Cost effectiveness of newborn screening for cystic fibrosis: a simulation study.

BACKGROUND: Early detection of cystic fibrosis (CF) by newborn screening (NBS) reduces the rate of avoidable complications. NBS protocols vary by jurisdiction and the cost effectiveness of these different protocols is debated. OBJECTIVE: To compare the cost effectiveness of various CF NBS options. METHODS: A Markov model was built to simulate the cost effectiveness of various CF-NBS options for a hypothetical CF-NBS program over a 5-year time horizon assuming its integration into an existing universal NBS program. NBS simulated options were based on a combination of tests between the two commonly used immunoreactive trypsinogen (IRT) cutoffs (96th percentile and 99.5th percentile) as first tier tests, and, as a second tier test, either a second IRT, pancreatic-associated protein (PAP) or CFTR mutation panels. CFTR mutation panels were also considered as an eventual third tier test. Data input parameters used were retrieved from a thorough literature search. Outcomes considered were the direct costs borne by the Quebec public health care system and the number of cases of CF detected through each strategy, including the absence of screening option. RESULTS: IRT-PAP with an IRT cutoff at the 96th percentile is the most favorable option with a ratio of CAD$28,432 per CF case detected. The next most favorable alternative is the IRT1-IRT2 option with an IRT1 cutoff at the 96th percentile. The no-screening option is dominated by all NBS screening protocols considered. Results were robust in sensitivity analyses. CONCLUSION: This study suggests that NBS for cystic fibrosis is a cost-effective strategy compared to the absence of NBS. The IRT-PAP newborn screening algorithm with an IRT cutoff at the 96th percentile is the most cost effective NBS approach for Quebec.

[Outcome of pregnancy in patients with haemophilia B--two case reports]. / Schwangerschaft bei Hämophilie B--Zwei Fallberichte.

BACKGROUND: Haemophilia B is a congenital coagulation disorder with a low activity of the coagulation factor IX. The means of transmission is recessively gender dependent. Usually the female carrier of the haemophilia B has normal activity of the coagulation factor. However, in very rare cases the factor-IX-activity may be reduced considerably, even in a female carrier (Lyon-hypothesis). Both for mother and the child, who has potentially inherited the disorder, there is a dramatically increased tendency for bleeding with the potential for developing further complications. PATIENTS: The deliveries of two conductors with a low activity of coagulation factor IX are presented. With a monitored substitution of factor-IX-concentrate it was possible to prolong the pregnancies nearly before the date of birth. In one case ended the pregnancy in a caesarean section, the second patient had a normal delivery. CONCLUSION: Today interdisciplinary treatment and exactly planning of the birth may led even high risk pregnancies to a successful end.

[Value of karyotyping women patients of couples referred for sterility]. / Place du caryotype féminin en assistance médicale à la procréation (AMP).

It has been known for some 25 years that there is a causal relation between chromosomal aberrations and male infertility and that the major indication for karyotyping an infertile man is still usually an abnormal sperm analysis. The value of karyotyping women in the routine work-up of couples referred for sterility has long been debated. A French recent cytogenetic study found an overall increased frequency of chromosomal aberrations in the female and confirmed that in some cases of poor reproductive outcome there may be a contribution of maternal chromosome aberrations. Indeed, the existence of a chromosome abnormality in the female partner was associated with the group of infertile men in which there was no apparent cause of infertility. These results emphasise the need for thorough genetic work-up in couples referred for sterility. This work-up should include karyotyping of the female for some indications explained in this work.

Cerebro-costo-mandibular syndrome in a father and a female fetus: early prenatal ultrasonographic diagnosis and autosomal dominant transmission.

Ultrasonography in a female fetus revealed cystic cervical hygroma, severe micrognathia, and vertebral and upper limb anomalies suggestive of cerebro-costo-mandibular syndrome (CCMS) which was diagnosed ultrasonographically at 16 weeks' gestation. The father is affected and presents with a Pierre Robin sequence, short stature and typical costovertebral anomalies. CCMS is a rare and severe disorder. The high frequency of sporadic cases, vertical transmission, and the excess of sibs affected via horizontal transmission suggest dominant autosomal mutation with possible germinal mosaicism. The vertical familial case detailed in the present report is a reminder of the high risk when one parent or one sibling is affected and the extreme variability of phenotype and costal ossification. Early prenatal ultrasound diagnosis is possible in a severely affected fetus.

[X-linked recessive chondrodysplasia punctata. Cytogenetic study and role of molecular biology]. / Chondrodysplasie ponctuée récessive liée à l'X. Etude cytogénétique et place de la biologie moléculaire.

UNLABELLED: Among the many acquired or constitutional causes of chondrodysplasia punctata, the X-linked recessive form is well individualized. CASE REPORT: A male newborn presented a dysmorphic syndrome with a marked nasal hypoplasia, a macroglossia and a short neck. The diagnosis of chondrodysplasia punctata was made by radiography whereas the chromosomal chart revealed the existence of an additional Y fragment in Xpter, effectuating a partial disomy Yp and a monosomy Xpter. Molecular biology showed a deletion of very small size, isolated and located between the gene missing aryl sulfatase E and the microsatellite DXS 1233, sping gene MRX2 (non-specific gene of mental retardation), and making it possible to give the reassuring elements as regards the psychomotor prognosis, sometimes compromised in this disorder. CONCLUSION: In case of chondrodysplasia punctata with dysmorphy, it is important to execute a chromosomal chart in the search for a chromosomal reorganization on the X and a study in molecular biology.

