Monozygotic twin pairs discordant for Hashimoto's thyroiditis share a high proportion of thyroid peroxidase autoantibodies to the immunodominant region A. Further evidence for genetic transmission of epitopic "fingerprints".

Thyroid peroxidase antibodies (TPOAbs) in patients with Hashimoto's thyroiditis (HT) predominantly react with two immunodominant regions (IDR-A, IDR-B). Theoretically, as shown for the level of TPOAbs, the autoantibody epitopic recognition of the IDRs could be under genetic control. To examine this, we compared the distribution of TPOAb epitopic fingerprints between healthy monozygotic (MZ) co-twins and siblings to patients with clinically overt HT with a control group of euthyroid subjects, matched for sex and age, but without autoimmune thyroid disease (AITD) among their first-degree relatives. Two ELISAs based on competition with rabbit antisera were used to determine the IDR specificities in 23 patients with HT, 6 MZ co-twins, 8 siblings to patients with HT, and 11 healthy euthyroid subjects without predisposition to AITD. The fraction of TPOAbs recognizing IDR-A was 19, 18, and 9% in HT patients, MZ-co-twins, and siblings, respectively, which was higher than the 0% found in the group of healthy subjects without predisposition to AITD (p = 0.007 vs. HT; p = 0.1078 vs. MZ co-twin and p = 0.069 vs. siblings). Moreover, the IDR-A fraction differed between healthy MZ-co-twins and ordinary siblings (18% vs. 9%, p = 0.0127). In conclusion, our data indicate that the propensity to produce autoantibodies directed against the IDR-A epitope of TPO is genetically determined. This finding may have implications with respect to inheritance of autoantibody specificities in other autoimmune diseases.

Influence of long-term postmenopausal hormone-replacement therapy on estimated structural bone strength: a study in discordant monozygotic twins.

Although postmenopausal hormone-replacement therapy (HRT) is known to prevent fractures, knowledge on the influence of long-term HRT on bone strength and its determinants other than areal bone mineral density is scarce. This study used a genetically controlled design with 24 monozygotic female twin pairs aged 54 to 72 years in which one cotwin was using HRT (mean duration 8 years) and the other had never used HRT. Estimated bone strength, cross-sectional area, volumetric bone mineral density, bone mineral mass, and cross-sectional density and mass distributions were assessed in the tibial shaft, distal tibia, and distal radius with peripheral computed tomography (pQCT). In the tibial shaft, HRT users had 9% [95% confidence interval (CI) 3%-15%] higher estimated bending strength than their nonusing cotwins. Larger cortical area and higher cortical bone mineral density accounted for this difference. The cortex was larger in the HRT users in the endocortical region. In the distal tibia, estimated compressive strength was 24% (95% CI 9%-40%) higher and in the distal radius 26% (95% CI 11%-41%) higher in the HRT users than in their nonusing cotwins owing to higher volumetric bone mineral density. No difference between users and nonusers was observed in total bone cross-sectional area in any measured bone site. The added mineral mass in the HRT users was distributed evenly within and between bone sites. In postmenopausal women, long-term HRT preserves estimated bone strength systemically by preventing bone mineral loss similarly in body weight-loaded and non-weight-loaded bone.

The Netherlands Twin Register biobank: a resource for genetic epidemiological studies.

In 2004 the Netherlands Twin Register (NTR) started a large scale biological sample collection in twin families to create a resource for genetic studies on health, lifestyle and personality. Between January 2004 and July 2008, adult participants from NTR research projects were invited into the study. During a home visit between 7:00 and 10:00 am, fasting blood and morning urine samples were collected. Fertile women were bled on day 2-4 of the menstrual cycle, or in their pill-free week. Biological samples were collected for DNA isolation, gene expression studies, creation of cell lines and for biomarker assessment. At the time of blood sampling, additional phenotypic information concerning health, medication use, body composition and smoking was collected. Of the participants contacted, 69% participated. Blood and urine samples were collected in 9,530 participants (63% female, average age 44.4 (SD 15.5) years) from 3,477 families. Lipid profile, glucose, insulin, HbA1c, haematology, CRP, fibrinogen, liver enzymes and creatinine have been assessed. Longitudinal survey data on health, personality and lifestyle are currently available for 90% of all participants. Genome-wide SNP data are available for 3,524 participants, with additional genotyping ongoing. The NTR biobank, combined with the extensive phenotypic information available within the NTR, provides a valuable resource for the study of genetic determinants of individual differences in mental and physical health. It offers opportunities for DNA-based and gene expression studies as well as for future metabolomic and proteomic projects.

