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Dyskeratosis Congenita

DC

Dyskeratosis congenita is a general term for genetic disorders that lead to excess skin pigmentation, nail dystrophy and mucosal leukoplakia. Patients suffer and may die from distinct grades of bone marrow failure.


Presentation

To date, mutations affecting ten different genes have been identified as possible DC triggers. However, each one of these genes may show a variety of different mutations that may yield distinct degrees of protein dysfunction. In this context, more than 50 mutations have been described for the DKC1 gene. Also, environmental factors seem to influence symptom onset and severity and even members of the same family, parents that inherited a determined genetic disorder to their children, may not necessarily present the same clinical picture. Even though the exact mechanisms behind such phenomena are not completely understood, these are the reasons for the heterogeneity in age of DC symptom onset, symptom progress, affected tissues and severity of pathological conditions.

Early symptom onset is generally associated with rapid and severe disease progress. Indeed, symptoms do usually not manifest until childhood or adolescence except in cases of the very severe Hoyeraal-Hreidarsson syndrome and Revesz syndrome. Mild cases may even progress asymptomatically until well into adulthood and manifest in form of one single symptom then [10]. These patients may, however, develop malignant neoplasms. TERC, TERT and TINF2 mutations tend to cause these less severe forms of the disease.

The classical symptom triad for DC is often triggered by DKC1 mutations and is characterized by excess skin pigmentation, nail dystrophy and mucosal leukoplakia. These symptoms usually manifest before the age of ten and are most likely followed by bone marrow failure in between ten more years. About 90% of these patients develop bone marrow failure before becoming 30 years old. Malignant neoplasms are less frequently observed here than in those patients suffering from mild forms of DC.

In detail, the following symptoms may be observed:

