title: Further delineation of the congenital form of X-linked dyskeratosis congenita (Hoyeraal-Hreidarsson syndrome).
abstract: Hoyeraal-Hreidarsson syndrome represents a severe variant of dyskeratosis congenita (Zinsser-Cole-Engman syndrome). This X-linked recessive, progressive, multisystemic disorder reported so far in 12 pedigrees is characterised by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, mental retardation, progressive combined immune deficiency and aplastic anaemia. Mutations in the DKC1gene on Xq28 have been identified in the X-linked form of dyskeratosis congenita and in some Hoyeraal-Hreidarsson syndrome patients. We report on two sibs and two other unrelated patients with the striking clinical features of Hoyeraal-Hreidarsson syndrome. Noticeably, all four had early digestive problems, with chronic, bloody diarrhoea and feeding problems causing one of the most difficult problems in the supportive treatment of this uniformly lethal condition. Pathological changes in the proliferative compartment of the digestive mucosa included alterations of the glandular architecture and focal rarefaction of the glands. This aspect seems consistent with altered telomerase function associated with a dyskerin mutation which may decrease the proliferative capacity of digestive epithelial cells. A missense mutation 146 C-->T (Thr49Met) in the DKC1gene was found in two unrelated patients, whereas mutation screening was negative for one single case. The absence of mutations of the DKC1gene in patients with Hoyeraal-Hreidarsson syndrome emphasises the probable implication of one or more other loci.
authors.affiliation: Clinical Genetics Unit, INSERM E9935, Hôpital Robert Debré, 48 boulevard Sérurier, 75019, Paris, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Sznajer
authors.forename: Clarisse
authors.initials: C
authors.lastname: Baumann
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Hubert
authors.initials: H
authors.lastname: Journel
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: Yves
authors.initials: Y
authors.lastname: Perel
authors.forename: Pascale
authors.initials: P
authors.lastname: Blouin
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Segura
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Cezard
authors.forename: Michel
authors.initials: M
authors.lastname: Peuchmaur
authors.forename: Tomy
authors.initials: T
authors.lastname: Vulliamy
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D003967:Diarrhea / Q000209:etiology* / Q000473:pathology; D019871:Dyskeratosis Congenita / Q000150:complications* / Q000235:genetics*; D015154:Esophageal Motility Disorders / Q000209:etiology; D006801:Humans; D007231:Infant, Newborn; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D013577:Syndrome
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins