Record 1 Strabismus in Williams syndrome (letter) Roy FH Am J Ophthalmol (UNITED STATES) Aug 1995, 120 (2) p266-7, ISSN 0002-9394 Languages: ENGLISH Document type: LETTER
Record 2 Strong correlation of elastin deletions, detected by FISH, with Williams syndrome: evaluation of 235 patients. Lowery MC; Morris CA; Ewart A; Brothman LJ; Zhu XL; Leonard CO; Carey JC; Keating M; Brothman AR Department of Pediatrics, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA. Am J Hum Genet (UNITED STATES) Jul 1995, 57 (1) p49-53, ISSN 0002-9297 Languages: ENGLISH Document type: JOURNAL ARTICLEWilliams syndrome (WS) is generally characterized by mental deficiency, gregarious personality, dysmorphic facies, supravalvular aortic stenosis, and idiopathic infantile hypercalcemia. Patients with WS show allelic loss of elastin (ELN), exhibiting a submicroscopic deletion, at 7q11.23, detectable by FISH. Hemizygosity is likely the cause of vascular abnormalities in WS patients. A series of 235 patients was studied, and molecular cytogenetic deletions were seen in 96% of patients with classic WS. Patients included 195 solicited through the Williams Syndrome Association (WSA), plus 40 clinical cytogenetics cases referred by primary-care physicians. Photographs and medical records of most WSA subjects were reviewed, and patients were identified as "classic" (n = 114) or "uncertain" (n = 39). An additional 42 WSA patients were evaluated without clinical information. FISH was performed with biotinylated ELN cosmids on metaphase cells from immortalized lymphoblastoid lines from WSA patients and after high-resolution banding analysis on clinical referral patients. An alpha-satellite probe for chromosome 7 was included in hybridizations, as an internal control. Ninety-six percent of the patients with classic WS showed a deletion in one ELN allele; four of these did not show a deletion. Of the uncertain WS patients, only 3 of 39 showed a deletion. Of the 42 who were not classified phenotypically, because of lack of clinical information, 25 patients (60%) showed a deletion. Thirty-eight percent (15/40) of clinical cytogenetics cases showed an ELN deletion and no cytogenetic deletion by banded analysis. These results support the usefulness of FISH for the detection of elastin deletions as an initial diagnostic assay for WS.
Record 3 (Williams-Beuren syndrome and celiac disease) Sindrome di Williams-Beuren associata a malattia celiaca. Chiaravalloti G; Rossomando V; Quinti S; Assanta N; Ughi C; Ceccarelli M Istituto di Clinica Pediatrica, Universita degli Studi, Pisa. Minerva Pediatr (ITALY) Jan-Feb 1995, 47 (1-2) p43-6, ISSN 0026-4946 Languages: ITALIAN Summary Languages: ENGLISH Document type: JOURNAL ARTICLE English AbstractThe authors describe a case of Williams syndrome-Coeliac Disease that they have observed at the age of three years and 10/12. There are few reports in the literature. We focus on the variability of clinical and biochemical aspects of Williams Disease and the necessity for an adequate gastroenterologic follow-up (anti-gliadine antibody and anti-endomisium antibody) in these patients with little growth in terms of weight and height and intestinal alterations present in superior measure in companion with the reported standards for the same syndrome.
Record 4 The human calcitonin receptor gene (CALCR) at 7q21.3 is outside the deletion associated with the Williams syndrome. Perez Jurado LA; Li X; Francke U Department of Genetics, Stanford University School of Medicine, CA, USA. Cytogenet Cell Genet (SWITZERLAND) 1995, 70 (3-4) p246-9, ISSN 0301-0171 Languages: ENGLISH Document type: JOURNAL ARTICLEThe human calcitonin receptor (CTR) is a transmembrane peptide with dual action as a receptor for the hormone calcitonin and as an extracellular calcium sensor. Therefore, CTR dysfunction could lead to disorders of calcium metabolism associated with hypercalcemia, such as the Williams syndrome (WS). WS is a developmental disorder caused by a deletion at chromosome 7q11.23 that includes the elastin locus (ELN). We have mapped the CTR gene (CALCR) to chromosome band 7q21.3 by polymerase chain reaction and single-strand conformation analysis of somatic cell hybrids as well as fluorescence in situ hybridization (FISH) to metaphase chromosome spreads. Two-color FISH cohybridizing CTR and ELN probes confirmed that CALCR maps telomeric to ELN. Subsequent analysis of chromosome spreads from four WS patients revealed deletion of the ELN locus in all of them and normal hybridization of CTR probes to both chromosome 7 homologues, indicating that CALCR lies outside the deleted region.
