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Thiamine-Responsive Megaloblastic Anemia Syndrome

Synonyms: Rogers Syndrome, Thiamine-Responsive Myelodysplasia, TRMA

, MD and , MD, PhD.

Author Information
, MD
Departments of Pediatrics and Genetics and Genomic Sciences
Mount Sinai School of Medicine
New York, New York
, MD, PhD
Department of Genetics and Genomic Sciences
Mount Sinai School of Medicine
New York, New York

Initial Posting: ; Last Update: November 20, 2014.

Summary

Clinical characteristics.

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus. Onset of megaloblastic anemia is between infancy and adolescence. The anemia is corrected with pharmacologic doses of thiamine (vitamin B1) (25-75 mg/day compared to US RDA of 1.5 mg/day). However, the red cells remain macrocytic. The anemia can recur when thiamine is withdrawn. Progressive sensorineural hearing loss has generally been early and can be detected in toddlers; hearing loss is irreversible and may not be prevented by thiamine treatment. The diabetes mellitus is non-type I in nature, with age of onset from infancy to adolescence.

Diagnosis/testing.

The diagnosis of TRMA requires the presence of the phenotypic triad of megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus. Examination of the bone marrow reveals megaloblastic anemia with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts). SLC19A2, which encodes the high-affinity thiamine transporter, is the only gene in which pathogenic variants are known to cause TRMA. All individuals with the diagnostic phenotypic triad evaluated by sequence analysis have identifiable pathogenic variants in SLC19A2.

Management.

Treatment of manifestations: Treatment focuses on lifelong use of pharmacologic doses (25-75 mg/day) of thiamine (vitamin B1) in affected individuals.

Prevention of secondary complications: Complications secondary to poor glycemic control for diabetes or chronic anemia may occur. Ongoing management of the primary disease is essential.

Surveillance: At least yearly monitoring of the efficacy of the oral thiamine therapy and of disease progression, including: hematologic tests (CBC, reticulocyte count); assessment for glucose intolerance (fasting serum glucose concentration, OGTT, urine analysis); and hearing, ophthalmologic, and cardiac evaluations.

Pregnancy management: Good diabetic control prior to and during pregnancy is recommended.

Genetic counseling.

TRMA is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible for families in which the pathogenic variants have been identified.

Diagnosis

Clinical Diagnosis

The diagnosis of thiamine-responsive megaloblastic anemia syndrome (TRMA) is based on an obligate triad of clinical features:

  • Megaloblastic anemia occurring between infancy and adolescence:
    • Examination of the bone marrow reveals megaloblastic changes with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts).
    • The anemia is corrected with pharmacologic doses of thiamine (vitamin B1) (25-75 mg/day compared to US RDA of 1.5 mg/day). However, the red cells remain macrocytic, suggesting a persistent erythropoietic abnormality [Haworth et al 1982, Neufeld et al 1997]. Anemia can recur when thiamine is withdrawn.
  • Progressive sensorineural deafness. Hearing loss has generally been early and can be detected in toddlers. Whether hearing loss is congenital (prelingual) is unknown. Some affected individuals do not show hearing loss when they are younger, while symptoms of megaloblastic anemia and diabetes are present. There are reports that thiamine treatment may not prevent development of hearing loss [Borgna-Pignatti et al 2009, Akın et al 2011].
  • Diabetes mellitus that is non-type I in nature, with age of onset from infancy to adolescence. Insulin secretion is present but defective [Valerio et al 1998]. In some cases, insulin requirements are reduced with thiamine therapy [Neufeld et al 1997].

Testing

Even without thiamine supplementation, serum thiamine concentrations are normal; there is no evidence of acidosis or aciduria.

In vitro cell-based assays can assist in the diagnosis of TRMA. Studies of [3H]-thiamine uptake by control fibroblasts reveal a saturable process with apparent Km 400-550 nmol/L, while fibroblasts from individuals with TRMA entirely lack this high-affinity component [Stagg et al 1999].

TRMA cells, but not control cells, die of apoptosis in thiamine-depleted medium; accumulated organic acids suggest thiamine starvation [Stagg et al 1999].

Subtle thiamine transport defects at relatively high concentrations have been observed in red blood cells of individuals with TRMA [Rindi et al 1992, Rindi et al 1994].

Neither anti-insulin nor anti-islet cell antibodies have been found in individuals with TRMA [Neufeld et al 1997], but pancreatic histopathology has not been investigated.

Molecular Genetic Testing

Gene. SLC19A2, which encodes the high-affinity thiamine transporter, is the only gene in which pathogenic variants are known to cause TRMA.

