Biomedical subjects

A D Auerbach

Publications and source records attributed to A D Auerbach.

At least 19 recordsLinked to original sources

PubMed2004

A note on competing risks in survival data analysis.

Survival analysis encompasses investigation of time to event data. In most clinical studies, estimating the cumulative incidence function (or the probability of experiencing an event by a given time) is of primary interest. When the data consist of patients who experience an event and censored individuals, a nonparametric estimate of the cumulative incidence can be obtained using the Kaplan-Meier method. Under this approach, the censoring mechanism is assumed to be noninformative. In other words, the survival time of an individual (or the time at which a subject experiences an event) is assumed to be independent of a mechanism that would cause the patient to be censored. Often times, a patient may experience an event other than the one of interest which alters the probability of experiencing the event of interest. Such events are known as competing risk events. In this setting, it would often be of interest to calculate the cumulative incidence of a specific event of interest. Any subject who does not experience the event of interest can be treated as censored. However, a patient experiencing a competing risk event is censored in an informative manner. Hence, the Kaplan-Meier estimation procedure may not be directly applicable. The cumulative incidence function for an event of interest must be calculated by appropriately accounting for the presence of competing risk events. In this paper, we illustrate nonparametric estimation of the cumulative incidence function for an event of interest in the presence of competing risk events using two published data sets. We compare the resulting estimates with those obtained using the Kaplan-Meier approach to demonstrate the importance of appropriately estimating the cumulative incidence of an event of interest in the presence of competing risk events.

Humans↗

PubMed2001

Endoscopic sinus surgery in cystic fibrosis: do patients benefit from surgery?

OBJECTIVE: To examine the effects of endoscopic sinus surgery on the pulmonary status of cystic fibrosis (CF) patients through the objective parameters of steroid use, pulmonary function tests (PFTs), and inpatient hospital days (IHDs). METHODS: Retrospective chart review of all patients with CF who underwent endoscopic sinus surgery from 1993 to 1999 at a tertiary care children's hospital. Preoperative pulmonary function, inhaler and steroid use, and IHDs were compared to postoperative parameters within a 1-year period. RESULTS: Sixty-six patients, including eight lung transplant patients, underwent a total of 112 endoscopic sinus surgery procedures; 25 patients underwent more than one procedure. Patients were taking oral steroids preoperatively in 28% of procedures and inhaled steroids in 40%. Postoperatively, there was no statistically significant change in oral or inhaled steroid use, or in postoperative pulmonary function. If the index hospitalization, which was often for reasons not related to sinus disease, was considered part of the preoperative time period, endoscopic sinus surgery (ESS) was noted to result in a marked reduction (9.5 days (adjusted), P=0.001) in hospital days during the subsequent 6 months. If the date of the procedure alone was used to define pre- and postoperative time periods, the reduction in postoperative days was more modest and not statistically significant (3.5 days (adjusted), P=0.21). CONCLUSIONS: Although we found no statistically significant difference in PFTs, or steroid requirements following ESS, ESS may have resulted in a reduced need for hospitalization in the 6 months following the procedure. Future prospective studies in a larger number of patients and using more detailed outcome measures are needed to better evaluate the effects of endoscopic sinus surgery in pediatric patients with CF.

Adolescent↗

PubMed2001

Somatic mosaicism in Fanconi anemia: evidence of genotypic reversion in lymphohematopoietic stem cells.

