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.
On the nosology and pathogenesis of Wolf–Hirschhorn syndrome: Genotype–phenotype correlation analysis of 80 patients and literature review†
Article first published online: 16 OCT 2008
Copyright © 2008 Wiley-Liss, Inc.
American Journal of Medical Genetics Part C: Seminars in Medical Genetics
Special Issue: Wolf-Hirschhorn Syndrome and the 4p-Related Syndromes
Volume 148C, Issue 4, pages 257–269, 15 November 2008
How to Cite
Zollino, M., Murdolo, M., Marangi, G., Pecile, V., Galasso, C., Mazzanti, L. and 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., 148C: 257–269. doi: 10.1002/ajmg.c.30190
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.
- Issue published online: 28 OCT 2008
- Article first published online: 16 OCT 2008
- Wolf–Hirschhorn syndrome;
- 4p deletion
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.