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Update on the clinical features and natural history of Wolf–Hirschhorn (4p-) syndrome: Experience with 87 patients and recommendations for routine health supervision

Authors

  • Agatino Battaglia,

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    • Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, via dei Giacinti, 2, 56018 Calambrone (Pisa), Italy.
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    • Dr. Agatino Battaglia is Contract Professor of Child Neuropsychiatry at the Postgraduate Medical School, University of Pisa, Italy; and Adjunct Professor of Pediatrics at the University of Utah Health Sciences Center, Division of Medical Genetics, Department of Pediatrics, Salt Lake City, UT. He is board certified in Clinical Pediatrics and in Neurology. He is Director of the Clinical Dysmorphology Unit, Head of the Center for the Study of Congenital Malformation Syndromes, and Director of Research in Neuropsychiatric Genetics, at the Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, Calambrone (Pisa), Italy. He has a strong research interest in clinical dysmorphology, neuropsychiatric genetics, and clinical neurophysiology.

  • Tiziana Filippi,

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    • Dr. Tiziana Filippi is board certified in Child Neuropsychiatry. She has a temporary professional contract at the Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, Calambrone (Pisa), Italy. She has research interests in Neuropsychiatric Genetics and clinical dysmorphology.

  • John C. Carey

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    • Dr. John C. Carey is a Clinical Geneticist, Professor of Pediatrics at the University of Utah Health Sciences Center, Division of Medical Genetics, Department of Pediatrics, Salt Lake City, UT. He is the Editor-in-Chief of the American Journal of Medical Genetics.


  • How to cite this article: Battaglia A, Filippi T, Carey JC. 2008. Update on the clinical features and natural history of Wolf–Hirschhorn (4p-) syndrome: Experience with 87 patients and recommendations for routine health supervision. Am J Med Genet Part C Semin Med Genet.

Abstract

Wolf–Hirschhorn syndrome (WHS) is a well-known multiple congenital anomalies/mental retardation syndrome, firstly described in 1961 by Cooper and Hirschhorn. Its frequency is estimated as 1/50,000–1/20,000 births, with a female predilection of 2:1. The disorder is caused by partial loss of material from the distal portion of the short arm of chromosome 4 (4p16.3), and is considered a contiguous gene syndrome. No single gene deletions or intragenic mutations have been shown to confer the full WHS phenotype. Since the disorder was brought to the attention of geneticists, many additional cases have been published. Only in 1999, however, were the first data on the natural history brought to the attention of the medical community. The purpose of the present study is to help delineate in more detail and over a longer period of time, the natural history of WHS, in order to establish appropriate health supervision and anticipatory guidance for individuals with this disorder. We have collected information on 87 patients diagnosed with WHS (54 females and 33 males) both in USA and Italy. Age at first observation ranged between newborn and 17 years. Twenty patients have been followed from 4 months to 23 years. The deletion proximal breakpoint varied from 4p15.32 to 4p16.3, and, by FISH, was terminal and included both WHSCR. Deletion was detected by standard cytogenetics in 44/87 (50.5%) patients, whereas FISH was necessary in the other 43 (49.5%). Array-CGH analysis at 1 Mb resolution was performed in 34/87 patients, and, in 15/34 (44%), showed an unbalanced translocation leading to both a 4p monosomy and a partial trisomy for another chromosome arm. Six more patients had been previously shown to have an unbalanced translocation by karyotype analysis or FISH with a WHS-specific probe. Sixty-five of 87 patients had an apparent pure, de novo, terminal deletion; and 1/87 a tandem duplication of 4p16.1p16.3 associated with 4p16.3pter deletion. Age at diagnosis varied between 7 months gestation and 16 years. Ninety-three percent had a seizure disorder with a good outcome; 80% had prenatal onset growth deficiency followed by short stature and slow weight gain; 60% had skeletal anomalies; 50% had heart lesions; 50% had abnormal tooth development; and 40% had hearing loss. Distinctive EEG findings were seen in 90%. Structural CNS anomalies were detected in 80%. Global developmental delay of varying degrees was present in all patients. Almost 50% was able to walk either alone or with support. Hypotonia was present in virtually all patients. A global improvement was observed in all individuals, over time. Our survey has also shown how the characteristic facial phenotype tends to be less pronounced in those patients with a smaller deletion, and microcephaly is not observed in the patients with certain cryptic unbalanced translocations. © 2008 Wiley-Liss, Inc.

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