Somatic mosaicism has been observed previously in the lymphocyte population of patients with Fanconi anemia (FA). To identify the cellular origin of the genotypic reversion, we examined each lymphohematopoietic and stromal cell lineage in an FA patient with a 2815-2816ins19 mutation in FANCA and known lymphocyte somatic mosaicism. DNA extracted from individually plucked peripheral blood T cell colonies and marrow colony-forming unit granulocyte-macrophage and burst-forming unit erythroid cells revealed absence of the maternal FANCA exon 29 mutation in 74.0%, 80.3%, and 86.2% of colonies, respectively. These data, together with the absence of the FANCA exon 29 mutation in Epstein-Barr virus-transformed B cells and its presence in fibroblasts, indicate that genotypic reversion, most likely because of back mutation, originated in a lymphohematopoietic stem cell and not solely in a lymphocyte population. Contrary to a predicted increase in marrow cellularity resulting from reversion in a hematopoietic stem cell, pancytopenia was progressive. Additional evaluations revealed a partial deletion of 11q in 3 of 20 bone marrow metaphase cells. By using interphase fluorescence in situ hybridization with an MLL gene probe mapped to band 11q23 to identify colony-forming unit granulocyte-macrophage and burst-forming unit erythroid cells with the 11q deletion, the abnormal clone was exclusive to colonies with the FANCA exon 29 mutation. Thus, we demonstrate the spontaneous genotypic reversion in a lymphohematopoietic stem cell. The subsequent development of a clonal cytogenetic abnormality in nonrevertant cells suggests that ex vivo correction of hematopoietic stem cells by gene transfer may not be sufficient for providing life-long stable hematopoiesis in patients with FA.

Base Sequence↗

PubMed2001

Physician views on caring for hospitalized patients and the hospitalist model of inpatient care.

We surveyed 241 board-certified internists affiliated with a large teaching hospital (Boston, Mass) before implementing a hospitalist service to determine attitudes towards providing inpatient care and the hospitalist model. Of physicians surveyed, 66% responded. Most disagreed that inpatient care is "an inefficient use of my time," only 10% felt a hospitalist service would improve patient satisfaction, and 54% felt it would hurt patient-doctor relationships. Multivariable analyses suggest that physicians physically furthest from their inpatient site were had more favorable attitudes toward the hospitalist model; more experienced and busier physicians were more negative. Future investigations should determine strategies for implementing the hospitalist model which address physicians' concerns.

Academic Medical Centers↗

PubMed2001

Evaluation of growth and hormonal status in patients referred to the International Fanconi Anemia Registry.

OBJECTIVES: 1) To determine the extent of short stature in patients with Fanconi anemia (FA); 2) to determine the extent and nature of endocrinopathy in FA; 3) to assess the impact on height of any endocrinopathies in these patients; and 4) to study the correlation, if any, between height, endocrinopathy, and FA complementation group. STUDY DESIGN: Fifty-four patients with FA, 30 males and 24 females from 47 unrelated families, were prospectively evaluated in a Pediatric Clinical Research Center. The patients ranged in age from 0.1-31.9 years, with the mean age at assessment 8.6 years. RESULTS: Endocrine abnormalities were found in 44 of the 54 FA patients tested (81%), including short stature, growth hormone (GH) insufficiency, hypothyroidism, glucose intolerance, hyperinsulinism, and/or overt diabetes mellitus. Twenty-one of 48 (44%) participants had a subnormal response to GH stimulation; 19 of 53 (36%) had overt or compensated hypothyroidism, while 8 of 40 participants had reduced thyroid-hormone binding. Two patients were diabetic at the time of study; impaired glucose tolerance was found in 8 of 40 patients (25%), but most surprisingly, hyperinsulinemia was present in 28 of 39 (72%) participants tested. Significantly, spontaneous overnight GH secretion was abnormal in all patients tested (n = 13). In addition, participants demonstrated a tendency toward primary hypothyroidism with serum tetraiodothyronine levels at the lower range of normal, while also having thyrotropin (thyroid-stimulating hormone) levels at the high end of normal. Sixteen patients were assigned to FA complementation group A, (FA-A), 12 to FA-C, and 5 to FA-G; 10 of the 12 participants in FA-C were homozygous for a mutation in the intron-4 donor splice site of the FANCC gene. Patients in groups FA-A and FA-G were relatively taller than the group as a whole (but still below the mean for the general population), whereas those in FA-C had a significantly reduced height for age. GH response to stimulation testing was most consistently normal in participants from FA-G, but this did not reach statistical significance. The tendency toward hypothyroidism was more pronounced in participants belonging to complementation groups FA-C and FA-G, whereas insulin resistance was most evident in patients in FA-G, and least evident in those in FA-C. Short stature was a very common finding among the patients with a mean height >2 standard deviations below the reference mean (standard deviation score: -2.35 +/- 0.28). Patients with subnormal GH response and those with overt or compensated hypothyroidism were shorter than the group with no endocrinopathies. The heights of those participants with glucose or insulin abnormalities were less severely affected than those of normoglycemic, normoinsulinemic participants, although all were significantly below the normal mean. The mean height standard deviation score of patients with entirely normal endocrine function was also >2 standard deviations below the normal mean, demonstrating that short stature is an inherent feature of FA. CONCLUSION: Endocrinopathies are a common feature of FA, primarily manifesting as glucose/insulin abnormalities, GH insufficiency, and hypothyroidism. Although short stature is a well-recognized feature of FA, 23 patients (43%) were within 2 standard deviations, and 5 of these (9% of the total) were actually above the mean for height for the general population. Those patients with endocrine dysfunction are more likely to have short stature. These data indicate that short stature is an integral feature of FA, but that superimposed endocrinopathies further impact on growth. The demonstration of abnormal endogenous GH secretion may demonstrate an underlying hypothalamic-pituitary dysfunction that results in poor growth.