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Thiamine-Responsive Megaloblastic Anemia Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
SLC19A2Sequence analysis 2Nearly 100% 3
Deletion/duplication analysis 4Very rare; observed in 1 family to date
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2.

Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Nearly all individuals with the diagnostic phenotypic triad evaluated by sequence analysis have identifiable pathogenic variants in SLC19A2. To date, more than 40 families with 33 distinct pathogenic variants have been identified [Diaz et al 1999, Raz et al 2000, Scharfe et al 2000, Gritli et al 2001, Neufeld et al 2001, Ozdemir et al 2002, Lagarde et al 2004, Ricketts et al 2006, Bergmann et al 2009, Onal et al 2009, Pichler et al 2012, Shaw-Smith et al 2012, Yilmaz Agladioglu et al 2012]. Homozygosity by descent has been the most common finding. Seven individuals from six families were compound heterozygotes with distinct pathogenic variants from each parent [Bergmann et al 2009, Pichler et al 2012, Shaw-Smith et al 2012].

4.

Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • A clinical diagnosis of TRMA should be considered in individuals with megaloblastic anemia with normal vitamin B12/folic acid levels, with or without diabetes or hearing loss; response to oral thiamine makes the diagnosis highly likely.
  • Identification of two SLC19A2 pathogenic variants by sequence analysis confirms the diagnosis.

One genetic testing strategy is molecular genetic testing of SLC19A2, the only gene in which pathogenic variants are known to cause thiamine-responsive megaloblastic anemia syndrome.

  • Sequence analysis should be performed first.
  • If only one or no pathogenic variant is identified, deletion/duplication analysis of SLC19A2 can be considered next.

An alternative genetic testing strategy is use of a multi-gene panel that includes SLC19A2 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Genomic testing. If single gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of TRMA, genomic testing may be considered. Such testing may include whole exome sequencing (WES), whole genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

Notes regarding WES and WGS. (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single gene testing or multi-gene molecular genetic testing panels; (2) most laboratories confirm positive results using a second, well-established method; (3) nucleotide repeat expansions and epigenetic alterations cannot be detected; (4) deletions/duplications larger than 8-10 nucleotides are not detected effectively [Biesecker & Green 2014].

Clinical Characteristics

Clinical Description

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by megaloblastic anemia, sensorineural hearing loss, and diabetes mellitus.

  • The earliest findings of significant bone marrow problems have been in the first year of life and the latest in teenage years.
  • Hearing defects may be present at an early age and in some families may even be present at birth [Setoodeh et al 2013]. Progressive sensorineural hearing loss is irreversible and may not be prevented by thiamine treatment. The basis of the sensorineural deafness is obscure; it is not known if the deafness is caused by abnormalities of the cochlea or of the auditory nerve. However, animal studies suggest that selective inner hair cell loss in the cochlea could be the cause of hearing defects in TRMA [Liberman et al 2006].
  • Non-type I diabetes mellitus has appeared before school age in many (though not all) individuals. High-dose thiamine supplementation may delay onset of diabetes mellitus, and high-dose thiamine invariably improves the hematologic picture. Whether hearing can be improved or hearing loss delayed by high-dose thiamine has been difficult to study, and the answer is unclear; however, some reports have found that thiamine did not prevent the development of hearing loss in infants with TRMA [Borgna-Pignatti et al 2009, Akın et al 2011].

In addition to the triad of clinical features that characterize TRMA, other findings have been observed, each in only a subset of individuals:

Genotype-Phenotype Correlations

No genotype-phenotype correlation has been discerned. Homozygous null mutations in SLC19A2, regardless of position within the gene sequence, result in TRMA, as do all of the reported missense mutations (however, bias of ascertainment may have occurred).

Nomenclature

The synonym "Rogers syndrome" derives from the first report of the disease in a child with diabetes mellitus, sensorineural deafness, and megaloblastic anemia who responded to thiamine (vitamin B1) treatment.

One case report suggests "thiamine-responsive myelodysplasia" as an alternative name for the syndrome [Bazarbachi et al 1998].

Prevalence

Approximately 40 pedigrees are known.

TRMA is exceedingly rare outside of consanguineous pairings or isolated populations. Cases have been observed in various ethnicities including Israeli Arab and Lebanese populations, an Alaskan kindred of native and ethnic Russian descent, and kindreds from Brazil, Japan, Oman, Tunisia, Italy (Venetian and other), Iran, India, and Pakistan, as well as Kashmiri families in Great Britain, ethnic Kurds, persons of northern European heritage, and African Americans [Raz et al 2000, Neufeld et al 2001, Lagarde et al 2004, Bergmann et al 2009, Pichler et al 2012, Shaw-Smith et al 2012, Yilmaz Agladioglu et al 2012].

