Fetus with multiple congenital anomaly syndrome caused by novel variant in ATP1A2.

We report a 32-year-old G3P1 at 35 weeks 3 days with a dichorionic, diamniotic twin gestation who presented for evaluation secondary to ventriculomegaly (VM) in one twin. Fetal ultrasound and MRI demonstrated microcephaly, severe VM, compression of the corpus callosum, scalp and nuchal thickening, elongated ears, bilateral talipes, right-sided congenital diaphragmatic hernia (CDH), and loss of normal cerebral architecture, indicative of a prior insult in the affected twin. The co-twin was grossly normal. The family pursued a palliative care pathway for the affected twin and was delivered at 37 weeks and 6 days. The affected twin passed away within the first hour of life due to respiratory compromise. Postmortem trio exome sequencing identified a homozygous likely pathogenic variant in ATP1A2 (c.2439+1G>A). Although this variant is novel, it is predicted to affect the donor split site in intron 17, resulting in a frameshift and complete loss-of-function of the gene. Biallelic loss of function variants in this gene have been reported in seven individuals with multiple anomalies similar to those in the affected twin. However, only one other individual with a possible CDH has been previously reported. Our case suggests that CDH be included in the phenotypic spectrum of this disorder and reports the first frameshift mutation causing this autosomal recessive multiple congenital anomaly syndrome.

A population-based twin study of the symptomatic diagnostic criteria for major depression that occur within versus outside of major depressive episodes.

BACKGROUND: Are genetic risk factors for current depressive symptoms good proxies for genetic risk factors for syndromal major depression (MD)? METHODS: In over 9000 twins from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, the occurrence of all nine DSM symptomatic criteria for MD in the last year was assessed at personal interview and then grouped by their temporal co-occurrence. The DSM criteria which occurred outside (OUT) v. inside of (IN) MD episodes were then separated. We calculated tetrachoric correlations for OUT and IN depressive criteria in monozygotic (MZ) and dizygotic (DZ) pairs and fitted univariate and bivariate ACE twin models using OpenMx. RESULTS: The mean twin correlations (±95% CIs) for IN depressive criteria were substantially higher than for OUT depressive criteria in both MZ [+0.35 (0.32-0.38) v. 0.20 (0.17-0.24)] and DZ pairs [0.20 (0.17-0.24) v. 0.10 (0.04-0.16]. The mean IN-OUT cross-correlation in MZ and DZ pairs was modest [+0.15 (0.07-0.24) and +0.07 (0.03-0.12)]. The mean heritability estimates for the nine In v. Out depressive criteria was 0.31 (0.22-0.41) and 0.15 (0.08-0.21), in MZ and DZ pairs, respectively. The mean genetic correlation between the nine IN and OUT depressive criteria was +0.07 (-0.07 to 0.21). CONCLUSIONS: Depressive criteria occurring outside depressive episodes are less heritable than those occurring within. These two ways criteria can manifest are not closely genetically related. Current depressive symptoms - most of which are occurring outside of depressive episodes - are not, for genetic studies, good proxies for MD.

Postzygotic mosaicism of a novel PTPN11 mutation in monozygotic twins discordant for metachondromatosis.

Genetic mosaicism caused by postzygotic mutations is of a great interest due to its role in human disease. Monozygotic twins arising from a single zygote are considered as genetically identical, and any differences likely to be caused by postzygotic events. Thus, phenotypically discordant monozygotic twins offer a unique opportunity to study genotype-phenotype correlation. Here, we present a three-generation family starting from a pair of monozygotic twins discordant for metachondromatosis due to postzygotic p.(Gln175His) variant in the PTPN11 gene. Both phenotypically discordant monozygotic twins harbor p.(Gln175His), however significant differences in mosaic ratio is observed not only between twins, but also within different tissue types within one individual. Phenotypic manifestation of p.(Gln175His) in examined family clearly depends on allele variant fraction (VAF). Individuals harboring constitutional mutation (VAF 50%) present typical metachondromatosis. Milder phenotype is observed in twin harboring high-level mosaicism in the tissue of ectodermal origin (VAF 45%), but not in a blood (VAF 5%). Finally, her twin sister harboring low-level mosaicism in blood (VAF 2%) and nonblood (VAF 12%) tissues is phenotypically normal. Our results provide insights into biological role of mosaicism in disease and further support the usefulness of nonblood tissues as an optimal source of DNA for the identification of postzygotic mutations in phenotypically discordant monozygotic twins.

