Greek Warrior Helmet Research Articles

Wolf-hirschhorn Syndrome in Malaysia

Introduction: Wolf–Hirschhorn syndrome (WHS) is rare but a well-known clinical condition due to partial deletion of the short arm of chromosome 4 (4p). It is distinguished by a distinctive facial appearance known as the “Greek warrior helmet”, impaired growth and development, intellectual incapacity and seizures. The features of WHS vary between individuals based on the size and location of the missing piece of chromosome 4. Methods: Six cases of unsuspected WHS were diagnosed from 2011 to 2020 using conventional cytogenetic and fluorescent in situ hybridization (FISH) with a WHS probe. Result: Four of them had a visible cytogenetic deletion on chromosome 4p whereas the remaining two were evaluated with fluorescent in situ hybridization (FISH) using a WHS probe. Conclusion: Conventional cytogenetic testing may yield normal findings and it does not rule out the syndrome. Targeted FISH with a WHS probe is a better option.

Ayurvedic Approach Towards Wolf-Hirschhorn Syndrome: A Case Report

Wolf-Hirschhorn Syndrome is a rare chromosomal disorder caused by the partial deletion (structural aberration) of the short arm of chromosome 4. It is also known as 4P syndrome. The disease was first reported by Cooper, Hirschhorn and Wolf. The characteristic features of the patient depend on the extent of deletion of the genetic materials. The patient has craniofacial dysmorphism and the dysmorphic features are collectively known as Greek Warrior Helmet Facies. There is no direct correlation available for Wolf-Hirschhorn Syndrome in Ayurveda. Since it is a congenital pathology occurring due to chromosomal aberration it may be understood as a Sahaja vyadhi caused due to Beeja dosha. Here in this case the micro/partial deletion of genetic materials from short arm of chromosome 4 is due to the Beeja dosha that has occurred during the formation of Garbha (zygote). This Beeja dosha is responsible for the manifestation of different presentation in Wolf-Hirschhorn Syndrome which can be understood as a Vyadhi Sankara i.e., syndrome. The patient was presented with the features of facial dysmorphism, hypospadias, developmental delay and seizures. Hence the case was diagnosed as Vyadhija Phakka with Vataja Apasmara. In the present case the focus was mainly in the correction of developmental delay and to prevent the relapse of seizures. An integrated treatment protocol comprising Phakka chikitsa and Vataja Apasmara chikitsa were administered. Though there was no change in the facial dysmorphisms, but significant improvements were observed in the gross motor, language and communication milestones after the treatment.

Wolf-Hirschhorn syndrome with intrauterine growth restriction in a fetus: A case report

Introduction: Wolf-Hirschhorn syndrome (WHS), a genetic syndrome caused by deletion of the short arm of chromosome 4 (4p), is clinically characterized by “Greek warrior helmet” facial appearance, growth retardation, intellectual disability, seizures, skeletal anomalies, congenital cardiovascular defects, and other systemic defects. The severity of the WHS phenotype is related to the size of the missing 4p terminal fragment. In this article, we report and analyze a case of atypical WHS manifestations that revealed a 21-Mb deletion of the 4p terminal fragment in prenatal amniotic fluid examination by copy number variation sequencing (CNV-seq). Patient concerns: In our case, the fetal ultrasound results presented with intrauterine growth restriction and ocular hypertelorism and were characterized by atypical manifestations such as persistent left superior vena cava, nuchal fold thickness, and extrahepatic portosystemic shunt at 21 + 6 weeks of gestational age. Diagnosis: A fetus with WHS was detected by noninvasive prenatal screening and further diagnosed by chromosome karyotype analysis and CNV-seq. Interventions: After genetic counseling, the couple opted to terminate her pregnancy. Outcomes: Cytogenetic examination of the fetus revealed karyotype 46,XX,del(4)(p15.3). The CNV results showed a 21-MB deletion at the 4p16.3-p15.31 locus. Lessons: The WHS phenotype is atypical in fetuses. Prenatal molecular genetic testing combined with ultrasound screening is an effective method for diagnosing fetal WHS and can help clinicians offer subsequent clinical genetic counseling, manage fetal WHS, and guide the next pregnancy.

