Further delineation of the congenital form of X-linked dyskeratosis congenita (Hoyeraal-Hreidarsson syndrome)

Abstract

Hoyeraal-Hreidarsson syndrome represents a severe variant of dyskeratosis congenita (Zinsser-Cole-Engman syndrome). This X-linked recessive, progressive, multisystemic disorder reported so far in 12 pedigrees is characterised by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, mental retardation, progressive combined immune deficiency and aplastic anaemia. Mutations in the DKC1gene on Xq28 have been identified in the X-linked form of dyskeratosis congenita and in some Hoyeraal-Hreidarsson syndrome patients. We report on two sibs and two other unrelated patients with the striking clinical features of Hoyeraal-Hreidarsson syndrome. Noticeably, all four had early digestive problems, with chronic, bloody diarrhoea and feeding problems causing one of the most difficult problems in the supportive treatment of this uniformly lethal condition. Pathological changes in the proliferative compartment of the digestive mucosa included alterations of the glandular architecture and focal rarefaction of the glands. This aspect seems consistent with altered telomerase function associated with a dyskerin mutation which may decrease the proliferative capacity of digestive epithelial cells. A missense mutation 146 C-->T (Thr49Met) in the DKC1gene was found in two unrelated patients, whereas mutation screening was negative for one single case. The absence of mutations of the DKC1gene in patients with Hoyeraal-Hreidarsson syndrome emphasises the probable implication of one or more other loci.

Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis

“…Telomere length in PBMCs is associated with longevity (38). Inherited defects in telomere maintenance, e.g., in dyskeratosis congenita, lead to BM failure (39,40) and progressive combined immunodeficiency (41). In RA patients, telomeres of mature CD4ϩ T cells are shortened by 1,000-1,500 bp, a defect already present in naive cells untouched by immune responses.…”

Dyskeratosis Congenita - A Disease of Dysfunctional Telomere Maintenance

“…Mutations in DKC1 may be inherited or occur de novo during early embryogenesis or reflect maternal germ cell mosaicism. Mutations have also been identified in patients with HHS, establishing that HHS is a severe variant of DC [14,[16][17][18].…”

“…immunodeficiency, growth retardation, and gut abnormalities, and these patients usually die before the age of 5 years [12][13][14]. DC is a rare inherited condition recognized by the classical diagnostic triad of reticular pigmentation of the skin, nail dystrophy, and mucosal leukoplakia [1][2][3].…”

The role of telomere biology in bone marrow failure and other disorders

“…Additional features include epiphora, blepharitis, premature gray hair, alopecia, developmental delay, short stature, cerebellar hypoplasia, microcephaly, esophageal stenosis, urethral stenosis, pulmonary fibrosis, liver disease, avascular necrosis of hips or shoulders, epithelial cancers, myelodysplastic syndrome (MDS), and leukemia (Alter 2005;Walne et al 2005;Yamaguchi 2007). Hoyeraal-Hreidarsson (HH) Syndrome is a severe form of DC with BMF, immunodeficiency, microcephaly, cerebellar hypoplasia, intrauterine growth retardation, and developmental delay (Sznajer et al 2003;Vulliamy et al 2006). Revesz Syndrome, characterized by bilateral exudative retinopathy, bone marrow hypoplasia, nail dystrophy, fine hair, cerebellar hypoplasia, and growth retardation, also appears to be in the DC disease spectrum (Kajtar and Mehes 1994;Revesz et al 1992).…”