Differential Diagnosis

The combination of megaloblastic red cell changes and ringed sideroblasts in individuals with thiamine-responsive megaloblastic anemia syndrome (TRMA) is unique among anemias influenced by metabolic or nutritional causes. Among acquired anemias, this combination is most suggestive of myelodysplastic syndromes in which megaloblastosis and sideroblasts are often noted. TRMA should not be confused with myelodysplastic disorders of premalignant potential.

Phenotypic overlap exists between TRMA and Wolfram syndrome, or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), including diabetes mellitus, optic atrophy, and deafness. Notably missing in Wolfram syndrome are megaloblastic anemia and thiamine responsiveness. Wolfram syndrome is caused by pathogenic variants in WFS1. The encoded protein is a novel transmembrane glycoprotein of 100 kd located in the endoplasmic reticulum, where it is thought to play a role in membrane trafficking, protein processing, or regulation of calcium homeostasis.

The combination of diabetes mellitus and deafness calls to mind mitochondrial disorders [Fischel-Ghodsian 1999], but the macrocytic anemia, megaloblastic bone marrow, and response to thiamine distinguish TRMA from these disorders (see Mitochondrial Disorders Overview). Inheritance in TRMA is unequivocally autosomal recessive, which sets it apart from disorders with apparent maternal transmission and mitochondrial inheritance.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to SimulConsult®, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with thiamine-responsive megaloblastic anemia syndrome (TRMA), the following evaluations are recommended:

  • Peripheral blood count and bone marrow analysis for evidence of megaloblastic anemia
  • Serum folate concentration, serum vitamin B12 concentration, and serum iron studies to exclude other entities
  • Fasting serum glucose concentration, oral glucose tolerance test (OGTT), and urinalysis to diagnose diabetes mellitus
  • Hearing test
  • Ophthalmologic evaluation
  • Cardiac evaluation, including echocardiography
  • Medical genetics consultation

Treatment of Manifestations

Management focuses on lifelong use of pharmacologic doses (25-75 mg per day) of thiamine (vitamin B1) in affected individuals. High-dose thiamine may ameliorate diabetes mellitus in the short term and perhaps even for decades [Valerio et al 1998]. Whether treatment with thiamine from birth, or even prenatally, could reduce the hearing defect is a matter of conjecture.

See Deafness and Hereditary Hearing Loss Overview for treatment strategies for hearing loss.

Prevention of Primary Manifestations

See Treatment of Manifestations.

Prevention of Secondary Complications

Complications secondary to poor glycemic control for diabetes or chronic anemia may occur. Ongoing management of the primary disease is essential.

Surveillance

The following are recommended at least yearly to monitor the efficacy of the oral thiamine therapy as well as disease progression:

  • Hematologic tests: CBC, reticulocyte count
  • Assessment for glucose intolerance: fasting serum glucose concentration, OGTT, urinalysis
  • Hearing test
  • Ophthalmologic evaluation
  • Cardiac evaluation

Pregnancy Management

While there are no published studies evaluating pregnancy outcome in affected women, good diabetic control prior to and during pregnancy is recommended.

Evaluation of Relatives at Risk

Supplementation with pharmacologic doses of thiamine (vitamin B1) (25-75 mg/day compared to US RDA of 1.5 mg/day) is recommended as early as possible for at-risk sibs until their genetic status can be determined.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

If the insulin release defect is intrinsic to the SLC19A2-defective islet cells, one could expect islet cell transplantation and cochlear transplantation to be potential cures for TRMA-related diabetes and hearing loss, respectively. One case report documents successful recovery of hearing function by cochlear implantation [Hagr 2014].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Stem cell transplantation could potentially be an effective treatment for the marrow findings of TRMA; however, vitamin therapy alone is satisfactory, as the risk outweighs the benefit of possible restoration of the transporter to the marrow.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one SLC19A2 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of an SLC19A2 pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with TRMA are obligate heterozygotes (carriers) for a pathogenic variant in SLC19A2.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC19A2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SLC19A2 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the SLC19A2 pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like TRMA) have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the SLC19A2 pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • American Diabetes Association (ADA)
    ATTN: Center for Information
    1701 North Beauregard Street
    Alexandria VA 22311
    Phone: 800-342-2383 (toll-free information/support); 703-549-1500
    Email: AskADA@diabetes.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • my baby's hearing
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Thiamine-Responsive Megaloblastic Anemia Syndrome: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SLC19A21q24​.2Thiamine transporter 1SLC19A2 databaseSLC19A2

