Dyskeratosis Congenita

Back

Background

Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, was first described in 1906. It is a rare, progressive bone marrow failure syndrome characterized by the triad of reticulated skin hyperpigmentation, nail dystrophy, and oral leukoplakia. Evidence exists for telomerase dysfunction, ribosome deficiency, and protein synthesis dysfunction in this disorder. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy.[1, 2]

Pathophysiology

To date, there are 14 genes that have been identified with dyskeratosis congenita (DKC): ACD,DCK1, TERC, TERT, NOP10, NHP2, TINF2, USB1, TCAB1, CTC1, PARN,RTEL1, WRAP53, and C16orf57.[3, 4, 5, 6] DKC is genetically heterogeneous, with X-linked recessive (Mendelian Inheritance in Man [MIM] 305000), autosomal dominant (MIM 127550), and autosomal recessive (MIM 224230) subtypes based on different patterns of inheritance. DKC is related to telomerase dysfunction[7, 8] ; all genes associated with this syndrome (ie, DKC1, TERT, TERC, NOP10) encode proteins in the telomerase complex responsible for maintaining telomeres at the ends of chromosomes regarding shortening length, protection, and replication.[9]

In the X-linked recessive form, the gene defect lies in the DKC1 gene (located at Xq28), which encodes for the protein dyskerin. Dyskerin is composed of 514 amino acids and has a role in ribosomal RNA processing and telomere maintenance.[10, 11, 12, 13] Modification of dyskerin by SUMOylation has been shown to stabilize the protein. In addition, a mutation in the DKC1 gene is also found on exon 15, revealing a duplication, which adds a lysine residue on a polylysine tract on the C-terminus. All in all, there have been over 50 mutations found in DKC1.[14, 15, 16, 17] One study found that mutations in SHQ1 (a dyskerin chaperone) affect dyskerin function.[18] Loss of DKC1 has been reported to induce oxidative stress independent of telomere shortening.[13]

In the autosomal dominant form, mutations in the RNA component of telomerase (TERC) or telomerase reverse transcriptase (TERT) are responsible for disease phenotype.[8, 19, 20] One study reported an RNA-binding protein, human antigen R (HuR), that facilitates TERC methylation and promotes TERT/TERC complex assembly.[21] Mutations in either HuR or TERC can weaken the HuR-TERC binding and reduce TERC methylation, resulting in decreased telomerase activity.[21]

Another gene implicated in DKC, TINF2, encodes a key component of the protein shelterin, which plays a role in telomere homeostasis.[13] Mutations in TINF2 could lead to DKC or Revesz syndrome, a rare variant of DKC.[6] Both an autosomal dominant inheritance pattern and de novo occurrence have been associated with TINF2 mutations.[13, 22] In cases of DKC caused by TINF2 mutations, basal ganglia calcification and pulmonary fibrosis have been reported.[22, 23] Revesz syndrome mainly manifests as bilateral exudative retinopathy (including hemorrhages and other vascular irregularities), intrauterine growth restriction, intracranial calcifications, and neurocognitive defects.[6, 24, 25]

Defects in the NOP10 gene were found in association with autosomal recessive DKC.[26] NOP10 encodes small nucleolar ribonucleoproteins (snoRNP) associated with the telomerase complex. In persons with autosomal dominant DKC and in terc-/- knockout mice, genetic anticipation (ie, increasing severity and/or earlier disease presentation with each successive generation) has been reported.[13, 27] Another case report found a novel, homozygous WRAP53 (antisense to TP53) Arg298Trp mutation underlying DKC.[28]

A heterozygous mutation was found on the conserved telomere maintenance component 1 gene (CTC1). This implication is also associated with a pleiotropic syndrome, Coats plus.[29, 30]

Homozygous autosomal recessive mutations in RTEL1 lead to similar phenotypes that parallel with Hoyeraal-Hreidarsson (HH) syndrome, a severe variant of DKC characterized by cerebellar hypoplasia, bone marrow failure, intrauterine growth restriction and immunodeficiency.[6] It is associated with short, heterogeneous telomeres. In the presence of functional DNA replication, RTEL1 mutations produce a large amount of extrachromosomal T-circles. Enzymes remove the T-circles and therefore shorten the telomere. RTEL1 has a role in managing DNA damage by increasing sensitivity; therefore, mutations on this gene cause both telomeric and nontelomeric causes of DKC.[31, 32, 33, 34]

Patients with DKC have reduced telomerase activity and abnormally short tracts of telomeric DNA compared with normal controls.[35, 36] Telomeres are repeat structures found at the ends of chromosomes that function to stabilize chromosomes. With each round of cell division, the length of telomeres is shortened and the enzyme telomerase compensates by maintaining telomere length in germline and stem cells. Because telomeres function to maintain chromosomal stability, telomerase has a critical role in preventing cellular senescence and cancer progression. Rapidly proliferating tissues with the greatest need for telomere maintenance (eg, bone marrow) are at greatest risk for failure. DKC1 has been found to be a direct target of the c-myc oncogene, strengthening the connection between DKC and malignancy.[37]

