Dyskeratosis congenita

Panel testing recommended at Breda Genetics for this condition:

Congenital dyskeratosis and differential diagnosis (ACD, CTC1, DKC1, NHP2, NOP10, PARN, POT1, RETL1, SNORD118, TERC, TERT, TINF2, WRAP53)


Dyskeratosis congenita (DC), also called Zinsser-Cole-Engman syndrome, is a multisystem disorder due to telomere loss. All affected individuals have a telomeric shortening increased in relation to age. The disease was first described by Zinsser in 1906, and is characterized by:

  • genodermatosis, manifesting with the classic mucocutaneous clinical triad of nail dystrophy, skin pigmentation abnormalities and oral leukoplakia;
  • bone marrow failure. Individuals with dyskeratosis congenita have an increased risk of developing myelodysplastic syndromes, leukemia, solid tumors and pulmonary fibrosis.

The phenotype is variable and other abnormalities may be present. Bone marrow failure is the leading cause of early death, along with a predisposition to tumor lesions and fatal pulmonary complications.
Currently 11 genes are associated with dyskeratosis congenita, and the modes of inheritance can be autosomal dominant, recessive or X-linked, depending on the mutated gene.

Detailed clinical description

The mucocutaneous triad is typical of the classical forms of dyskeratosis congenita. Nails can be thin, underdeveloped and chipped. In severe cases, they may disappear with the advancement of the disease and age. In other cases, the dermatoglyphics may disappear. Pigmentation anomalies mainly affect the neck and chest with the presence of cross-linked hyper- or hypo-pigmentation, which can worsen with age. The formation of white plaques in the oral cavity may be the clinical sign of onset or develop only when the disease progresses.
Bone marrow failure is one of the most frequent clinical signs at onset, it can develop at any age and can progress over time. Affected individuals have a high risk of developing leukemia and solid tumors, particularly squamous cell carcinoma of the neck and head, and anorectal adenocarcinomas. Solid tumors can be a clinical sign of onset in individuals who do not show bone marrow failure.

Other clinical signs include eye abnormalities (such as epiphora, blepharitis, eyelash abnormalities), alopecia, early onset gray hair, tooth abnormalities (periodontal diseases, taurodontism), psychomotor retardation, short stature, microcephaly, hypogonadism, esophageal and urethral stenosis, osteoporosis, liver disease. These additional signs, however, are not present in all patients or may appear and worsen only with advancing age. More rarely, heart defects or deafness are observed.

Two forms of congenital dyskeratosis with more severe clinical pictures are Hoyeraal Hreidarsson syndrome and Revesz syndrome, both with onset in early childhood. In the first form, in addition to the classic picture of congenital dyskeratosis, cerebellar hypoplasia is present, often with psychomotor retardation, immunodeficiency and intrauterine growth retardation. The second form presents with additional signs of bilateral exudative retinopathy and, in the first cases described, patients also presented with intracranial calcifications, intrauterine growth retardation, alopecia, and brittle hair. Patients with these two forms have shorter telomeres than patients with classic dyskeratosis congenita.

Telomere shortening quantification test is performed using the flow-FISH methodology on patient lymphocytes. A telomere length below the first percentile for the patient’s age is a result supporting the diagnosis of dyskeratosis congenita with a sensitivity of 97% and a specificity of 91%.

The presence of the characteristic clinical signs in an affected individual, with shortening of telomeres and/or with the identification of a pathogenic variant in one of the genes associated with dyskeratosis congenita is sufficient to establish the diagnosis.

Prevalence and penetrance

In 2015, some estimates reported at least 400 families worldwide with members affected by the disease. Prevalence on Orphanet is estimated at 1-9 in 1,000,000. Since DKC1, the most frequently mutated gene, is located on the X chromosome, the most common mode of inheritance is X-linked and with males to females ratio of about 3:1. Female carriers of the X-linked mutations have a milder phenotype, although severe cases are also described.
Considering the variability between affected individuals (including intra-family) and that complications can increase with age, penetrance appears to be incomplete.