Adolescent↗

PubMed2000

Physician attitudes toward and prevalence of the hospitalist model of care: results of a national survey.

PURPOSE: We sought to determine the availability and utilization of, as well as physician attitudes toward, the hospitalist model in the United States. SUBJECTS AND METHODS: Using a telephone survey, we asked physicians who were board certified in internal medicine about their inpatient practice arrangements, the availability of hospitalist services, and their attitudes toward the hospitalist model. All physicians were generalists in active clinical practice. Using multivariable methods, we determined factors associated with attitudes toward the hospitalist model. RESULTS: We were able to contact 787 of 2,829 physicians who were randomly selected from a national list of board-certified internists, of whom 400 agreed to participate. Most respondents were familiar with the term "hospitalist" and had hospitalist services available in their community, and 28% used hospitalists for their inpatients. Few (2%) reported the presence of the "mandatory" hospitalist model. Physicians reported that the model was more commonly available in Western states (84% vs. 55% to 63% in other regions, P<0.0001). Seventy-three percent thought hospitalist systems would reduce continuity of care. Only 28% thought that patients would prefer care from an inpatient specialist, but 51% thought patients might get better care, and 47% thought patients might get more cost-effective care in a hospitalist system. In multivariable models, physicians who were in solo practice, those in specialties with more inpatient practice, and those who had more patients hospitalized each month responded more negatively about the model, whereas those with hospitalists in their community were more positive. CONCLUSIONS: Although agreeing that quality of care and efficiency might be improved, physicians were concerned about patient-doctor relationships and patient satisfaction in a hospitalist model. Future studies should determine the effect of the hospitalist model on these outcomes.

Attitude of Health Personnel↗

PubMed2000

Resource use and survival of patients hospitalized with congestive heart failure: differences in care by specialty of the attending physician. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments.

BACKGROUND: Previous studies suggest that specialty care is more costly but may produce improved outcomes for patients with acute cardiac illnesses. OBJECTIVE: To determine whether patients with congestive heart failure who are cared for by cardiologists experienced differences in costs, care patterns, and survival compared with patients of generalists. DESIGN: Prospective cohort study. SETTING: 5 U.S. teaching hospitals between 1989 and 1994. PATIENTS: 1298 patients hospitalized with an exacerbation of congestive heart failure. MEASUREMENTS: Hospital costs; average daily Therapeutic Intervention Scoring System (TISS) score; and survival censored at 30, 180, and 365 days and 31 December 1994. RESULTS: Compared with patients of generalists, patients of cardiologists were younger (mean age, 63.3 and 71.4 years; P < 0.001) and had lower Acute Physiology Scores at the time of admission (35.1 and 36.7; P < 0.001) but were more likely to have a history of ventricular arrhythmias (21.0% and 10.2%; P < 0.001). At 6 months, 201 (27%) patients of cardiologists and 149 (27%) patients of generalists had died. After adjustment for sociodemographic characteristics and severity of illness, patients of cardiologists incurred costs that were 42.9% (95% CI, 27.8% to 59.8%) higher and average daily TISS scores that were 2.83 points (CI, 1.96 to 3.68 points) higher than those of patients of generalists. Patients of cardiologists were more likely to undergo right-heart catheterization (adjusted odds ratio, 2.9 [CI, 1.7 to 4.9]) or cardiac catheterization (adjusted odds ratio, 3.9 [CI, 2.4 to 6.2]) and had higher odds for transfer to an intensive care unit and electrocardiographic monitoring. Adjusted survival did not differ significantly between groups at 30 days; however, there was a trend toward improved survival among patients of cardiologists at 1 year (adjusted relative hazard, 0.82 [CI, 0.65 to 1.04]) and at maximum follow-up (adjusted relative hazard, 0.80 [CI, 0.66 to 0.96]). CONCLUSIONS: In this observational study of patients hospitalized with congestive heart failure, cardiologist care was associated with greater costs and resource use and no difference in survival at 30 days of follow-up. Whether the trend toward better survival at longer follow-up represents differences in care or unadjusted illness severity is uncertain.

