[Spontaneous rupture of a splenic artery aneurysm during the early puerperium].

A 35-year-old otherwise healthy woman was found unconscious on the floor of her room in the delivery ward 3 days after giving birth by a cesarean section. Following primary evaluation and resuscitation, a relaparotomy for assumed internal bleeding was performed, and active bleeding from a splenic artery aneurysm was discovered. The following case report reminds us yet again that the puerperium is a highly unique period in a woman's life during which submerged pathologies surface, and therefore, poses a great challenge to the caring physician. In this article, the authors report the sequence of events leading from the patient's admittance to the cesarean section to her subsequent relaparotomy. A brief review is presented on the literature related to splenic artery aneurysm rupture during pregnancy and the puerperium.

Fish based preimplantation genetic diagnosis to prevent DiGeorge syndrome.

PURPOSE: To report the performance of fluorescence in-situ hybridization in the setting of preimplantation genetic diagnosis in order to diagnose embryos affected by DiGeorge syndrome. DESIGN: Case report. SETTING: Academic referral center. PATIENT: A 32 year-old female affected by DiGeorge syndrome. INTERVENTION(S): History and physical examination, karyotyping, amniocentesis, preimplantation genetic diagnosis, fluorescence in-situ hybridization. MAIN OUTCOME MEASURE(S): Avoidance of pregnancy with embryo affected by DiGeorge syndrome. RESULT(S): Termination of pregnancy with an affected embryo followed by fluorescence in-situ hybridization based preimplantation genetic diagnosis and delivery of healthy offspring. CONCLUSION(S): The combination of preimplantation genetic diagnosis with fluorescence in-situ hybridization is recommended to prevent pregnancies with DiGeorge syndrome affected embryos in properly selected patients.

Improved accuracy of postpartum blood loss estimation as assessed by simulation.

OBJECTIVE: Caregivers underestimate the amount of blood loss, but this almost five decades-old assumption has not been validated. We aimed at assessing the accuracy of estimated blood loss by obstetrical teams during a simulated Postpartum hemorrhage (PPH) scenario. STUDY DESIGN: a prospective study conducted as part of the simulation-based training course, using sophisticated mannequin simulators adapted for obstetrical training by specially designed devices. SETTING: Part of the simulation-based training course. POPULATION: Obstetrical teams consisted of physicians and obstetrical nurses. METHODS: Each of the participating obstetrical teams assessed blood loss during PPH scenarios. Their estimates were compared to the actual predefined 3.5-liter blood loss. An intervention group underwent a similar course in which they recorded their estimations after 1, 2 and 3.5 liters were lost. OUTCOME MEASURES: Blood loss estimates after completion of the scenario in both groups. RESULTS: Fifty obstetrical teams took part in the study. Eight comprised the interventional group. The average estimated blood loss was 1,780 ml (49% underestimation) for non-interventional teams. The interventional groups estimated blood loss to be 2,400 ml (32% underestimation). The main method of estimating blood loss was 'gut feeling', followed by verbalized guesses of team members and assessments of the 'patient's' hemodynamic status. CONCLUSIONS: Accuracy of blood loss estimations by a simulation-based PPH scenario was 50-60%. Measurements at predetermined intervals significantly improved accuracy of these estimations. Our study suggests that implementation of periodic estimations of blood loss in the management of PPH might improve clinical judgment.

Preconceptional and prenatal screening for fragile X syndrome: experience with 40,000 tests.

OBJECTIVES: To determine the carrier frequency of fragile X syndrome, and the rate of expansion from premutation (PM) carrier to full mutation (FM) fetus. METHODS: Results were analyzed on women with no family history of fragile X syndrome, or who were PM/FM carriers, who were tested between January 1994 and June 2004. PM was defined 55-199 repeats, FM above 200. RESULTS: Out of 40 079 women screened, 5 FM and 255 PM carriers were detected. There was no significant difference in carrier frequency between those with versus those without family history of mental retardation or developmental abnormalities: 1 in 128 (28/3596) versus 1 in 157 (232/36 483). However, the median of repeats differed significantly: 58 and 66 repeats, respectively, (P < 0.0001). Invasive prenatal diagnosis was carried out in 370 pregnancies (7 FM and 363 PM). Thirty FM fetuses were detected. There was a lower expansion rate in cases without a family history: 10% (17/169 PMs) compared to 50% (11/22 PMs) in those with a history, but this could be accounted for by the difference in allele size. CONCLUSION: There is now sufficient information on screening parameters and prenatal diagnosis of fragile X syndrome to offer testing to women of reproductive age.