Monochorionic twins with the same blood karyotype of 46,XY/47,XYY but different phenotypes.

We report the case of a 13-year-old woman who was pregnant with phenotypically discordant monochorionic twins: one with cystic hygroma and hydrops, the other one normal. Fetal blood sampling was performed by intrahepatic blood collection for karyotyping of both fetuses, revealing the same genotype of 46,XY/47,XYY in 2:1 proportion. Phenotypic discordance in monozygotic twins can have various causes, such as placental vascular anatomy, differences in allocation of the number of blastomeres or genetic postzygotic events.

Maternal plasma and amniotic fluid angiogenic factors and their receptors in monochorionic twin pregnancies complicated by twin-to-twin transfusion syndrome.

OBJECTIVE: Angiogenic factors play a role in human placentation and may be aberrant in severe twin-to-twin transfusion syndrome (TTTS). The aim of this study was to investigate the maternal plasma and amniotic fluid angiogenic factor and receptor concentrations in twin pregnancies complicated by TTTS and to evaluate the effects of fetoscopic laser ablation. METHODS: A prospective cohort of monochorionic (MC) twins complicated by severe TTTS (n = 23) was studied between October 2006 and December 2007. A cohort of uncomplicated dichorionic (DC) (n = 12) and MC (n = 7) pregnancies were studied for comparison. Circulating angiogenic factors and their receptors were measured in the maternal plasma and the recipient twin's amniotic fluid by enzyme-linked immunosorbent assay and/or FAST Quant human angiogenesis array. RESULTS: Plasma vascular endothelial growth factor (VEGF)-C concentrations were significantly lower in TTTS than in uncomplicated twin pregnancies (P < 0.0001). In contrast, plasma angiopoietin (Ang)-2 levels and the ratio of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) to placental growth factor (PlGF) levels were significantly increased in TTTS (P < 0.01). Plasma VEGF-D was significantly increased in advanced stage TTTS (Stage III/IV cohort; P < 0.01). This was independent of fetal size, amniotic fluid volumes or the number of apparent placental arteriovenous anastomoses. In TTTS pregnancies, amniotic fluid VEGF-C, VEGF-A, Ang-1 and the sVEGFR-1/PlGF ratio were increased compared to paired maternal plasma concentrations (P < 0.0001) while amniotic fluid concentrations of PlGF, Ang-2 and soluble tyrosine kinase with immunoglobulin-like/epidermal growth factor-like domains 2 (sTie-2) were significantly lower than plasma concentrations (P < 0.0001). No significant association between maternal plasma and amniotic fluid concentrations of angiogenic factors was noted. Plasma PlGF was transiently decreased after fetoscopic laser ablation, returning to baseline by 1 week (P = 0.0314). Fetoscopic laser ablation also affected plasma sVEGFR-1/PlGF ratio with a transient increase after therapy, followed by a significant reduction to below basal concentrations by 1 week (P = 0.0102). Only VEGF-D was significantly different (+8.3%; P = 0.0155) in amniotic fluid immediately after the completion of fetoscopic laser ablation. CONCLUSION: Maternal angiogenic activity is decreased in severe TTTS, with an increased sVEGFR-1/PlGF ratio and concentrations of Ang-2 and VEGF-D in the maternal plasma compared to uncomplicated MC twin pregnancies. Maternal circulating PlGF concentrations decrease and the sVEGFR-1/PlGF ratio increases transiently in response to fetoscopic laser ablation, but in general the angiogenic factor and receptor concentrations studied are altered little by this therapy.