Adult↗

PubMed2000

8th International HUGO-Mutation Database Initiative Meeting, April 9, 2000, Vancouver, Canada.

The 8th International HUGO-Mutation Database Initiative Meeting was held on April 9, 2000, in Vancouver, Canada. Meeting highlights are here described. The discussion predominantly revolved around the concept of a central mutation database, which would serve as a repository of gene sequence variants for the community. Specifications for such a central database were prepared and presented by a working group including bioinformatics experts, LSDB operators, central database operators, and an industry representative. Refinement of the specifications and consideration of the implementation of such a database was conducted through a consortium of public and private collaborators and funding. Members were urged to generate broad community support for the project.

Canada↗

PubMed2000

Patient characteristics associated with care by a cardiologist among adults hospitalized with severe congestive heart failure. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments.

OBJECTIVES: The goal of this study was to determine factors associated with receiving cardiologist care among patients with an acute exacerbation of congestive heart failure. BACKGROUND: Because cardiologist care for acute cardiovascular illness may improve care, barriers to specialty care could impact patient outcomes. METHODS: We studied 1,298 patients hospitalized with acute exacerbation of congestive heart failure who were cared for by cardiologists or generalist physicians. Using multivariable logistic models we determined factors independently associated with attending cardiologist care. RESULTS: Patients were less likely to receive care from a cardiologist if they were black (adjusted odds ratio [AOR] 0.53, 95% confidence interval [CI] 0.35, 0.80), had an income of less than $11,000 (AOR 0.65, 95% CI 0.45, 0.93) or were older than 80 years of age (AOR 0.23, 95% CI 0.12, 0.46). Patients were more likely to receive cardiologist care if they had college level education (AOR 1.89, 95% CI 1.02, 3.51), a history of myocardial infarction (AOR 1.59, 95% CI 1.17, 2.16), a serum sodium less than 133 on admission (AOR 1.96, 95% CI 1.30, 2.95) or a systolic blood pressure less than 90 on admission (AOR 1.97, 95% CI 1.20, 3.24). Patients who stated a desire for life extending care were also more likely to receive care from a cardiologist (AOR 1.40, 95% CI 1.04, 1.90). CONCLUSIONS: After adjusting for severity of illness and patient preferences for care, patient sociodemographic factors were strongly associated with receiving care from a cardiologist. Future investigations are required to determine whether these associations represent unmeasured preferences for care or inequities in our health care system.

Adult↗

PubMed2000

Haematopoietic cell transplantation in patients with Fanconi anaemia using alternate donors: results of a total body irradiation dose escalation trial.

