The distribution of ages at diagnosis for 1441 patients with Gaucher disease in the Gaucher Registry.
Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, Rosenbloom BE, Scott CR, Wappner RS, Weinreb NJ, Zimran A. The Gaucher RegistryDemographics and Disease Characteristics of 1698 Patients With Gaucher Disease. Arch Intern Med. 2000;160(18):2835-2843. doi:10.1001/archinte.160.18.2835
The Gaucher Registry, the largest database of patients with Gaucher disease (GD) worldwide, was initiated to better delineate the progressive nature of the disorder and determine optimal therapy. This report describes the demographic and clinical characteristics of 1698 patients with GD before they received enzyme replacement therapy.
Physicians worldwide who treat patients with GD were invited to submit prospective and retrospective data for an ongoing registry, using standardized data collection forms, for central processing and review.
Most patients were from the United States (45%) and Israel (17%), but patients are from 38 countries. Most (94%) had type 1 GD, fewer than 1% had type 2, and 5% had type 3. Mutant allele frequency data, available for 45% of patients, showed the most common alleles to be N370S (53%), L444P (18%), 84GG (7%), and IVS2+1 (2%). Twenty-five percent of L444P homozygotes (13 of 52 patients) had type 1 GD phenotype. Mean age at diagnosis in patients with the N370S/N370S genotype was 27.2 years (SD, 19.7 years); in L444P/L444P patients, 2.3 years (SD, 3.2 years). Histories of bone pain and radiological bone disease were reported by 63% and 94% of patients, respectively; both were more likely in asplenic patients than in patients with spleens. Mean spleen and liver volumes were 19.8 and 2.0 multiples of normal, respectively. Anemia and thrombocytopenia were present in 64% and 56%, respectively. Thrombocytopenia was present in 13% of asplenic patients.
The Gaucher Registry permits a comprehensive understanding of the clinical spectrum of GD because of the uniquely large sample size. The Registry will be useful in evaluating the effects of specific therapies in GD and the possible influences of environment, ethnicity, and genotype on the natural history of the disorder.
GAUCHER disease (GD), the most prevalent inherited lysosomal storage disorder, is caused by deficient glucocerebrosidase activity.1,2 The resulting accumulation of glucocerebroside in the lysosomes of macrophages leads to hepatosplenomegaly, anemia, thrombocytopenia, and various bone manifestations. Less frequently, the lymphatic system, lungs, skin, eyes, and kidneys may also be affected.3- 6 Gaucher disease is classified into 3 types based on the nature of its effects on the central nervous system. Type 1, the most common variant, is nonneuronopathic, type 2 has infantile onset of severe central nervous system involvement and inevitable death in early childhood, and type 3 has onset of mild central nervous system involvement in adolescence or early adulthood, with a more indolent neurologic course.7 Within all subtypes, particularly within type 1 and least within type 2, there is substantial clinical variability in terms of severity of symptoms, physical manifestations, and the course and natural history of the illness.8- 10
Issues surrounding the effective management of GD include the chronicity of GD and its variable signs, symptoms, severity, and rate of progression in affected organs; the incomplete understanding of its natural history; the role of splenectomy and potential adjunctive therapies; the influence of comorbid conditions11 and coexistent biochemical abnormalities12; and the expected clinical outcomes in response to treatments, including enzyme replacement therapy (ERT). In an effort to address these and other issues, the Gaucher Registry (hereafter also referred to as "the Registry") was initiated by the Genzyme Corporation, Cambridge, Mass, in April 1991, after the Food and Drug Administration approved alglucerase injection (Ceredase) for the treatment of patients with type 1 GD. As large prospective randomized trials are difficult for such rare conditions, a long-term registry was established to expand the knowledge gained from the smaller clinical trials conducted during the drug development process. The 1995 National Institutes of Health Technology Assessment Conference on Gaucher Disease recommended such a registry, recognizing that "answering the many questions concerning the management of Gaucher disease will require a cooperative effort of considerable scale."13
The Gaucher Registry is now the largest database in existence for documenting information about patients with GD. The availability of this large, international database provides an opportunity to pool data from a substantial number of geographically dispersed patients and enables statistical analyses to examine previously published and anecdotal observations involving only small cohorts of patients. This report from the International Collaborative Gaucher Group (ICGG) describes the cross-sectional demographic and disease characteristics of patients in the Registry.
A committee of 10 GD specialists oversees the scientific direction of the Gaucher Registry. The Registry collects a standardized set of data on patients with GD. All physicians caring for patients with GD throughout the world are eligible to participate in the Registry and, thus, join the ICGG. Participating physicians submit demographic, medical history, medical management, clinical outcome, and, if applicable, treatment regimen information. All patients enrolled in the Registry, regardless of disease severity or treatment status, were eligible for the analyses. Patient data from physicians who did not consent to contribute to the manuscript were removed from the analyses (n = 37).
