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The main cause of mortality, usually in early childhood, is bone marrow failure. Mutations in several telomere biology genes have been reported to cause <jats:styled-content style=\"fixed-case\">HH<\/jats:styled-content> in about 60% of the <jats:styled-content style=\"fixed-case\">HH<\/jats:styled-content> patients, but the genetic defects in the rest of the patients are still unknown. Understanding the aetiology of <jats:styled-content style=\"fixed-case\">HH<\/jats:styled-content> and its diverse manifestations is challenging because of the complexity of telomere biology and the multiple telomeric and non\u2010telomeric functions played by telomere\u2010associated proteins in processes such as telomere replication, telomere protection, <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> damage response and ribosome and spliceosome assembly. Here we review the known clinical complications, molecular defects and germline mutations associated with <jats:styled-content style=\"fixed-case\">HH<\/jats:styled-content>, and elucidate possible mechanistic explanations and remaining questions in our understanding of the disease.<\/jats:p>","DOI":"10.1111\/bjh.13442","type":"journal-article","created":{"date-parts":[[2015,5,5]],"date-time":"2015-05-05T05:12:50Z","timestamp":1430802770000},"page":"457-471","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":138,"title":["Unraveling the pathogenesis of Hoyeraal\u2013Hreidarsson syndrome, a complex telomere biology disorder"],"prefix":"10.1111","volume":"170","author":[{"given":"Galina","family":"Glousker","sequence":"first","affiliation":[{"name":"Department of Genetics The Silberman Institute of Life Sciences Hebrew University of Jerusalem Jerusalem 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