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Thiamine-Responsive Megaloblastic Anemia Syndrome (View All in OMIM)

249270THIAMINE-RESPONSIVE MEGALOBLASTIC ANEMIA SYNDROME; TRMA
603941SOLUTE CARRIER FAMILY 19 (THIAMINE TRANSPORTER), MEMBER 2; SLC19A2

Molecular Genetic Pathogenesis

Defect of a high-affinity thiamine transporter, SLC19A2, causes TRMA; however, it is still unclear how the absence of SLC19A2 expression results in the seemingly divergent disorders of megaloblastic anemia, diabetes mellitus, and deafness. Biochemical studies on fibroblasts or erythrocytes from individuals with TRMA showed that absence of the high-affinity component of thiamine transport results in low intracellular thiamine concentrations [Rindi et al 1992, Stagg et al 1999]. Defective RNA ribose synthesis caused by intracellular thiamine deficiency is thought to be the cause of megaloblastic changes in TRMA [Boros et al 2003]. Slc19a2 knockout mouse models have been developed [Oishi et al 2002, Fleming et al 2003]; the animal models manifest megaloblastic changes, diabetes mellitus, and sensorineural deafness (the main features of TRMA) when dietary thiamine levels are decreased [Oishi et al 2002]. While the mechanism of megaloblastic changes is still to be elucidated, these models showed defects in insulin secretion and selective loss of inner hair cells in cochlea [Oishi et al 2002, Liberman et al 2006].

Questions regarding TRMA disease pathogenesis that still require explanation include why individuals with TRMA do not have manifestations seen in dietary thiamine deficiency [Mandel et al 1984, Poggi et al 1984, Abboud et al 1985] and why the findings in TRMA are organ specific.

Recent studies showed that a second high-affinity thiamine transporter, encoded by SLC19A3, has major roles in intestinal thiamine uptake using mouse models, accounting for the absence of overt thiamine deficiency in persons with TRMA [Reidling et al 2010]. In support of this, two Japanese brothers with a Wernicke’s-like encephalopathy were reported to have compound heterozygous pathogenic variants in SLC19A3 [Kono et al 2009]. In addition, the difference in distribution of expression of the two thiamine transporters is critical in TRMA: in pancreatic endocrine cells, the expression of SLC19A2 is much higher than that of SLC19A3 and TRMA-associated SLC19A2 mutants disrupt thiamine uptake significantly [Mee et al 2009]. Similarly, it is hypothesized that in TRMA, the other affected tissues (namely, bone marrow and cochlea) do not express or minimally express SLC19A3 [Eudy et al 2000, Rajgopal et al 2001].

Gene structure. SLC19A2 spans approximately 22.5 kb and has six exons with 236 bp 5' UTR and 1,620 bp 3' UTR [Diaz et al 1999, Dutta et al 1999]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. SLC19A2 pathogenic variants are distributed throughout the gene with no apparent clustering or mutation hot spots. The majority of SLC19A2 pathogenic variants known to date are predicted to be null for protein because of nonsense or frameshift mutations. Ten missense mutations have been reported. Such mutations would likely severely disrupt the folding and membrane targeting of the transporter. Consistently, Balamurugan & Said [2002] showed that introducing several of these mutations into transfected HeLa cells resulted in impaired thiamine uptake [Balamurugan & Said 2002].

Normal gene product. The 497-amino acid protein, the high-affinity thiamine transporter 1, is predicted to have 12 transmembrane domains.

Abnormal gene product. Pathogenic variants result in either a truncated protein from a premature stop codon or aberrantly folded protein caused by missense mutations in transmembrane domains.

References

Literature Cited

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Chapter Notes

Author History

George A Diaz, MD, PhD (2006-present)
Judith C Fleming, PhD; Children's Hospital and Harvard Medical School (2003-2006)
Ellis J Neufeld, MD, PhD; Children's Hospital and Harvard Medical School (2003-2006)
Kimihiko Oishi, MD (2006-present)

Revision History

  • 20 November 2014 (me) Comprehensive update posted live
  • 20 September 2012 (me) Comprehensive update posted live
  • 8 April 2010 (me) Comprehensive update posted live
  • 19 November 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for SCL19A2
  • 22 June 2006 (ca) Comprehensive update posted to live Web site
  • 24 October 2003 (me) Review posted to live Web site
  • 25 August 2003 (ejn) Original submission
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