Recurrent obstetric management mistakes identified by simulation.

OBJECTIVE: To develop a simulation-based curricular unit for labor and delivery teams involved in obstetric emergencies to detect and address common mistakes. METHODS: A simulation-based curricular unit for hands-on training of four obstetric emergency scenarios was developed using high-tech mannequins and low-tech simulators. The scenarios were eclamptic seizure, postpartum hemorrhage, shoulder dystocia, and breech extraction. The obstetric teams consisted of at least one resident and two midwives. Checklists of actions expected from the teams were handed out to the course's tutors who observed the "event." All sessions were videotaped and then reviewed and analyzed by the trainees themselves, who were guided by two experienced tutors. We identified the most commonly occurring mistakes by summing up checklists and by watching the recorded sessions. RESULTS: Between February 2004 and April 2006, 60 residents in obstetrics and gynecology and 88 midwives underwent the simulation-based course. Forty-two labor and delivery teams completed all four sessions. The most common management errors were delay in transporting the bleeding patient to the operating room (82%), unfamiliarity with prostaglandin administration to reverse uterine atony (82%), poor cardiopulmonary resuscitation techniques (80%), inadequate documentation of shoulder dystocia (80%), delayed administration of blood products to reverse consumption coagulopathy (66%), and inappropriate avoidance of episiotomy in shoulder dystocia and breech extraction (32%). Eighteen trainees were invited for repeated sessions at least 6 months after the first training day, and their scores were significantly higher in the latter sessions (79.4+/-4.3 versus 70+/-5.3 for the second and first simulated eclampsia sessions). CONCLUSION: A curricular unit based on simulation of obstetric emergencies can identify pitfalls of management in labor and delivery rooms that need to be addressed.

Isolated levocardia: prenatal diagnosis, clinical importance, and literature review.

OBJECTIVE: Isolated levocardia is a rare type of situs inversus in which the heart is in the normal levo position, but the abdominal viscera are in the dextro position. We aim to describe our experience with prenatal diagnosis and management in fetuses with isolated levocardia. METHODS: Of all the cases referred to our tertiary ultrasound unit, 3 cases of isolated levocardia were diagnosed. Patients and fetuses were evaluated every 4 weeks until delivery and postnatally. RESULTS: Two of the 3 fetuses had interruption of the inferior vena cava with azygous continuation. However, postnatal evaluation revealed polysplenia in 1 neonate and asplenia in another. Polysplenia was also diagnosed in the third neonate, who had a normal inferior vena cava on antenatal examination. One neonate had a small ventricular septal defect. CONCLUSIONS: Fetal isolated levocardia is associated with a good outcome, in which other malformations are excluded. Therefore, we suggest conservative management in such cases.

Embryonic karyotype in recurrent miscarriage with parental karyotypic aberrations.

OBJECTIVE: To assesses chromosomal aberrations in the abortus in recurrent miscarriage, in the presence of parental chromosomal aberrations. DESIGN: Retrospective comparative cohort study. SETTING: Tertiary referral unit in university hospital. PATIENT(S): One thousand one hundred eight patients with 3-16 miscarriages before 20 weeks gestation; 113 patients with and 995 without chromosomal aberrations. INTERVENTION(S): Karyotyping by standard G-banding techniques of both parents, and of 205 abortuses collected at curettage. MAIN OUTCOME MEASURE(S): The incidence of the euploidic and aneuploidic abortuses according to the parental karyotype. RESULT(S): Two hundred three abortuses were successfully karyotyped. In 164 embryos of patients with no parental chromosomal aberrations, 23.2% (38/164) had chromosome aberrations. Of the 39 abortuses karyotyped in patients with chromosomal aberrations, 17 had normal karyotypes, 8 had balanced translocations, 2 had inversions identical to the parents, and 12 (30.8%) had abnormal karyotypes. This difference is not statistically significant (odd ratio 1.47, 95% confidence interval 0.63-3.39). Only 4 of the 39 karyotyped abortuses had an unbalanced translocation. CONCLUSION(S): Parental karyotyping was not particularly predictive of a subsequent miscarriage as a result of chromosomal aberrations as 43.5% of abortuses were euploidic, and the parental aberration was only passed on to the abortus in 10% of cases.

Cortistatin inhibits growth hormone release from human fetal and adenoma pituitary cells and prolactin secretion from cultured prolactinomas.