Anemia
  • Of all the congenital bone marrow failure syndromes, two of them-Fanconi anemia and dyskeratosis congenita-represent a real challenge in terms of conditioning for HCT and require special attention.[ncbi.nlm.nih.gov]
  • KEYWORDS: acute myeloid leukemia; aplastic anemia; dyskeratosis congenita; posttransplant lymphoproliferative disorder[ncbi.nlm.nih.gov]
  • This wide spectrum of diseases ranging from classic DC to aplastic anemia can be regarded as disorders of defective telomere maintenance-"the telomereopathies."[ncbi.nlm.nih.gov]
  • ., Extramural MeSH terms Anemia, Aplastic/blood Anemia, Aplastic/etiology Anemia, Aplastic/pathology Biomarkers Bone Marrow/pathology Bone Marrow Diseases/blood Bone Marrow Diseases/etiology Bone Marrow Diseases/pathology Cell Differentiation/genetics[ncbi.nlm.nih.gov]
  • Blood samples need to be analyzed and will typically show pancytopenia, but in many cases only one or two of anemia, thrombocytopenia and leukopenia will be detected. Bone marrow biopsies may reveal aplastic anemia.[symptoma.com]
Nail Abnormality
  • The classic triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia is diagnostic of DC, but substantial clinical heterogeneity exists; the clinically severe variant Hoyeraal Hreidarsson syndrome (HH) also includes cerebellar hypoplasia[ncbi.nlm.nih.gov]
  • They may have tan or gray spots on their skin, nail abnormalities, and hair loss from their eyebrows, eyelashes and scalp.[sites.google.com]
  • Dyskeratosis congenita is a rare form of bone marrow failure, (which results in decreased numbers of red blood cells, white blood cells and platelets) with associated skin/nail abnormalities, and thickened white patches in the mouth.[nicklauschildrens.org]
  • Affected individuals are therefore boys who display, at the latest at the age of 10, skin, phanerian and mucosal abnormalities: reticular patterns on the skin, melanodermia, nail abnormalities (striated patterns, deformed nails, reduction in size or even[afdc.asso.fr]
  • Overview Dyskeratosis congenita of Zinsser-Cole-Engman: An inherited condition characterized by recurring painful mouth ulcers, skin pigmentation and nail abnormalities.[checkorphan.org]
Hypoxemia
  • He had severe hypoxemia with elevated alveolar-arterial oxygen gradient in the setting of liver disease. Technetium-99m-labeled macroaggregated albumin scan showed abnormally high uptake in the brain, confirming hepatopulmonary syndrome.[ncbi.nlm.nih.gov]
Respiratory Insufficiency
  • Careful management of a potentially difficult airway and a higher likelihood of respiratory insufficiency further complicate patient care.[ncbi.nlm.nih.gov]
Dental Caries
  • Further examination revealed dystrophic nails, numerous dental caries, and blepharitis. Chromosomal analysis on leukocytes showed significant telomere shortening consistent with DC.[ncbi.nlm.nih.gov]
  • The patient presented normal skin, nails, and hair, but oral examination revealed a number of ulcers, leukoplakia, gingival recessions, alveolar bone loss, and dental caries.[ncbi.nlm.nih.gov]
  • Abnormality Percentage of patients Abnormal skin pigmentation 89 Nail dystrophy 88 Bone marrow failure 85.5 Leucoplakia 78 Epiphora 30.5 Learning difficulties /developmental 25.4 delay/mental retardation Pulmonary disease 20.3 Short stature 19.5 Extensive dental[europeanmedical.info]
  • caries, esophageal webs, genitourinary defects, restrictive pulmonary disorder Rarely associated with usual interstitial pneumonia causing death from respiratory failure ( Mayo Clin Proc 2005;80:817 ) Although probably an inherited DNA repair defect[pathologyoutlines.com]
Gingival Recession
  • The patient presented normal skin, nails, and hair, but oral examination revealed a number of ulcers, leukoplakia, gingival recessions, alveolar bone loss, and dental caries.[ncbi.nlm.nih.gov]
Osteoporosis
  • Other findings include carious teeth, premature graying of hair, and osteoporosis. Approximately 50% of patients develop pancytopenia.[ncbi.nlm.nih.gov]
  • Dyskeratosis congenita is a premature aging syndrome characterized by muco-cutaneous features and a range of other abnormalities, including early greying, dental loss, osteoporosis, and malignancy.[ncbi.nlm.nih.gov]
  • Other clinical manifestations may include epiphora, lung fibrosis, liver cirrhosis, osteoporosis, and a predisposition to develop a variety of malignancies.[eurekaselect.com]
  • Other features include pulmonary fibrosis, hair loss, osteoporosis, avascular necrosis of the joints, liver disease and short stature.[jewishgeneticdiseases.org]
Lacrimation
  • Ophthalmologic manifestations include blepharitis, conjunctivitis, obliteration of the lacrimal puncta, nasolacrimal duct obstruction, ectropion, and loss of eyelashes.[ncbi.nlm.nih.gov]
  • Patients have extremely short telomeres for their age and a complex phenotype including oral leukoplakia, abnormal skin pigmentation, and dysplastic nails in addition to bone marrow failure, pulmonary fibrosis, stenosis of the esophagus, lacrimal ducts[ncbi.nlm.nih.gov]
  • Other clinical manifestations may include continuous lacrimation due to atresia of the lacrimal ducts, lung fibrosis, liver cirrhosis, osteoporosis and various neurological abnormalities including mental retardation and basal ganglia calcification (Chan[link.springer.com]
  • […] due to atresia of the lacrimal ducts, often thrombocytopenia, anemia, testicular atrophy in the male carriers, and predisposition to cancer.[en.wikipedia.org]
  • Keratinization of the lid margins, absent lacrimal puncta, trichiasis, cicatrizing conjunctivitis, entropion, ectropion, blepharitis, sparse eyelashes, and symblephara are important features.[disorders.eyes.arizona.edu]
Blepharitis
  • Ophthalmologic manifestations include blepharitis, conjunctivitis, obliteration of the lacrimal puncta, nasolacrimal duct obstruction, ectropion, and loss of eyelashes.[ncbi.nlm.nih.gov]