Analysis of 270 families in the DKC registry found that mutations in dyskerin (DKC1), TERT, and TERC only account for 64% of patients, with an additional 1% due to NOP10, suggesting that other genes associated with this syndrome are, as yet, unidentified. In addition to the mutations that directly affect telomere length, studies also indicate that a DKC diagnosis should not be based solely on the length of the telomere, but also the fact that there are defects in telomere replication and protection.[9] In addition, revertant mosaicism has been a new recurrent event in DKC.[38]

Studies have also shown the significance of DNA methylation. A study in patients with DKC has shown changes in the CpG sites affiliated with the internal promoter region of the PR domain, specifically containing 8 (PRDM8) when compared with healthy control groups.[21, 39]

Etiology

Mutations in DKC1 have been shown to cause the X-linked form of dyskeratosis congenita (DKC). Specifically, the presence of a missense mutation on DKC1 in females has been shown to compromise telomerase RNA levels, putting them at increased risk for penetrant telomere phenotypes that may be associated with increased clinical morbidity.[40]

The inheritance pattern of most cases of DKC is X-linked recessive, but autosomal dominant and recessive patterns have been reported. Autosomal dominant DKC is associated with TERC,TERT, and TINF2 mutations in some cases, and NOP10, TERT, NHP2, and RTEL1 mutations have been associated with some cases of autosomal recessive DKC. Fifty percent of DKC patients with the clinical phenotypes have a mutation in their genes.[14]

Epidemiology

Frequency

Dyskeratosis congenita (DKC) is estimated to occur in 1 in 1 million people. More than 200 individuals have been reported in the literature.

Race

No racial predilection has been reported. The DKC registry includes patients from all over the world, with families from at least 40 different countries currently in the registry.

Sex

The male-to-female ratio is approximately 3:1.

Age

Patients usually present during the first decade of life, with the skin hyperpigmentation and nail changes typically appearing first.

Prognosis

Dyskeratosis congenita (DKC) is a multisystem disorder that carries a poor prognosis (mean survival of 30 y), with most deaths related to infections, bleeding, and malignancy. In the DKC registry, approximately 70% of affected individuals died of bone marrow failure or its complications, and these deaths occurred at a median age of 16 years. Therapeutic interventions are mostly palliative, but BMT and SCT for aplastic anemia have been tried with variable success. Wide variation in clinical phenotype may occur in individuals, suggesting that other genetic or environmental factors may be contributory. The prognosis is worse for the X-linked and autosomal forms compared with the autosomal dominant form.

Hoyeraal-Hreidarsson (HH) syndrome is also associated with mutations in DKC1.[41] Mutations in this gene have been described in patients with HH syndrome, which is characterized by intrauterine growth restriction, microcephaly, intellectual disability, cerebellar malformation, immunodeficiency, and progressive bone marrow failure.[41] Mucosal ulcerations have been found in a few patients. Some authorities hypothesize that HH syndrome may be a severe variant of DKC in which affected individuals die before the development of mucocutaneous findings.[41]  Patients with HH syndrome have significantly shorter telomeres than those with the milder form of disease.[41]

In addition, studies have also found that not only are shortened telomeres associated with HH syndrome, but more so are telomere dysfunction and telomere protection.[16] The severe neurologic deficits in this severe form point to an important role of the DKC1 gene in brain function.

The biology of telomere shortening is not only associated with DKC, but it has comorbid associations with neuropsychiatric conditions. A cohort study with 6 pediatric and 8 adult subjects showed that 83% of the children and 88% of the adult had a comorbid neuropsychiatric condition. These conditions include schizophrenia, anxiety, intellectual disability, attention-deficit/hyperactivity disorder, adjustment disorder, mood disorders, or pervasive developmental disorders.[42]

Mortality/morbidity

In an analysis of individuals with DKC, approximately 70% of patients died either directly from bone marrow failure or from its complications at a median age of 16 years. Eleven percent died from sudden pulmonary complications; a further 11% died of pulmonary disease in the bone marrow transplantation (BMT) setting. Seven percent died from malignancy (eg, Hodgkin disease, pancreatic carcinoma). Fatal opportunistic infections such as Pneumocystis carinii pneumonia and cytomegalovirus infection have been reported.

History

The mucocutaneous features of dyskeratosis congenita (DKC) typically develop between ages 5 and 15 years. The median age of onset of the peripheral cytopenia is 10 years.

Physical Examination

The triad of reticulated hyperpigmentation of the skin, nail dystrophy, and leukoplakia characterizes dyskeratosis congenita (DKC). The syndrome is clinically heterogeneous; in addition to the diagnostic mucocutaneous features and bone marrow failure, affected individuals can have a variety of other clinical features.

The minimum requirement to diagnose DKC is the presence of 2 of 4 major features of the mucocutaneous triad and bone marrow failure 2 or more of the other somatic symptoms. Late diagnosis leads to inappropriate treatment and increased mortality/morbidity.[3]

Cutaneous findings

The primary finding is abnormal skin pigmentation, with tan-to-gray hyperpigmented or hypopigmented macules and patches in a mottled or reticulated pattern. Reticulated pigmentation occurs in approximately 90% of patients. Poikilodermatous changes with atrophy and telangiectasia are common. The cutaneous presentation may clinically and histologically resemble graft versus host disease. The typical distribution involves the sun-exposed areas, including the upper trunk, neck, and face.

