Mutation analysis of the growth factor genes PlGF, Flt1, IGF-I, and IGF-IR in intrauterine growth restriction with abnormal placental blood flow.

OBJECTIVE: The objective of our study was to investigate a possible role of pathogenic mutations in the growth factor genes insulin like growth factor I (IGF-I) and placental growth factor (PlGF) and their receptors IGF-IR and fms-like tyrosine kinase 1 (Flt1) in the pathogenesis of placental dysfunction. METHODS: We analyzed two patient groups with IUGR (intrauterine growth restriction), 18 mother-child pairs with absent or reversed enddiastolic flow (ARED) in the umbilical artery and 12 mother-child pairs with preserved enddiastolic flow (PED) in the presence of a bilateral abnormal uterine artery Doppler waveform (Notching). The control group comprised of 50 healthy mother-child pairs. RESULTS: Sequencing did not show a pathogenic mutation in any of the analyzed genes. However, we detected three novel polymorphisms in the IGF-IR gene. In addition, we identified one unknown polymorphism in exon 1 of the non-coding region of PlGF and 2 novel variants in exons 1 and 6 of Flt1. CONCLUSION: In summary, our results do not provide evidence for a relevant role of pathogenic mutations in the genes IGF-I, IGF-IR, PlGF, and Flt1 in the etiology of IUGR with ARED or PED flow.

The 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is not associated with HELLP syndrome.

Plasminogen activator inhibitor-1 (PAI-1) is a major inhibitor of fibrinolysis, and a single nucleotide insertion/deletion (4G/5G) polymorphism in the promoter region of the PAI-1 gene has been identified. Subjects homozygous for the 4G allele have the highest PAI-levels due to increased PAI-1 gene transcription. Pre-eclampsia, and one of its most severe forms, the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, are characterized by increased placental thrombosis based on a procoagulatory state in the mother. Several studies have investigated the role of the PAI-1 4G/5G polymorphism in pre-eclampsia, but no study has focused especially on HELLP syndrome. Therefore we aimed to assess the association between HELLP syndrome and the 4G/5G polymorphism in the PAI-1 gene. Genotyping of the PAI-1 4G/5G promoter polymorphism was performed in 102 Caucasian women with HELLP syndrome and 102 Caucasian women with uncomplicated pregnancies. The 4G/4G genotype was more frequent in women with HELLP syndrome than in controls (35.3% vs. 22.5%, respectively) but this difference was not significantly different (P = 0.129). The frequency of the 4G allele was 0.588 in patients and 0.515 in controls. These data suggest that women carrying a 4G/4G genotype of the PAI-1 gene are not at increased risk for developing HELLP syndrome and are thus in line with the majority of previous studies on the association between the PAI-1 4G/5G polymorphism and pre-eclampsia.

Genetic analysis of the angiotensinogen gene in pre-eclampsia: study of german women and review of the literature.

AIMS: To evaluate the influence of the angiotensinogen (AGT) gene on the individual predisposition to pre-eclampsia, we screened the AGT gene for pathogenic mutations and an association of identified polymorphisms in German women with pre-eclampsia. METHODS: The study population consisted of 67 German primi- and multigravid patients with pre-eclampsia or superimposed pre-eclampsia and 100 controls with uncomplicated singleton pregnancies. The initial screening for mutations was carried out in a subgroup of pre-eclampsia patients by single-strand conformation polymorphism analysis and direct sequencing. RESULTS: Fifteen single nucleotide polymorphisms (SNPs) were detected, of which 14 had been described before. Allelic frequencies of the detected SNPs were estimated in the total study population. Only the promoter polymorphism g.-570C>T was associated with pre-eclampsia (p = 0.038) but after adjustment for multiple testing p was >0.05. The well-known M268T [M235T] polymorphism was not associated with pre-eclampsia. CONCLUSION: Our results do not indicate an association of the AGT gene with pre-eclampsia. Data from previously published studies are conflicting: positive results were reported in at least 4 studies, negative results in 10 studies. A possible influence, if existing at all, is obviously very small. AGT therefore does not play a major role in the etiology of pre-eclampsia.