The Registry collects longitudinal data retrospectively and prospectively. Participating physicians are supplied with data collection forms, definitions of terms, and instructions for form completion. To ensure patient anonymity, a unique Registry number identifies each patient. Approval of the Registry data collection process at participating institutions may include institutional review boards or ethics committees and patient informed consent, as dictated by local policies. The data collected by physicians or their designees are submitted for central processing. Clinical and data management personnel review the forms for missing data, incomplete information, and discrepancies with previously submitted data. Double-key entry is used to add each form to the database. Electronic audits detect out-of-range values, inconsistencies, errors, and omissions. Data inconsistencies are investigated by telephone or mail for resolution.
Physicians are encouraged to collect and submit data on clinical variables in accordance with the assessments recommended by Charrow et al.14 They include, but are not limited to, the following: demographic variables; disease characteristics such as spleen status and genotype; laboratory values of hemoglobin, platelets, aspartate aminotransferase, and acid phosphatase (nonprostatic tartrate resistant); and liver and spleen volume measurements. Organ volumes were obtained by means of magnetic resonance imaging (MRI), computed tomography (CT), or ultrasound. Organ data submitted in linear dimensions are converted to volumetric equivalents using the formula developed by Elstein et al.15 Organ volumes are ultimately expressed as multiples of predicted normal for body weight (ie, approximately 2.5% and 0.2% of body weight for liver and spleen, respectively).16 Symptoms and manifestations of skeletal involvement associated with GD are also collected and include bone pain (self-reported as incidence and severity of pain), bone crises, and radiological and imaging evidence of bone disease by radiologist report. Patients with 1 or more skeletal manifestations (Erlenmeyer flask deformity, osteopenia, marrow infiltration, avascular necrosis, infarction, fracture, lytic lesion, or joint replacement) are considered to have bone disease. Avascular necrosis, infarction, fracture, and joint replacement are considered severe manifestations of bone disease.
We herein present a cross section of patients with GD enrolled in the Registry in a state unmodified by ERT, including assessments of patients before initiation of ERT (in those patients who received ERT) and patients who never received ERT. Patient data are presented at time of first ERT infusion for those patients who have received ERT, or at the time of the most recent submission of data for patients who have never received ERT. For patients who have received ERT, laboratory assessments include results from 8 weeks before to 2 weeks after first infusion, and organ assessments include results from 6 months before to 6 weeks after first infusion. The reported history of bone symptoms (ie, pain and crises) and the radiological manifestations of bone disease include all events occurring before or within 6 weeks after first ERT infusion. For those patients who have never received ERT, all reported bone events are summarized.
To elucidate differences in relative severity of the clinical manifestations, hematologic and visceral variables are presented using categories roughly analogous to mild, moderate, and severe. At times, data are stratified by spleen status to control for the effect of splenectomy on the variables of interest. The "with-spleen" cohort includes all patients with spleen present, including those who have had a partial splenectomy. The "without-spleen" cohort includes patients who have undergone a total splenectomy. Spleen volume measurements are only presented for those patients who have not undergone any splenectomy procedure.
Variables are summarized using descriptive statistics, including mean, SD, SE, median, minimum, and maximum. Differences in levels of hematologic and visceral variables between spleen status groups were tested by means of 2-sample t test.17 Association between spleen status and category of hematologic and visceral variables was tested using the row mean score result of Cochran-Mantel-Haenszel (CMH) test.17 To evaluate differences in the proportions of patients reporting history of bone symptoms and manifestations between spleen status cohorts, the Pearson χ2 test was used.17 All data analyses were performed using SAS statistical software (SAS version 6.12; SAS Institute Inc, Cary, NC).18 Due to missing information on individual variables, analyses of subgroups were necessary.
As of September 18, 1998, a total of 1698 patients with GD were enrolled in the Registry. Of these, 78% have received ERT. Annual enrollment has averaged approximately 250 patients per year.
Data have been submitted by 522 physicians from 38 countries. As shown in Table 1, most enrolled patients are from the United States (45%) and Israel (17%). Most participating physicians who have contributed data to the Registry are hematologists or oncologists, pediatricians, clinical geneticists, and internists. The average number of patients contributed per physician is 3, ranging from 1 to 257.
In the Gaucher Registry, 46% of patients are male and 54% are female. The present mean age is 34.7 years (SD, 19.5 years), ranging from less than 1 to 90 years. Age at diagnosis ranges from birth to 81 years (mean, 17.4 years), with nearly half of the patients receiving a diagnosis before 10 years of age (Figure 1). Among patients with type 1 disease who received a diagnosis before 10 years of age, 68% received the diagnosis before 5 years of age.
Method of diagnosis was provided for 574 Registry patients (34%). Among these patients, GD was diagnosed by means of enzyme assay alone (13%); DNA analysis alone (3%); bone marrow biopsy alone (21%); another method alone (3%), including but not limited to organ biopsy (eg, liver or spleen and splenectomy); or some combination of these 4 methods (59%). Diagnosis in 72% was made by means of enzyme assay alone or in combination with another method.
