simple, but the preparations, aftercare and major risks associated with the treatment make it a highly demanding procedure.

Finding the right donor
In order to carry out stem cell transplantation, a donor must be found whose tissue type (HLA) matches that of the recipient. Ideally they should be identical. Tissue type is inherited from both parents, and each child has a 25 per cent chance of having the same tissue type as a sick sibling. The best solution is to transplant bone marrow from a healthy sibling with the same tissue type. If this is not possible a suitable donor may be located in national and international registers of volunteer stem cell donors or in stored, frozen blood from umbilical cords. The “Tobias Registry” in Sweden contains approximately 40,000 registered voluntary donors, and worldwide registers of donors contain more than twenty million names.

Before the stem cell transplantation the patient must receive the correct treatment in order for the new bone marrow to engraft, and to prevent the donor cells starting to attack the cells of the sick child. Preparations entail the recipient receiving chemotherapy to ensure the existing blood cells do not reject the new stem cells. Treatment can be extremely taxing for the patient as chemotherapy also impairs the barrier function of the mucous membranes. There is a major risk of developing serious infections and for this reason the person needs to be kept in isolation for many weeks, or sometimes months, prior to and after the transplantation.

This is what happens during a transplant
In a blood stem cell transplant bone marrow is removed from the hip bone of the donor by suction, after which it is collected in a container. The bone marrow is then administered to the recipient by means of a drip directly into a blood vessel, approximately the same method as is used in blood transfusions. A few stem cells are also found in blood and there are now methods for collecting these cells. An alternative to taking bone marrow from the hip bone is to pass donor blood through a special centrifuge which filters out stem cells, while the rest of the blood is returned to the donor. The stem cells are collected in a container in the same way that bone marrow is, and administered to the recipient in the same way. A third alternative is to use the blood found in the umbilical cords of newborns. The blood of newborns has very high levels of blood stem cells and the small amount of blood remaining in the umbilical cord of a healthy newborn can be frozen and saved for later transplantations.

When blood stem cells from whatever source have been transferred to the patient they find their way into the recipient’s bone marrow cavities (the medullary cavities, found in the bones in various parts of the body), and grow there to supply the recipient with a new immune system.

Practical advice


National and regional resources in Sweden

Department of Paediatric Immunology, Medical Faculty, The Queen Silvia Children's Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

Department of Paediatrics, Skåne University Hospital, SE-205 02 Malmö, Sweden. Tel: +46 40 33 10 00.

Department of Clinical Genetics, Laboratory Centre, Building 6M, Norrland University Hospital, SE-901 85 Umeå, Sweden. Here research is underway into telomere length and specific genetic diagnoses.

Resource personnel

Professor Anders Fasth, The Queen Silvia Children's Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: anders.fasth@gu.se.

Professor Rolf Ljung, Paediatric Centre, Skåne University Hospital, SE-205 02 Malmö, Sweden. Tel: +46 40 33 10 00, email: rolf.ljung@med.lu.se.

Courses, exchanges of experience, recreation

PIO, The Primary Immunodeficiency Organization in Sweden, offers training, support, information and the opportunity to meet others in the same situation. PIO publishes information and organizes regular lectures and information meetings for people with primary immunodeficiency disorders, their relatives and other interested parties. Weekend courses are held annually for children and young people with primary immunodeficiency disorders and their families. Regular joint meetings over several days are held with members of the Nordic immunodeficiency organizations. For further information contact PIO. Find address under “Organizations for the disabled/patient associations etc.” below.

IPOPI, the International Patient Organization for Patients with Primary Immunodeficiencies, of which PIO is an affiliate, arranges a conference in conjunction with a biennial international medical conference for doctors and nurses interested in immunodeficiency. IPOPI conferences are conducted in English. For further information, contact PIO, under “Organizations for the disabled/patient associations etc..”

Organizations for the disabled/patient associations etc.

PIO, The Primary Immunodeficiency Organization in Sweden, Mellringevägen 120 B, SE-703 53 Örebro, Sweden. Tel: +46 19 673 21 24, email: info@pion, www.pio.nu.

Courses, exchanges of experience for personnel

SLIPI, Swedish Physicians’ Association for Primary Immunodeficiencies organizes meetings and conferences, www.slipi.nu.

SISSI - Swedish Nurses’ Association for Primary Immunodeficiencies.The association publishes a worksheet and has regular conferences for members. In alternate years this is organized in collaboration with ESID, IPOPI and INGID, www.sissi.nu.

ESID - European Society for Immunodeficiencies.
The Society has regular international conferences and summer schools for doctors and researchers, www.esid.org.

INGID - International Nursing Group for Immunodeficiencies. The Group arranges international meetings in collaboration with ESID and the international patient organization IPOPI, www.ingid.org.

Research and development

Research into genetic aspects of dyskeratosis congenita and the function of telomeres is being carried out by Professor Inderjeet Dokal, Academic Unit of Paediatrics, Institute of Cell and Molecular Science, Barts Hospital, London and Queen Mary’s School of Medicine and Dentistry, London, UK.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. These leaflets may be ordered or printed out. (See under "Mer hos oss" in the right hand column.)


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Dietz AC, Orchard PJ, Baker KS, Giller RH, Savage SA, Alter BP et al. Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita. Bone Marrow Transplant. 2011; 46: 98-104.

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Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S, Mason P et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nature Genet 1998; 19: 32-38.

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Marrone A, Walne A, Dokal I. Dyskeratosis congenita: telomerase, telomeres and anticipation. Curr Opin in Genet Dev 2005, 15: 249-257.

Vulliamy T, Dokal I. Dyskeratosis congenita. Semin Hematol 2006; 43: 157-166.

Vulliamy TJ, Marrone A, Knight SW, Walne A, Mason PJ, Dokal I. Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. Blood 2006; 107: 2680-2685.

Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 2001; 413: 432-435.

Walne AJ, Bhagat T, Kirwan M, Gitiaux C, Desguerre I, Leonard N, et al. Mutations in the telomere capping complex in bone marrow failure and related syndromes. Haematologica. 2013; 98: 334-338.

Database references

OMIM (Online Mendelian Inheritance in Man)
Search: dyskeratosis congenita

GeneReviews (University of Washington)
www.genetests.org (select "GeneReviews", then "Titles")
search: dyskeratosis congenita

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Professor Anders Fasth, The Queen Silvia Children's Hospital, Gothenburg, Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2014-10-16
Version: 3.0
Date of publication of Swedish version: 2014-06-23

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.


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