A practical approach to dental care for patients with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome is a polymalformative chromosomal disorder caused by a deletion in the distal region of the short arm of chromosome 4. The disease is considered rare (1/50,000 births) and predominantly affects females (2:1). In addition to the characteristic facial phenotype ("Greek warrior helmet"), its clinical manifestations include epilepsy, developmental and psychomotor delay, intellectual disability, cardiac and respiratory complications, and eating problems. The most prevalent oral manifestations are hypodontia, delayed tooth eruption, morphological dental abnormalities, dental malocclusions, cleft lip/palate and ogival palate. Based on our clinical experience, Wolf-Hirschhorn syndrome does not represent an absolute contraindication for any type of dental procedure. The feasibility of dental treatment will depend mainly on the degree of epilepsy control and on the level of collaboration, this latter conditioned by the severity of the intellectual disability and communication difficulties.

Wolf-Hirschhorn syndrome. Description of five cases characterized by means of single nucleotide polymorphism microarrays

Wolf-Hirschhorn syndrome is a polymalformative entity due to the microdeletion in the distal region of the short arm of chromosome 4 (4p16.3), which produces a series of clinical manifestations that can vary depending on the type and size of the genetic defect in this contiguous gene syndrome. Five patients are presented, three of them female, all with the primary clinical findings, characterized by "Greek warrior helmet appearance" facial feature, growth retardation and psychomotor development delay. In addition to the partial deletion in the distal region of the short arm of chromosome 4, two additional genetic alterations were found in two patients, through the use of single nucleotide polymorphism arrays. The clinical characteristics of Wolf-Hirschhorn syndrome are highlighted in order to guide the diagnosis, provide interdisciplinary medical care and, through its confirmation, provide adequate family genetic counseling.

Prenatal diagnosis of Wolf-Hirschhorn syndrome: a case report

This study reported a case of fetal developmental retardation indicated by ultrasound from 17+2 to 34+5 gestations. Single nucleotide polymorphism (SNP) array was performed to detect the copy number variation in the whole genome for the fetus and parents. A 2.42 Mb deletion at 4p16.3 was found in the fetus, but in neither parents, which suggesting a de novo mutation. Thus, the fetus was finally diagnosed with Wolf-Hirschhorn syndrome. No obvious 'Greek warrior helmet' appearance or other facial deformity was observed in the delivered fetus. Key words: Wolf-Hirschhorn syndrome; Ultrasonography, prenatal; Fetal growth retardation; Loss of heterozygosity; DNA copy number variations

Wolf-Hirschhorn Syndrome (WHS), A Case Report and Review of Literature Submit Manuscript