CONTEXT: Cortistatin (CST) is a neuropeptide that shares high homology with somatostatin and binds with high affinity to all somatostatin receptor (SSTR) subtypes. Many of its endocrine and biological activities overlap with those of somatostatin. OBJECTIVE/DESIGN: The objective of the study was to assess the direct in vitro effects of CST on human pituitary hormone secretion. SETTING: This study was performed in the endocrine laboratory of a tertiary academic medical center. MATERIALS: Primary cell cultures of human fetal (21-25 wk gestation) pituitary tissues and cultured hormone-secreting adenoma cells were used in this study. INTERVENTIONS: Cell cultures were incubated with CST-14 or CST-17, somatostatin, GHRH, SSTR analogs, and ghrelin analogs, and hormone secretion was analyzed. OUTCOME MEASURES: GH and prolactin (PRL) medium concentrations were tested by hormone assay, and SSTR mRNA was tested by RT-PCR. RESULTS: CST-14 (10 nm) inhibited GH secretion by up to 65% in all fetal pituitary specimens after 4-h incubation (P < 0.05). CST-14 or CST-17 (10 nm) inhibited basal GH secretion in six of the 13 GH-cell adenomas and two of the three GH-PRL mixed adenomas. CST-17 (100 nm) suppressed the GH response to GHRH and ghrelin analog (10 nm each) by 30-50% in adenomas (P < 0.05). Three PRL-adenomas treated with CST-17 (10 nm) showed a 20-40% inhibition of PRL release (P < 0.05), whereas in three others no suppression or mild response was achieved at this concentration. A comparable inhibition of PRL secretion was obtained with SSTR5-selective analog but significantly less with SSTR2-preferential compounds. RT-PCR revealed the expression of both SSTR2 and SSTR5 in all GH-cell and mixed adenomas studied and all PRL-secreting adenomas studied, except for two of the CST-resistant prolactinomas, in which SSTR5 was absent. CONCLUSIONS: This is the first report of in vitro CST suppression of human GH and PRL in cultured pituitary tissues. The regulation of PRL release from cultured adenomas appears to be primarily mediated by SSTR5.

Chromosomal abnormalities and birth defects among couples with colchicine treated familial Mediterranean fever.

OBJECTIVE: To determine whether colchicine prescribed for familial Mediterranean fever is teratogenic. STUDY DESIGN: Reproductive histories were analyzed from 326 couples referred for prenatal diagnosis because 1 partner was affected. Numbers of chromosomal abnormalities and birth defects were compared with numbers expected from published rates. RESULTS: There were 901 pregnancies, and amniocentesis had been performed in 566, all but 3 conceived while taking colchicine. Seven numerical chromosomal abnormalities were found, not statistically significantly greater than the 4.99 expected from maternal age and gestation of diagnosis (P = .24): unbalanced structural abnormalities were 6, compared with 3.22 expected (P = .11). There were 7 birth defects, a considerably lower rate than reported in local malformation registers. CONCLUSION: The current policy of routine amniocentesis in pregnancies of couples taking colchicine should not be changed until sufficient data accumulates to establish whether the higher number of chromosomal anomalies in this group is significant.

Chromosome aberration and environmental physical activity: Down syndrome and solar and cosmic ray activity, Israel, 1990-2000.

The possibility that environmental effects are associated with chromosome aberrations and various congenital pathologies has been discussed previously. Recent advances in the collection and computerization of data make studying these potential associations more feasible. The aim of this study was to investigate a possible link between the number of Down syndrome (DS) cases detected prenatally or at birth yearly in Israel over a 10-year period compared with the levels of solar and cosmic ray activity 1 year before the detection or birth of each affected child. Information about 1,108,449 births was collected for the years 1990-2000, excluding 1991, when data were unavailable. A total of 1,310 cases of DS were detected prenatally or at birth--138 in the non-Jewish community and 1,172 in the Jewish population. Solar activity indices--sunspot number and solar radio flux 2,800 MHz at 10.7 cm wavelength for 1989-1999--were compared with the number of DS cases detected. Pearson correlation coefficients (r) and their probabilities (P) were established for the percentage of DS cases in the whole population. There was a significant inverse correlation between the indices of solar activity and the number of cases of DS detected--r=-0.78, P=0.008 for sunspot number and r=-0.76, P=0.01 for solar flux. The possibility that cosmophysical factors inversely related to solar activity play a role in the pathogenesis of chromosome aberrations should be considered. We have confirmed a strong trend towards an association between the cosmic ray activity level and the incidence of DS.