Other cutaneous findings may include alopecia of the scalp, eyebrows, and eyelashes; premature graying of the hair; hyperhidrosis; hyperkeratosis of the palms and soles; and adermatoglyphia (loss of dermal ridges on fingers and toes).

Nail findings

Nail dystrophy is seen in approximately 90% of patients, with fingernail involvement often preceding toenail involvement. Progressive nail dystrophy begins with ridging and longitudinal splitting. Progressive atrophy, thinning, pterygium, and distortion eventuate in small, rudimentary, or absent nails.

Mucosal findings

Mucosal leukoplakia occurs in approximately 80% of patients and typically involves the buccal mucosa, tongue, and oropharynx. The leukoplakia may become verrucous, and ulceration may occur. Patients also may have an increased prevalence and severity of periodontal disease.

Other mucosal sites may be involved (eg, esophagus, urethral meatus, glans penis, lacrimal duct, conjunctiva, vagina, anus). Constriction and stenosis can occur at these sites, with subsequent development of dysphagia, dysuria, phimosis, and epiphora.

Hematological findings (bone marrow failure)

Approximately 90% of patients have peripheral cytopenia of one or more lineages, with a median age of onset of 10 years. This is the initial presentation in some cases, especially in cryptic variants of DKC, where (pan-)cytopenia is also the most frequent clinical manifestation.[43] Bone marrow failure is a major cause of death, with approximately 70% of deaths related to bleeding and opportunistic infections as a result of bone marrow failure.

Pulmonary complications

Approximately 20% of individuals with DKC develop pulmonary complications, including pulmonary fibrosis and abnormalities of pulmonary vasculature.[44] The recommendation is that DKC patients avoid taking drugs with pulmonary toxicity (eg, busulfan) and that they have their lungs shielded from radiation during BMT.

Increased risk of malignancy

Patients have an increased prevalence of malignant mucosal neoplasms, particularly squamous cell carcinoma of the mouth, nasopharynx,[45] esophagus, rectum, vagina, or cervix. These often occur within sites of leukoplakia. The prevalence of squamous cell carcinoma of the skin is also increased. Other malignancies reported include Hodgkin lymphoma, adenocarcinoma of the gastrointestinal tract, and bronchial and laryngeal carcinoma. Malignancy tends to develop in the third decade of life.

Neurologic system findings

Patients may have learning difficulties and intellectual disability.

Ophthalmic system findings

DKC reportedly is associated with retinal vasculopathy,[25, 46] conjunctivitis, blepharitides, pterygium, proliferative retinopathy, frosted branch angiitis,[47] sparse eyelashes, ectropion, entropion, and trichiasis.[4] Lacrimal duct stenosis resulting in epiphora (ie, excessive tearing) occurs in approximately 80% of patients. Exudative retinopathy is a common presentation of Coats disease or familial exudative vitreoretinopathy, but DKC should also be considered in such cases.[48] Retinitis caused by CMV, an opportunistic pathogen commonly found among immunocompromised patients, is also a possible clinical feature of DKC.[49]

Dental findings

DKC may also present with multiple dental changes, including caries, periodontal disease, and taurodontism.[4]

Skeletal system findings

Patients may have mandibular hypoplasia, osteoporosis, avascular necrosis, and scoliosis.

Gastrointestinal system findings

These may include esophageal webs, posterior pharyngeal wall squamous cell carcinoma, hepatic angiosarcoma,[50] hepatosplenomegaly, cirrhosis,[51]  and diffuse mesangial sclerosis (and subsequent end-stage renal disease) in one pediatric case.[52]

Genitourinary system findings

Hypospastic testes, hypospadias, and ureteral stenosis are reported.

Female carriers

Female carries of DKC may have subtle clinical features. One study showed that 3 of 20 female carriers had clinical features that included a single dystrophic nail, a patch of hypopigmentation, or mild leukoplakia.

Immunological defects

Decreased B cells, decreased natural killer (NK) cells, and dysgammaglobulinemia result in frequent infections. Immune defects are commonly found in conjunction with other DKC symptoms, but they have also been found to precede these symptoms.[14]  There has also been an association with hypothyroidism and hypogonadism.[53]

Laboratory Studies

Perform appropriate tests to screen for bone marrow failure, pulmonary disease, neurologic disease, and mucosal malignancies. Specific tests depend on the clinical findings and may include a CBC count, chest radiography, pulmonary function tests, and stool tests for occult blood. Elevated von Willebrand factor levels have been associated with fatal vascular complications after bone marrow transplantation and may be a marker for patients with a predisposition for endothelial deterioration.

Imaging Studies

Several reports note that radiographs show calcification of the basal ganglia.

