Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1
Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1
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DOI：
10.1046/j.1365-2141.1999.01690.x
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发表时间：
1999-11-01
影响因子：
6.5
通讯作者：
Dokal, I
中科院分区：
文献类型：
--
作者：
Knight, SW;Heiss, NS;Dokal, I
Hoyeraal-Hreidarsson（HH）综合征是一种多系统疾病，影响男孩，其特征是再生障碍性贫血（AA），免疫缺陷，小头畸形，小脑发育不全和生长迟缓。其发病机制尚不清楚。X连锁先天性角化不良（DC）是一种遗传性骨髓衰竭综合征，其特征是皮肤色素沉着、指甲营养不良和白斑，通常在生命的前十年末期发展。AA发生在>90%的DC病例中。我们推测，在基因突变负责X-连锁DC（DKC 1）可能占HH综合征，由于疾病之间的表型相似性方面的AA和性别偏见。因此，我们分析了DKC 1基因在两个HH家庭。在一个家族中，在两个受影响的兄弟中发现了外显子5中361位（A->G）的核苷酸变化;在另一个家族中，在受影响的男孩中发现了外显子3中146位（C->T）的核苷酸变化。这两个从不错义的DKC 1突变的发现表明HH是DC的严重变体。他们还表明，DKC 1的突变可以引起非常广泛的临床表现。患有原因不明的AA或免疫缺陷的男孩应检测DKC 1的突变，即使他们可能缺乏DC的诊断特征。
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 never 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.