Molecular genetics

At present, the genes associated with dyskeratosis congenita are ACD, CTC1, DKC1, NHP2, NOP10, PARN, RETL1, TERC, TERT, TINF2 and WRAP53. Mutations in these genes were found in 70% of individuals with a clinical diagnosis of the disease. All of these genes encode proteins or transcribe RNA that play a role in the process of maintaining and stabilizing the ends of chromosomes.

Dyskeratosis congenita caused by mutations in the DKC1 gene is transmitted in an X-linked manner. Pathogenic mutations in this gene have been identified in 20% -25% of cases. The gene encodes dyskerin, a nucleolar protein found in small nucleolar ribonucleoproteins (snoRP). SnoRPs modify specific uridine residues of ribosomal RNA into pseudouridine, stabilizing the entire molecule. It is also a component of the telomerase complex. Most of the mutations are missense and occur along the entire coding sequence of the gene. Individuals with mutations in the DCK1 gene may also have a typical picture of Hoyeraal Hreidarsson syndrome.

Dyskeratosis congenita caused by mutations in the TINF2 gene is autosomal dominant. Pathogenic variants in this gene were identified in 12% -20% of cases. The coded protein is a subunit of the shelterin complex that protects the integrity of telomeres, influencing their structure and length. The mutations identified so far are clustered in exon 6 and are mainly missense. Mutations in this gene can give even the most severe picture of Revesz or Hoyeraal Hreidarsson syndrome. Some patients with a mutation in this gene develop aplastic anemia within ten years of age; other individuals with heterozygous mutations may be asymptomatic.

Dyskeratosis congenita caused by mutations in the TERC gene is inherited in an autosomal dominant manner. Pathogenic variants in this gene were identified in 5% -10% of cases. The gene transcribes the RNA component of telomerase. The mutations reported so far are single nucleotide changes and small deletions.
The forms of DC associated with mutations in this gene show great variability in the severity of the clinical picture. Tissue-restricted mosaicism has been found in a limited number of patients heterozygous for a mutation in this gene. In particular, the mutation has not been identified in peripheral blood cells, but is present in DNA extracted from other cells (eg, fibroblasts). The assumption is that this type of mosaicism results from a reverse mutation in peripheral blood cells that involves the loss of the allele with the mutation, especially in patients with congenital dyskeratosis but without bone marrow failure. It is plausible that a selective advantage of revertant hematopoietic cells allows them to more successfully populate the bone marrow, resulting in the impossibility of detecting the pathogenic variant in the DNA extracted from these cells.

Dyskeratosis congenita caused by mutations in the RETL1 gene can be autosomal dominant or autosomal recessive. Pathogenic variants in this gene have been identified in 2% -8% of cases. The gene encodes a DNA helicase which plays a crucial role in maintaining telomere structure and DNA repair. The mutations reported so far are missense and deletions, including a large deletion that involves the loss of the entire exon 15.

Dyskeratosis congenita associated with TERT mutation is transmitted in an autosomal dominant or recessive manner. Pathogenic variants in this gene have been identified in 1% -7% of cases. The gene encodes the catalytic subunit of telomerase. The mutations reported so far are missense, stopgain, frameshift and small deletions and are distributed throughout the whole gene. Individuals with a heterozygous mutation may present with bone marrow failure or isolated pulmonary fibrosis in adulthood, and present the least severe clinical pictures of all forms of the disease. However, individuals with biallelic mutations in the same gene may present with typical pictures of Hoyeraal Hreidarsson syndrome.

Dyskeratosis congenita caused by mutations in the CTC1 gene is autosomal recessive. Pathogenic variants in this gene are identified in 1% -3% of cases. The gene encodes a subunit of the accessory factor-alpha that stimulates the activity of DNA-polymerase α-primase, an enzyme involved in triggering DNA replication. It is also involved in a complex associated with telomeres along with STN1 and TEN1. Most of the mutations found are missense, deletions and frameshift. Affected individuals with mutations in this gene may have a clinical picture without the triad of the classic form of dyskeratosis congenita, but more often they have cytopenia, intracranial calcifications, cysts, ataxia, osteopenia, and intrauterine growth retardation.

