Markku Ryynanen

Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome.

Keratitis-ichthyosis-deafness syndrome (KID) is a rare ectodermal dysplasia characterized by vascularizing keratitis, profound sensorineural hearing loss (SNHL), and progressive erythrokeratoderma, a clinical triad that indicates a failure in development and differentiation of multiple stratifying epithelia. Here, we provide compelling evidence that KID is caused by heterozygous missense mutations in the connexin-26 gene, GJB2. In each of 10 patients with KID, we identified a point mutation leading to substitution of conserved residues in the cytoplasmic amino terminus or first extracellular domain of Cx26. One of these mutations was detected in six unrelated sporadic case subjects and also segregated in one family with vertical transmission of KID. These results indicate the presence of a common, recurrent mutation and establish its autosomal dominant nature. Cx26 and the closely related Cx30 showed differential expression in epidermal, adnexal, and corneal epithelia but were not significantly altered in lesional skin. However, mutant Cx26 was incapable of inducing intercellular coupling in vitro, which indicates its functional impairment. Our data reveal striking genotype-phenotype correlations and demonstrate that dominant GJB2 mutations can disturb the gap junction system of one or several ectodermal epithelia, thereby producing multiple phenotypes: nonsyndromic SNHL, syndromic SNHL with palmoplantar keratoderma, and KID. Decreased host defense and increased carcinogenic potential in KID illustrate that gap junction communication plays not only a crucial role in epithelial homeostasis and differentiation but also in immune response and epidermal carcinogenesis.

On what grounds do women participate in prenatal screening

Along with the rapid biomedical development of prenatal screening tests, target groups attitudes and decision‐making about, and the acceptance of, screening procedures have come into focus. To understand users decision‐making, it is essential to understand users knowledge and perceptions of a procedure. The aim of this study was to examine Finnish womens knowledge and perceptions of, and stated reasons to participate in, two prenatal screening tests: serum screening and mid‐trimester ultrasound screening. Subjects (n=1035) for the serum screening survey were catered for in the maternity care centres of two Finnish towns, where serum screening is available for all pregnant women. After one reminder, 88 per cent returned the questionnaire. Subjects (n=497) for the mid‐trimester ultrasound screening survey were catered for in the obstetrical and gynaecological outpatient clinic of the city hospital of another town; the response rate was 85 per cent. Womens perceptions of the studied prenatal screening tests, serum screening and mid‐trimester ultrasound screening, differed significantly, even though both are used to detect fetal malformations. Serum screening was far more often perceived to be connected with finding diseases or abnormalities than ultrasound screening. Another interesting finding was that the stated reasons for screening in general and the subjective reasons for participation were different. Reassurance was the personal reason most often mentioned in both the serum screening and the ultrasound group. Almost all women had the most superficial knowledge about serum screening; they knew whether it had been offered and that it is done to screen for Down syndrome. The greatest gaps in knowledge concerned the sensitivity of serum screening, its use in screening for congenital nephrosis, and diagnostic tests and their risks. Knowledge was poorer among women without a high school education. When counselling women about prenatal screening tests, more emphasis should be given to the sensitivity of serum screening, all of its screening uses, and the possible diagnostic tests and their risks. The fact that ultrasound screening can detect conditions which may lead to the possibility of a selective abortion should also be explained more fully.

Women's decision-making in prenatal screening

With serum screening (MS-AFP and hCG testing for Downs syndrome) women have to make several decisions in a limited time: whether to participate in the screening in the first place; then, if increased risk for fetal abnormality is detected, whether to have a diagnostic test, and finally, what to do if fetal abnormality is detected. The aim of this study was to examine how women themselves in an unselected population describe their decision-making in the different phases of serum screening. Women receiving a positive result from serum screening in two Finnish towns from September 1993 to March 1994 and a group of individually matched controls were invited to semistructured interviews; 45 index and 46 control women (79% of those invited) participated between their 29th and 37th weeks of gestation (mean 31 weeks). Although serum screening was most often presented as voluntary or as an option, half the women described participation as a routine or self-evident act; only one-fourth of the women described actively deciding about participation. After a positive screening result, womens reactions to diagnostic tests, and their intentions if disability would be detected, varied greatly. Most of the women actively decided about having diagnostic tests, but for 23% participation in diagnostic testing was called a self-evident act. Womens intentions regarding abortion varied from a firm decision to abort to a firm decision not to abort, and many remained ambivalent. Prenatal screening, which demands the making of several decisions in a limited time and is offered to all pregnant women as part of established maternity care, is not based on every participants active decision-making and thus creates an ethical problem. This problem should receive special attention from those who develop, introduce and decide on new health care practices.