Dermoscopic Findings

The dermatoscope is another useful tool used to examine cutaneous findings associated with dyskeratosis congenita (DKC). The image seen is typically described as pigmented lines made up of brown dots and globules arranged in a netlike pattern.[56]

Genetic Testing

Mutational analysis may be useful in confirming the diagnosis. Mutations in the TERC gene and in the TERT gene, the gene for telomerase reverse transcriptase (another member of the ribonucleoprotein complex), have been identified in a subset of patients with aplastic anemia.[57] Genetic testing for occult dyskeratosis congenita (DKC) should be considered in patients with aplastic anemia. However, a 2006 genetic analysis of the TERC gene among 284 children with either aplastic anemia or myelodysplastic syndrome found only 2 mutations in the TERC gene.[58]

Patients and family members without a known mutation can be screened with a new test, leukocyte subset flow fluorescence in situ hybridization, which can identify very short telomeres in both clinically apparent and silent disease.[59]

The flow-FISH (fluorescent in situ hybridization) technique is also a cost-effective method that can also be used to measure telomere length.[60]

One study found significant overlap in symptomatology between dyskeratosis congenita (DKC) and four other genetic syndromes (causative genes in parentheses): poikiloderma with neutropenia (USB1), Dubowitz syndrome (LIG4), and ectodermal dysplasia/short stature syndrome (GRHL2).[55] Patients with these disorders may present with somatic features resembling DKC, which may confound diagnosis and subsequently delay management.[55] Therefore, genetic testing for USB1, LIG4, and GRHL2 is suggested in addition to the conventional DKC workup.[55]

Histologic Findings

Skin biopsy specimens from the areas of reticulated pigmentation typically show nonspecific changes, including mild hyperkeratosis, epidermal atrophy, telangiectasia of the superficial blood vessels, and melanophages in the papillary dermis. Interface changes have also been reported, with mild basal layer vacuolization and a lymphocytic inflammatory infiltrate in the upper dermis.

Medical Care

The only long-term, curative treatment option for bone marrow failure in dyskeratosis congenita (DKC) patients is hematopoietic stem cell transplantation (SCT), although long-term outcomes remain poor, with an estimated 10-year survival rate of 23%.[61] Nonmyeloablative hematopoietic SCT conditioning regimens (ie, reduced-intensity conditioning) with fludarabine may offer better outcomes. A 2007 review showed a 22% mortality rate with reduced-intensity conditioning in DKC treatment versus a 71% mortality rate with traditional myeloablative regimens.[62] Similarly, a 2016 study has shown that reduced-intensity conditioning, that is, chemotherapy without radiation for those receiving SCT, has improved overall survival post treatment.[63] The success rate of SCT is limited because of a high prevalence of fatal pulmonary complications, which likely reflect preexisting pulmonary disease in these patients.[64] Drugs that cause pulmonary toxicity (eg, busulfan) and exposure to unnecessary radiation should be avoided in these patients. The best candidates for SCT may be patients with sibling donors and with no preexisting pulmonary disease.

Short-term treatment options for bone marrow failure in patients with DKC include anabolic steroids (eg, oxymetholone), granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and erythropoietin.[65]

Oxymetholone has a 70% response rate, yet adversely affects female patients through its liver toxicity and strong masculinizing adverse effects.[66] An androgen derivative drug that functions similarly to oxymetholone is danazol. This drug has been reported to have good hematological response and a better adverse effect profile for women, although concerns regarding liver toxicity remain.[66] Androgen therapy (eg, danazol) has been recommended as a first-line treatment in DKC patients after hematopoietic SCT for prophylaxis against pulmonary fibrosis.[61]

Approximately 50% of patients experience a temporary increase in blood counts with androgen therapy; the duration of treatment is limited by adverse effects. In addition, reports have described splenic peliosis and rupture in patients treated concomitantly with androgens and granulocyte colony-stimulating factor.[67] One study found that androgen therapy does not produce a difference in telomere attrition rates.[68]

Many DKC patients are at high risk of cancer; therefore, proton therapy has been a better treatment option than strong radiation, because of its ability to spare normal tissue and deliver a nontoxic form of radiation therapy.[69]

The elucidation of the genetic basis of X-Iinked DKC enables prenatal testing and carrier detection. Early diagnosis of DKC through genetic analysis also may help identify patients for early harvest and storage of their bone marrow for use after anticipated marrow failure. In the future, patients with DKC may be candidates for hematopoietic gene therapy.

Findings have shown that the internal fragment of dyskerin, GSE24.2, has been able to reduce the pathological effects caused by the DKC1 mutation.[70]

An association with sirtuins, specifically SIRT6, is another important target for DKC patients. It was found that sirtuins have properties to increase the longevity of proteins. Specifically with DKC patients, they has proven the ability to protect the telomeric chromatin shortening from deacetylation of histones at the replication sites.[71]

Surgical Care

To date, the only curative therapy is bone marrow transplantation; however, surgical preparation in itself can cause harm to the patient.[72]

Complications

Patients with dyskeratosis congenita (DKC) should avoid drugs with pulmonary toxicity (eg, busulfan) and should have their lungs shielded from radiation during bone marrow transplantation. Additionally, some authorities recommend routine endoscopic surveillance beginning at age 30 in known cases of DKC, along with general precautions like sun and tobacco avoidance.