More rarely, mutations have been found in the genes ACD (AD or AR inheritance), NHP2 (AR inheritance), NOP10 (AR inheritance), PARN (AD or AR inheritance) and WRAP53 (AD or AR inheritance).

In general, patients with mutations in the DKC1, TINF2, and biallelic mutations in the PARN, RTEL1 and ACD genes have more complex phenotypes than patients with mutations in other genes.
Individuals with dominant dyskeratosis congenita caused by mutations in the RTEL1 and ACD genes can clinically manifest the disease later than patients with the recessive forms associated with the same genes.
Patients for whom mutations in the aforementioned genes have not been identified often have the most severe phenotypes, including Hoyeraal Hreidarsson syndrome and Revesz syndrome.

Differential diagnosis

Considering the classic presentation of congenital dyskeratosis characterized primarily by the mucocutaneous triad, some disorders with similar clinical signs are hereditary osteo-onychodysplasia, total onychodystrophy, and keratoderma with nail dystrophy and motor-sensory neuropathy.

In cases of congenital dyskeratosis where the presenting clinical sign is bone marrow failure, the differential diagnosis can include Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome.

The differential diagnosis may also include acquired aplastic anemia, which is often caused by immune-mediated destruction of hematopoietic stem cells leading to pancytopenia. It is often progressive and can occur at any age. Telomere length quantification test can help identify individuals with aplastic anemia and dyskeratosis congenita.

Idiopathic pulmonary fibrosis, which is the most common form of idiopathic interstitial pneumonia and causes progressive pulmonary fibrosis. Individuals with dyskeratosis congenita can develop idiopathic pulmonary fibrosis and it is plausible that the latter may be the first manifestation of the disease in young individuals.

Genetic testing strategy

The most suitable choice for pursuing genetic confirmation is certainly the next generation sequencing panel analysis that includes the ACD, CTC1, DKC1, NHP2, NOP10, PARN, RETL1, TERC, TERT, TINF2 and WRAP53 genes. For patients descended from Ashkenazi Jews it is possible to proceed with a specific analysis for the mutation c.3791G>A (p.Arg1264His) in the RTEL1 gene in the first instance. In the event of negative results, large deletions/duplication testing can be carried out in the genes of the panel.

To date, genetic confirmation is obtained in about 70% of clinical cases. Panel analysis can be performed successfully on the basis of whole exome or whole genome sequencing, which can pave the way for the identification of mutations in genes not yet associated with the disease. Solutions based on whole genome sequencing also allow for the screening of copy number variations (CNVs), i.e. large deletions and large duplications on the entire genome.

Panel testing recommended at Breda Genetics for this condition:

Congenital dyskeratosis and differential diagnosis (ACD, CTC1, DKC1, NHP2, NOP10, PARN, POT1, RETL1, SNORD118, TERC, TERT, TINF2, WRAP53)


Dyskeratosis Congenita. Savage SA. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2009 Nov 12 [updated 2016 May 26]. PMID: 20301779

Dyskeratosis Congenita. Garofola C, Gross GP. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018-. 2018 Oct 27. PMID: 29939532

Telomeres in health and disease. Chatterjee S. J Oral Maxillofac Pathol. 2017 Jan-Apr;21(1):87-91. PMID: 28479693

Telomere-driven diseases and telomere-targeting therapies. Martínez P, Blasco MA. J Cell Biol. 2017 Apr 3;216(4):875-887. PMID: 28254828

Evaluation and Management of Hematopoietic Failure in Dyskeratosis Congenita. Agarwal S. Hematol Oncol Clin North Am. 2018 Aug;32(4):669-685. PMID: 30047419

The genomics of inherited bone marrow failure: from mechanism to the clinic. Wegman-Ostrosky T, Savage SA. Br J Haematol. 2017 May;177(4):526-542. PMID: 28211564

Aplastic anemia. Young NS, Scheinberg P, Calado RT. Curr Opin Hematol. 2008 May;15(3):162-8. PMID: 18391779

OMIM: 300126

Orphanet: ORPHA1775

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