  • Further examination revealed dystrophic nails, numerous dental caries, and blepharitis. Chromosomal analysis on leukocytes showed significant telomere shortening consistent with DC.[ncbi.nlm.nih.gov]
  • Rather than being confined to anterior segment abnormalities like conjunctivitis, blepharitis and nasolacrimal duct obstruction which are reported in the literature, dyskeratosis congenita can cause significant visual loss due to retinal vasculitis and[ncbi.nlm.nih.gov]
  • Keratinization of the lid margins, absent lacrimal puncta, trichiasis, cicatrizing conjunctivitis, entropion, ectropion, blepharitis, sparse eyelashes, and symblephara are important features.[disorders.eyes.arizona.edu]
  • Various additional clinical findings have been reported and may include: developmental delay, short stature, microcephaly, blepharitis, epiphora, periodontal disease, taurodontism, decreased teeth/root ratio, esophageal stenosis, liver disease, urethral[orpha.net]
Hyperpigmentation
  • , confirmed by detection of a 214 C T mutation in the DKC1 gene, and provide a detailed description of mottled pigmentary changes of the skin, specifically numerous small, whitish macules dispersed against a background of diffuse, finely reticulated hyperpigmentation[ncbi.nlm.nih.gov]
  • We describe a case of acquired monosomy 7 myelodysplastic syndrome (MDS) in a boy with congenital adrenocortical insufficiency, genital anomalies, growth delay, skin hyperpigmentation, and chronic lung disease.[ncbi.nlm.nih.gov]
  • In addition to the classic triad of nail dystrophy, hyperpigmentation and oral leucoplakia, the patient had actinic keratosis (AK) and photodamaged skin, hitherto under-recognized features of this condition.[ncbi.nlm.nih.gov]
  • BACKGROUND: Dyskeratosis congenita is a rare multisystem bone marrow failure genetic disorder characterized by reticular skin hyperpigmentation, nail dystrophy, and oral leukoplakia.[ncbi.nlm.nih.gov]
  • The patient developed hyperpigmentation of the face, neck and chest region, arms, shoulders and legs. In addition, he had dry skin, deformed fingernails and toenails, sparse hair and eyebrows and hyperkeratosis of the dorsum of the hands and feet.[ncbi.nlm.nih.gov]
Alopecia
  • […] short stature, microcephaly, blepharitis, epiphora, periodontal disease, taurodontism, decreased teeth/root ratio, esophageal stenosis, liver disease, urethral stenosis, osteoporosis, avascular necrosis of femur and/or humerus, premature hair greying/alopecia[orpha.net]
  • The patient had diffuse alopecia over the scalp. The nails were brittle with vertical ridges [Figure 4]. There was no abdominal organomegaly or free fluid.[e-ijd.org]
  • Cutaneous signs: Hyperpigmentation, telangiectasia, atrophy (poïkilodermia) Dystrophic nails and palmoplantar keratoderma, hyperhidrosis Mucosal leucoplakia Dental caries or loss ( 18%) Blepharitis, conjunctivitis, epiphora (36%) Sparse eyebrows / eyelashes Alopecia[atlasgeneticsoncology.org]
  • The case reported is the first in a Negro and showed the previously unrecorded abnormalities: schizophrenia, scarring alopecia, and congenital malformation of the middle ear.[jamanetwork.com]
  • Cerebellar hypoplasia Small cerebellum Underdeveloped cerebellum [ more ] 0001321 1%-4% of people have these symptoms Global developmental delay 0001263 Percent of people who have these symptoms is not available through HPO Acute myeloid leukemia 0004808 Alopecia[rarediseases.info.nih.gov]
Skin Lesion
  • Case 2 A 30 year old male, admitted under orthopedics for chronic hip pain, was referred to the dermatology department for his skin lesions. Skin lesions began appearing since the age of 10.[ibimapublishing.com]
  • Skin care and an adequate oral hygiene are very important measures to prevent skin lesions, tooth loss and even certain malignancies. The prognosis associated with DC is poor and life expectancy is less than 30 years.[symptoma.com]
  • Similar skin lesions were also present in many of his family members as shown in the pedigree. This triad of skin, mucosa, and nail changes is classical of DC. The pattern of transmission was autosomal dominant.[japi.org]
  • Skin lesions in Bloom’s, Kindler’s and Rothmund-Thomson syndromes may be similar to that seen in DKC, but are more sun sensitive and also differ in associated features [ 1 ].[ncbi.nlm.nih.gov]
  • Devriendt et al. (1997) presented photographs of the linear skin lesions of the palmar aspects of the hands.[ncbi.nlm.nih.gov]
Hypopigmented Macule
  • The hypopigmented macules showed no discernible erythema upon rubbing or the local application of heat. The naevus anaemicus-like macules may be a relatively common but under-recognized feature in DC.[ncbi.nlm.nih.gov]
  • Herein, we report a 31-year-old male with history of recurrent febrile episodes who was found to have reticulate skin pigmentation interspersed with hypopigmented macules involving the face, neck and extremities, hyperkeratosis of palms and soles, nail[ncbi.nlm.nih.gov]
  • (c and d) Picture showing hypopigmented macules with reticular hyperpigmentation on the trunk and upper limb Click here to view Retrospective history revealed significant weight loss in the last 6 months but was not investigated.[meajo.org]
  • Case presentation Herein, we report a 31-year-old male with history of recurrent febrile episodes who was found to have reticulate skin pigmentation interspersed with hypopigmented macules involving the face, neck and extremities, hyperkeratosis of palms[bmcmedgenet.biomedcentral.com]
  • Palms and soles were smooth with numerous atrophic hypopigmented macules and absent dermatoglyphics. A few discrete white keratotic patches were evident over tongue.[ibimapublishing.com]
Eczema
  • Cutaneous findings include eczema and ichthyosis. Who is at Risk for Developing this Disease? DC is a very rare genetic disease involving mutations in the telomere complex.[dermatologyadvisor.com]

