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Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal‐Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1
Author(s) -
Knight S. W.,
Heiss N. S.,
Vulliamy T. J.,
Aalfs C. M.,
McMahon C.,
Richmond P.,
Jones A.,
Hennekam R. C. M.,
Poustka A.,
Mason P. J.,
Dokal I.
Publication year - 1999
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.1999.01690.x
Subject(s) - dyskeratosis congenita , microcephaly , bone marrow failure , missense mutation , immunodeficiency , genetics , aplastic anemia , mutation , biology , immunology , telomere , gene , bone marrow , haematopoiesis , immune system , stem cell
Hoyeraal‐Hreidarsson (HH) syndrome is a multisystem disorder affecting boys characterized by aplastic anaemia (AA), immunodeficiency, microcephaly, cerebellar‐hypoplasia 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 first 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 finding 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 immunodeficiency should be tested for mutations in DKC1 even though they may lack diagnostic features of DC.