Background: Wolf-Hirschhorn Syndrome (WHS) is a congenital malformation syndrome characterized by growth deficiency and varying developmental delays based on genomic deletions and characteristic facies. The majority of WHS cases are caused by a deletion of 4p16.3 regions on chromosome 4, which includes the Wolf-Hirschhorn Syndrome Candidate genes (WHSC1 and WHSC2). WHSC1 protein is required to inhibit DNA damage by regulating the methylation of histones. The diagnosis of WHS is established by detection of a heterozygous deletion of the Wolf-Hirschhorn Syndrome Critical Region (WHSCR) with 4p16.3 at approximately 1.4-1.9 kb from the terminus. The WHSCR region is restricted to a 165-kb interval in the 4p16.3. Some of the associated structural defects, such as cleft lip and palate, occur more frequently in individuals with greater than 3 megabase (Mb) deletions. The quantity of base deletions is an important factor in explaining phenotypic variability WHS. The deletion size has a partial correlation to severity, but not a direct correlation, as the phenotypic affect may be more or less severely affected than would be expected by the size of the deleted megabase. Most individuals affected by this disorder have distinctive facial features, such as a broad, flat nasal bridge and a high forehead described as the “Greek warrior helmet” appearance in which the eyes are protruding and widely spaced. Other facial features include a shortened distance between the nose and the upper lip (a short philtrum), a down-turned mouth, a small chin (micrognathia), poorly formed ears with small holes (pits) of flaps of skin (tags), a small head (microcephaly). Intellectual disability ranges from mild to severe in people with WHS. Compared to people with other forms of intellectual disability, their socialization skills are strong, while verbal, communication, and language skills tend to be weaker. Case: We present the identification during routine obstetric sonographic imaging of growth restricted fetus affected by WHS with co-morbid oligohydramnios and abnormal prenatal obstetrics ultrasound studies, which showed micrognathia, echogenic kidneys and echogenic bowel, in addition to a three-week discrepancy between the estimated ultrasound age and the gestational age by last menstrual period (LMP), compatible with intrauterine growth restriction (IUGR). Prenatal genetic testing demonstrated female karyotype with a satellite chromosome on chromosome 4 short arm and mosaicism for an additional marker chromosome (47, XX, 4ps, +mar (8)/46, XX, 4ps). The prenatal diagnostic approach included fetal sonographic assessment and molecular cytogenetic investigation. After engaging in a multidisciplinary informed consent process at our institution, the patient chose to continue prenatal care and not electively terminate the pregnancy. Conclusion: A 4p deletion on chromosome 4 can be associated with subtle chromosome imbalances in other chromosomes. For example, the t(4;8)(p16;p23) translocation may be undetected in routine cytogenetics, suggesting that this translocation may be more the most frequent translocation after the most common reciprocal translocation in humans, t(11q;22q). The extent of the Mb deleted within the 4p region located on chromosome 4 correlates with the severity of the WHS phenotype. Genetic counseling provides families with information on the nature and implications of inherited genetic disorders, as a means of facilitating shared health care decisions.

Analyses of Genotypes and Phenotypes of Ten Chinese Patients with Wolf-Hirschhorn Syndrome by Multiplex Ligation-dependent Probe Amplification and Array Comparative Genomic Hybridization.

Background:Wolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome that is typically caused by a deletion of the distal portion of the short arm of chromosome 4. However, there are few reports about the features of Chinese WHS patients. This study aimed to characterize the clinical and molecular cytogenetic features of Chinese WHS patients using the combination of multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (array CGH).Methods:Clinical information was collected from ten patients with WHS. Genomic DNA was extracted from the peripheral blood of the patients. The deletions were analyzed by MLPA and array CGH.Results:All patients exhibited the core clinical symptoms of WHS, including severe growth delay, a Greek warrior helmet facial appearance, differing degrees of intellectual disability, and epilepsy or electroencephalogram anomalies. The 4p deletions ranged from 2.62 Mb to 17.25 Mb in size and included LETM1, WHSC1, and FGFR3.Conclusions:The combined use of MLPA and array CGH is an effective and specific means to diagnose WHS and allows for the precise identification of the breakpoints and sizes of deletions. The deletion of genes in the WHS candidate region is closely correlated with the core WHS phenotype.

Greek Warrior Helmet Facies (Wolf-hirschhorn Syndrome)

Wolf-Hirschhorn syndrome (WHS) is caused by a chromosomal deletion of the band 4p16.3 with characteristic craniofacial features -’Greek warrior helmet’5 facies (prominent glabella, hypertelorism, broad beaked nose and frontal bossing), high-arched eyebrows, protruding eyes, epicanthal folds, short philtrum, distinct mouth with downturned corners, micrognathia, dysplastic ears, preauricular tags. Till date there are very few case reports of Wolf-Hirschhorn syndrome.Here we report a case that had characteristic dysmorphic facies (Figure 1) ‘Greek warrior helmet’ and was diagnosed as a case of WHS. But presence of Meningo-encephalocele and lissencephaly is rarely reported in literature in association with Wolf-hirschhorn syndrome till date. J Nepal Paediatr Soc 2014;34(3):239-243 DOI: http://dx.doi.org/10.3126/jnps.v34i3.10289

Wolf-Hirschhorn syndrome (WHS) - literature review on the features of the syndrome.