Allogeneic haematopoietic cell transplantation (HCT) is the only therapeutic modality capable of correcting the haematologic manifestations of Fanconi anaemia (FA). However, HCT from alternative donors has been associated with poor survival. Between June 1993 and July 1998, 29 FA patients (median age 12.1 years; range 3.7-48.5 years) were enrolled in a prospective phase I-II dose escalation study. All patients were treated with cyclophosphamide 40 mg/kg, total body irradiation (TBI) 450 cGy or 600 cGy and antithymocyte globulin (ATG), followed by HCT from an alternative donor. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A for 6 months, short course methylprednisolone (2 mg/kg/day) between days +5 and +19 and marrow T-cell depletion by counterflow elutriation. The probability of developing grade III-IV toxicity was 17% (95% CI 3-31%). For the 25 marrow recipients, the probability of neutrophil engraftment (ANC 0.5 x 109/l by day 45) was 63% (95% CI 42-82%). Probabilities of grade II-IV acute GVHD and chronic GVHD were 32% (95%CI 10-54%) and 0% respectively. With a median follow-up of 18 months, the probability of survival for the entire cohort at 1 year was 34% (95% CI 17-51%). The presence of lymphocyte somatic mosaicism [i.e. the presence of diepoxybutane (DEB)-insensitive cells] was associated with a significantly increased risk of graft failure. Disappointingly, the use of higher dose TBI and post-transplant ATG did not improve engraftment. More effective peritransplant immunosuppression, especially in FA patients with somatic mosaicism, was required to overcome the barrier of graft rejection. New conditioning regimens adapted to each individual's alkylator sensitivity are needed to improve the outcome of alternative donor HCT for FA.

Adolescent↗

PubMed2000

Fanconi anaemia group A (FANCA) mutations in Israeli non-Ashkenazi Jewish patients.

Fanconi anaemia (FA) is a genetically heterogeneous disease with at least eight complementation groups (A-H). In the present study, we investigated the molecular basis of the disease in 13 unrelated Israeli Jewish (non-Ashkenazi) patients with FA. All 43 exons of the Fanconi anaemia A (FANCA) gene were amplified from genomic DNA and screened for mutations by single-strand conformation polymorphism and DNA sequencing. We identified four ethnic-specific mutations: (1) 2172-2173insG (exon 24), the first 'Moroccan mutation': (2) 4275delT (exon 43), the second 'Moroccan mutation'; (3) 890-893del (exon 10), the 'Tunisian mutation'; and (4) 2574C > G (S858R), the 'Indian mutation'. The tetranucleotide CCTG motif, previously identified as a mutation hotspot in FANCA and other human genes, was found in the vicinity of 2172-2173insG and 890-893del. According to our study, the four mutations account for the majority (88%) of the FANCA alleles in the Israeli Jewish (non-Ashkenazi) FA population. A screening of 300 Moroccan Jews identified three carriers of the first 'Moroccan mutation', but we did not find any carrier of the second 'Moroccan mutation' among 140 Moroccan Jews, nor any carrier of the 'Tunisian mutation' among 50 Tunisian Jews. Two 'Indian mutation' carriers were identified among 53 Indian Jews. All carriers within each ethnic group had the same haplotype, suggesting a common founder for each mutation.

Adolescent↗

PubMed2000

Stem cell transplantation for the treatment of Fanconi anaemia using a fludarabine-based cytoreductive regimen and T-cell-depleted related HLA-mismatched peripheral blood stem cell grafts.

We have employed a new cytoreductive regimen to transplant two patients with Fanconi anaemia (FA), using T cell-depleted two HLA-allele disparate related peripheral blood stem cell transplants (PBSCTs). Patient 1, a 5-year-old male with FA and aplastic anaemia, initially received an HLA two-antigen mismatched unrelated cord blood transplant and failed to engraft. He received fludarabine (Flu) and cyclophosphamide (Cy), followed by a CD34(+) E-rosette(-) (CD34(+)E(-)), T cell-depleted, granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCT from his HLA B-DRB1 mismatched father. He received anti-thymocyte globulin (ATG), steroids, FK506 and G-CSF after transplant for rejection and graft-versus-host disease (GVHD) prophylaxis. The patient is now 23 months after SCT with no evidence of GVHD and with full haematopoietic and immune reconstitution. Patient 2, a 10-year-old boy with FA and myelodysplastic syndrome, received single-dose total body irradiation (SDTBI), Flu and Cy followed by a CD34(+)E(-), T-cell-depleted, G-CSF-mobilized PBSCT from his HLA B-DRB1 mismatched sister. He also received ATG, steroids, FK506 and G-CSF after transplant. The patient is now 12 months after SCT in complete remission with no evidence of GVHD. Absolute neutrophil counts (ANC) of > 1 x 10(9)/l were achieved on day 11 and day 10 post transplant respectively. Both patients are fully engrafted. In summary, we report two successful T-cell-depleted stem cell transplants from mismatched related donors for the treatment of Fanconi anaemia, using a fludarabine-based cytoreduction. Both patients experienced minimal toxicity, rapid engraftment and no GVHD.

