Name: Autosomal recessive dyskeratosis congenita-5 | Acronym: DKCB5
Alt. names: Dyskeratosis congenita, autosomal recessive 5

Gene: RTEL1 | MOI: Autosomal recessive | Mechanism of action:

No. of cases in DB: 0 | First reported in: 2013

Last updated on: 2023-05-26 09:32:13 by

OMIM: 615190

Orphanet: 1775

MONDO: -

DOID: -

ClinGen:

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.

Description of management option has not been reviewed yet.