A comprehensive neuropsychiatric study of elderly twins: the Older Australian Twins Study.

The Older Australian Twins Study (OATS) was recently initiated to investigate genetic and environmental factors and their associations and interactions in healthy brain ageing and ageing-related neurocognitive disorders. The study extends the classic MZ-DZ design to include one or two equivalently aged siblings for each twin pair and utilizes the rich resources of the Australian Twin Registry. The study has a number of distinguishing features including comprehensive psychiatric, neuropsychological, cardiovascular, metabolic, and neuroimaging assessments, a longitudinal design and links with a brain donor program. The study measures many behavioral and environmental factors, but in particular lifetime physical and mental activity, physical and psychological trauma, loss of parent early in life, later losses and life events, early-life socioeconomic environment, alcohol and drug use, occupational exposure, and nutrition. It also includes comprehensive cardiovascular assessment, blood biochemistry, genetics and proteomics. The socio-demographic and health data on the first 172 pairs of twins participating in this study are presented. Prevalence of mild cognitive impairment is 12.8% and of dementia 1.5% in the sample. The target sample size is 1000, with at least 400 pairs of twins aged 65-90 years. The cohort will be assessed every two years, with in-depth assessments being repeated. OATS offers an excellent opportunity for collaboration with other similar studies as well as researchers who share the same interests.

HDL subspecies in young adult twins: heritability and impact of overweight.

The association between abdominal obesity and atherogenic lipid profile emerges from complex interactions of genes and environment. We aimed to explore the heritability and effects of overweight on serum lipid profile (high-density lipoprotein-cholesterol (HDL-C), HDL mean particle size, percentages of HDL(2b, 2a, 3a, 3b, and 3c,) low-density lipoprotein-cholesterol (LDL-C), LDL peak particle size and triglycerides (TGs)) in healthy, young adults. HDL-C, LDL-C, and TG were measured in 52 monozygotic (MZ) and 89 dizygotic (DZ) twin pairs, aged 23-32 years, chosen to represent a wide range of BMIs (17.6-42.9 kg/m2). Of them, 24 MZ and 26 DZ pairs were chosen at random for measurements of HDL mean and LDL peak particle sizes and percentages of HDL subspecies. The heritabilities of the lipid parameters adjusted for BMI were HDL-C 73%, HDL mean particle size 56%, HDL subspecies 46-63%, LDL-C 79%, LDL peak particle size 49%, and TG 64%. Genetic and environmental correlations between BMI and HDL-C, LDL-C, and TG were modest (0.3-0.4). Abdominal overweight (waist circumference>or=94 cm for males and >or=80 cm for females) associated with decreased HDL-C, increased LDL-C, and TG concentrations, smaller HDL mean particle size, lower HDL2b, and higher HDL3c percentages in both genders. Within MZ twins, controlling for genetic influences, within-pair differences in HDL3c percentage were associated with those in waist (r=0.46, P=0.032) and BMI (r=0.51, P=0.013). In conclusion, serum lipid parameters, including LDL peak and HDL mean particle sizes and HDL subspecies distribution are under strong genetic control. Overweight associated with significant lipid profile changes, particularly, small HDL3c increased in overweight independent of genetic influences.

Genetic dominance influences blood biomarker levels in a sample of 12,000 Swedish elderly twins.

In twin studies of cardiovascular disease biomarkers the dizygotic correlations are often estimated to be less than half of monozygotic correlations indicating a potential influence of nonadditive genetic factors. Using a large and homogenous sample, we estimated the additive and dominance genetic influences on levels of high density lipoprotein, low density lipoprotein, apolipoprotein A-I, apolipoprotein B, total cholesterol, triglycerides, glucose, hemoglobin Alc and c-reactive protein, all of which are biomarkers associated with cardiovascular disease. The blood biomarkers were measured on 12,000 Swedish twins born between 1911 and 1958. The large sample allowed us to obtain heritability estimates with considerable precision and provided adequate statistical power for estimation of dominance genetic components. Our study showed complete absence of the shared environment component for the investigated traits. Dominant genetic component was shown to be significant for low density lipoprotein (0.18), glucose (0.31), Hemoglobin Alc (0.55), and c-reactive protein (0.27). To our knowledge, this is the first statistically significant evidence for dominance genetic variance found for low density lipoprotein, glucose, hemoglobin Alc, and c-reactive protein in a population based twin sample. The study highlights the importance of acknowledging nonadditive genes underlying the risk of developing cardiovascular diseases.