Patients who undergo hematopoietic stem cell transplantation (SCT) for treatment should be warned of the increase risk of posttransplantation lymphoproliferative disorders.[73] A special case reported a patient with the TINF2 mutation treated with hematopoietic SCT who experienced irreversible leukoencephalopathy.[74] Other post-transplantation complications include iron overload and other late effects.[66]

DKC patients are also at risk for low bone mineral density, necessitating the need for continual monitoring.[75]

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Erythropoietin (Epogen, Procrit)

Clinical Context:  Erythropoietin stimulates division and differentiation of erythroid progenitor cells.

Filgrastim (Neupogen)

Clinical Context:  Filgrastim activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils.

Class Summary

These agents are used to stimulate bone marrow in patients with cytopenia of one or more cell lineage.

Author

David T Robles, MD, PhD, FAAD, Dermatologist, Oak Tree Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Arthur Yukuang Chang, MS,

Disclosure: Nothing to disclose.

Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

Jacquiline Habashy, DO, MSc, Resident Physician, Department of Dermatology, Western University of Health Sciences College of Osteopathic Medicine of the Pacific

Disclosure: Nothing to disclose.

Specialty Editors

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Additional Contributors

Jean Paul Ortonne, MD, Chair, Department of Dermatology, Professor, Hospital L'Archet, Nice University, France

Disclosure: Nothing to disclose.

Philip Fleckman, MD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington

Disclosure: Nothing to disclose.

Acknowledgements

Jonathan M Olson, MD Fellow, Division of Dermatology, University of Washington Medical Center