Chromosomal factors of infertility in candidate couples for ICSI: an equal risk of constitutional aberrations in women and men.

To assess the frequency of chromosomal aberrations in French candidates for intracytoplasmic sperm injection (ICSI), and to explore the existence of a female chromosomal factor in some cases of couple infertility, a collaborative retrospective clinical and cytogenetic study was performed, launched by the Association des Cytogénéticiens de Langue Franciaise (ACLF). The karyotypes of 3208 patients [2196 men (68.4%), 1012 (31.6%) women] included in ICSI programmes over a 3-year period in France were collected. A total of 183 aberrant karyotypes was diagnosed, corresponding to an abnormality frequency of 6.1% (134/2196) for men and 4.84% (49/1012) for women. The following frequencies of abnormalities were observed respectively for men and women: 1.23% (n = 27) and 0.69% (n = 7) for reciprocal translocations, 0.82% (n = 18) and 0.69% (n = 7) for Robertsonian translocations, 0.13% (n = 3) and 0.69% (n = 7) for inversions, 3.32% (n = 73) and 2.77% (n = 28) for numerical sex chromosome aberrations, and 0.59% (n = 13) and 0% for other structural aberrations. Among the male patients of this latter group, 0.40% (n = 9) had a Y chromosome abnormality. Among the male patients with numerical sex chromosome abnormalities, 2.23% (n = 49) were 47,XXY, 0.32% (n = 7) were 47,XYY, and 0.77% (n = 17) had a mosaicism for numerical sex chromosome anomalies. All the female patients with sex chromosome abnormalities (2.77%, n = 28) had mosaicism for numerical sex chromosome anomalies. Even if these cases-the significance of which was sometimes questioned-were disregarded in the analysis, 2.08% (21/1012) of abnormal karyotypes remained in women. An overall increased frequency of chromosomal aberrations was found, and this confirmed that in some cases of poor reproductive outcome there may be a contribution of maternal chromosome aberrations. Indeed, the existence of a chromosome abnormality in the female partner was associated with the group of infertile men in which there was no apparent cause of infertility.

Informed consent to serum screening for Down syndrome: are women given adequate information?

To assess the information given to women during a maternal serum screening (MSS) programme, we prospectively applied a questionnaire to 504 pregnant women attending for amniocentesis after a screen-positive result. The survey based on 200 usable questionnaires (39.7 per cent of our study population) showed that MSS was imposed as mandatory by 41.5 per cent of providers and done without their patients' agreement by 16 per cent. After release of the test results, 6.5 per cent of women believed that they were carrying a Down syndrome-affected fetus and 21.5 per cent thought the risk was about 50-50. A total of 38.5 per cent of the pregnant women were not informed of the risk of miscarriage after amniocentesis and 67.5 per cent believed that there was no possibility of a false-negative result with MSS. Information given over the telephone was particularly poorly understood compared with information provided during an outcome visit, since women who learned of their test result during such a visit scored significantly higher (69 per cent) when questioned about the risk of carrying a Down syndrome-affected fetus, compared with women informed of their test results by telephone (38.7 per cent) or by letter (47 per cent). We therefore suggest routine consultation with an antenatal care professional before testing to enable pregnant women to give their informed consent to MSS.

Cross-species characterization of the promoter region of the cystic fibrosis transmembrane conductance regulator gene reveals multiple levels of regulation.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene is highly conserved within vertebrate species. Its pattern of expression in vivo seems to be tightly regulated both developmentally and in a tissue-specific manner, but shows differences with species. To identify transcriptional regulatory elements in the CFTR promoter region, we have used a combined approach based both on the analysis of the chromatin structure in vivo in rat tissues and on evolutionary clues (i.e. phylogenetic footprinting). In CFTR-expressing tissues, 15 DNase I-hypersensitive sites were identified within a 36 kb region encompassing exon 1. Eleven of them are clustered in a 3.5 kb region that exhibits eleven phylogenetic footprints observed when comparing sequences from eight mammalian species representing four orders (Primates, Artiodactylia, Lagomorpha and Rodentia). Comparison of the two sets of data allows the identification of two types of regulatory elements. Some are conserved between species, such as a non-consensus cAMP response element (CRE) and a PMA-responsive element (TRE) located respectively at positions -0.1 and -1.3 kb relative to ATG. Some are species-specific elements such as a 300 bp purine.pyrimidine (Pu.Py) stretch that is present only in rodents. Analysis of protein/DNA interactions in vitro with rat tissue protein extracts on the conserved elements revealed that the TRE site binds a specific heterodimeric complex composed of Fra-2, Jun D and a protein immunologically related to Jun/CRE-binding protein in the duodenum, whereas the CRE-like site binds ATF-1 ubiquitously. Functional analysis in Caco-2 cells showed that the CRE-like site supports a high basal transcriptional activity but is not able by itself to induce a response to cAMP, whereas the TRE site acts as a weak transactivator stimulated by PMA. Lastly, we found that the rodent-specific Pu.Py stretch confers nuclease S1 hypersensitivity under conditions of acidic pH and supercoiling. This indicates a non-B DNA conformation and thus reinforces the biological significance of non-random Pu.Py strand asymmetry in the regulation of transcription. Thus the tight transcriptional regulation of CFTR expression involves the combination of multiple regulatory elements that act in the chromatin environment in vivo. Some of them are conserved throughout evolution, such as the CRE-like element, which is clearly involved in the basal level of transcription; others are species-specific.