Dyskeratosis congenita (DKC) is a bone marrow failure syndrome characterized by severely shortened telomeres and diverse clinical symptoms. The classic presentation of DKC includes nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) is a severe ... Dyskeratosis congenita (DKC) is a bone marrow failure syndrome characterized by severely shortened telomeres and diverse clinical symptoms. The classic presentation of DKC includes nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) is a severe clinical variant of DKC that is characterized by intrauterine growth failure, microcephaly, developmental delay, immunodeficiency, bone marrow failure, and cerebellar hypoplasia. Patients with mutations in the RTEL1 gene tend to present with HHS (summary by Walne et al., 2013). For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).
Lamm et al. (2009) reported a family in which 4 sibs, born of unrelated European parents, presented with Hoyeraal-Hreidarsson syndrome. The patients had nail dystrophy, leukoplakia, bone marrow failure, severe ... - Autosomal Recessive Dyskeratosis Congenita 5 Lamm et al. (2009) reported a family in which 4 sibs, born of unrelated European parents, presented with Hoyeraal-Hreidarsson syndrome. The patients had nail dystrophy, leukoplakia, bone marrow failure, severe B-cell immunodeficiency, intrauterine growth retardation, growth retardation, microcephaly, cerebellar hypoplasia, and esophageal dysfunction. Three of the sibs died between ages 3 and 7 years, whereas the fourth was alive at age 22 years following bone marrow transplantation. A paternal great-uncle died of pulmonary fibrosis at age 58 years. Telomere length in patient leukocytes was shorter than controls, but telomere length in fibroblasts was normal. Telomere lengths in blood cells derived from the parents and paternal grandfather were also shortened. Patient leukocytes and fibroblasts showed impaired growth in culture and early senescence. A significant fraction of telomeres in patient fibroblasts showed activation of the DNA damage response (DDR), an indication of their uncapped state. In addition, telomeric 3-prime overhangs were diminished in patient blood cells and fibroblasts, consistent with a defect in telomere structure. Since telomerase activity was normal, Lamm et al. (2009) hypothesized that the defect in telomere maintenance in these cells resulted in a defect in the recruitment or activation of telomerase, not in its catalytic core. The telomere shortening also likely activates the DDR and impairs cell proliferation, even in cells with normal telomere length such as fibroblasts. Walne et al. (2013) reported 10 patients from 7 unrelated families with severe autosomal recessive DKC manifest clinically as HHS, including the family previously reported by Lamm et al. (2009). The phenotype was relatively homogeneous and included onset in early childhood of global bone marrow failure and immunodeficiency mainly affecting the B cell lineage. Most, but not all, patients had microcephaly, intrauterine and extrauterine growth retardation, developmental delay, and cerebellar hypoplasia. None had abnormal skin pigmentation, and less than half had nail dystrophy or leukoplakia. Telomere lengths were significantly shorter compared to controls. Deng et al. (2013) also studied the family with HHS previously reported by Lamm et al. (2009) and Walne et al. (2013). The fourth sib had died of pulmonary fibrosis after successful bone marrow transplantation. Telomeres in blood cells derived from the patients were severely shortened, and cultured lymphoblastoid cell lines showed progressive telomere shortening until reaching senescence, despite the presence of active telomerase. Primary fibroblasts had normal average telomere length, but showed telomere dysfunction-induced foci and grew much slower than normal fibroblasts. Ectopic expression of TERT (187270) failed to stabilize telomere length and prevent senescence of patient fibroblasts. Le Guen et al. (2013) reported 3 patients, including 2 sibs, with severe DKCB5 manifest as Hoyeraal-Hreidarsson syndrome. All had intrauterine growth retardation diagnosed between 19 and 21 weeks of gestation, and all showed low birth weight and length as well as microcephaly. All patients had cerebellar atrophy on brain imaging; 1 also had a dysmorphic corpus callosum. Laboratory studies showed bone marrow failure with immunodeficiency, including lymphopenia, hypogammaglobulinemia, anemia, and thrombocytopenia. Two patients had oral leukoplakia and diarrhea, one of whom developed pancolitis and esophageal stenosis. Two patients died of infection in early childhood. The third child was alive at age 5 years. The cellular phenotype in these patients consisted of short telomeres and hallmarks of genomic instability, including spontaneous DNA damage, anaphase bridges, telomeric aberrations, and accelerated cellular senescence, consistent with defective DNA replication and repair. Ballew et al. (2013) reported an 8-year-old boy with severe DKCB5 manifest as Hoyeraal-Hreidarsson syndrome. He had the classic triad of DKC, including nail dystrophy, abnormal skin pigmentation, and oral