Wolf-Hirschhorn syndrome (WHS) is a congenital disorder associated with 4 chromosome microdeletion. The patients suffer from various deformities. Among them, mental and growth retardation, even in the fetus, are observed. Most of the characteristics concern facial features. The "Greek warrior helmet appearance" is the most characteristic feature and refers to the facial view with prominent glabella, high arched eyebrow, broad nasal bridge and hypertelorism. Another characteristic feature is microcephalia with micrognathia. The features are more pronounced in infants. Clefts of lip and/or palate are observed in almost half of the cases. The characteristic thing is that the more genetic material is missing, the more pronounced are the dimorphic features of the syndrome. Mostly, the dental status does not differ much from that of the healthy individuals. It had been proven though that WHS-patients are more prone to anomalies in dental structures. Cone-shaped and taurodontic teeth were observed. Multiple tooth agenesis (mainly at premolars and molars) with over-retained deciduous dentition might be associated with MSX1-gene impairment.

Prenatal ultrasound findings observed in the Wolf‐hirschhorn syndrome: Data from the registry of congenital malformations in auvergne

Wolf-Hirschhorn syndrome (WHS) is associated with facial dysmorphism including high forehead, high nasal bridge, hypertelorism and severe mental retardation. WHS results from a 4p16.3 deletion. Only a small number of reports have been made on the prenatal ultrasound findings observed in WHS. Here we report our experience on 10 cases of WHS ascertained prenatally between 1983 and 2009 through the CEMC-Auvergne registry of congenital malformations. The assumption that a "Greek warrior helmet" facies is pathognomonic of WHS could lead to misdiagnosis. Other clinical findings such as severe and early onset intrauterine growth retardation, facial dysmorphism (high forehead, high nasal bridge, low-set ears, micrognathia, hypertelorism), atrial or ventricular septal defect, and renal dysplasia should help obstetricians to suspect the diagnosis of WHS prenatally.

Prenatal diagnosis of 4p deletion with aortic valve stenosis

Wolf-Hirschhorn syndrome (WHS) is caused by variable sized terminal deletions of the short arm of chromosome 4 (chromosomal region 4p16.3) and usually presents as severe intrauterine growth retardation with characteristic dysmorphic features (hypertelorism, a short philtrum with downturned corners of the mouth and a ‘Greek warrior helmet appearance’ of the face), developmental delay and epilepsy. Often WHS is only diagnosed postnatally but prenatal diagnosis has been reported in the presence of intrauterine growth retardation with facial dysmorphism, cardiac malformations (ventricular septal defect, arrhythmia) or other associated malformations (oesophageal atresia, renal hypoplasia, diaphragmatic hernia, foot deformity, choroid plexus cysts, corpus callosumagenesis, hypospadias), or in the present of a parental balanced translocation. Here we present the prenatal diagnosis of WHS based on the prenatal onset of growth delay and characteristic facial features and aortic valve stenosis.

Three-dimensional sonographic features of a fetus with Wolf-Hirschhorn syndrome.

We present a case of fetal Wolf-Hirschhorn syndrome diagnosed by conventional two-dimensional and three-dimensional ultrasonography. Conventional two-dimensional ultrasonography revealed a diaphragmatic hernia, nuchal edema, and suspected hypospadias. Three-dimensional ultrasonography clearly showed a flattening of the face, a high forehead, a broad nasal bridge continuing to the forehead, exophthalmos, and micrognathia (resembling the appearance of a Greek warrior helmet), but conventional two-dimensional ultrasonography did not depict these findings. Prenatal chromosomal analysis confirmed the diagnosis of Wolf-Hirschhorn syndrome [46XY, del(4)(p15.2)]. Here we demonstrate how three-dimensional ultrasonography provided a novel visual depiction of the facial dysmorphism, which helped substantially in prenatal counseling.