Workup

While the classical symptom triad of excess skin pigmentation, nail dystrophy and mucosal leukoplakia may directly prompt the tentative diagnosis of DC, symptoms resulting from bone marrow failure require a more thorough workup. Blood samples need to be analyzed and will typically show pancytopenia, but in many cases only one or two of anemia, thrombocytopenia and leukopenia will be detected. Bone marrow biopsies may reveal aplastic anemia.

Spirometric tests and diagnostic imaging of the lungs is indicated to assess lung function and to detect possible lung cancer. Further images may be helpful to confirm or rule out the presence of malignant neoplasms in other tissues.

Additional diagnostic measures need to be adjusted to the individual case. If mucosal leukoplakia is present but hyperpigmentation and nail dystrophy are not, histopathologic analysis of a corresponding biopsy provide information regarding the nature of mucosal alterations. This applies similarly to dermatological findings. Ophthalmologic, urological and neuropsychiatric symptoms require their own workup.

Genetic testing and confirmation of known mutations may be diagnostic, but about one in three patients does not present any of the aforementioned gene disorders. Thus, failure to detect any genetic defect does not rule out DC [13]. Flow fluorescence in situ hybridization may be used on subsets of leukocytes, particularly on lymphocytes, to measure telomere length and to detect abnormally short telomeres [14].

Treatment

DC therapy consists in delay of bone marrow failure, palliative treatment of present symptoms and life style adaptions to avoid disease progress. There is no cure for DC.