Trophoblasts isolated from the maternal circulation: in vitro expansion and potential application in non-invasive prenatal diagnosis.

Prenatal diagnosis based on rare fetal cells in maternal blood is currently not a feasible option. An effort was made to improve cell yields by targeting trophoblast cells. After sorting, the HLA-G-positive cell fraction was analyzed directly or after culture. In situ hybridization technology was applied to prove fetal cell source in samples from women carrying a male fetus and to predict gender in samples without previous knowledge of fetal sex. In vitro culture led to a significant increase in fetal cells and accurate gender prediction in 93% of these samples. This approach might be useful for non-invasive prenatal diagnosis.

Nitric oxide stimulates growth hormone secretion from human fetal pituitaries and cultured pituitary adenomas.

Nitric oxide (NO), a highly reactive free radical, has been identified as a neurotransmitter in the central and peripheral nervous system. NO synthase (NOS) is the enzyme responsible for NO production from L-arginine and plays an important role in regulating the release of several hypothalamic peptides. In the pituitary, NO was found to increase growth hormone (GH) secretion in several in vitro and in vivomodels. However, its role in human GH regulation is unknown. The aim of this study was to investigate the regulatory effects of NO on human GH and prolactin secretion using primary cell cultures of human fetal pituitaries and cultured hormone-secreting adenomas. Incubation of the human fetal pituitaries (21-24 wk gestation) in the presence of sodium nitroprusside (SNP; 1 mM), a NO donor, for 4 h resulted in a 50-75% increase in GH secretion, similar to the stimulatory effect evoked by growth hormone-releasing hormone (GHRH) (10 nM). However, fetal PRL secretion was not affected by SNP. GH release was also stimulated (40-70% increase) by SNP in 60% of the cultured GH-secreting adenomas studied. SNP-induced GH release was inhibited in both fetal and adenomatous cells by PTI0, a NO scavenger. The addition of cGMP (0.1-1 mM), the second messenger of multiple NO actions, enhanced fetal and adenomatous GH secretion by 55-95%. Neuronal NOS (nNOS) was expressed in normal (fetal and adult) human pituitary tissues and in GH-secreting adenomas. Examination of its functional expression using L-arginine (1 microM) yielded a 35% increase in GH release from cultured GH-secreting adenoma. This response was blocked by a NOS inhibitor with high selectivity for the neuronal enzyme and by a guanylyl cyclase inhibitor. In conclusion, NO stimulates human GH in cultured fetal pituitaries and GH-secreting adenomas. Cyclic GMP is probably involved in this hormonal regulation.

CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: a case-control study of female patients and several ethnic groups in the Israeli Jewish population.

The human small-conductance Ca(2+)-activated potassium channel gene KCNN3 has been involved in mechanisms underlying neuronal function and plasticity. A multiallelic CAG repeat polymorphism within the KCNN3 has been associated with schizophrenia and bipolar disorder. We have previously reported in a family-based study that longer CAG repeats are preferentially transmitted to patients with anorexia nervosa (AN). The present study extends the analysis of KCNN3 allele distribution to a larger series of AN female patients and control groups, incorporating information on ethnicity and co-morbidities associated with AN. The data analysis is presented while considering separately the two alleles of each individual, namely a minor (shorter) and a major (longer) allele. This study has found that the KCNN3 allele distribution in the general Israeli population does not differ significantly in at least four Jewish ethnic groups of Ashkenazi, North African, Iraqi, and Yemenite origin. These have been used as control groups in a matched case-control analysis that has demonstrated a significant over-representation of KCNN3 alleles with longer CAG repeats among AN patients (P < 0.001 for the major allele and P = 0.035 for allele sum). Under dichotomization, a significantly higher prevalence of the L allele (>19 repeats) has been observed among AN patients (P < 0.001). While considering AN and co-morbid phenotypes, a tendency towards longer (L) alleles has been observed in the subset of patients with obsessive-compulsive disorder (OCD) co-morbidity. These findings further implicate KCNN3 as a significant contributor to predisposition to AN.

Analysis of fetal blood cells in the maternal circulation: challenges, ongoing efforts, and potential solutions.