Record 5 Genetic approaches to cardiovascular disease. Supravalvular aortic stenosis, Williams syndrome, and long-QT syndrome. Keating MT Howard Hughes Medical Institute, University of Utah Health Sciences Center, Salt Lake City 84112, USA. Circulation (UNITED STATES) Jul 1 1995, 92 (1) p142-7, ISSN 0009-7322 Languages: ENGLISH Document type: JOURNAL ARTICLEBACKGROUND: Although family history can be an important risk factor for cardiovascular disease, relatively little is known about the nature of specific genetic risk factors. One approach to this problem is to identify and characterize genes responsible for inherited disorders in the hope that this information will also provide mechanistic insight into common forms of cardiovascular disease. METHODS AND RESULTS: Over the last decade, it has become possible to identify genes that cause human disease by use of the techniques of molecular genetics, specifically genetic linkage analysis, positional cloning, and mutational analyses. We have used these techniques to study three inherited cardiovascular disorders: supravalvular aortic stenosis, Williams syndrome, and long-QT syndrome. We have discovered that the vascular pathology of supravalvular aortic stenosis and Williams syndrome results from mutations involving the elastin gene on chromosome 7q11.23. These mutations include intragenic deletions, translocations, and complete deletion of the elastin gene, suggesting that a quantitative reduction in elastin during vascular development is pathogenically important. To date, only the elastin gene has proved important for supravalvular aortic stenosis. By contrast, genetic linkage analyses in families with long-QT syndrome indicate that at least four distinct genes can cause this disorder. We have identified three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Recently, we demonstrated that mutations in a putative cardiac potassium channel gene, HERG, are responsible for the chromosome 7-linked form of long-QT syndrome, whereas mutations in the cardiac sodium channel gene SCN5A cause the chromosome 3-linked form of this disorder. HERG mutations and potassium channel biophysics suggest a dominant-negative molecular mechanism and reduced repolarization currents. By contrast, SCN5A mutations probably cause subtle alterations of cardiac sodium channel function and prolonged depolarizing currents. CONCLUSIONS: Molecular genetic analyses of long-QT syndrome, supravalvular aortic stenosis, and Williams syndrome have begun to unravel the mechanisms underlying these inherited disorders. Rapid genetic testing for Williams syndrome is now available using a simple cytogenetic test, fluorescence in situ hybridization, but additional work will be required for long-QT syndrome and autosomal-dominant supravalvular aortic stenosis. Improved diagnosis and mechanistic understanding of these disorders should lead to rational treatment and prevention.
Record 6 Ischemic stroke and intracranial multifocal cerebral arteriopathy in Williams syndrome. Soper R; Chaloupka JC; Fayad PB; Greally JM; Shaywitz BA; Awad IA; Pober BR Department of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA. J Pediatr (UNITED STATES) Jun 1995, 126 (6) p945-8, ISSN 0022-3476 Languages: ENGLISH Document type: JOURNAL ARTICLEWe describe an otherwise healthy 2-year-old patient with Williams syndrome who had a stroke as a result of intracranial multivessel focal and segmental stenotic disease. The diagnosis of Williams syndrome was confirmed by elastin gene deletion testing. Combined magnetic resonance imaging and magnetic resonance angiography, and transcranial Doppler flow studies, were used in diagnosing and monitoring the course of the disease.
Record 7 Cerebral artery stenoses in Williams syndrome cause strokes in childhood. Kaplan P; Levinson M; Kaplan BS Children's Hospital of Philadelphia, PA 19104-4399, USA. J Pediatr (UNITED STATES) Jun 1995, 126 (6) p943-5, ISSN 0022-3476 Languages: ENGLISH Document type: JOURNAL ARTICLEExtensive narrowing of lumens of many cerebral arteries caused strokes with brain damage and chronic hemipareses in two children with Williams syndrome. Increased irritability, loss of consciousness, and seizures were initial signs. Arterial stenoses are not limited to the supravalvular aorta and pulmonary arteries in patients with Williams syndrome.