leukoplakia, as well as microcephaly, speech and developmental delay, cerebellar hypoplasia, esophageal stricture, bone marrow failure, and decreased telomere lengths. - Autosomal Dominant Dyskeratosis Congenita 4 Ballew et al. (2013) provided evidence for autosomal dominant DKC due to heterozygous RTEL1 mutations. In 1 family the heterozygous sib of a patient with autosomal recessive DKC/Hoyeraal-Hreidarsson syndrome had hypocellular bone marrow and short telomeres, but no additional features of the disorder. The authors recommended monitoring of the boy for the development of DKC-related complications. Their mother, who was heterozygous for the same pathogenic mutation, also had shortened telomeres. In a second family, 2 brothers had Hoyeraal-Hreidarsson syndrome associated with a heterozygous RTEL1 mutation (R1010X; 608833.0012). Their mother, who also carried the heterozygous mutations, was clinically unaffected, but had short telomeres. Ballew et al. (2013) postulated genetic anticipation in this family. In a third family, a 25-year-old man with autosomal dominant dyskeratosis congenita-4 due to a heterozygous RTEL1 mutation (A645T; 608833.0013) had mild developmental delay, learning difficulties, ADHD, depression, short stature, bone marrow failure, and short telomeres. His sister had nail dysplasia, short stature, and dental caries. These findings suggested that RTEL1 mutations can be pathogenic in the heterozygous state. Lamm et al. (2009) and Deng et al. (2013) reported that a relative of sibs with biallelic RTEL1 mutations, who carried a heterozygous mutation (M492I; 608833.0003), died of pulmonary fibrosis at age 58 years.
In 10 patients from 7 families with severe autosomal recessive dyskeratosis congenita, Walne et al. (2013) identified 11 different mutations in the RTEL1 gene (see, e.g., 608833.0001-608833.0006). The initial mutations were identified ... - Biallelic RTEL1 Mutations In 10 patients from 7 families with severe autosomal recessive dyskeratosis congenita, Walne et al. (2013) identified 11 different mutations in the RTEL1 gene (see, e.g., 608833.0001-608833.0006). The initial mutations were identified by exome sequencing of 1 family. The remaining 6 families, including a family originally reported by Lamm et al. (2009), were found from a larger cohort of 23 families with a similar phenotype. All mutations segregated with the disease in an autosomal recessive pattern of inheritance. The patients had significantly higher levels of telomeric circles, produced as a consequence of incorrect processing of telomere ends, compared to controls. The report supported a disease-causing mechanism that results in the shortening of telomeres without impacting the function of the telomerase complex. No RTEL1 mutations were found in 102 index cases with milder forms of dyskeratosis congenita or related bone marrow-failure syndromes, suggesting that RTEL1 mutations are specific for the severe phenotype. In 3 patients, including 2 sibs, with DKCB5 manifest as Hoyeraal-Hreidarsson syndrome, Le Guen et al. (2013) identified compound heterozygous mutations in the RTEL1 gene (608833.0007-608833.0010). The mutations, which were found by whole-genome linkage analysis combined with whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. None of the mutations were found in the dbSNP, Exome Variant Server, or 1000 Genomes databases or in 160 in-house control exomes. In a boy with severe DKCB5 manifest as Hoyeraal-Hreidarsson syndrome, Ballew et al. (2013) identified compound heterozygous mutations in the RTEL1 gene R998X (608833.0004) and E615D (608833.0011). The mutations were found by whole-exome sequencing and were not present in several large control databases, including UCSC GoldenPath, Exome Variant Server, KAVIAR, dbSNP, and 1000 Genomes, or in 366 in-house exomes. - Heterozygous RTEL1 Mutations In 2 brothers with severe autosomal dominant dyskeratosis congenita manifest as Hoyeraal-Hreidarsson syndrome, Ballew et al. (2013) identified a heterozygous mutation in the RTEL1 gene (R1010X; 608833.0012). The mutation, which was identified by whole-exome sequencing, was also present in the clinically unaffected mother, who had shortened telomeres. The mutation was found to have a minor allele frequency of 0.015% in the Exome Sequencing Project database, but was not found in the 1000 Genomes, Kaviar, or dbSNP databases. Ballew et al. (2013) identified a heterozygous mutation in the RTEL1 gene (E615D; 608833.0011) in the mother and brother of a boy with HHS due to biallelic RTEL1 mutations. The mother and brother were clinically unaffected, but both had shortened telomeres. The brother also had hypocellular bone marrow and was being followed for development of DKC. The findings suggested that heterozygosity for the E615D mutation may also cause certain disease manifestations, consistent with autosomal dominant inheritance. In a 25-year-old man with autosomal dominant dyskeratosis congenita-4, Ballew et al. (2013) identified a heterozygous mutation in the RTEL1 gene (A645T; 608833.0013). His sister had nail dysplasia, short stature, and dental caries, but DNA was not available from her or from the parents.