title: Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1.
abstract: 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.
authors.affiliation: Department of Haematology, Imperial College School of Medicine, Hammersmith Hospital, London, U.K.
authors.forename: S W
authors.initials: SW
authors.lastname: Knight
authors.forename: N S
authors.initials: NS
authors.lastname: Heiss
authors.forename: T J
authors.initials: TJ
authors.lastname: Vulliamy
authors.forename: C M
authors.initials: CM
authors.lastname: Aalfs
authors.forename: C
authors.initials: C
authors.lastname: McMahon
authors.forename: P
authors.initials: P
authors.lastname: Richmond
authors.forename: A
authors.initials: A
authors.lastname: Jones
authors.forename: R C
authors.initials: RC
authors.lastname: Hennekam
authors.forename: A
authors.initials: A
authors.lastname: Poustka
authors.forename: P J
authors.initials: PJ
authors.lastname: Mason
authors.forename: I
authors.initials: I
authors.lastname: Dokal
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000741:Anemia, Aplastic / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities*; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D007223:Infant; D008297:Male; D008831:Microcephaly / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D013577:Syndrome
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins