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.