Ethnicity was provided for 514 Registry patients (30%). Among this subgroup, 68% identified themselves as Jewish (Ashkenazi and Sephardic combined); 21% were non-Jewish white. Other ethnicities constituting at least 1% of Registry patients were Arabic (5%), Hispanic (2%), and African American (1%).
Clinical disease type, as determined by participating physicians, was available for 1643 Registry patients (97%). Of those, 94% had type 1, fewer than 1% had type 2, and 5% had type 3 disease.
Genotype data were available for 766 Registry patients (45%) (Table 2). Among these patients, 84% had one N370S allele, and 23% were homozygous for N370S. A total of 30% of patients had one L444P allele, with 8% L444P homozygous. Among the 1532 alleles analyzed, 84% were characterized. The N370S mutation was found in 53%; the L444P mutation, in 18%.
The association among genotype, age at diagnosis, and disease type is presented in Table 3. The mean age at diagnosis was older than 10 years for the patients with N370S/?, N370S/N370S, N370S/L444P, and N370S/rare allele genotypes; mean age at diagnosis was younger than 10 years for patients with N370S/84GG, L444P/L444P, L444P/?, and N370S/IVS2+1 genotypes. Among patients with type 1 disease, 82% had 1 of the following 4 genotypes: N370S/?, N370S/N370S, N370S/L444P, and N370S/84GG. All patients with the N370S allele have reported type 1 disease. Among 52 patients homozygous for L444P, mean age at diagnosis was 2.3 years (SD, 3.2 years), with 39 (75%) having type 3 disease. The remainder of these patients clinically have type 1 disease.
Spleen status was available for 1632 Registry patients (96%). Of these, 1170 (72%) were designated as the with-spleen cohort, which included 54 patients who had undergone a partial splenectomy. The without-spleen cohort included the 28% of patients who had had a total splenectomy.
The hematologic characteristics of the patients are summarized in Table 4. Among patients with spleens, the median hemoglobin value was 112 g/L, 69% had hemoglobin values of no greater than 120 g/L, and 25% had hemoglobin values of less than 100 g/L. In the without-spleen cohort, the median hemoglobin value was 120 g/L, 54% had hemoglobin values of no greater than 120 g/L, and 10% had hemoglobin values of less than 100 g/L. Severity of anemia was associated with the presence of spleen (CMH, P<.001).
Among patients with spleens who had platelet counts available, the median platelet count was 85 × 109/L, 76% had platelet counts of less than 120 × 109/L, and 26% had platelet counts of less than 60 × 109/L. In the without-spleen cohort, the median platelet count was 219 × 109/L, 14% had platelet counts of less than 120 × 109/L, and 3% had platelet counts of less than 60 × 109/L. Severity of thrombocytopenia was also associated with the presence of spleen (CMH, P<.001).
Table 5 shows the hepatic (with and without spleen) and splenic volumes of patients, reported as multiples of normal. The median liver volume in those with spleen present was 1.7 times normal. In 77% of these patients, liver volume was at least 1.25 times normal; in 17%, greater than 2.5 times normal. In the without-spleen cohort, the median liver volume was 2.2 times normal; 88% had liver volumes of at least 1.25 times normal; and 40%, greater than 2.5 times normal. The liver volumes were significantly larger in the without-spleen compared with the with-spleen cohort (t test, P<.001). Among the 432 patients with their spleens intact, the median spleen volume was 15.2 times normal, and 87% had a spleen at least 5 times normal.
The history of skeletal symptoms and radiological manifestations of the Registry patients are summarized in Table 6. Ninety-four percent of patients had radiological evidence of 1 or more manifestations of bone disease. Sixty-three percent of patients had a history of bone pain, with 33% reporting at least 1 incident of bone crises. The most common radiological manifestations of bone disease included Erlenmeyer flask deformity (46%), osteopenia (42%), marrow infiltration (40%), infarction (25%), avascular necrosis (25%), and multiple manifestations (59%).
Table 7 summarizes the history of skeletal manifestations, stratified by spleen status, age at diagnosis (<10 vs ≥10 years), and the 5 most prevalent genotypes. A greater proportion of patients in the without-spleen cohort reported a history of bone pain, bone crises, and radiological manifestations of severe bone disease (χ2, P<.001). A history of bone crises was more common among patients who received a diagnosis before 10 years of age (χ2, P<.001), whereas the history of bone pain and severe radiological signs of bone disease were comparable in those who received a diagnosis of GD before and after 10 years of age. Among patients with genotype and skeletal information available, many individuals with genotypes that include at least one N370S allele reported an episode of bone pain or had some radiological evidence of severe bone disease. Histories of bone pain and severe bone disease were reported least often in L444P homozygotes (21% vs 48%, respectively) compared with the other 4 most commonly reported genotypes. This observation is most likely a function of age, as patients with the L444P/L444P genotype are younger on average (data not shown) than those in the other genotype groups and have had less opportunity for these manifestations to develop.