The invasive procedures amniocentesis and chorionic villus sampling (CVS) are routinely applied in pregnancies at risk for fetal abnormalities and the results obtained are the gold standard for prenatal diagnosis. Because these methods of fetal cell procurement involve a 0.5-2% risk for fetal loss, they are recommended mainly in cases at high risk for fetal genetic or cytogenetic abnormalities. The development of a reproducible, reliable, noninvasive method based on retrieval of rare fetal cells from the maternal circulation will render testing feasible for the general population. Despite intensive investigation, a satisfactory, clinically acceptable method has not yet emerged. Several cell types have been targeted to this end, mostly nucleated red blood cells (NRBC), CD34+ hematopoietic progenitors, and trophoblasts. Although these cell types have been unequivocally proven to be present in the maternal circulation, each bears a significant disadvantage, rendering their application in clinical testing currently impossible: NRBC cannot be expanded in culture, thereby ruling out metaphase chromosome analysis, an essential component of prenatal diagnosis. CD34+ cells do posses the potential for in vitro proliferation, however, they have been found to persist in the maternal circulation after delivery, thereby complicating diagnosis in consecutive pregnancies. Trophoblasts are not consistently detected in the maternal circulation. Moreover, due to the lack of a definitive fetal cell marker and a reliable sorting method, foolproof fetal cell identification of any of these cell types is not possible. This report outlines the obstacles that impede development of a method for noninvasive fetal cell sampling for prenatal genetic diagnosis, along with a description of our efforts to analyze simultaneously two fetal blood cell types, NRBC and CD34+ cells in maternal blood during pregnancy, and the problems encountered. This work and that of others lead us to suggest potential future directions to help develop this important technique.

Genetic and biochemical analyses of Israeli osteogenesis imperfecta patients.

Osteogenesis imperfecta (OI) is clinically characterized by abnormal bone fragility, with most patients harboring heterozygote germline mutations in the COL1A1 or COL1A2 genes that encode the chains of type I procollagen, the major protein in bone. More than 250 mutations in both genes in OI patients have been reported, mostly missense mutations affecting glycine residues in the triple helical domains of the two chains. These mutations disrupt protein folding and structure, and their effects often can be detected by the analysis of proteins synthesized but cultured fibroblasts or, less often, osteoblasts. In this study, mutational analysis of all the COL1A1 and part of the COL1A2 was performed using exon-specific PCR amplification followed by denaturing gradient gel electrophoresis (DGGE) analysis and complemented by DNA sequencing in 57 Israeli OI patients from 55 unrelated families. Protein analysis was also performed using cultured fibroblasts obtained from a subset of these OI patients. Of 57 OI patients analyzed, 35 had OI type 1, 12 has OI type III, 8 had OI type IV, and 2 had OI type II. Fourteen different pathogenic mutations (10 novel) were identified in the COL1A1 gene: 3 missense, 5 nonsense, 3 insertion/deletion frameshift, 2 splice junction mutations, and 1 in frame deletion. We conclude that COL1A1 mutations underlie a subset of Israeli OI patients, that most commonly in OI type I, the mutations are contained within the COL1A1 gene, and that there are no predominant mutations in Jewish OI patients. Lastly, the use of protein analyses complements genetic analyses.

Prenatal diagnosis of Down syndrome: ten year experience in the Israeli population.

Second trimester maternal serum biochemical markers, introduced between 1990 and 1995, were supplemented with new ultrasound methods at 14-16 weeks and first trimester biochemical markers between 1995 and 2000. This study evaluated the effectiveness of a Down syndrome (DS) prevention program among the Israeli Jewish population between 1990 and 2000. We collected data on the total number of prenatal tests performed on Israeli Jewish women, DS cases detected prenatally and DS livebirths in Israel during these years. We also studied the use of the newer screening tests in 1990, 1992, and 2000. Between 1990 and 1995, use of chromosomal studies for DS in this population increased from 11.3% to 21.6% and the percentage of cases detected prenatally from 53% to 70%. However, between 1996 and 2000, even with the new screening methods, the utilization rate remained similar (20.7% and 19.8%, respectively) and the percentage detected prenatally decreased to 61% in 2000. The total cost per case detected increased from $47,971 US dollars in 1990 to $75,229 US dollars in 1992, and to $190,171 US dollars in 2000. Between 1990 and 1995, improvement in the percentage of cases detected prenatally was associated with a significant increase in the amniocentesis rate-both are attributed to the introduction of second trimester maternal serum biochemical marker tests. Unexpectedly, the introduction between 1995 and 2000 of new genetic methods to assess the DS risk did not improve the percentage detected or reduce the amniocentesis rate, and was accompanied by an increased cost per case detected.

The cell adhesion molecules N-cadherin and neural cell adhesion molecule regulate human growth hormone: a novel mechanism for regulating pituitary hormone secretion.