Child, Preschool↗

PubMed1999

The PISSLRE gene: structure, exon skipping, and exclusion as tumor suppressor in breast cancer.

In sporadic breast cancer, loss of heterozygosity (LOH) frequently occurs in three discrete regions of the long arm of chromosome 16q, the most telomeric of which is located at 16q24.3. Among the genes mapped to this region, PISSLRE is a plausible candidate tumor suppressor gene. It codes for a putative cyclin-dependent kinase that, as with other members of this family, is likely to be involved in regulating the cell cycle and therefore may have a role in oncogenesis. We characterized the genomic structure of PISSLRE and found that the splicing of this gene is complex. A variety of different transcripts were identified, including those due to cryptic splice sites, exon skipping, insertion of intronic sequences, and exon scrambling. The last phenomenon was observed in a rare PISSLRE transcript in which exons are joined at a nonconsensus splice site in an order different from that predicted by the genomic sequence. To screen the PISSLRE gene in breast tumors with ascertained LOH at 16q24.3, we have analyzed each exon by single-strand conformational polymorphism. No variation was found in the coding sequence, leading us to conclude that another tumor suppressor must be targeted by LOH in sporadic breast cancer.

Alternative Splicing↗

PubMed1999

Mutation analysis of the Fanconi anaemia A gene in breast tumours with loss of heterozygosity at 16q24.3.

The recently identified Fanconi anaemia A (FAA) gene is located on chromosomal band 16q24.3 within a region that has been frequently reported to show loss of heterozygosity (LOH) in breast cancer. FAA mutation analysis of 19 breast tumours with specific LOH at 16q24.3 was performed. Single-stranded conformational polymorphism (SSCP) analysis on cDNA and genomic DNA, and Southern blotting failed to identify any tumour-specific mutations. Five polymorphisms were identified, but frequencies of occurrence did not deviate from those in a normal control population. Therefore, the FAA gene is not the gene targeted by LOH at 16q24.3 in breast cancer. Another tumour suppressor gene in this chromosomal region remains to be identified.

Breast Neoplasms↗

PubMed1998

Characterization and screening for mutations of the growth arrest-specific 11 (GAS11) and C16orf3 genes at 16q24.3 in breast cancer.

Loss of heterozygosity involving the long arm of chromosome 16 is a frequent event seen in a number of human carcinomas, including breast, prostate, hepatocellular, and ovarian cancers. A region found to be commonly deleted in breast and prostate carcinomas is located at 16q24.3, which suggests the presence of a tumor suppressor gene that may be altered in these two malignancies. A detailed physical and transcription map of this region that includes the loci defining the smallest region of deletion has been constructed. This report describes the characterization of a transcript located in this region, the growth arrest-specific 11 (GAS11) gene, which was viewed as a potential tumor suppressor gene due to the expression of its mouse homolog specifically during growth arrest. The gene consists of 11 exons spanning approximately 25 kb. Northern blot analysis identified two ubiquitously expressed mRNAs of 3.4 and 1.8 kb produced by the use of alternative polyadenylation sites. Another gene, C16orf3 (chromosome 16 open reading frame 3), was found to lie within intron 2 of GAS11. This gene appears intronless, is transcribed in the orientation opposite to that of GAS11, and is expressed at low levels. These genes were examined for mutations in breast tumor DNA, and both were excluded as tumor suppressor genes involved in breast cancer.

Alleles↗

PubMed1998

New recessive syndrome characterized by increased chromosomal breakage and several findings which overlap with Fanconi anemia.