Record 8 Association of Chiari I malformation and Williams syndrome. Pober BR; Filiano JJ Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA. Pediatr Neurol (UNITED STATES) Jan 1995, 12 (1) p84-8, ISSN 0887-8994 Languages: ENGLISH Document type: JOURNAL ARTICLETwo Williams syndrome patients are presented who had neurologic symptoms secondary to Chiari malformation type I. Both patients had many of the well-known medical problems found in Williams syndrome. In addition, Patient 1 developed headache, diplopia, and tinnitus at 26 years of age. Neurologic examination revealed intermittent nystagmus and brisk reflexes. Magnetic resonance imaging demonstrated Chiari malformation type I; neurologic symptoms abated following surgery. Patient 2 had a normal neurologic examination at 2 years of age except for hyperreflexia and tight heel cords. At age 10 years, she had generalized contractures, decreased strength and wasting of hand musculature, and hyperreflexia. Magnetic resonance imaging documented Chiari malformation type I. Both patients have significant dysphagia and fusion of cervical spine segments noted on radiography. Morphometric analyses of intracranial contents based on midsagittal magnetic resonance images were performed. This analysis suggests that, compared to age-matched controls, the posterior fossa size is selectively diminished in Williams syndrome, whereas the cerebellum is normal in size. This "mismatch" between the size of the posterior fossa bony compartment and its neural contents may place Williams syndrome patients at high risk for developing Chiari malformation type I.
Record 9 Deletions of the elastin gene at 7q11.23 occur in approximately 90% of patients with Williams syndrome. Nickerson E; Greenberg F; Keating MT; McCaskill C; Shaffer LG Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Am J Hum Genet (UNITED STATES) May 1995, 56 (5) p1156-61, ISSN 0002-9297 Languages: ENGLISH Document type: JOURNAL ARTICLETo investigate the frequency of deletions of the elastin gene in patients with Williams syndrome (WS), we screened 44 patients by both FISH and PCR amplification of a dinucleotide repeat polymorphism. FISH was performed using cosmids containing either the 5' or the 3' end of the elastin gene. PCR analysis was performed on the patients and their parents with a (CA)n repeat polymorphism found in intron 17 of the elastin locus. Of the 44 patients screened, 91% were shown to be deleted by FISH. Using the DNA polymorphism, both maternally (39%) and paternally (61%) derived deletions were found. Four patients were not deleted for elastin but have clinical features of WS. Since deletions of elastin cannot account for several features found in WS, these patients will be valuable in further delineation of the critical region responsible for the WS phenotype. Although PCR can be useful for determining the parental origin of the deletion, our results demonstrate that FISH analysis of the elastin locus provides a more rapid and informative test to confirm a clinical diagnosis of WS. The presence of two copies of the elastin locus in a patient does not, however, rule out WS as a diagnosis.
Record 10 Strabismus in Williams syndrome. Kapp ME; von Noorden GK; Jenkins R Cullen Eye Institute, Baylor College of Medicine, Houston, Texas. Am J Ophthalmol (UNITED STATES) Mar 1995, 119 (3) p355-60, ISSN 0002-9394 Languages: ENGLISH Document type: JOURNAL ARTICLEPURPOSE: Williams syndrome is a rare genetic disorder, consisting of mental retardation, supravalvular aortic stenosis, elfin facies, and specific ocular findings, including strabismus. We undertook this study to evaluate the characteristics of the strabismus in Williams syndrome. METHODS: We examined 32 patients with Williams syndrome to determine the prevalence and define the features of the strabismus in this patient population. RESULTS: Twenty-five of the 32 patients (78%) had strabismus, esotropia being the predominant form in 23 of the 25 patients. Of the 19 patients with Williams syndrome who had infantile esotropia, seven had dissociated vertical deviation, ten had oblique dysfunction, and six had amblyopia. CONCLUSIONS: When the patients with Williams syndrome were compared to the general population, no statistically significant difference was found in the clinical characteristics of infantile esotropia between the two groups. Because of the high prevalence of esotropia in patients with Williams syndrome (72%) compared to the general population (0.1%), we postulate a genetic link between Williams syndrome and the hereditary form of infantile esotropia.