Pituitary GH secretion is regulated by hypothalamic hormones and peripheral factors. Cell-cell contact may also have an important role in regulating pituitary hormone expression and secretion. The role of pituicyte cell-cell contact mediated by N-cadherin and neural cell adhesion molecule (N-CAM) was studied in the regulation of GH secretion. RT-PCR showed N-cadherin mRNA expression in eight of 12 of GH-secreting adenomas compared with one of seven of prolactin-cell adenomas. N-cadherin and N-CAM were similarly expressed in adenomas and in adult and fetal normal pituitary tissues. The effects of CAM homophilic binding on GH secretion from dispersed human fetal pituitary cultures were studied by manipulating CAM mediated cell-cell contact using either soluble N-cadherin-Fc or pituitary cells cocultured with NIH-3T3 cells stably expressing CAMs. CAM stimulation increased GH secretion from pituitary fetal cultures by 40-60% (P < 0.05) and also from cultured GH adenoma cells by 40-75% (P < 0.05). Disrupting N-cadherin homophilic binding by anti-N-cadherin antibody decreased fetal, but not tumorous GH secretion by 40% (P < 0.05). This study indicates that pituitary cell-cell contact mediated by homophilic interactions between adhesion molecules regulates human GH secretion.

Frequency of Down's syndrome and neural-tube defects in the same family.

BACKGROUND: There is evidence that some mothers of infants with Down's syndrome have abnormal metabolism of folate and methyl, as well as mutations in folate genes, which are features that are also seen in neural-tube defects (NTD). We therefore investigated whether Down's syndrome and NTD arise more often in the same family than would be expected from the incidence of each disorder considered separately. METHODS: We studied two series of families using information obtained from medical records about maternal age, pregnancy outcome, congenital malformations, and karyotype: the first, 493 families from Israel who were at high risk of NTD (445 with a history of NTD and 48 with isolated hydrocephalus); and the second, 516 families from the Ukraine at high risk of Down's syndrome. FINDINGS: In the families at risk of NTD, there were a total of 11 pregnancies affected by Down's syndrome in 1492 at-risk pregnancies (compared with 1.87 expected on the basis of maternal age), which was a significant increase (p<0.00001). In the families at risk of Down's syndrome, there were seven NTD pregnancies in 1847 at risk, compared with 1.37 expected (p<0.001). INTERPRETATION: In this study, we provide direct evidence of a link between Down's syndrome and NTD. Folate supplementation before conception has the potential to reduce the frequency of Down's syndrome.

Bloom syndrome and Fanconi's anemia: rate and ethnic origin of mutation carriers in Israel.

BACKGROUND: The Bloom syndrome gene, BLM, was mapped to 15q26.1 and its product was found to encode a RecQ DNA helicase. The Fanconi's anemia complementation group C gene was mapped to chromosome 9q22.3, but its product function is not sufficiently clear. Both are recessive disorders associated with an elevated predisposition to cancer due to genomic instability. A single predominant mutation of each disorder was reported in Ashkenazi Jews: 2281delATCTGAinsTAGATTC for Bloom syndrome (BLM-ASH) and IVS4 + 4AT for Fanconi's anemia complementation group C. OBJECTIVES: To provide additional verification of the mutation rate of BLM and FACC in unselected Ashkenazi and non-Ashkenazi populations analyzed at the Sheba Medical Center, and to trace the origin of each mutation. METHODS: We used polymerase chain reaction to identify mutations of the relevant genomic fragments, restriction analysis and gel electrophoresis. We then applied the Pronto kit to verify the results in 244 samples and there was an excellent match. RESULTS: A heterozygote frequency of 1:111 for BLM-ASH and 1:92 for FACC was detected in more than 4,000 participants, none of whom reported a family history of the disorders. The Pronto kit confirmed all heterozygotes. Neither of the mutations was detected in 950 anonymous non-Ashkenazi Jews. The distribution pattern of parental origin differed significantly between the two carrier groups, as well as between each one and the general population. CONCLUSIONS: These findings as well as the absence of the mutations in non-Ashkenazi Jews suggest that: a) the mutations originated in the Israelite population that was exiled from Palestine by the Roman Empire in 70 AD and settled in Europe (Ashkenazi), in contrast to those who remained; and b) the difference in origin distribution of the BS and FACC mutations can be explained by either a secondary migration of a subgroup with a subsequent genetic drift, or a separate geographic region of introduction for each mutation.