We describe four cases with several findings of Fanconi anemia (FA), but without hypersensitivity to DNA cross-linking that is the distinguishing characteristic of FA. Two of the cases are male and female sibs of Hispanic origin, age 6 years and 11 months, respectively. Both have short stature, failure to thrive, absent thumbs, short palpebral fissures, and skin pigmentation abnormalities. The girl also has developmental "dysplasia" of her hips. Presently, both siblings are hematologically normal. Elevated baseline chromosome breakage was observed in the boy, but not in the girl. Neither sib showed elevated diepoxybutane (DEB)-induced chromosomal breakage. In a subsequent pregnancy, prenatal studies showed slightly elevated baseline and DEB induced chromosome breakage (greater than normal, but lower than the established range for FA). The fetus had intrauterine growth retardation and an absent right thumb. A review of cases referred to the International Fanconi Anemia Registry for DEB testing showed one additional case with similar findings. That patient, a girl, of Caucasian English ancestry, age 14 years, had short stature, a history of failure to thrive, skin pigmentation abnormalities, absent right thumb, hypoplastic left thumb, and hydrocephalus that resolved spontaneously. Elevated baseline chromosome breakage was observed in skin fibroblasts but not in lymphocytes. We postulate that these cases represent a previously undescribed autosomal recessive syndrome. These and other previously reported cases provide evidence for alternative genetic mechanisms that may result in developmental anomalies similar to those seen in FA.

Abnormalities, Multiple↗

PubMed1998

Construction of a high-resolution physical and transcription map of chromosome 16q24.3: a region of frequent loss of heterozygosity in sporadic breast cancer.

A breast cancer tumor suppressor gene has been localized to chromosome 16q24.3 by loss of heterozygosity (LOH) studies of breast tumor DNA. To identify candidate genes for this suppressor function, we have constructed a detailed physical map extending approximately 940 kb from the telomere of the long arm of chromosome 16 that encompasses the minimum LOH interval. This contig consists of a minimum overlapping set of 35 cosmids and a single PAC clone that were aligned by restriction enzyme site mapping. Cosmids were initially identified by screening filters with markers localized to the region by physical mapping using mouse/human somatic cell hybrids, and subsequently cosmid ends were used to complete the contig. A total of seven known genes, including PRSM1, PISSLRE, and the recently cloned Fanconi anemia A (FAA) gene, and potential transcripts from exon-trapping experiments have been located to this contig. A minimum of 14 new transcripts have been identified based on homology of trapped exons with database sequences. This contig and expressed sequence map will form the basis for the identification of the breast cancer tumor suppressor gene in this region.

Breast Neoplasms↗

PubMed1998

Identification of Alu-mediated deletions in the Fanconi anemia gene FAA.

Fanconi anemia (FA) is an autosomal recessive syndrome associated with hypersensitivity to DNA cross-linking agents and predisposition to neoplasia. Eight complementation groups (A-H) have been described, but the only FA genes cloned so far are FAC and FAA. We have recently identified 40 different germline mutations, including microdeletions, microinsertions, and point mutations in genomic DNA from 97 FA patients from the International Fanconi Anemia Registry (IFAR) by single-strand conformational polymorphism (SSCP) analysis. Interestingly, only one mutant allele was identified in many of these patients. Haplotype analysis with intragenic polymorphisms, as well as cDNA analysis of some patients suggested the presence of large deletions that would not be detected by SSCP analysis. In this study, we report the occurrence of Alu-mediated genomic deletions in FAA. Two different deletions of 1.2 kb and 1.9 kb were found. Both deletions include exons 16 and 17 and remove a 156-bp segment from the transcript causing a shorter in-frame message. Sequence analysis revealed that introns 15 and 17 are rich in partial and complete Alu repeats. There are at least four head-to-tail arranged Alu elements in intron 17 and one in intron 15, all oriented in the 3'-->5' direction. Sequence analysis of the deletions showed that the 5' breakpoints occurred at different sites in the same Alu element in intron 15, while the 3' breakpoints were located in different Alu repeats in intron 17. Numerous Alu repeats are present in FAA, suggesting that Alu-mediated recombination might be an important mechanism for the generation of FAA mutations.

Base Sequence↗