Altered expression of angiogenesis-related placental genes in pre-eclampsia associated with intrauterine growth restriction

Aim. The normal endovascular invasion of trophoblast cells and spiral artery remodeling are impaired in pre-eclampsia. Neither the circulating factor secreted by the placenta nor the cause of the widespread endothelial dysfunction in pre-eclampsia has yet been identified. In an attempt to identify novel factors, we performed a gene expression profiling study of placental tissue from women with and without pre-eclampsia. Material and methods. The study group comprised two pre-eclamptic patients with intrauterine growth restriction while the control group comprised three healthy women with uncomplicated pregnancies. Gene expression was studied using Affymetrix Human Genome U133 Plus 2 micro arrays. We focused on genes associated with angiogenesis. Some of the micro array analysis results were verified using real-time reverse transcription polymerase chain reaction (RT-PCR). Results. Gene expression profiling revealed that the expression level of nine genes – ECGF1, JAG1, Palladin, COL18A1, TNFSF12, VEGF, ANPEP, PDGFRA and SERPIN12 – was downregulated whereas the level of four genes – EPAS1, FLT1, SIGLE10 and ANG4 – was upregulated in the study group compared with the control group. The real-time RT-PCR results from JAG1, COL18A1 and FLT1 genes were in accordance with the gene expression results. Conclusion. Our results show new targets for research to understand the mechanisms leading to pre-eclampsia.

The influence of smoking on the pregnancy‐associated plasma protein A, free β human chorionic gonadotrophin and nuchal translucency

Objective To analyse the effects of smoking on first trimester parameters used in prenatal screening for Downs Syndrome.

Evaluation of factor V Leiden, prothrombin and methylenetetrahydrofolate reductase gene mutations in patients with severe pregnancy complications in northern Finland.

Background: Thrombosis in placenta may lead to severe pregnancy complications. Most important inherited thrombophilias are factor V Leiden mutation, prothrombin mutation, and methylenetetrahydrofolate reductase mutation. The aim of our research was to evaluate the prevalence of inherited thrombophilias in severe pregnancy complications and in normal pregnancies. Material and Methods: The study subjects with severe preeclampsia, intrauterine growth restriction, placental abruption or fetal death were collected during the period 1999–2004 from Oulu University Hospital. We also collected during the same period voluntary parturients with normal pregnancy outcome as the control group. FVL, FII, and MTHFR gene mutations of the patients and controls were analyzed. Results: We found a significant difference in the prevalence of FVL mutation between the groups. There were 9.5% FVL mutations in the study group compared to 1.8% in the control group; the observed difference between prevalences was 7.7% (95% CI 2.0–13.4). No statistical difference was found in the FII or MTHFR mutations between the groups. All FV and FII mutations were heterozygous and all the MTHFR mutations homozygous. Conclusion: Women with thrombophilia have a risk for severe pregnancy complications. Randomized controlled trials are needed to assess the influence of low-molecular-weight heparin in pregnant women with thrombophilia.

The secretion of PAPP-A, ADAM12, and PP13 correlates with the size of the placenta for the first month of pregnancy

OBJECTIVESnPregnancy Associated Protein A (PAPP-A), A Disintegrin and Metalloproteinase 12 (ADAM12) and Placental Protein 13 (PP13) are secreted from the placental trophoblastic tissue and are involved in normal implantation and placental development. The aim of the study was to assess the connection between the secretion of these proteins and the growth of the gestational sac and the placenta.nnnSTUDY DESIGNnIn an observational longitudinal study at Oulu University Hospital, women with naturally conceived pregnancies were followed-up weekly to pregnancy week 11.nnnMAIN OUTCOME MEASURESnPAPP-A, ADAM12 and PP13 serum concentrations and their correlation with the volumes of the gestational sac and the placenta were assessed using three-dimensional ultrasonography.nnnRESULTSnThe study group consisted of 41 women. The PAPP-A, ADAM12 and PP13 serum concentrations increased continuously from pregnancy week 4 to week 11 and correlated closely with each other. The serum concentrations of PAPP-A, ADAM12 and PP13 also correlated with the volumes of the gestational sac and the placenta up to pregnancy week 8.nnnCONCLUSIONSnThe secretion of PAPP-A, ADAM12 and PP13 is closely related to the size of the placenta in the beginning of pregnancy. After 8 weeks of pregnancy, which is the time for luteoplacental shift, the correlation disappears, possibly reflecting the morphologic transformation in the placenta.