Association of surrogate and direct measures of adiposity with risk of metabolic syndrome in rural Chinese women.

BACKGROUND: Most studies linking obesity and metabolic syndrome (MS) have used body mass index (BMI) and waist circumference (WC) to measure obesity. While BMI is correlated with direct measures of total and central adiposity, it is influenced by lean body and bone mass. We hypothesize that direct measures of adiposity may help develop further insight into the link between obesity and MS, thus more accurately identifying individuals at high risk for MS. AIM OF THE STUDY: We examined how surrogate and direct measures of adiposity were associated with MS risk and if direct adiposity measures enhanced BMI and WC identification of MS risk. METHODS: 3,734 Chinese female twins aged 20-39 years were studied. Percent body fat (%BF) and proportion of trunk fat to total BF (%TF) were assessed by DEXA. Graphic plots and generalized estimating equations were used to examine the associations of adiposity measures with MS and its components. Concordance of adiposity measures and MS abnormalities between monozygotic (MZ) and dizygotic (DZ) twin pairs were compared. RESULTS: The prevalence of MS increased for high BMI (>or=23 kg/m(2)), %BF (>or=32), WC (>or=80 cm), and (to a lesser degree) %TF (>or=50). Below those thresholds, the prevalence of MS was low (0-5.3%). %TF was independently associated with higher risk of MS and its components even after adjusting for BMI and WC. As a result, among women with normal BMI and WC, high %TF was associated with 1.3-2.0-fold elevated risk of MS components. In contrast, women with high BMI but normal WC and %TF neither have significantly increased risk of MS, nor for any component other than high BP. MZ twins showed higher concordance for MS and its components than DZ twins. CONCLUSIONS: In this lean Chinese rural female sample, BMI >or= 23 and WC >or= 80 were associated with a markedly increased risk of MS, which was further enhanced by elevated %TF. Even in women with a normal BMI and WC, %TF was independently associated with MS and its components. Twin analysis findings suggest that adiposity measurements and MS risk are influenced by genetics.

Maternal serum markers of placental damage in uncomplicated dichorionic and monochorionic pregnancies in comparison with monochorionic pregnancies complicated by severe twin-to-twin transfusion syndrome and the response to fetoscopic laser ablation.