Bone marrow failure may initially be treated with androgens like oxymetholone [15]. Such treatment may improve anemia and possibly thrombocytopenia. However, long-term effects are not to be expected.

Because androgen therapy in pediatric patients may accelerate growth, corticosteroids may supplement the former. Not only do corticosteroids reduce growth acceleration, they may also serve to counteract the hemorrhagic diathesis caused by thrombocytopenia.

Hematopoietic growth hormones such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor may be administered to stimulate proliferation of neutrophil precursors. As is the case for androgen therapy, effects are usually transient.

Bone marrow or stem cell transplantation may eventually cure aplastic anemia but not premature cell aging in other tissues [16]. Success of transplantations may depend on immunosuppressive therapy, but DC patients are very sensitive towards chemotherapy and irradiation. Busulfan and melphalan should be avoided. Potentially lethal pulmonary complications may occur after stem cell transplantation which is why this therapeutic measure should be reserved for patients mainly suffering from bone marrow failure.

If DC patients develop malignant neoplasms, they should be surgically removed if at all possible. As has been mentioned above, chemotherapy and irradiation are not suitable therapeutic options.

Additionally, any habits that accelerate aging should strictly be avoided. Tobacco and alcohol are not to be consumed by DC patients. Skin care and an adequate oral hygiene are very important measures to prevent skin lesions, tooth loss and even certain malignancies.

Prognosis

The prognosis associated with DC is poor and life expectancy is less than 30 years. Only palliative therapy may be provided, although bone marrow and stem cell transplantations may cure aplastic anemia. Nevertheless, about 70% of DC patients eventually die from bone marrow failure and consequences. Gene mutations triggering DC affect all organ systems and predispose for infections, hemorrhages and malignant degeneration of rapidly dividing cell types.

It has been suggested that prognosis is somewhat better in DC forms triggered by mutations that are inherited with an autosomal dominant traits.

Etiology

X-linked inheritance has been shown for mutations in DKC1, a gene encoding for the nucleolar protein dyskerin. Such mutations account for about half of all DC cases [1].

Less frequently observed are gene defects affecting TERC (telomerase RNA component), TERT (telomerase reverse transcriptase) and TINF2 whose gene products are required for telomere replication, catalytic activity of telomerases and telomere protection, respectively, and that are inherited with an autosomal dominant trait.

TERT mutations may also be inherited in an autosomal recessive manner and this applies for additional proteins, too [4].

Epidemiology

While DKC1 mutations account for the majority of DC cases, there are several other genes whose gene products interfere with telomerase function and telomere replication. Penetrance varies and environmental factors significantly affect symptom onset and severity. Thus, DC is a very heterogenous disease that is diagnosed if characteristic symptoms such as excess skin pigmentation, nail dystrophy and leukoplakia are detected. Indeed, bone marrow failure is of utmost clinical importance but less obvious than the aforementioned symptoms and is therefore not part of the original definition of DC. And although this generic term comprises several genetic disorders, DC is a rare disease and incidence rates have been estimated to be less than 1 per 1,000,000 individuals [5].

Because the majority of mutations that account for DC is X-linked, males are affected more frequently than females [6]. Symptoms often manifest during childhood, but due to the above mentioned heterogeneity, age at symptom onset, symptoms themselves and severity may vary widely.

Sex distribution
Age distribution

Pathophysiology

Chromosomes consist of DNA strands whose ends are formed by non-coding sequence repeats called telomeres. In humans, they may measure several thousand base pairs. However, during DNA replication after successful mitosis, telomeres are shortened. At one point, telomeres are too short for further cell division, chromosomal stability can no longer be guaranteed and cells either remain in a senescent state of indivisibility or undergo apoptosis to avoid malignant degeneration. Indeed, telomere shortening seems to be the molecular basis of aging.