Record 11 The neuropathology of Williams syndrome. Report of a 35-year-old man with presenile beta/A4 amyloid plaques and neurofibrillary tangles. Golden JA; Nielsen GP; Pober BR; Hyman BT Pathology Service (Neuropathology), Massachusetts General Hospital, Boston. Arch Neurol (UNITED STATES) Feb 1995, 52 (2) p209-12, ISSN 0003-9942 Languages: ENGLISH Document type: JOURNAL ARTICLEOBJECTIVE: To study neuropathologically Williams syndrome in a 35-year-old patient. METHODS: Sections from multiple regions of the brain were examined with luxol fast blue and hematoxylineosin staining, and selected sections were stained with the silver impregnation technique (Bielschowsky technique) and Congo red. In addition, immunohistochemistry with monoclonal antibodies against glial fibrillary acidic protein, beta/A4 amyloid, paired helical filaments, and phosphorylated tau protein was performed on cortical, hippocampal, amygdaloid, and basal ganglian sections. RESULTS: No specific macroscopic or microscopic abnormalities were recognized that are specific for Williams syndrome. The histopathologic examination did, however, demonstrate the presence of Alzheimer-type changes, including beta/A4 amyloid-containing senile plaques and scattered neurofibrillary tangles in neocortex and medial temporal lobe structures (entorhinal cortex, CA1 area of the hippocampus, and amygdala). Plaques were most numerous in the amygdala (7/mm2) and in the entorhinal cortex (4/mm2). Neurofibrillary tangles were less numerous (< 1/mm2), except in the hippocampus, where approximately 2/mm2 were found. CONCLUSIONS: To our knowledge, ours represents the first neuropathologic description of a patient with Williams syndrome. Although Williams syndrome is usually sporadic, familial cases have been reported along with candidate chromosomal loci. If our findings are confirmed in additional patients with Williams syndrome, they may provide clues to other factors that are important in the pathogenesis of senile plaques (with beta/A4 amyloid deposition) and neurofibrillary tangles.
Record 12 A novel microsatellite DNA marker at locus D7S1870 detects hemizygosity in 75% of patients with Williams syndrome (letter) Gilbert-Dussardier B; Bonneau D; Gigarel N; Le Merrer M; Bonnet D; Philip N; Serville F; Verloes A; Rossi A; Ayme S; et al Am J Hum Genet (UNITED STATES) Feb 1995, 56 (2) p542-4, ISSN 0002-9297 Languages: ENGLISH Document type: LETTER
Record 13 Toward a molecular understanding of congenital heart disease. Payne RM; Johnson MC; Grant JW; Strauss AW Department of Pediatrics, Washington University School of Medicine, St Louis, Mo. Circulation (UNITED STATES) Jan 15 1995, 91 (2) p494-504, ISSN 0009-7322 Languages: ENGLISH Document type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIALBACKGROUND: This review discusses the incidence and importance of congenital heart disease (CHD), the reasons that investigation of causative mechanisms for human CHD has been slow, and the limitations of the multifactorial theory for the etiology of CHD. METHODS AND RESULTS: The molecular defects underlying three vasculopathies--Marfan's syndrome (fibrillin), supravalvar aortic stenosis, and Williams' syndrome (elastin)--and hereditary telangiectasia are presented to emphasize the role of microfibrils and extracellular matrix in the pathophysiology of these vascular defects. Animal models of CHD, including situs inversus, canine conotruncal malformations, and chick neural crest ablation, are examined to emphasize how such studies relate to human CHD, especially by pointing to single-gene defects for conotruncal malformations, candidate loci for situs inversus, and phenotypic variability caused by neural crest lesions. The crucial role of cardiac transcription factors in heart morphogenesis is emphasized by review of gene knockout studies of these factors, which cause fetal death secondary to heart maldevelopment. Several lines of evidence demonstrating genetic etiologies of human CHD are also presented, including the mapping of familial atrial septal defects, to prove that one anatomic type of CHD may be due to single-gene defects at different loci. Review of atrioventricular canal, both secondary to trisomy 21 and as an autosomal-dominant familial defect, reiterates this conclusion. The evidence that monosomy on chromosome 22 causes multiple types of CHD, including aortic arch and conotruncal defects as part of the CATCH-22 syndrome, is presented, with results supporting the idea that deletions at this site alone may cause 5% of surgically treated CHD. CONCLUSIONS: We conclude that (1) human CHD is frequently due to single-gene defects and that even sporadic defects may arise from a single-gene abnormality; (2) a common genetic defect may cause several apparently different forms of CHD; (3) elucidation of the genetic basis of CHD provides clues to normal cardiovascular developmental biology; (4) the same cardiac malformation can be caused by mutant genes at different loci; and (5) interactions of clinical investigators (cardiologists and cardiothoracic surgeons) with basic scientists should allow more rapid progress in defining the genetic basis of CHD. (91 Refs.)