The extreme chronicity and variable progression of GD make long-term, prospective natural history studies difficult. However, understanding the natural history of GD is critical to the development of rational procedures for monitoring and treating this lifelong disorder. Any attempt to develop empirical protocols should be based on a large patient population encompassing wide ranges in age and severity of disease. Although not as powerful as a true population-based survey, the Gaucher Registry is an important first step in this direction and provides a valuable resource for studying the epidemiology of GD and the prevalence of its complications. This report from the ICGG is the first published overview of Registry data and describes the cross-sectional demographic and disease characteristics of Registry patients in the untreated state.
As is common to all observational registries, the potential for selection and reporting bias is inevitable. More severely affected individuals probably are overrepresented, reflected in the high proportion (nearly 50%) of Registry patients who received a diagnosis of GD before 10 years of age, presumably because they had more severe disease and, therefore, earlier recognition. The mean age at diagnosis for Registry patients (17.4 years) was younger than those reported in earlier series (Zimran et al,10 Kolodny et al,19 and Grabowski et al20). Increased awareness of GD and improved diagnostic techniques may, in part, account for this difference. The Registry also may be biased toward patients receiving ERT, since many physicians may have learned about the Registry only when they sought ERT for their patients.
These data are also limited because they are abstracted from the clinical records of patients with GD and reflect variable worldwide practice patterns rather than a rigidly defined protocol. The actual frequency of assessments is determined according to the physician's perception of a patient's individualized need for medical care and routine monitoring and by published or local guidelines. Furthermore, the data reflect the use of different diagnostic modalities (eg, CT, MRI, or ultrasound) and the participation of multiple observers in the evaluation of patients for GD. Despite these limitations, many valuable inferences can be drawn from the data.
Submissions to the Registry can come from any part of the world; more than half of the cases have been reported from the United States and Israel. Thus, the data in the Registry may not be representative of the worldwide distribution of GD. With the availability of ERT and the accompanying increased awareness of the disorder, it is hoped that more cases worldwide will be diagnosed and submitted.
Among patients with GD and a reported method of diagnosis, more than 25% received a diagnosis by a method other than enzyme assay. At present, all sources recommend confirmation of the diagnosis by enzyme assay.14,21
The Registry represents the single largest source of genotype information on GD, with data on more than 700 patients. Of patients with type 1 disease, 82% had 1 of the following 4 genotypes: N370S/?, N370S/N370S, N370S/L444P, and N370S/84GG; 87% of patients with type 3 disease had the genotype L444P/L444P (data not shown). Although 39 (75%) of the 52 patients homozygous for the L444P mutation had type 3 (neuronopathic) disease, in 13 (25%), physicians reported clinical type 1 disease. This finding underscores the possibility of ethnic variability among patients with GD.22 Some genotypes that might be expected based on the allele frequencies were not observed, notably homozygosity for 84GG or IVS2+1. Whether this reflects a sample size that is still too small for detection or the in utero lethality of these genotypes is as yet unclear.
Caution must be exercised in attempting to predict phenotype and clinical course based on genotype. Homozygosity for the N370S mutation was uniformly associated with type 1 disease and a later age at diagnosis than any other mutation, consistent with previous studies.8,23 However, the mean age at diagnosis for patients homozygous for N370S was somewhat younger than that previously reported.24 Consistent with the generally more severe (neuronopathic) phenotype seen in most patients homozygous for the L444P mutation, mean age at diagnosis was much younger (2.3 years). Within the Registry in some individuals originally thought to have type 1 disease, neurologic involvement developed at a later age, consistent with type 3 disease. Conversely, the presence of type 1 disease in individuals homozygous for L444P suggests the importance of other factors besides genotype, particularly with respect to neurologic involvement.
In regard to clinical characteristics, more than two thirds of patients in the with-spleen cohort, which includes those with partial splenectomies, were anemic (hemoglobin, <120 g/L) or thrombocytopenic (platelet count <120 × 109/L). Although splenectomized patients were less frequently anemic, the effect of splenectomy on the platelet count was more dramatic. Seventy-six percent of patients in the with-spleen cohort were thrombocytopenic, compared with 13% in the without-spleen cohort (χ2, P<.001). Spleen size was more than 5 times predicted normal in 87% of cases, and 50% of patients had spleens of more than 15 times predicted normal size. Hepatomegaly (≥1.25 times predicted normal) was found in 79% of patients.
Splenectomized patients had larger livers and more frequently reported a history of bone pain, bone crises, and severe radiological evidence of bone disease. Brady et al25 and Fleshner et al26 hypothesize that splenectomy accelerates the consequences of glucocerebroside storage in extrasplenic sites (ie, liver and bone marrow). Another hypothesis suggests that splenectomy may be an indication of more severe disease, in which larger liver size and greater bone involvement may simply reflect their greater disease severity.27 Although the order of events cannot be discerned from the Registry data, χ2 tests reveal an association between spleen status and a history of bone symptoms and disease (P<.001). However, a cause-effect relationship between spleen status and a history of bone symptoms and disease should be interpreted with caution.