Telomerase is an enzyme capable of adding telomeric sequence repeats to shortened telomeres. It thus prolongs the life cycle of cells, particularly of stem cells and germ cells, and contributes to cellular cancer prevention. Telomerase dysfunctions will mainly affect tissues with fast rates of cell division, e.g., skin, skin appendages, mucosa and bone marrow - those tissues showing symptoms of DC. So far, all gene mutations that have been identified as possible triggers of DC could be linked to telomerase function, telomere protection and replication [7] [8]. DKC1, TERC and TERT gene products are part of the telomerase complex, while other affected proteins fulfill additional functions, e.g., telomere protection. Consequently, dysfunction of proteins defective in DC patients leads to reduced telomerase activity, premature telomere shortening and cellular senescence [9]. In fact, telomeric DNA in DC patients is significantly shorter than in healthy controls of the same age.

In detail, DKC1 encodes for dyskerin, a protein involved in ribosomal RNA metabolism that forms part of the telomerase complex. More than 50 DKC1 mutations have been described so far. Mutations in TERC affect the telomerase RNA component and this molecule serves as the template for telomere replication. TERT, telomerase reverse transcriptase, forms the catalytic subunit of the telomerase complex.

Prevention

No preventive measures can be recommended.

Families with known problems of DC may benefit from genetic counseling.

Summary

Dyskeratosis congenita (DC) is a general term utilized for a variety of genetic disorders whose most characteristic symptoms are excess skin pigmentation, nail dystrophy and mucosal leukoplakia. Disease progress often consists in malignant degeneration of precancerous mucosal lesions, development of squamous cell carcinoma, pulmonary fibrosis or lung cancer [1]. Also, the majority of DC patients eventually suffers from bone marrow failure and possibly subsequent hematologic malignancies

Because DC may be triggered by different gene mutations, it may be inherited with an X-linked or autosomal trait, in form of a dominant or recessive allele. To date, ten mutations affecting function and activity of telomerase or associated proteins have been described as potential causes of DC. Presumably, additional mutations may also account for DC since there is a considerable share of DC patients who does not display any of the known gene defects. These mutations lead to premature telomere shortening, tissue and stem cell senescence and predisposition for cancer [2].

The main cause of death in DC patients is bone marrow failure. Only a hematopoietic stem cell transplantation may be effective in avoiding it and in improving the patient's prognosis [3]. Otherwise, there is no causative treatment for DC and only palliative therapy can be provided.

Patient Information

Dyskeratosis congenita (DC) is a general term for genetic disorders associated with premature aging of cells.

Causes

Distinct gene mutations may trigger DC. All these mutations interfere with telomere protection and replication, whereby telomeres are non-coding DNA sequences that confer stability to chromosomes. Each time a cell divides, these telomeres are shortened a little bit. After a determined number of divisions, a cell cannot divide any longer without an increased risk for malignant degeneration and cancer development. Thus, the cell initiates what is called a programmed cell death. However, there are certain cell types that need to maintain their ability to divide, particularly stem cells located in the bone marrow. These cells dispose of an enzyme called telomerase whose function is to re-extend shortened telomeres. Telomerase activity is reduced in DC patients, telomeres are shortened prematurely and cells tend to age much faster than in healthy individuals.

Symptoms

The above explained mechanisms of reduced telomerase activity and accelerated telomere shortening mainly affect tissues characterized by a rapid turn over, e.g. skin, skin appendages, mucosa and bone marrow. Therefore, DC may manifest in form of excess skin pigmentation, nail dystrophy and mucosal leukoplakia, i.e., white patches that become visible on the oral mucosa, as well as bone marrow failure. The latter, in turn, leads to anemia, thrombocytopenia and leukopenia which manifest in fatigue, breathing difficulties, bluish discoloration of the skin, a tendency to bleed, bleeding gums and nosebleed and recurrent infections with any type of pathogen. DC patients also have a high risk of developing cancer.