Jonathan M Olson, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

References

  1. Jyonouchi S, Forbes L, Ruchelli E, Sullivan KE. Dyskeratosis congenita: a combined immunodeficiency with broad clinical spectrum--a single-center pediatric experience. Pediatr Allergy Immunol. 2011 May. 22(3):313-9. [View Abstract]
  2. Ballew BJ, Savage SA. Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol. 2013 Jun. 6(3):327-37. [View Abstract]
  3. Islam A, Rafiq S, Kirwan M, et al. Haematological recovery in dyskeratosis congenita patients treated with danazol. Br J Haematol. 2013 Sep. 162(6):854-6. [View Abstract]
  4. Pagon RA, Adam MP, Ardinger HH, eds. GeneReviews. Seattle, Wash: University of Washington; 1993-2016.
  5. Kilic SS, Cekic S. Juvenile Idiopathic Inflammatory Myopathy in a Patient With Dyskeratosis Congenita Due to C16orf57 Mutation. J Pediatr Hematol Oncol. 2016 Mar. 38 (2):e75-7. [View Abstract]
  6. Zhang J, Li M, Yao Z. Updated review of genetic reticulate pigmentary disorders. Br J Dermatol. 2017 Oct. 177 (4):945-959. [View Abstract]
  7. Bessler M, Du HY, Gu B, Mason PJ. Dysfunctional telomeres and dyskeratosis congenita. Haematologica. 2007 Aug. 92(8):1009-12. [View Abstract]
  8. Garcia CK, Wright WE, Shay JW. Human diseases of telomerase dysfunction: insights into tissue aging. Nucleic Acids Res. 2007. 35(22):7406-16. [View Abstract]
  9. Touzot F, Le Guen T, de Villartay JP, Revy P. Dyskeratosis congenita: short telomeres are not the rule. Science of Medicine. June 2012. 28(6-7):618-24.
  10. Mason PJ, Wilson DB, Bessler M. Dyskeratosis congenita -- a disease of dysfunctional telomere maintenance. Curr Mol Med. 2005 Mar. 5(2):159-70. [View Abstract]
  11. Walne AJ, Marrone A, Dokal I. Dyskeratosis congenita: a disorder of defective telomere maintenance?. Int J Hematol. 2005 Oct. 82(3):184-9. [View Abstract]
  12. Zeng XL, Thumati NR, Fleisig HB, Hukezalie KR, Savage SA, Giri N, et al. The accumulation and not the specific activity of telomerase ribonucleoprotein determines telomere maintenance deficiency in X-linked dyskeratosis congenita. Hum Mol Genet. 2011 Nov 4. [View Abstract]
  13. Ibáñez-Cabellos JS, Pérez-Machado G, Seco-Cervera M, Berenguer-Pascual E, García-Giménez JL, Pallardó FV. Acute telomerase components depletion triggers oxidative stress as an early event previous to telomeric shortening. Redox Biol. 2018 Apr. 14:398-408. [View Abstract]
  14. Allenspach EJ, Bellodi C, Jeong D, et al. Common variable immunodeficiency as the initial presentation of dyskeratosis congenita. J Allergy Clin Immunol. 2013 Jul. 132(1):223-6. [View Abstract]
  15. Brault ME, Lauzon C, Autexier C. Dyskeratosis congenita mutations in dyskerin SUMOylation consensus sites lead to impaired telomerase RNA accumulation and telomere defects. Hum Mol Genet. 2013 Sep 1. 22(17):3498-507. [View Abstract]
  16. Touzot F, Gaillard L, Vasquez N, et al. Heterogeneous telomere defects in patients with severe forms of dyskeratosis congenita. J Allergy Clin Immunol. 2012 Feb. 129(2):473-82, 482.e1-3. [View Abstract]
  17. Ratnasamy V, Navaneethakrishnan S, Sirisena ND, Grüning NM, Brandau O, Thirunavukarasu K, et al. Dyskeratosis congenita with a novel genetic variant in the DKC1 gene: a case report. BMC Med Genet. 2018 May 25. 19 (1):85. [View Abstract]
  18. Bizarro J, Meier UT. Inherited SHQ1 mutations impair interaction with NAP57/dyskerin, a major target in dyskeratosis congenita. Mol Genet Genomic Med. 2017 Nov. 5 (6):805-808. [View Abstract]
  19. Marrone A, Sokhal P, Walne A, Beswick R, Kirwan M, Killick S, et al. Functional characterization of novel telomerase RNA (TERC) mutations in patients with diverse clinical and pathological presentations. Haematologica. 2007 Aug. 92(8):1013-20. [View Abstract]
  20. Marrone A, Walne A, Tamary H, Masunari Y, Kirwan M, Beswick R, et al. Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Blood. 2007 Dec 15. 110(13):4198-205. [View Abstract]
  21. Tang H, Wang H, Cheng X, Fan X, Yang F, Zhang M, et al. HuR regulates telomerase activity through TERC methylation. Nat Commun. 2018 Jun 7. 9 (1):2213. [View Abstract]
  22. Abdollahi M, Gao MM, Munoz DG. Distinct pattern of neostriatal calcifications in dyskeratosis congenita: A case report and literature review. Clin Neuropathol. 2018 Nov/Dec. 37 (6):277-282. [View Abstract]
  23. Du H, Guo Y, Ma D, Tang K, Cai D, Luo Y, et al. A case report of heterozygous TINF2 gene mutation associated with pulmonary fibrosis in a patient with dyskeratosis congenita. Medicine (Baltimore). 2018 May. 97 (19):e0724. [View Abstract]
  24. Moussa K, Huang JN, Moore AT. Revesz syndrome masquerading as traumatic retinal detachment. J AAPOS. 2017 Oct. 21 (5):422-425.e1. [View Abstract]
  25. Gupta MP, Talcott KE, Kim DY, Agarwal S, Mukai S. Retinal findings and a novel TINF2 mutation in Revesz syndrome: Clinical and molecular correlations with pediatric retinal vasculopathies. Ophthalmic Genet. 2017 Jan-Feb. 38 (1):51-60. [View Abstract]
  26. Walne AJ, Vulliamy T, Marrone A, Beswick R, Kirwan M, Masunari Y, et al. Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum Mol Genet. 2007 Jul 1. 16(13):1619-29. [View Abstract]