Although the hematologic and visceral organ abnormalities may be severe and potentially life-threatening, it is the bone manifestations that usually result in the greatest morbidity and long-term disability.28 Radiographic evidence of bone involvement was present in 94% of Registry patients. Although bone involvement may be as mild as Erlenmeyer flask deformity, evidence of more serious involvement (avascular necrosis, infarction, fracture, lytic lesions, or joint replacement) was common. A history of bone pain was reported by almost two thirds of the patients; one third of patients reported a history of bone crises. These observations highlight the following important aspects of bone involvement in GD: (1) bone pain is at least as common as the well-recognized episodic bone crises; (2) significant bone involvement (documented radiographically) may be present in the absence of symptoms of bone pain; and (3) significant marrow involvement (demonstrated by fat replacement on MRI) may be the only radiographic sign of bone involvement and may be associated with bone pain.
Analyses of Registry data provide important evidence that disease severity cannot be defined by any single variable; patients may have a history of severe bone disease in the absence of significant hematologic abnormalities and vice versa. For example, among patients with skeletal and hematologic data at baseline, 313 presented with a history of severe bone disease. Of these, 252 (81%) did not have significant abnormalities in hemoglobin or platelet level or both. Only thorough objective assessments of each area of potential involvement, often requiring the use of several different methods (eg, x-ray, MRI, CT), can reveal the complete clinical picture in a specific patient.
The information presented herein adds to our understanding of patients with GD in a state unmodified by ERT. Ongoing data collection as part of the Gaucher Registry may help us to better define the natural history of the untreated disease and help us to measure the responses to particular treatment regimens for patients receiving ERT. Over time, these data should validate and improve the criteria for monitoring the course of the disease and its response to treatment.
Further refinement of the Registry may expand the areas of potential inquiry. The collection of additional information concerning quality of life (using the SF-36 Health Survey29), pregnancy course and outcome, neurologic and pulmonary involvement, and concurrent disease data is in progress. Future analyses of Registry data will focus on these areas, as well as on the effectiveness of ERT in patients receiving it and the course of GD in those who are not receiving treatment.
Accepted for publication May 3, 2000.
This study was supported in part by a grant from Genzyme Corporation, Cambridge, Mass.
Argentina: R. Kohan, MD, Noro Basack, MD, Alcira Fynn, MD, Leonardo Acosta, MD, Mario Aggio, MD, Hortensia Armendariz, MD, Luis Alberto Aversa, MD, Reinaldo Campestri, MD, Juan Cresto, MD, Eduardo Dibar, MD, Raquel Dodelson, MD, Marta Dragosky, MD, Isaac Kisinovsky, MD, Victoria Lanza, MD, Martin G. Leiva, MD, Natalio Roizman, MD. Australia: Jack Goldbatt, MD, Meredith Wilson, MD. Austria: Peter Kahr, MD. Belgium: Andries Louwagie, MD, C. Vermijlen, MD, J. Van Biervliet, MD, F. Eyskens, MD, A. Ferster, MD, Genevieve Laureys, MD, Esther Vamos, MD. Brazil: Gilda Porta, MD. Bulgaria: Briguita Radeva, MD. Canada: Dominick Amato, MD, Joe T. Clarke, MD, PhD, Georges Rivard, MD, Patrick Ferreira, MD, Janis