OBJECTIVE: Twin-to-twin transfusion syndrome (TTTS) is a morbid perinatal condition associated with abnormal placentation and is treated by fetoscopic laser ablation (FLA). We assessed basal maternal serum alphafetoprotein (MSAFP) and free beta-human chorionic gonadotrophin (f-betaHCG) in uncomplicated dichorionic (DC) and monochorionic (MC) twin pregnancies and a cohort of MC twin pregnancies complicated by severe TTTS. Changes in MSAFP and f-betaHCG post-FLA were measured as markers of placental coagulation. STUDY DESIGN: In a prospective case-cohort study, MC twins complicated by TTTS (n=23) were studied. A cohort of uncomplicated DC (n=12) and MC (n=6) twin pregnancies, which were appropriately grown for gestation with normal liquor volumes were also studied. Using solid phase, two site fluoroimmunometric assays, both MSAFP and f-betaHCG from uncomplicated and complicated cohorts were measured. Samples were taken, prior to FLA then at intervals after the procedures (6h, 24h and 1 week). RESULTS: The median multiples of median (MoM) were not significantly different in uncomplicated DC twin pregnancies for MSAFP 1.85 (95% CI 1.62-2.34) or fbetaHCG 1.66 (95% CI 1.21-2.04) compared to uncomplicated MC twin pregnancies (MSAFP 1.40 (95% CI 1.16-2.58) and fbetaHCG 1.70 (95% CI 0.32-3.35)). However, the median MSAFP MoM in MC twin pregnancies complicated by severe TTTS was increased (MSAFP 3.10 (95% CI 2.67-4.43); p<0.05) with a more significant increase being noted in median fbetaHCG (MoM 5.75 (95% CI 5.22-9.12); p<0.0001) compared to uncomplicated twin pregnancies. Post-FLA, the median MSAFP increased significantly at 6h by 445% (636.65 U/ml (95% CI 616-1216.9 U/ml)) and remained elevated at 1 week (553.4 U/ml (95% CI 203.7-3020.8 U/ml; p=0.001)). No significant difference in median fbetaHCG was noted post-FLA (p=0.36). This rise in MSAFP appears unrelated to the number of placental anastomoses coagulated or the total energy used. Also, in the small cohort in which amniodrainage alone was performed no rise in MSAFP was noted. CONCLUSIONS: MSAFP and fbetaHCG are increased in TTTS indicating an association with abnormal placentation. Post-FLA, a significant rise in MSAFP was noted for up to a week post-coagulation. This was not noted after amniodrainage.

Residual anastomoses in twin-to-twin transfusion syndrome treated with selective fetoscopic laser surgery: localization, size, and consequences.

OBJECTIVE: To study the localization and size of residual anastomoses in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery and correlate the findings with outcome. STUDY DESIGN: Placental injection in twin-to-twin transfusion syndrome placentas treated with laser was performed by using colored dye. RESULTS: A total of 77 twin-to-twin transfusion syndrome placentas were included in the study. Residual anastomoses (n = 48) were found in 32% (25/77) of lasered placentas. Most residual anastomoses were localized near the margin of the placenta. The majority of residual anastomoses (67%; 32/48) were very small (diameter, < 1 mm). Eleven of the 25 cases (44%) in the residual anastomoses group developed twin anemia-polycythemia sequence. CONCLUSION: Most residual anastomoses in twin-to-twin transfusion syndrome placentas treated with laser are very small and localized near the placental margin. Almost half of cases with residual anastomoses developed twin anemia-polycythemia sequence after laser surgery.

Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins.

BACKGROUND/AIMS: This study aimed to determine the heritability of serum alanine aminotransferase (S-ALT) and fasting serum insulin (fS-insulin) concentration as well as determine the association of these measures with liver fat content in young adult monozygotic (MZ) and dizygotic (DZ) twins. METHODS: Three hundred and thirteen individual twins were recruited from a population-based cohort (n = 4929). The study subjects represented a wide range of body mass indexes (BMI), were free of any diseases or regular medications and had an intake of less than two drinks of alcohol/day. To verify that S-ALT is a marker of liver fat, it was measured by proton magnetic resonance spectroscopy ((1)H MRS) in 66 subjects. Heritability estimations were performed using BMI- and gender-adjusted values. RESULTS: Intra-pair correlations were significantly higher in the MZ twins than the DZ twins for both S-ALT (0.65 for MZ and 0.04 for DZ) and fS-insulin (0.58 and 0.34, respectively). Heritability of S-ALT was 55% and that of fS-insulin 61%. In the 66 subjects S-ALT (r = 0.70 for women and r = 0.50 for men, p < or = 0.01 for both) and fS-insulin (r = 0.58 and r = 0.59, respectively, p < or = 0.01 for both) concentrations correlated significantly with liver fat content. CONCLUSIONS: These twin data suggest that approximately 60% of the variation in S-ALT, a marker of liver fat content, is genetically determined.

Fasting plasma total ghrelin concentrations in monozygotic twins discordant for obesity.

