On the nosology and pathogenesis of Wolf–Hirschhorn syndrome: Genotype–phenotype correlation analysis of 80 patients and literature review

Authors

  • Marcella Zollino,

    Corresponding author
    • Istituto di Genetica Medica, Università Cattolica Sacro Cuore, Policlinico “A. Gemelli”, L.go F. Vito, 1, 00168 Roma, Italy.
    Search for more papers by this author
    • Marcella Zollino, M.D., is Associate Professor in the Department of Medical Genetics, at Università Cattolica Sacro Cuore, Roma. Areas of expertise are clinical dysmorphology and clinical cytogenetics, mainly in the fields of Wolf–Hirschhorn syndrome, Ring 14 syndrome, MCA/MR syndromes associated with cryptic chromosome abnormalities, and haploinsufficiency syndromes. She is involved in evaluation and application of techniques for molecular karyotyping, including FISH, and array-CGH.

  • Marina Murdolo,

    Search for more papers by this author
    • Marina Murdolo, Ph.D., works at the Department of Medical Genetics at Università Cattolica del Sacro Cuore, Roma. Areas of expertise are molecular karyotyping techniques and DNA sequencing analysis, mainly in the field of Wolf–Hirschhorn syndrome.

  • Giuseppe Marangi,

    Search for more papers by this author
    • Giuseppe Marangi, M.D., is a resident in Medical Genetics at Università Cattolica del Sacro Cuore, Roma. His clinical and research interests include clinical dysmorphology and MCA/MR conditions caused by cryptic chromosome anomalies.

  • Vanna Pecile,

    Search for more papers by this author
    • Vanna Pecile, Ph.D., works as cytogeneticist at IRCCS Burlo Garofalo, Trieste. Her area of expertise is pre- and postnatal cytogenetics, including molecular karyotyping techniques.

  • Cinzia Galasso,

    Search for more papers by this author
    • Cinzia Galasso, M.D., is Associated Professor in the Department of Neuroscience, Paediatric Neurology Unit at Università di Tor Vergata, Roma. Her clinical and research interests are neurogenetics syndromes with mental retardation.

  • Laura Mazzanti,

    Search for more papers by this author
    • Laura Mazzanti, M.D., is Associate Professor in the Department of Obstetrics, Gynecology and Paediatrics at Università di Bologna. Her clinical and research interests include clinical dysmorphology and Turner syndrome.

  • Giovanni Neri

    Search for more papers by this author
    • Giovanni Neri, M.D., is Head of the Department of Medical Genetics, at Università Cattolica Sacro Cuore, Roma. Specific areas of expertise are X-linked mental retardation, Ring 14 syndrome, Costello-Noonan-CFC syndromes and clinical dysmorphology. As Head of the Department, he is involved in all the research and clinical activities in the Department.


  • How to cite this article: Zollino M, Murdolo M, Marangi G, Pecile V, Galasso C, Mazzanti L, Neri G. 2008. On the nosology and pathogenesis of Wolf–Hirschhorn syndrome: Genotype–phenotype correlation analysis of 80 patients and literature review. Am J Med Genet Part C Semin Med Genet.

Abstract

Based on genotype–phenotype correlation analysis of 80 Wolf–Hirschhorn syndrome (WHS) patients, as well as on review of relevant literature, we add further insights to the following aspects of WHS: (1) clinical delineation and phenotypic categories; (2) characterization of the basic genomic defect, mechanisms of origin and familiarity; (3) identification of prognostic factors for mental retardation; (4) chromosome mapping of the distinctive clinical signs, in an effort to identify pathogenic genes. Clinically, we consider that minimal diagnostic criteria for WHS, defining a “core” phenotype, are typical facial appearance, mental retardation, growth delay and seizures (or EEG anomalies). Three different categories of the WHS phenotype were defined, generally correlating with the extent of the 4p deletion. The first one comprises a small deletion not exceeding 3.5 Mb, that is usually associated with a mild phenotype, lacking major malformations. This category is likely under-diagnosed. The second and by far the more frequent category is identified by large deletions, averaging between 5 and 18 Mb, and causes the widely recognizable WHS phenotype. The third clinical category results from a very large deletion exceeding 22–25 Mb causing a severe phenotype, that can hardly be defined as typical WHS. Genetically, de novo chromosome abnormalities in WHS include pure deletions but also complex rearrangements, mainly unbalanced translocations. With the exception of t(4p;8p), WHS-associated chromosome abnormalities are neither mediated by segmental duplications, nor associated with a parental inversion polymorphism on 4p16.3. Factors involved in prediction of prognosis include the extent of the deletion, the occurrence of complex chromosome anomalies, and the severity of seizures. We found that the core phenotype maps within the terminal 1.9 Mb region of chromosome 4p. Therefore, WHSCR-2 should be considered the critical region for this condition. We also confirmed that the pathogenesis of WHS is multigenic. Specific and independent chromosome regions were characterized for growth delay and seizures, as well as for the additional clinical signs that characterize this condition. With the exception of parental balanced translocations, familial recurrence is uncommon. © 2008 Wiley-Liss, Inc.

Ancillary