Bormanis, MD, Cheryl R. Greenberg, MD, Harold Parsons, MD, Dean Reuther, MD, Lawrence Wong, MD. Czech Republic: Jiri Zeman, MD, M. Snopek, MD. Denmark: Susanne Kjaergarrd, MD, M. Karle, MD, Henrik Birgens, MD. Ecuador: Renato Perez-Morgan, MD. Finland: Timo Timonen, MD, Tapio Nousiainen, MD. France: Jean Yves Cahn, MD, Claudia Autrand, MD, A. Babin, MD, Francis Bauters, MD, Isabelle Berkelmans, MD, Christophe Bologna, MD, C. Bonnier, MD, Mireille Bost, MD, Daniel Briancon, MD, Arnaud Chalvon, MD, Guy Chaurand, MD, Jean Pierre Clauvel, MD, Rague Demolombe, MD, Anne Deville, MD, Jean Francois Dor, MD, M. Dereyfus, MD, M. Duc, MD, Jean Foa, MD, Op Fontaine, MD, Helder Gil, MD, Nathalie Guffon, MD, Jean Robert Harle, MD, Eric Houvenagel, MD, Claude Largilliere, MD, Pierre Le Prise, MD, Michel Le Porrier, MD, Margareth Macro, MD, Francoise Mechinaud, MD, Martine Meyer, MD, P. Minard, MD, Francis Oberlin, MD, Gerard Panelatti, MD, Gerard Ponsot, MD, Sophie Ravill, MD, Philippe Reinert, MD, Patrick Rispal, MD, Jean Roche, MD, Christian Rose, MD, Jean Luc Tranvouez, MD, S. P. Vernant, MD; Medicins Membres du Comite d'Evaluation du Traitement de la Maladie de Gaucher: N. Bauman, MD, Nadia Belmatoug, MD, Thierry Billette de Villemeur, MD, C. Broissand, MD, Claude Carbon, MD, P. Guibaud, MD, Jean Michel Guillard, MD, Raoul Herbrecht, MD, P. Kaminksky, MD, I. Maire, MD, L. Poenaru, MD, Gerard Ponsot, MD, Jean-Marie Saudubray MD, Gilbert Schaison, MD, Marie T. Vanier, MD, M. Vidailhet, MD. Germany: Claus Niederau MD, Michael Beck, MD, W. Altmayer, MD, H. Arnold, MD, C. Kronshnable, MD, A. Rolfs, MD, S. Schweitzer, MD. Greece: T. Marinakis, MD, Vasilis Seitanidis, MD. Hungary: Lazlo Marodi, MD. Ireland: E. Naughten, MD, O. Smith, MD, I. Temperley, MD. Israel: Ari Zimran, MD, Rina Zaizov, MD, Ian Cohen, MD, Ayala Abrahamov, MD. Italy: B. Bembi, MD, G. Mariani, MD, Florina Giona, MD, F. Massolo, MD, S. Zoboli, MD, G. Andria, MD, S. De Virgiliis, MD, R. Gatti, MD, P. Leoni, MD, R. Parini, MD. Japan: Masanori Adachi, MD, Hiroyuki Ida, MD, Tetsuya Ito, MD, Taki Michio, MD, Kanji Nagashima, MD, Nauya Shimabukuro, MD, Tsutomu Takahashi, MD, Yukitoshi Takahashi, MD, Oura Toshihiro, MD, Masahiro Tsuchida, MD, Takahiro Ueda, MD, Eto Yoshikatsu, MD. Jordan: A. Abbadi, MD. Korea: Hyon J. Kim, MD. Lebanon: Ibrahim Dabbous, MD. New Zealand: John Morreau, MD, Margaret Lewis, MD. Norway: T. G. Abrahamsen, MD, M. Sjo, MD. People's Republic of China: Yamei Hu, MD. Philippines: Ernesto Vincent Flores, MD. Poland: Anna Tylki-Szymanska, MD. Portugal: Manuel Abecassis, MD, Jose Barbot, MD, Maria Costa, MD, Sameiro Ferreira, MD, Teresa Ferreira, MD, Elisa Leao, MD, Ana Lemos, MD, Manuela Malho, MD, Conceiaco Martins, MD, Fernando Principe, MD, Alberto Rosa, MD, Rosa Silva, MD, Teresa Tasso, MD, J. Teixeira, MD. Russia: Alexander Jarowaj, MD. Saudi Arabia: Pinar T. Ozand, MD, PhD. South Africa: Rene Heitner, MD. Spain: G. Martin-Nunez, MD, A. Aguilar, MD, M. Amerigo, MD, R. Aporta, MD, M. Campo, MD, P. Giraldo, MD, E. Luno, MD, J. Martinez-Odriozola, MD, I. Rodriguez, MD, D. Salvatierra, MD, P. Sanjurjo, MD, A. Santos, MD, J. Zarate, MD, L. Gonzalez, MD, M. Rodriguez, MD, A. Ibanez, MD, C. Tortajada, MD, V. Palacin, MD, F. Garcia, MD, I. Heiniger, MD, J. Garcia de Jalon, MD, Juan Perez Calvo, MD, F. Torralba, MD, A. Medina, MD, M. A. Queipo de Llano, MD, K. Atutxa, MD, J. C. Gomez, MD, G. Antequera, MD, A. Leon, MD, A. Ruiz de