Participation in prenatal screening tests and intentions concerning selective termination in Finnish maternity care.

Aims: The study examined how prenatal screening tests are presented to women, factors associated with women’s participation in screening, their experience of decision-making and intentions concerning pregnancy termination, and hospital data on rates of selective terminations. Methods: Questionnaires were given to pregnant women visiting maternity centres in two Finnish towns in which serum screening was offered (n = 1,035) and in one town where midtrimester ultrasound screening was offered (n = 497). Response rates to the questionnaires were 88 and 85%, respectively. Other questionnaires asking about selective terminations following detected fetal disorders were sent in 1993 to all public hospitals with obstetrics or gynaecology departments (response rate 100%). Results: The serum screening test had usually been offered to women as a free choice, but for 22% of them it was presented as a routine procedure. Most women (92%) underwent serum screening and most (86%) found the decision to participate or not easy. In almost every aspect of presentation and participation studied, serum and ultrasound screening differed from each other. 85% of respondents to ultrasound screening answered that it was offered as a routine procedure. Close acquaintance with a person with congenital disability was negatively associated with participation in serum screening and with the intention to terminate pregnancy in case of a detected disability. 27% of women in the serum screening survey and 22% in the ultrasound survey declared that they would have declined pregnancy termination if a fetal disorder had been detected. However, according to the hospitals’ data, only 13% of pregnancies with a serious fetal disorder detected were continued. Conclusions: All prenatal screening tests, including ultrasound examinations, require an adequate process of informed consent. Because the aim of such tests is to detect fetal malformations and syndromes, health care professionals should discuss the implications with women before they decide. Because acquaintance with a disabled person was found to associate with participation in screening and with intentions about selective termination, women’s perceptions of lives of the disabled should receive more attention in future studies.

Strong family history of uterine leiomyomatosis warrants fumarate hydratase mutation screening

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome characterized by cutaneous and uterine leiomyomas and renal cell cancer. HLRCC is caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. A Finnish family with nine closely related women with uterine leiomyomas was detected by an alert gynecologist. No cutaneous or renal cell tumors were reported in the family when it was referred to genetic analyses. Samples were available from seven patients, and a novel germline FH mutation was detected in five of them. Mutation carriers were symptomatic, had multiple tumors and were diagnosed at an early age. This study emphasizes the importance of considering FH mutation screening when gynecologists encounter families with multiple severe uterine leiomyoma cases. Due to possibility of phenocopies more than one patient should be tested. Early mutation detection allows regular screening of the mutation carriers and enables early detection of possible highly aggressive renal tumors. It may also affect family planning as multiple myomas at early age may significantly reduce fertility.

Do symptomatic endometriosis and uterine fibroids appear together

OBJECTIVES: Endometriosis and uterine fibroids are common gynecological disorders in fertile women. It has been suggested that these two disorders may be associated with each other. In this study, we tested whether this connection exists. In addition, we wanted to evaluate whether they both affect fertility independently of each other. MATERIALS AND METHODS: The prevalence of endometriosis and uterine fibroids was investigated in three groups of patients: Symptomatic patients requiring surgery either for endometriosis (n=182), or for uterine fibroids (n=240) and asymptomatic patients undergoing laparoscopic sterilization (n=183). The prevalences were examined in three age groups: 35–39 yrs, 40–44 yrs and ≥ 45 yrs. The significance of both diagnoses on fertility was assessed using logistic regression analysis. RESULTS: Uterine fibroids were detected in 25.8% (47/182) of patients with endometriosis. Endometriosis was detected in 19.6% (47/240) of patients with uterine fibroids. 5.5% (10/183) women undergoing sterilization had endometriosis and 19.3% (17/183) had uterine fibroids. Both uterine fibroids and endometriosis were, independently of each other, related to subfertility (OR, 95% CI: 3.8, 2.3–6.5; 6.8, 4.0–11.6, respectively). CONCLUSIONS: The results suggest that symptomatic endometriosis appears together with symptomatic uterine fibroids. Both diseases seem to decrease female fertility independently of each other.