Ghrelin is a hormone that is involved in the regulation of food intake. Neuronal, endocrine, and genetic factors have been shown to regulate plasma ghrelin levels; but the determinants of fasting ghrelin concentrations are not yet fully understood. The main aim was to explore the roles of adiposity and genetic differences in determining fasting plasma total ghrelin levels. We measured total ghrelin levels in a population of 23 monozygotic twin pairs discordant for obesity. In addition, 2 variants of ghrelin gene, namely, Arg51Gln and Leu72Met, were genotyped in 3 populations of monozygotic twin pairs: 23 obesity-discordant, 43 lean-concordant, and 46 obesity-concordant twin pairs. In discordant twins, lean co-twins had higher fasting plasma total ghrelin levels (950 pg/mL, SD = 328 pg/mL) than obese twins (720 pg/mL, SD = 143 pg/mL; P = .003). Arg51Gln-polymorphism of the ghrelin gene was equally distributed between the twin groups. However, there were significant differences in genotype frequencies at the Leu72Met polymorphism between the discordant and obese-concordant groups (P = .003) and between the discordant and lean-concordant groups (P = .011), but not between the 2 concordant groups. In the discordant group, there were fewer Met carriers (4%) than among the obese (17%) or the lean-concordant groups (15%). Plasma total ghrelin levels are affected by acquired obesity independent of genetic background. The Leu72 allele is particularly common among monozygotic twins discordant for obesity, suggesting that this ghrelin allele is more permissive in the regulation of energy balance. The ghrelin gene may thus play a role in the regulation of variability of body weight, such that Leu72 allele carriers are more prone to weight variability in response to environmental factors.

Adiponectin concentration and insulin indicators following overfeeding in identical twins.

UNLABELLED: Low adiponectin levels have been associated with high body mass index, low insulin sensitivity, and diabetes. OBJECTIVE: To assess the relationships between changes in serum adiponectin concentration and adiposity, glucose, and insulin in response to long-term overfeeding in identical twins and to calculate the twin resemblance in serum adiponectin concentrations. SUBJECTS AND DESIGN: Twenty-four sedentary young men [mean (+/-SD) age, 21+/-2 yr] who constituted 12 pairs of healthy identical twins were studied for metabolic and adiponectin changes in response to overfeeding. INTERVENTION: Subjects were overfed by 84,000 kcal over a 100-day period. OUTCOME MEASURES: The overfeeding study provides an opportunity to examine the relationships between adiponectin and changes in body weight, adiposity, plasma glucose and insulin. RESULTS: Serum adiponectin concentration correlated positively with body weight (r= 0.41, p=0.05) at baseline but not with indicators of adiposity or with visceral fat. No relationship existed between baseline adiponectin concentration and body weight or adiposity gains with overfeeding. However, serum adiponectin decreased significantly by -2.35+/-0.48 microg/ml (p=0.001) in response to overfeeding. Baseline adiponectin levels correlated negatively with changes in plasma fasting glucose levels (r=-0.53, p=0.01) and homeostasis model assessment index (r=-0.41, p=0.05), independently of fat mass. The intrapair coefficient for twin resemblance (r=0.75, p=0.001) strongly suggests that baseline serum adiponectin concentration is a familial trait. CONCLUSIONS: These data provide evidence that adiponectin concentration is a familial trait in normal-weight individuals, that it decreases when challenged by positive energy balance, and that its overfeeding-induced variations are correlated with glucose and insulin levels.

Similarities and differences in lipidomics profiles among healthy monozygotic twin pairs.

Differences in genetic background and/or environmental exposure among individuals are expected to give rise to differences in measurable characteristics, or phenotypes. Consequently, genetic resemblance and similarities in environment should manifest as similarities in phenotypes. The metabolome reflects many of the system properties, and is therefore an important part of the phenotype. Nevertheless, it has not yet been examined to what extent individuals sharing part of their genome and/or environment indeed have similar metabolomes. Here we present the results of hierarchical clustering of blood plasma lipid profile data obtained by liquid chromatography-mass spectrometry from 23 healthy, 18-year-old twin pairs, of which 21 pairs were monozygotic, and 8 of their siblings. For 13 monozygotic twin pairs, within-pair similarities in relative concentrations of the detected lipids were indeed larger than the similarities with any other study participant. We demonstrate such high coclustering to be unexpected on basis of chance. The similarities between dizygotic twins and between nontwin siblings, as well as between nonfamilial participants, were less pronounced. In a number of twin pairs, within-pair dissimilarity of lipid profiles positively correlated with increased blood plasma concentrations of C-reactive protein in one twin. In conclusion, this study demonstrates that in healthy individuals, the individual genetic background contributes to the blood plasma lipid profile. Furthermore, lipid profiling may prove useful in monitoring health status, for example, in the context of personalized medicine.

