Balkan Journal of Medical Genetics

PHENOTYPIC VARIATIONS IN WOLFHIRSCHHORN SYNDROME
Sukarova-Angelovska E, Kocova M, Sabolich V, Palcevska S, Angelkova N
*Corresponding Author: Doz. Elena Sukarova-Angelovska, Pediatric Clinic, Medical Faculty, Vodnjanska 17, 1000 Skopje, Republic of Macedonia. Tel.: +389-70358582. Fax: +389-22439301. E-mail: Esukarova@doctor.com
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INTRODUCTION

Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disorder due to the deletion of the short arm of chromosome 4. The first description of the syndrome was published by Cooper and Hirschhorn [1] and Hirschhorn et al. [2]; it was afterwards confirmed by Wolf et al. [3]. The syndrome occurs in approximately 1:50,000 newborns [4]. Approximately 120 cases have been described thus far using conventional karyotyping [5]. Recently-used molecular techniques increase the number of diagnosed cases due to the detection of smaller deletions of the short arm of chromosome 4 [6,7]. Common features of the syndrome include microcephaly, characteristic facial dysmorphism, frequently cited as a Greek helmet-like forehead, broad forehead with prominent glabella and shallow orbital arches; hyperthelorism, short and broad nose; short upturned philtrum and low-set dysplastic ears. Severe psychomotor delay is present in most cases. Seizures usually occur within the first 2 years of life and have variable presentation. Less frequent features are midline defects: congenital heart defect, cleft palate, hypospadia, as well as skeletal abnormalities, club foot, mesomelia, radioulnar synostosis, fused vertebrae and ribs, and hip dislocation. Growth is severely affected [8]. The infants are born small for gestational age. Receding of postnatal growth velocity continues in early childhood, the height of affected children is 3SDS (standard deviation score) below the mean. Some of the patients have a short life span, mainly because of the lower respiratory infections and multiple anomalies. However, the children with smaller deletions have a better survival rate [9]. Most cases are caused by a de novo deletion of chromosome 4p, while in 20.0% of cases, translocation in the parental karyotype that includes chromosome 4, is responsible for the loss of the part of chromosome 4 in the offspring [4,10,11]. Other structural rearrangements including this region, such as inversions, are a rare cause of WHS. Mosaic state of deletion of chromosome 4p(p15- pter) has been described in two cases so far, and has highly non specific clinical presentation [12,13]. Mosaicism in parental cells could be the reason for occurrence of overt WHS in the offspring [14]. Some investigators speculate that parental imprinting is a responsible mechanism for the phenotype, since the majority of deleted chromosomes 4 are of paternal origin [15]. The critical region for WHS is located on the terminal part of the chromosome 4p, with a length of approximately 1-5 Mbp. In rare cases the cytogenetically visible deletion is interstitial. It has been estimated that the minimal critical region of the deleted region is 165 kb from the telomere and is up to 750 kb in length, most frequently between loci FGFR3 and D4S168 [7,16]. However, it is a gene-rich region and produces severe clinical presentation in most cases. In 80.0% of cases, the deletion is large, up to 4p14 [9]. The remaining 20.0% of patients have smaller deletions, mostly on the 4p16.3 band, a presentation called Pit-Roger-Danks syndrome [17]. This minor deletion leads to less severe and frequently uncharacteristic clinical presentation. Multiple genes are responsible for the clinical presentation. However, haploinsuficiency of the WHSC1 gene that encodes a DNA binding protein, is mostly believed to be a cause for the pleiotropic effects. The WHSC1 gene is responsible for chromatin remodeling, and therefore causes insufficient regulation of many genes [18]. Zolino et al. [10] suggested that other genes outside the critical region contributed to the phenotype. An additional gene within the WHS critical region, LETM1, involved in Ca binding signaling, is responsible for the seizures in these patients [4,10,]. The gene has been located at the proximal side of the Wolf-Hirschhorn critical region (WHCR) and has an influence on the mitochondrial ion homeostasis [19].

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