The terminal 760 kb region on 4p16 is unlikely to be the critical interval for growth delay in Wolf–Hirschhorn syndrome

In a recent issue of the journal, Concolino et al 1 describe a patient with severe growth retardation and a ring chromosome 4, in which a 760 kb deletion within...

P03.38: Prenatal forehead edema in 4p‐ deletion, the “Greek warrior helmet” profile revisited

Deletion of short arm of chromosome 4 is difficult to ascertain in prenatal, and can be missed. A prenatal suspicion of 4p- syndrome was thoroughly investigated by using two-dimensional and three-dimensional sonography, with a description of the fetal face dysmorphological pattern. The cytogenetic confirmation, obtained by Fish technique on a apparently normal karyotype allowed a precise description of the prenatal abnormalities permitting to evoke chromosome 4p deletion. Post-interruption tri-dimensional helicoidal scanner of the fetal face was done. The main anomaly discovered using two-dimensional sonography was presence of a strikingly thick prefrontal edema (8 mm, twice the normal values, at 22 weeks: 3.81 ± 0.62 mm). Three-dimensional sonography showed the classical postnatal profile, with the phenotypic aspect of “Greek warrior helmet”. Nasal bones were normal in size and placement, confirmed by helicoidal scanner. Prenatal diagnosis of deletion 4p syndrome can be tricky, and it is the presence of an important prefrontal edema, associated with more subtle face anomalies (short philtrum, microretrognathia) which should trigger the cytogenetic research of 4p- deletion, even with only borderline growth retardation.

Prenatal forehead edema in 4p- deletion: the ‘Greek warrior helmet’ profile revisited

Deletion of short arm of chromosome 4 is difficult to ascertain prenatally, and can be missed. A prenatal suspicion of 4p- syndrome was thoroughly investigated by using two-dimensional and three-dimensional sonography, with a description of the fetal face dysmorphological pattern. The cytogenetic confirmation, obtained by karyotype and FISH technique, allowed a precise description of the prenatal abnormalities. Post-termination tridimensional helicoidal scanner of the fetal face was performed. The main anomaly discovered using two-dimensional sonography was the presence of a strikingly thick prefrontal edema (8 mm, twice the normal values, at 22 weeks: 3.81 +/- 0.62 mm). Three-dimensional sonography showed the classical postnatal profile, with the phenotypic aspect of a 'Greek warrior helmet'. Nasal bones were normal in size and placement, confirmed by helicoidal scanner. Prenatal diagnosis of 4p deletion syndrome can be difficult, and it is the presence of prefrontal edema, associated with more subtle facial anomalies (short philtrum, microretrognathia) which should trigger cytogenetic investigation for 4p- deletion, even with only borderline growth retardation.

Prenatal diagnosis of de novo pure partial monosomy 4p (4p15.1 → pter) in a growth‐restricted fetus with a Greek warrior helmet face and unilateral facial cleft on three‐dimensional ultrasound

