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

Hoyeraal-Hreidarsson (HH) syndrome is a multisystem disorder affecting boys characterized by aplastic anaemia (AA), immunodeficiency, microcephaly, ce rebellar-hypoplasia and growth retardation. Its pathogenesis is unknown. X- linked dyskeratosis congenita (DC) is an inherited bone-marrow-failure synd rome characterized by skin pigmentation, nail dystrophy and leucoplakia whi ch usually develop towards the end of the first decade of life. AA occurs i n >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 phenoty pic similarities between the disease in respect of AA and gender bias. We t herefore analysed the DKC1 gene in two HH families. In one family a nucleot ide change at position 361(A-->G) in exon 5 was found in both affected brot hers; in the other family a nucleotide change at position 146(C-->T) in exo n 3 was found in the affected boys. The finding of these two never missense DKC1 mutations demonstrates that HH is a severe Variant of DC. They also s how that mutations in DKC1 can give rise to a very wide clinical spectrum o f manifestations. Boys with unexplained AA or immunodeficiency should be te sted for mutations in DKC1 even though they may lack diagnostic features of DC.