Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal‐Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1

Abstract

Summary. Hoyeraal-Hreidarsson (HH) syndrome is a multisystem disorder affecting boys characterized by aplastic anaemia (AA), immunode®ciency, microcephaly, cerebellarhypoplasia and growth retardation. Its pathogenesis is unknown. X-linked dyskeratosis congenita (DC) is an inherited bone-marrow-failure syndrome characterized by skin pigmentation, nail dystrophy and leucoplakia which usually develop towards the end of the ®rst decade of life. AA occurs in >90% of cases of DC. We speculated that mutations in the gene responsible for X-linked DC (DKC1) may account for the HH syndrome, due to the phenotypic similarities between the disease in respect of AA and gender bias. We therefore analysed the DKC1 gene in two HH families. In one family a nucleotide change at position 361(A ! G) in exon 5 was found in both affected brothers; in the other family a nucleotide change at position 146(C ! T) in exon 3 was found in the affected boys. The ®nding of these two novel missense DKC1 mutations demonstrates that HH is a severe variant of DC. They also show that mutations in DKC1 can give rise to a very wide clinical spectrum of manifestations. Boys with unexplained AA or immunode®ciency should be tested for mutations in DKC1 even though they may lack diagnostic features of DC.

Telomerase in the human organism

“…Because of the early mortality, typically within the ®rst few years of life, the cutaneous features of DKC may not develop with the same penetrance in HHS. Three missense mutations in the dyskerin gene have been identi®ed in patients with HHS (Knight et al, 1999;Yaghmai et al, 2000). One results in a conservative S121G substitution within the region of dyskerin homologous to TruB family pseudouridine synthases, a substitution not detected in DKC patients (Knight et al, 1999).…”

Unrelated cord blood transplantation in a girl with Hoyeraal–Hreidarsson syndrome

“…1 We report the case of a 40-month-old girl with classical features of HHS, including cerebellar hypoplasia, oral ulceration and BM failure. She is the 19th case of HHS and only the 4th female reported in the medical literature.…”

“…This particular patient encountered prompt and sustained engraftment, from an HLAmatched elder sibling donor, at the time of publication 1-year post-BMT. 7 Knight et al 1 report the use of an unrelated BMT in a 23-month-old boy; unfortunately, no information was provided regarding the conditioning regimen. At the time of publication, this patient was still alive 37 months post-BMT and experiencing significant medical and developmental complications of the underlying condition and the immune reconstitution process.…”

“…[1][2][3][4] HHS creates significant mortality and morbidity, with BM failure and immunodeficiency being the most serious manifestation of the condition, occurring in over 80% of patients. The natural history of HHS is that of death secondary to complications of BM failure or infection that usually occurs in the first decade of life.…”

“…1,7,8 Cossu et al 7 chose a non-BU, non-TBI-containing regimen consisting of fludarabine, rabbit antithymocyte globulin and low-dose melphalan. This particular patient encountered prompt and sustained engraftment, from an HLAmatched elder sibling donor, at the time of publication 1-year post-BMT.…”