Diagnosis

A tentative diagnosis may be based on the presence of several of the above mentioned symptoms. Laboratory analyses of blood and bone marrow samples confirm low cell counts of virtually all cell types. If the patient presents alterations that cannot be clearly identified, tissue biopsies may be taken and histopathologically examined. Diagnostic imaging may be applied to evaluate the condition of the patient's lungs and to detect possible tumors. A new diagnostic technique allows for measuring the length of telomeres. Abnormally short telomeres support the diagnosis of DC.

Positive testing for gene mutations known to trigger DC may confirm the diagnosis. However, about one in three DC patients suffers from other, as of yet unknown mutations that cannot be easily detected with genetic analysis.

Treatment

There is no cure for DC. Therapy with androgens or growth hormones may stimulate production of red and white blood cells in the bone marrow. The tendency to bleed may be somewhat counteracted with corticosteroids. However, these drugs only mediate short- to mid-term effects. Patients who suffer mainly from bone marrow failure may benefit from bone marrow or stem cell transplantation. Otherwise, only supportive therapy can be provided.

DC patients should avoid consumption of tobacco and alcohol. Skin care and good oral hygiene are also important and may delay the onset of certain symptoms.

References

Article

  1. Alder JK, Parry EM, Yegnasubramanian S, et al. Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene. Hum Mutat. 2013; 34(11):1481-1485.
  2. Nishio N, Kojima S. Recent progress in dyskeratosis congenita. Int J Hematol. 2010; 92(3):419-424.
  3. Nelson ND, Bertuch AA. Dyskeratosis congenita as a disorder of telomere maintenance. Mutat Res. 2012; 730(1-2):43-51.
  4. Allenspach EJ, Bellodi C, Jeong D, et al. Common variable immunodeficiency as the initial presentation of dyskeratosis congenita. J Allergy Clin Immunol. 2013; 132(1):223-226.
  5. Dokal I. Dyskeratosis congenita. Hematology Am Soc Hematol Educ Program. 2011:480-486.
  6. Karunakaran A, Ravindran R, Arshad M, Ram MK, Laxmi MK. Dyskeratosis congenita: a report of two cases. Case Rep Dent. 2013:845125.
  7. Islam A, Rafiq S, Kirwan M, et al. Haematological recovery in dyskeratosis congenita patients treated with danazol. Br J Haematol. 2013; 162(6):854-856.
  8. Ballew BJ, Joseph V, De S, et al. A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. PLoS Genet. 2013; 9(8):e1003695.
  9. Touzot F, Le Guen T, de Villartay JP, Revy P. [Dyskeratosis congenita: short telomeres are not the rule]. Med Sci (Paris). 2012; 28(6-7):618-624.
  10. Scoggins RB, Prescott KJ, Asher GH, et al. Dyskeratosis congenita with Fanconi-type anemia: investigations of immunologic and other defects. Clin Res. 1971; 19:409.
  11. Dokal I, Vulliamy T. Dyskeratosis congenita: its link to telomerase and aplastic anaemia. Blood Rev. 2003; 17(4):217-225.
  12. Rackley S, Pao M, Seratti GF, et al. Neuropsychiatric conditions among patients with dyskeratosis congenita: a link with telomere biology? Psychosomatics. 2012; 53(3):230-235.
  13. Bessler M, Wilson DB, Mason PJ. Dyskeratosis congenita. FEBS Lett. 2010; 584(17):3831-3838.
  14. Alter BP, Baerlocher GM, Savage SA, et al. Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood. 2007; 110(5):1439-1447.
  15. Giri N, Pitel PA, Green D, Alter BP. Splenic peliosis and rupture in patients with dyskeratosis congenita on androgens and granulocyte colony-stimulating factor. Br J Haematol. 2007; 138(6):815-817.
  16. Sinha S, Trivedi V, Krishna A, Rao N. Dyskeratosis congenita- management and review of complications: a case report. Oman Med J. 2013; 28(4):281-284.

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Last updated: 2019-07-11 20:50