  27. Ruggero D, Grisendi S, Piazza F, Rego E, Mari F, Rao PH. Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. Science. 2003 Jan 10. 299(5604):259-62. [View Abstract]
  28. Shao Y, Feng S, Huang J, Huo J, You Y, Zheng Y. A unique homozygous WRAP53 Arg298Trp mutation underlies dyskeratosis congenita in a Chinese Han family. BMC Med Genet. 2018 Mar 7. 19 (1):40. [View Abstract]
  29. Keller RB, Gagne KE, Usmani GN, Asdourian GK, Williams DA, Hofmann I, et al. CTC1 Mutations in a patient with dyskeratosis congenita. Pediatr Blood Cancer. 2012 Aug. 59(2):311-4. [View Abstract]
  30. Painho T, Conceição C, Kjöllerström P, Batalha S. Retinopathy and bone marrow failure revealing Coats plus syndrome. BMJ Case Rep. 2018 Mar 9. 2018:[View Abstract]
  31. 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 Aug. 9(8):e1003695. [View Abstract]
  32. Kuang FM, Tang LL, Zhang H, Xie M, Yang MH, Yang LC, et al. [Recurrent pulmonary infection and oral mucosal ulcer]. Zhongguo Dang Dai Er Ke Za Zhi. 2017 Apr. 19 (4):452-457. [View Abstract]
  33. Marsh JCW, Gutierrez-Rodrigues F, Cooper J, Jiang J, Gandhi S, Kajigaya S, et al. Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms. Blood Adv. 2018 Jan 9. 2 (1):36-48. [View Abstract]
  34. Ungar RA, Giri N, Pao M, Khincha PP, Zhou W, Alter BP, et al. Complex phenotype of dyskeratosis congenita and mood dysregulation with novel homozygous RTEL1 and TPH1 variants. Am J Med Genet A. 2018 Jun. 176 (6):1432-1437. [View Abstract]
  35. Alter BP, Rosenberg PS, Giri N, Baerlocher GM, Lansdorp PM, Savage SA. Telomere length is associated with disease severity and declines with age in dyskeratosis congenita. Haematologica. 2011 Nov 4. [View Abstract]
  36. Gadalla SM, Katki HA, Shebl FM, Giri N, Alter BP, Savage SA. The Relationship between DNA Methylation and Telomere Length in Dyskeratosis Congenita. Aging Cell. 2011 Oct 8. [View Abstract]
  37. Alawi F, Lee MN. DKC1 is a direct and conserved transcriptional target of c-MYC. Biochem Biophys Res Commun. 2007 Nov 3. 362(4):893-8. [View Abstract]
  38. Jongmans MC, Verwiel ET, Heijdra Y, et al. Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita. Am J Hum Genet. 2012 Mar 9. 90(3):426-33. [View Abstract]
  39. Weidner CI, Lin Q, Birkhofer C, Gerstenmaier U, Kaifie A, Kirschner M, et al. DNA methylation in PRDM8 is indicative for dyskeratosis congenita. Oncotarget. 2016 Mar 8. 7 (10):10765-72. [View Abstract]
  40. 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 Nov. 34(11):1481-5. [View Abstract]
  41. Martínez P, Blasco MA. Telomere-driven diseases and telomere-targeting therapies. J Cell Biol. 2017 Apr 3. 216 (4):875-887. [View Abstract]
  42. Rackley S, Pao M, Seratti GF, et al. Neuropsychiatric conditions among patients with dyskeratosis congenita: a link with telomere biology?. Psychosomatics. 2012 May-Jun. 53(3):230-5. [View Abstract]
  43. Schmitt K, Beier F, Panse J, Brümmendorf TH. [(Pan-)cytopenia as first manifestation of kryptic telomeropathies in adults]. Dtsch Med Wochenschr. 2016 Oct. 141 (21):1578-1580. [View Abstract]
  44. Vettukattil JJ. Is the Hepatic Factor a miRNA that Maintains the Integrity of Pulmonary Microvasculature by Inhibiting the Vascular Endothelial Growth Factor?. Curr Cardiol Rev. 2017. 13 (3):244-250. [View Abstract]
  45. Qureishi A, Lamyman A, Silva P, Cox G. Posterior pharyngeal wall squamous cell carcinoma arising in a patient with dyskeratosis congenita. J Laryngol Otol. 2012 Dec. 126(12):1299-301. [View Abstract]
  46. Gleeson M, O'Marcaigh A, Cotter M, Brosnahan D, Vulliamy T, Smith OP. Retinal vasculopathy in autosomal dominant dyskeratosis congenita due to TINF2 mutation. Br J Haematol. 2012 Dec. 159(5):498. [View Abstract]
  47. Zheng XY, Xu J, Li W, Li SS, Shi CP, Zhao ZY, et al. Frosted Branch Angiitis in Pediatric Dyskeratosis Congenita: A Case Report. Medicine (Baltimore). 2016 Mar. 95 (12):e3106. [View Abstract]
  48. Peene G, Smets E, Legius E, Cassiman C. Unilateral Coats'-like disease and an intragenic deletion in the TERC gene: A case report. Ophthalmic Genet. 2018 Apr. 39 (2):247-250. [View Abstract]
  49. Parchand S, Barwad A. Cytomegalovirus Retinitis as a Presenting Feature of Multisystem Disorder: Dyskeratosis Congenita. Middle East Afr J Ophthalmol. 2017 Oct-Dec. 24 (4):219-221. [View Abstract]
  50. Olson TS, Chan ES, Paessler ME, et al. Liver failure due to hepatic angiosarcoma in an adolescent with dyskeratosis congenita. J Pediatr Hematol Oncol. 2014 May. 36(4):312-5. [View Abstract]
  51. Calado RT, Brudno J, Mehta P, Kovacs JJ, Wu C, Zago MA, et al. Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology. 2011 May. 53(5):1600-7. [View Abstract]
  52. Kamel A, Sayari T, Jellouli M, Hammi Y, Louzir RG, Gargah T. Diffuse Mesangial Sclerosis in a Child With Dyskeratosis Congenita Leading to End-stage Renal Disease. Iran J Kidney Dis. 2016 Nov. 10 (6):416-418. [View Abstract]
  53. Kutbay NO, Yurekli BS, Erdemir Z, Karaca E, Unal I, Yaman B, et al. A case of dyskeratosis congenita associated with hypothyroidism and hypogonadism. Hormones (Athens). 2016 Apr. 15 (2):297-9. [View Abstract]
  54. Penmatsa C, Jampanapalli SR, Bezawada S, Birapu UK, Radharapu VK. Zinsser-Cole-Engman Syndrome: A Rare Case Report. J Clin Diagn Res. 2016 Jun. 10 (6):ZD07-9. [View Abstract]