Record 14 (A successful surgical case of supravalvular aortic stenosis with Williams syndrome: the investigations of the procedures) Ichihara T; Watanabe T; Yasuura K; Tanaka M; Abe T; Tsuji A; Nagashima M Department of Thoracic Surgery, Nagoya University School of Medicine, Japan. Kyobu Geka (JAPAN) Oct 1994, 47 (11) p929-33, ISSN 0021-5252 Languages: JAPANESE Summary Languages: ENGLISH Document type: JOURNAL ARTICLE English AbstractWe experienced a successful surgical case in which a 3-year-old boy with a characteristic elfin face, heart murmur, and mental retardation, underwent extended patch aortoplasty using equine pericardium for congenital supravalvular aortic stenosis. The aortography performed before operation, and demonstrated diffuse stenosis just above the aortic valve, which was a typical hour-glass type. The preoperative peak systolic pressure gradient between the left ventricle and ascending aorta was 120 mmHg, and was improved postoperatively. In this procedure only one cusp was incised, resulting in no deformity of the aortic valve and no obstruction of coronary arteries. In conclusion this method was excellent for the diffuse type of supravalvular aortic stenosis.
Record 15 Molecular pathology of the elastic fibers. Christiano AM; Uitto J Department of Dermatology, Jefferson Medical College, Philadelphia, PA 19107-5541. J Invest Dermatol (UNITED STATES) Nov 1994, 103 (5 Suppl) p53S-57S, ISSN 0022-202X Languages: ENGLISH Document type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIALElastic fibers form a network that contributes to the elasticity and resilience of tissues such as the skin. Histopathologic and ultrastructural abnormalities in the elastic fibers have been observed in several diseases of the skin and other tissues. Recent cloning of several genes involved in elastic fiber architecture has lead to the approach of the study of elastic fiber genodermatoses through molecular analysis. However, in genodermatoses, such as pseudoxanthoma elasticum, many of the genes encoding elastic fiber components have been excluded by genetic linkage analysis. In recent years, mutations in several of the genes encoding elastic fiber proteins have been demonstrated in other diseases. These include mutations in the fibrillin 1 gene in the Marfan syndrome, and genetic linkage of congenital contractural arachnodactyly to fibrillin 2, and, most recently, demonstration of abnormalities in the Menkes syndrome gene in X-linked cutis laxa. The first disorders to involve mutations in the elastin gene itself are, surprisingly, cardiovascular and neurobehavioral disorders, such as supravalvular aortic stenosis and Williams syndrome. These findings suggest that additional, as yet undiscovered, components of the elastic fiber network in the skin may hold the key to unraveling the molecular basis of the elastin-related genodermatoses. (45 Refs.)
Record 16 Williams syndrome--oral presentation of 45 cases. Hertzberg J; Nakisbendi L; Needleman HL; Pober B Department of Dentistry, Children's Hospital, Boston, MA 02115. Pediatr Dent (UNITED STATES) Jul-Aug 1994, 16 (4) p262-7, ISSN 0164-1263 Languages: ENGLISH Document type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIALForty-five patients with Williams syndrome (WS) were evaluated for oral abnormalities. The mean age of the patients was 9.25 years, the median age was 6.7 years, and the majority (62.2%) were male. Hypodontia was present in 11.1% of the patients. Abnormal tooth morphology was noted in 12.5% of the primary dentitions and 40.7% of the permanent dentitions. With the exception of the primary mandibular central incisors of males, all mesiodistal incisor crown dimensions were statistically significantly smaller when compared with norms (P < 0.05). At least one hypoplastic enamel defect was present in 9.4% of patients with primary teeth and in 18.5% with permanent teeth. No patients exhibited generalized enamel hypoplasia. More than half of the patients (59.1%) were both caries and restoration free, while only 13.6% presented with clinically active caries. Tongue thrusting was present in 67.7% of the sample, while more than 50% of the patients present with excessive interdental spacing. Patients exhibited a higher than normal prevalence of Class II and III occlusions, open and deep bites and anterior crossbites. No single dental finding was pathognomonic of WS, however two constellations of findings, each occurring in approximately one-third of the sample, were observed: 1) microdontia, anterior crossbite, tongue thrusting, and excessive interdental spacing, and 2) microdontia, deep or open bite, and excessive interdental spacing. (34 Refs.)
Record 17 Rupture of inferior phrenic artery aneurysm. An unusual complication of mesenteric arteritis due to postcoarctectomy syndrome. Shirai T; Amano J; Fujii N; Hirabayashi S; Suzuki A Department of Thoracic and Cardiovascular Surgery, Hokushin General Hospital, Tokyo, Japan. Chest (UNITED STATES) Oct 1994, 106 (4) p1290-1, ISSN 0012-3692 Languages: ENGLISH Document type: JOURNAL ARTICLEPostcoarctectomy syndrome was developed in a boy with Williams syndrome. Angiogram revealed widespread changes of visceral arteries and extravasation of the contrast material from the right inferior phrenic artery. Emergency laparotomy was successful. This unusual complication makes clear that the mesenteric arteritis after coarctectomy can cause aneurysm with a risk of rupture.