Prenatal DiagnosisVolume 24, Issue 11 p. 934-936 Letter to the Editor Prenatal diagnosis of de novo pure partial monosomy 4p (4p15.1 → pter) in a growth-restricted fetus with a Greek warrior helmet face and unilateral facial cleft on three-dimensional ultrasound Chih-Ping Chen, Corresponding Author Chih-Ping Chen Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China Institute of Clinical Nursing, College of Nursing, National Yang-Ming University, Taipei, Taiwan, Republic of ChinaDepartment of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of ChinaSearch for more papers by this authorChin-Yuan Hsu, Chin-Yuan Hsu Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of ChinaSearch for more papers by this authorChen-Chi Lee, Chen-Chi Lee Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of ChinaSearch for more papers by this authorWen-Lin Chen, Wen-Lin Chen Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of ChinaSearch for more papers by this authorLi-Feng Chen, Li-Feng Chen Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of ChinaSearch for more papers by this authorWayseen Wang, Wayseen Wang Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan, Republic of ChinaSearch for more papers by this author Chih-Ping Chen, Corresponding Author Chih-Ping Chen Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China Institute of Clinical Nursing, College of Nursing, National Yang-Ming University, Taipei, Taiwan, Republic of ChinaDepartment of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of ChinaSearch for more papers by this authorChin-Yuan Hsu, Chin-Yuan Hsu Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of ChinaSearch for more papers by this authorChen-Chi Lee, Chen-Chi Lee Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of ChinaSearch for more papers by this authorWen-Lin Chen, Wen-Lin Chen Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of ChinaSearch for more papers by this authorLi-Feng Chen, Li-Feng Chen Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, Republic of ChinaSearch for more papers by this authorWayseen Wang, Wayseen Wang Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan, Republic of ChinaSearch for more papers by this author First published: 24 November 2004 https://doi.org/10.1002/pd.975Citations: 12AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume24, Issue11November 2004Pages 934-936 RelatedInformation

Mild Wolf-Hirschhorn phenotype and partial GH deficiency in a patient with a 4p terminal deletion.

Wolf-Hirschhorn syndrome (WHS) is caused by a variably-sized deletion of chromosome 4 involving band 4p16 whose typical craniofacial features are "Greek warrior helmet appearance" of the nose, microcephaly, and prominent glabella. Almost all patients show mental retardation and pre- and post-natal growth delay. Patient was born at term, after a pregnancy characterized by intra-uterine growth retardation (IUGR). Delivery was uneventful. Developmental delay was evident since the first months of life. At 2 years, he developed generalized tonic-clonic seizures. Because of short stature, low growth velocity and delayed bone age, at 4 years he underwent growth hormone (GH) evaluation. Peak GH after two provocative tests revealed a partial GH deficiency. Clinical observation at 7 years disclosed a distinctive facial appearance, with microcephaly, prominent eyes, and beaked nose. Brain MRI showed left temporal mesial sclerosis. GTG banded karyotype was normal. Because of mental retardation, subtelomeric fluorescence in situ hybridization (FISH) analysis was performed, disclosing a relatively large deletion involving 4p16.2 --> pter (about 4.5 Mb), in the proband, not present in the parents. The smallest deletion detected in a WHS patient thus far includes two candidate genes, WHSC1 and WHSC2. Interestingly, that patient did not show shortness of stature, and that could be due to the haploinsufficiency of other genes localized in the flanking regions. Contribution of GH alterations and possible GH therapy should be further considered in WHS patients.

Mouse models for the Wolf-Hirschhorn deletion syndrome.

Wolf-Hirschhorn syndrome (WHS) is a deletion syndrome caused by segmental haploidy of chromosome 4p16.3. Its hallmark features include a 'Greek warrior helmet' facial appearance, mental retardation, various midline defects and seizures. The WHS critical region (WHSCR) lies between the Huntington's disease gene, HD, and FGFR3. In mice, the homologs of these genes map to chromosome 5 in a region of conserved synteny with human 4p16.3. To derive mouse models of WHS and map genes responsible for subphenotypes of the syndrome, five mouse lines bearing radiation-induced deletions spanning the WHSCR syntenic region were generated and characterized. Similar to WHS patients, these animals were growth-retarded, were susceptible to seizures and showed midline (palate closure, tail kinks), craniofacial and ocular anomalies (colobomas, corneal opacities). Other phenotypes included cerebellar hypoplasia and a shortened cerebral cortex. Expression of WHS-like traits was variable and influenced by strain background and deletion size. These mice represent the first animal models for WHS. This collection of nested chromosomal deletions will be useful for mapping and identifying loci responsible for the various subphenotypes of WHS, and provides a paradigm for the dissection of other deletion syndromes using the mouse.