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Dyskeratosis congenita

This is part of Rare diseases.

Diagnosis: Dyskeratosis congenita

Synonyms: Hoyeraal-Hreidarsson syndrome

Innehåll


Date of publication: 2011-03-14
Version: 2.0

ICD 10 code

D84.8

The disease

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

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 the 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.

Occurrence

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

Cause

Dyskeratosis congenita is caused by defective maintenance of the telomeres, which are regions at the ends of chromosomes whose function it is to protect the ends of chromosome strands. Telomeres consist of short sequences of DNA which are duplicated between 100 and 1,000 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 telemere becomes very slightly shorter. When it has shortened to a critical length the cell is unable to divide and dies.

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

To date, mutations have been identified 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. 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 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. As yet, no mutation explaining the occurrence of dyskeratosis congenita has been identified in the majority of those with the disease.

Heredity

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 TER, TINF and sometimes TERT 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 disorder and do not pass it down.

Figure: Autosomal dominant inheritance

Autosomal recessive inheritance occurs in mutations in NOP10 and NHP2 and sometimes in TERT. This means that both parents are healthy carriers of a mutated gene. When two healthy carriers have a child, there is a 25 per cent risk that the child will inherit the mutated genes (one from each parent) in which case he or she 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.

Symptoms

Variants of dyskeratosis congenita have different degrees of severity. The condition is associated with premature ageing, adherent white patches on the mucous membranes of the oral cavity (leukoplakia), skin pigmentation abnormalities, nail dystrophy and bone marrow failure (aplastic anaemia). Many other organs can also be affected.

Symptoms of dyskeratosis congenita usually develop in the first decade of life, but onset may be 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 may in some cases present early and be the first sign of the disorder. Sometimes 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 other autosomal dominant inherited form. Variation in the severity of the autosomal recessive form can be 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, impaired ability to perspire and hyperkeratosis (a thickened horny layer 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).

Nails

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

Mucous membranes

Symptoms usually include leukoplakia (white patches or plaques) presenting on the oral mucous tissues. These lesions sometimes become ulcerous and wart-like, and may be premalignant in nature. 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 may 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 red and white blood cell (erythrocyte and leukocyte) deficiency and blood platelet (thrombocyte) deficiency. Poor 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 (manifesting as bruises or tiny spots resembling pin-pricks) as well as bleeding from the gum, nose and urinary tract. Approximately one year later the white blood cell count also drops, causing symptoms including recurrent throat, ear and pulmonary infections. Fatigue is a result of an excessively low red blood count.

Lungs

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.

Others

The illness can result in a failure to grow, both before and after birth, and 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. 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-Hreidarssons syndrome

Hoyeraal-Hreidarsson syndrome is found only in boys. The disease is a more severe variant of the X-linked recessive form of dyskeratosis congenital. Children with the disease have impaired growth and are born with smaller than average heads (microcephaly) and brain abnormalities. Children also have abnormaliltes in their mucous membranes and suffer from progressive bone marrow failure, leading to death in early childhood.

Diagnosis

It is not possible to make a diagnosis based solely on symptoms from the skin or mucous membranes. Other symptoms and signs, such as reduced telomere length, may lead to the disease being suspected. Only DNA-based diagnostic techniques make a definite diagnosis possible. If the mutation is known in the family, pre-natal diagnosis and embryo screening are possible.

Treatment/interventions

As several organs are affected, different specialists are involved in treatment. They 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 may be 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.

Haematopoietic stem cell transplantation

Haematopoietic stem cell transplantation (commonly called bone marrow transplant) is used to treat aplastic anaemia associated with dyskeratosis congenita. Individuals with this disorder are particularly sensitive to the 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 (hematopoietic stem cells) in the bone marrow. Blood-forming stem cells can develop into red blood cells (erythrocytes), different kinds of white blood cells including lymphocytes and blood platelets (thrombocytes). A 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 as possible and in good physical condition. For this reason, it is important to carry out the transplantation at an early stage. The intervention itself is fairly simple, but the preparations, aftercare and major risks make it a highly demanding procedure.

Finding the right donor
In order to carry out a stem cell transplant, a donor must be found whose tissue type (HLA antigen) 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 bone marrow donor programmes or in stored, frozen blood from umbilical cords. The “Tobias Registry” in Sweden contains approximately 40,000 registered voluntary donors, and the names of more than fifteen million other donors are contained in registers outside Sweden.

Preparations
For the new bone marrow to engraft, and to prevent the donor’s blood cells attempting to attack the cells of the sick child, thorough preparations are required. The recipient receives chemotherapy to ensure the existing sick blood cells do not reject the new stem cells. Treatment is not without problems as chemotherapy also impairs the barrier function of the mucous membranes. There is a major risk of developing serious infection and for this reason the child needs to be kept in isolation for a period of weeks or sometimes months prior to and after the transplantation.

The transplantation
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 used in blood transfusions. A few stem cells are also found in the 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 as bone marrow, and also 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 marrow cavities (in the bones in various parts of the body), and grow there to supply the recipient with a new immune system.

Children should have early contact with the dental services, preferably a pedodontist (paediatric dental specialist) 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 those in contact with the child, including personnel at day care and school, with clear information to increase understanding of the condition.

Practical advice

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National and regional resources in Sweden

Paediatric Immunology, Department of Oncology/Immunology, The Queen Silvia Children's Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.
The Children's Clinic at Skåne University Hospital, SE-205 02 Malmö, Sweden. Tel: +46 40 33 10 00.

Resource personnel

Professor Anders Fasth, The Queen Silvia Children's Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, fax: +46 31 84 30 10, e-post anders.fasth@pediat.gu.se.

Professor Rolf Ljung, The Children's Clinic, Skåne University Hospital, SE-205 02 Malmö, Sweden. Tel: +46 40 33 10 00, fax: +46 40 33 62 26, email: rolf.ljung@med.lu.se.

Courses, exchanges of experience, recreation

PIO, The Primary Immunodeficiency Organisation 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” below.

IPOPI, the International Patient Organisation 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.”

Organizations for the disabled/patient associations

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

Courses, exchanges of experience for personnel

SLIPI, Swedish Physicians’ Association for Primary Immunodeficiencies organises 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 (R&D)

Research into the genetic aspect 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

An information leaflet on dyskeratosis congenita summarising the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2007-126-1211.) Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

Literature

Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A 2005; 102: 15960-15964.

Bessler M, Wilson DB, Mason PJ. Dyskeratosis congenita. FEBS Lett. 2010 May 21. FEBS Lett 2010; 584: 3831-3838.

Calado RT, Young NS.Telomere diseases. N Engl J Med 2009; 361: 2353-2365.

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 2010; April 12. [Epub ahead of print]

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.

Hoyeraal HM, Lamvik J, Moe PJ. Congenital hypoplastic thrombocytopenia and cerebral malformations in two brothers. Acta Paediatr Scand 1970; 59: 185-191.

Hreidarsson S, Kristjansson K, Johannesson G, Johannsson JH. A syndrome of progressive pancytopenia with microcephaly, cerebellar hypoplasia and growth failure. Acta Paediatr Scand 1988; 77: 773-775.

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.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: dyskeratosis congenita

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

Orphanet
www.orpha.net/data/patho/Pro/en/DyskeratosisCongenita-FRenPro477.pdf

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: 2011-03-14
Version: 2.0
Publication date of the Swedish version: 2010-11-18

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

 

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