Guinaldo, MD, R. Salinas, MD, M. Barbera, MD, V. Conesa, MD, G. Ferriols, MD, P. Pastor, MD, R. Gallardo, MD, M. J. Aguado, MD, G. Perez, MD, J. M. Lite, MD, A. Baldellou, MD, D. Espinos, MD, I. Loyola, MD, L. Lamberti, MD, G. Morales, MD, R. Rosquett, MD, B. Garcia, MD, F. Forcadas, MD, R. Franco, MD, M. Capa, MD, M. Pardo, MD, T. Toll, MD, G. Diaz, MD, J. Albaladejo, MD, L. Munoz, MD, G. Hidalgo, MD, J. R. Calabuig, MD, J. Dalmau, MD, G. Garcia, MD, G. Garijo, MD, C. Girona, MD, M. Dominguez, MD, J. Morillas, MD, J. Nieto, MD, C. Garcia, MD, F. Galan, MD, P. Delgado, MD, A. Figuerdo, MD, F. Fabiani, MD, R. Santos, MD, A. Cabrera, MD, L. Guerra, MD, C. Mendoza, MD, F. Torres, MD, J. Jiminez-Perez, MD. Sweden: Anders Erikson, MD, PhD, Hakan Forsberg, MD, Lars Skogsberg, MD, C. Stolt, MD, Stefan Borulf, MD, Maria Halldin, MD, Lars Almersson, MD, Bo Angelin, MD, Henry Ascher, MD, PhD, Kurt Bohman, MD, B. Haggmark, MD, Olof Hasslow, MD, R. Hast, MD, Peter Holmquist, MD, Thomas Hybbinette, MD, P. G. Nilsson, MD, Bengt Simonsson, MD, Anna Trela, MD, H. Wadenvik, MD, Kristina Wallman, MD. Switzerland: V. Blauenstein, MD. The Netherlands: Carla Hollak, MD, J. B. C. De Klerk, MD, D. Bosman, MD. Turkey: Mubeccel Demirkol, MD. Great Britain: Ashok Vellodi, MD, F. Alexander, MD, M. Bain, MD, C. Barton, MD, P. Bolton-Maggs, MD, P. Carter, MD, K. Cheetham, MD, John Connell, MD, Simon Court, MD, E. Eastham, MD, A. Gray, MD, C. Hatton, MD, A. Hoffbrand, MD, M. Joyner, MD, J. Ramage, MD, Paul Riley, MD, S. Shalet, MD, C. Singer, MD, J. G. Smith, MD, R. Stevens, MD, Alison Thomson, MD, J. E. W. Van Den Pette, MD, Michael Webster, MD, V. L. Wooley, MD, J. Edward Wraith, MD. United States: Joan Esplin, MD, Gregory Pastores, MD, Neal Weinreb, MD, Norman Barton, MD, Gregory Grabowski, MD, Joel Charrow, MD, Paige Kaplan, MD, Barry Rosenbloom, MD, John Barranger, MD, PhD, Harry Dunn, MD, Robert Steiner, MD, Jeffrey Wisch, MD, Kenneth Rosenbaum, MD, C. Ronald Scott, MD, Ernest Beutler, MD, Robert Greenstein, MD, Rebecca Wappner, MD, Louis J. Elsas II, MD, Priya Kishnani, MD, David Kuter, MD, Seymour Packman, MD, C. Scott, Jr, MD, Judith Westman, MD, Alan Glassberg, MD, Edward Kaye, MD, Anda Norbergs, MD, Jewell Ward, MD, PhD, Terry DeClue, MD, Michael Haut, MD, Margaret Heisel, MD, Harry Miller, MD, Arthur Sawitsky, MD, William Schlueter, MD, Katherine Sims, MD, Steven Allen, MD, Salvatore J. Bertolone, MD, Robert Bona, MD, Paul W. Bowman, MD, Howard Britton, MD, Richard Brown, MD, Raul Castillo, MD, Debra Day-Salvatore, MD, Kimberly Dunsmore, MD, Peter Gabor, MD, Vincent Giusti, MD, T. John Gribble, MD, Stephen Guertin, MD, David Kronn, MD, Thomas Markello, MD, Anthony Pisciotta, MD, Mohammad Shurafa, MD, Richard Steingart, MD, Gail M. Wagner, MD, Alison Whelan, MD, H. Allen, MD, Robert Allen, MD, Georgianne Arnold, MD, W. Perry Ballard, MD, Ashok Bapat, MD, Martin Barnett, MD, Joseph Baron, MD, John Belmont, MD, Robert Bolin, MD, Raymond Brig, MD, John Ciche, MD, Marilyn Cowger, MD, James Daniels, MD, Reggie Duerst, MD, Thomas Duffy, MD, Robert Erichson, MD, Sherron Helms, MD, Alfred Kalman, MD, Edwin Kolodny, MD, Boris Kousseff, MD, Jose F. Leis, MD, Seymour Levine, MD, Linda Lipstate, MD, Jeffrey Marcus, MD, Barry Portnoy, MD, Ellen W. Roback, MD, Frank Senecal, MD, Mary Simmonds, MD, N. Tede, MD, Mary Votaw, MD, Laurie Weisberg, MD, Ilene Weitz, MD, Julian Williams, MD, Arthur Zinn, MD, Neil Abramson, MD, Steve Albella, MD, Daniel Ambruso, MD, Anastasios Angelides, MD, Pamela Arn, MD, M. Avedon, MD, R. Bachman, MD, J. Baker, MD, William Barry, MD, John Benear, MD, A. Bick, MD, Carter Bishop, MD, Lloyd