Vascular endothelial growth factor in monochorionic twins with twin-twin transfusion syndrome.

OBJECTIVE: The purpose of this study was to determine vascular endothelial growth factor (VEGF) concentrations in the donor and the recipient in monochorionic twin pregnancies with twin-twin transfusion syndrome (TTTS) and single pregnancies in order to investigate the involvement of VEGF in the pathophysiology of TTTS. METHODS: Six twin pregnancies in 11 monochorionic twin pregnancies complicated with TTTS and 11 single control pregnancies were compared. Gestational age-matched fetal blood and placental samples were obtained at birth. Serum VEGF concentration in the umbilical vein was measured by an enzyme-linked immunoabsorbant assay. Tissue protein expression of VEGF was determined by using immunohistochemistry. Western blot analysis and scanning densitometry were used to quantify and compare the VEGF expression in the terminal villi. RESULTS: Serum VEGF concentrations in the umbilical vein in both donors and recipients tended to be higher than those in the controls. Immunolocalization of VEGF in terminal villous placenta samples in both donors and recipients was mainly observed in the syncytiotrophoblastic layer and vascular endothelial cells with less intense staining in stromal cells. The expression of VEGF in the donor placenta increased significantly (p=0.006) compared to that in the control placenta, but the expression of VEGF in the recipients tended to be higher than in the controls. CONCLUSION: Intrauterine circulatory imbalance may induce changes in VEGF expression and these alterations may be involved in both donor and recipient in the pathogenesis of TTTS, due to the maintenance of hemodynamic stability between the circulation of the twins.

XX Maleness and XX true hermaphroditism in SRY-negative monozygotic twins: additional evidence for a common origin.

CONTEXT: Differentiation of testicular tissue in 46,XX individuals is seen either in XX males, the majority of them with SRY gene, or in individuals, usually SRY(-), with ovotesticular disorder of sex development (OT-DSD). Although they are sporadic cases, there are some reports on familial recurrence, including coexistence of XX maleness and OT-DSD in the same family. OBJECTIVE: We report on a case of SRY(-) 46,XX monozygotic twins with genital ambiguity. METHODS: Hormonal evaluation included testosterone, FSH, and LH measurements. SRY gene was investigated by PCR and two-step PCR in peripheral leukocytes and gonadal tissues, respectively. Direct DNA sequencing of the DAX-1 coding sequence was performed. Real-time PCR for SOX9 region on chromosome 17 was obtained. RESULTS: Both twins had a 46,XX karyotype. Twin A had a 1-cm phallus with chordee, penoscrotal hypospadias, and palpable gonads. Serum levels of FSH (2.34 mIU/ml), LH (8.8 mIU/ml), and testosterone (1.6 ng/ml) were normal, and biopsies revealed bilateral testes. Twin B had a 0.5-cm phallus, perineal hypospadias, no palpable gonad on the right, and a left inguinal hernia. Hormonal evaluation revealed high FSH (8.2 mIU/ml) and LH (15 mIU/ml) and low testosterone (0.12 ng/ml). Upon herniotomy, a right testis (crossed ectopia) and a small left ovotestis were found. SRY gene was absent in both peripheral leukocytes and gonadal tissue samples. Neither DAX-1 mutations nor SOX9 duplication was identified. CONCLUSIONS: This case provides evidence that both XX maleness and XX OT-DSD are different manifestations of the same disorder of gonadal development.