  55. Walne AJ, Collopy L, Cardoso S, Ellison A, Plagnol V, Albayrak C, et al. Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis. Haematologica. 2016 Oct. 101 (10):1180-1189. [View Abstract]
  56. Güngör Ş, Erdemir AV, Göncü EK, Gürel MS, Özekinci S. A case of dyskeratosis congenita with dermoscopic and reflectance confocal microscopic features. J Am Acad Dermatol. 2015 Jul. 73 (1):e11-3. [View Abstract]
  57. Dokal I, Vulliamy T. Dyskeratosis congenita: its link to telomerase and aplastic anaemia. Blood Rev. 2003 Dec. 17(4):217-25. [View Abstract]
  58. Field JJ, Mason PJ, An P, Kasai Y, McLellan M, Jaeger S. Low frequency of telomerase RNA mutations among children with aplastic anemia or myelodysplastic syndrome. J Pediatr Hematol Oncol. 2006 Jul. 28(7):450-3. [View Abstract]
  59. Alter BP, Baerlocher GM, Savage SA, Chanock SJ, Weksler BB, Willner JP, et al. Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood. 2007 Sep 1. 110(5):1439-47. [View Abstract]
  60. Dokal I, Vulliamy T, Mason P, Bessler M. Clinical utility gene card for: dyskeratosis congenita. Eur J Hum Genet. 2011 Nov. 19(11):[View Abstract]
  61. Elmahadi S, Muramatsu H, Kojima S. Allogeneic hematopoietic stem cell transplantation for dyskeratosis congenita. Curr Opin Hematol. 2016 Nov. 23 (6):501-507. [View Abstract]
  62. Ostronoff F, Ostronoff M, Calixto R, Florêncio R, Domingues MC, Souto Maior AP, et al. Fludarabine, cyclophosphamide, and antithymocyte globulin for a patient with dyskeratosis congenita and severe bone marrow failure. Biol Blood Marrow Transplant. 2007 Mar. 13(3):366-8. [View Abstract]
  63. Nelson AS, Marsh RA, Myers KC, Davies SM, Jodele S, O'Brien TA, et al. A Reduced-Intensity Conditioning Regimen for Patients with Dyskeratosis Congenita Undergoing Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2016 May. 22 (5):884-8. [View Abstract]
  64. Gadalla SM, Sales-Bonfim C, Carreras J, Alter BP, Antin JH, Ayas M, et al. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Dyskeratosis Congenita. Biol Blood Marrow Transplant. 2013 Jun 8. [View Abstract]
  65. Erduran E, Hacisalihoglu S, Ozoran Y. Treatment of dyskeratosis congenita with granulocyte-macrophage colony-stimulating factor and erythropoietin. J Pediatr Hematol Oncol. 2003 Apr. 25(4):333-5. [View Abstract]
  66. Calado RT, Clé DV. Treatment of inherited bone marrow failure syndromes beyond transplantation. Hematology Am Soc Hematol Educ Program. 2017 Dec 8. 2017 (1):96-101. [View Abstract]
  67. 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 Sep. 138(6):815-7. [View Abstract]
  68. Khincha PP, Bertuch AA, Gadalla SM, Giri N, Alter BP, Savage SA. Similar telomere attrition rates in androgen-treated and untreated patients with dyskeratosis congenita. Blood Adv. 2018 Jun 12. 2 (11):1243-1249. [View Abstract]
  69. Hartman RI, Hill-Kayser CE. Proton therapy and radiation sensitivity in dyskeratosis congenita. J Pediatr Hematol Oncol. 2014 Jan. 36(1):e51-3. [View Abstract]
  70. Machado-Pinilla R, Carrillo J, Manguan-Garcia C, et al. Defects in mTR stability and telomerase activity produced by the Dkc1 A353V mutation in dyskeratosis congenita are rescued by a peptide from the dyskerin TruB domain. Clin Transl Oncol. 2012 Oct. 14(10):755-63. [View Abstract]
  71. Serravallo M, Jagdeo J, Glick SA, Siegel DM, Brody NI. Sirtuins in dermatology: applications for future research and therapeutics. Arch Dermatol Res. 2013 May. 305(4):269-82. [View Abstract]
  72. Sinha S, Trivedi V, Krishna A, Rao N. Dyskeratosis congenita- management and review of complications: a case report. Oman Med J. 2013 Jul. 28(4):281-4. [View Abstract]
  73. Bohn OL, Whitten J, Spitzer B, et al. Posttransplant lymphoproliferative disorder complicating hematopoietic stem cell transplantation in a patient with dyskeratosis congenita. Int J Surg Pathol. 2013 Oct. 21(5):520-5. [View Abstract]
  74. Isoda T, Mitsuiki N, Ohkawa T, et al. Irreversible leukoencephalopathy after reduced-intensity stem cell transplantation in a dyskeratosis congenita patient with TINF2 mutation. J Pediatr Hematol Oncol. 2013 May. 35(4):e178-82. [View Abstract]
  75. Shankar RK, Giri N, Lodish MB, Sinaii N, Reynolds JC, Savage SA, et al. Bone mineral density in patients with inherited bone marrow failure syndromes. Pediatr Res. 2017 Sep. 82 (3):458-464. [View Abstract]
  76. Glousker G, Lingner J. When Telomerase Causes Telomere Loss. Dev Cell. 2018 Feb 5. 44 (3):281-283. [View Abstract]
  77. Bongiorno M, Rivard S, Hammer D, Kentosh J. Malignant transformation of oral leukoplakia in a patient with dyskeratosis congenita. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017 Oct. 124 (4):e239-e242. [View Abstract]
  78. Alter BP. Inherited bone marrow failure syndromes: considerations pre- and posttransplant. Blood. 2017 Nov 23. 130 (21):2257-2264. [View Abstract]
  79. Thanos A, Todorich B, Hypes SM, Yonekawa Y, Thomas B, Randhawa S, et al. Retinal vascular tortuosity and exudative retinopathy in a family with dyskeratosis congenita masquerading as familial exudative vitreoretinopathy. Retin Cases Brief Rep. 2017 Winter. 11 Suppl 1:S187-S190. [View Abstract]