Blakeman, DO, Caroline Block, MD, Robert C. Bolin, MD, Joseph Bowen, MD, M. Bradley, MD, Ruben Burkman, MD, S. Burroughs, MD, F. Burton, MD, Rorberto Cano, MD, J. P. Carlson, MD, Dennis Casciato, MD, Alan Chanin, MD, Kathryn Cheek, MD, George Conklin, MD, Javier Corral, MD, John D. Cronin, MD, Gary Crouch, MD, Timothy Crowley, MD, Marco Da Silva, MD, Richard Damico, MD, Elizabeth Danish, MD, William Darpini, MD, Mark Davidner, MD, Mellar Davis, MD, Mark Dayton, MD, Herbert Dean, MD, Thomas Detesco, MD, Allen Divine, MD, Sam Doppelt, MD, Leopoldo Eisenberg, MD, Irwin Epstein, MD, Benjamin Esparaz, MD, Donald Feinstein, MD, Stephen Fillman, MD, Eugene Frenkel, MD, David Freyer, DO, Burcham Fuqua, MD, John Geil, MD, Foster Gesten, MD, Joan Gill, MD, Stephen Glasser, MD, David Gnarra, MD, Harry Goldman, MD, Michael Goldstein, MD, Bruce Gould, MD, John Gribbon, MD, Jack Halickman, MD, Jack Haling, MD, Craig Harcup, MD, David Harris, MD, Taru Hays, MD, Glen Heggie, MD, Laurel Herbst, MD, Robert Hertzig, MD, Lonnie Herzog, MD, Charles Hess, MD, George Hoganson, MD, Charles Hollen, MD, Jane T. Horton, MD, Cathryn Howarth, MD, Jane Hoyme, MD, Cheryl Huckins, MD, Robert Hudson, MD, Forrest Huntington, MD, Russell Hurst, MD, Carol Hurvitz, MD, Joseph Intile, MD, Andrew Israel, MD, William James, MD, Todd Jansen, MD, Christine Johnson, MD, Michael Johnson, MD, Pamela Karnes, MD, Ben Katz, MD, Joyce Kaynard, MD, Steven Keenholtz, MD, Ross Kendall, MD, Cecil Kim, MD, William Kirsh, DO, Allen Kline, MD, Karis Kremers, MD, Kenneth Lazarus, MD, Raymond Lee, MD, Lawrence Leichtman, MD, Carolyn Levin, MD, Bruce Lewis, MD, Yong K. Liu, MD, Marilyn Manco-Johnson, MD, Harold Margolis, MD, Reuben E. Matalon, MD, Peter Mathews, MD, Leonard A. Marrano, MD, Marilyn L. Matthews, MD, Barbara McAneny, MD, Philip McCarthy, MD, Bryant McCarry, MD, James McFarland, MD, Scott McKercher, MD, Philip McMahill, MD, Gerald Mendel, MD, Adrian Meyer, MD, Margaret Millar, MD, Charles Mize, MD, Dennis Morgan, MD, Rebecca Moroose, MD, Philip Moskowitz, MD, Karl Muench, MD, S. Murkutla, MD, Joe Muscato, MD, William Myers, MD, Mark Olson, MD, Paul Oltman, MD, Ben Orman, MD, Stanley Ostrow, MD, G. Pai, MD, Kirk Panneton, MD, Michael Passero, MD, Dobromir Pencev, MD, Kelley Pendergrass, MD, David Peteet, MD, Howard Polish, MD, James Puckett, MD, S. K. Pundaleeka, MD, L. Terry Rabinowitz, MD, Georgia Reine, MD, R. Michael Roberts, MD, Robert Rodvien, MD, Abraham Rosenberg, MD, Stephen A. Ross, MD, Robert Rountree, MD, Guillermo Rubio, MD, Howard Saal, MD, David Sanchez, MD, Jasjeet Sangha, MD, Burton Schwartz, MD, Ron Scott, MD, Elizabeth Seiter, MD, Stuart Selonick, MD, Clifford Selsky, MD, Ronald Semerdjian, MD, Leonard Sender, MD, Maria Sgambati, MD, Panjak S. Schroff, MD, Dennis Slater, MD, Thomas Smith, MD, Jacques Souadjian, MD, William Spenser, MD, Philippa Sprinz, MD, Luther St. James, MD, Kimo Stine, MD, Catherine Stomatos, MD, Robert Stuber, MD, Margaret Sunderland, MD, June Symens, MD, Raymond Tannous, MD, David Tauben, MD, James I. Taylor, MD, Don Temple, MD, John Trieschman, MD, Loren K. Tschetter, MD, Coleen Wald-Stark, MD, Irwin Weinstein, MD, Chet Whitley, MD, PhD, Daniel Wilhelm, MD, Charles Winkler, MD, Jeffrey Wolf, MD, Jonathan Wright, MD, Yih-Ming Yang, MD, James E. Young, MD, Lilly Young, MD, Richard Zelkowitz, MD, Bruce Zietz, MD, Elinor Zorn, MD.
Reprints: Joel Charrow, MD, Section of Clinical Genetics, Children's Memorial Hospital-59, 2300 Children's Plaza, Chicago, IL 60614 (e-mail: email@example.com).