Maternal factor V Leiden mutation is associated with HELLP syndrome in Caucasian women.

OBJECTIVE: There is growing evidence that hypertensive pregnancy complications and other adverse pregnancy outcomes are associated with the presence of inherited or acquired thrombophilias. As hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome is one of the most severe forms of pre-eclampsia we aimed to assess the prevalence of the factor V Leiden, the prothrombin 20210G >A mutation and the methylenetetrahydrofolate reductase (MTHFR) 677C >T polymorphism in women with HELLP syndrome and in their fetuses from the same index pregnancy. DESIGN: The study was performed retrospectively in a case-control design. SAMPLE: Seventy-one mother-child pairs with HELLP syndrome and 79 control mother-child pairs with uncomplicated pregnancies were included in the study. METHODS: Genotyping of the three thrombophilic mutations was performed using the LightCycler technology. The chi-squared test was used for statistical analysis. Main outcome measures were maternal and fetal genotypes and their correlation with clinical parameters. RESULTS: Maternal heterozygosity for factor V Leiden was significantly more prevalent in the HELLP group than in controls (OR 4.45, 95% CI 1.31-15.31). No significant association was observed for maternal prothrombin mutation or MTHFR polymorphism (p=0.894, p=0.189, respectively). The fetal genotype was not associated with HELLP syndrome for any of the three mutations investigated. Analysis of gene-gene interactions and genotype-phenotype correlation with respect to clinical parameters and perinatal outcome revealed no further differences. CONCLUSIONS: Our study confirms that women heterozygous for factor V Leiden have an increased risk of developing HELLP syndrome, while the most frequent mutations of the prothrombin and MTHFR gene do not play a major role in the pathogenesis of HELLP syndrome.

Neither maternal nor fetal mutation (E474Q) in the alpha-subunit of the trifunctional protein is frequent in pregnancies complicated by HELLP syndrome.

OBJECTIVE: An association between maternal HELLP syndrome and fetal long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency has been proposed. LCHAD catalyzes the third step in the beta-oxidation of fatty acids in mitochondria. Whereas about 75% of LCHAD-deficient patients carry a G-to-C mutation at nucleotide position 1528 (Glu474Gln, E474Q) on both chromosomes, compound heterozygosity for E474Q on one chromosome and a second different LCHAD mutation on the other can be observed in up to 25% of LCHAD-deficiency cases; only very few patients carry two mutations different from E474Q. Genetic analysis of the mother alone is insufficient in case of compound heterozygosity. Since information on the fetal carrier status of the E474Q mutation in maternal HELLP syndrome is rare, we investigated the frequency of the E474Q mutation in families where the mother had HELLP syndrome. METHODS: The occurrence of the E474Q mutation was analyzed by PCR and RFLP in 103 mothers with HELLP syndrome, in 82 children of affected pregnancies and in 21 fathers in families where fetal DNA was not available. In addition, 103 control women with only uncomplicated pregnancies were investigated. RESULTS: The mutation E474Q was not detected in the study population. CONCLUSION: Neither maternal nor fetal heterozygosity for the E474Q mutation is a relevant factor of HELLP syndrome.

Functional upper airway obstruction in a child with Freeman-Sheldon syndrome.

Freeman-Sheldon syndrome is defined as a combination of microstomia, deep set eyes, small palpebral fissures, arthrogryposis with ulnar deviation of the hand, talipes equinovarus and generalized muscular hypertension. Respiratory and swallowing problems are frequently encountered in these patients due to small orifices of mouth and nose. Obstruction of the upper airway tract resulting in tracheostomy has only been described twice. The described child manifested the typical dysmorphic features of Freeman-Sheldon syndrome and suffered from serious respiratory distress and swallowing difficulties from birth. The boy died at the age of 7 months after accidental decannulation of the tracheostoma during sleep. He did not show anatomical or histopathological abnormalities in the pharyngeal, laryngeal or tracheal regions. We assume that the only explanation of the repeated obstructive episodes is a functional muscular obstruction.