Unilateral macrocystic dysplasia and contralateral agenesis in a monoamniotic twin.

OBJECTIVE: We present a case report of a congenital malformation of the uropoetic tract in one of the monoamniotic twins. CASE REPORT: A 24-year-old primigravida with male monochorionic monoamniotic twins was dia-gnosed with congenital malformation in fetus A at 24 weeks of gestation. Ultrasound verified macrocystic dysplasia and contralateral renal agenesis. Planned caesarean section was performed after the observational management of the patient in the 34th gestational week. In fetus B, a physiological finding was confirmed on the postpartum ultrasonography. In fetus A, CT examination of the abdomen confirmed the finding of left kidney agenesis and polycystic degeneration of the right kidney. Exitus letalis was stated on the newborns 5th day. CONCLUSION: The occurrence of the described combination of congenital malformation in monoamniotic twins is rare. When dysplasia significantly affects the function of the parenchyma, renal agenesis with multicystic dysplasia of the other kidney is a condition incompatible with life. For the intrauterine survival of the affected fetus, the normal renal function of the twin was important and thus the normal volume of amniotic fluid was maintained. As a result, the fetus did not develop extrarenal symptoms of the Potter sequence in the described case - especially pulmonary hypoplasia and the newborn was able to ventilate spontaneously. The death was caused by the consequences of renal failure associated with anuria.

Lessons from a 30 year follow-up of monozygotic twins with discordant phenotype due to a ring 13 chromosomal mosaicism in one of them.

At the 43rd annual meeting of the ASHG in 1993, the senior author reported monozygotic twins with discordant phenotype due to a ring 13 chromosomal mosaic syndrome in one of them. Her major manifestations included: intrauterine growth restriction (IUGR), failure to thrive (FTT), delayed developmental milestones/intellectual disability (DDM/ID), left hemihypoplasia of her body with leg length discrepancy, left profound deafness due to inner ear malformation, telecanthus, dental anomalies mainly on the left side, congenital torticollis due to Klippel-Feil anomaly, 13 ribs, scoliosis, dislocation of the left hip, and distinctive left hand and feet. A blood karyotype at age 31/2 was normal. Silver-Russell syndrome was initially suspected; however, at age 4, a karyotype on skin fibroblasts showed a ring 13 chromosomal mosaicism, 46,XX,15s+/46,XX,-13,+r(13),15s+, with a higher frequency on the left side of the body. Since then, we have been involved in the management of this patient for 30 years. This has ultimately allowed us to compare her achievements with her normal monozygotic twin. In this long term follow-up, we want to emphasize the importance of: (a) early recognition of genetic syndromes, especially of mosaicisms, and of early intervention programs, (b) the involvement of different specialists in the management of patients with MCA, and (c) mentioning how familial and socioeconomic issues may limit or enhance the full potential of patients with some genetic disorders.

The concordance rate of non-chromosomal congenital malformations in twins based on zygosity: a retrospective cohort study.

OBJECTIVE: To examine the concordance rate of non-chromosomal congenital malformations in twin pairs based on zygosity. DESIGN: Retrospective cohort study. SETTING: A tertiary hospital in Korea. POPULATION: Twin pairs born at Seoul National University Hospital between 2001 and 2019. METHODS: Congenital malformations were diagnosed by postnatal workups of neonates or autopsy in cases of stillborn infants. Zygosity was confirmed by sex, chorionicity and DNA analysis. MAIN OUTCOME MEASURES: Concordance rate of congenital malformations in twin pairs based on zygosity. RESULTS: In total, 3386 twin pairs were included. The risk of a congenital malformation in the index twin increased significantly if the co-twin had the congenital malformation, and the concordance rate was higher in monozygotic (MZ) than in dizygotic (DZ) twins (37.04 versus 16.77, P < 0.001). An increased risk of a congenital malformation in the presence of the same congenital malformation in the co-twin was observed only for malformations of the nervous system, eye/ear/face/neck, circulatory system, cleft lip/palate, genital organs, urinary system and musculoskeletal system. Significantly higher concordance rates in MZ than in DZ twin pairs were observed only for the nervous system (40.00 versus 0.00, P < 0.001), circulatory system (32.97 versus 19.74, P = 0.021), cleft lip/palate (44.44 versus 0.00, P = 0.017) and urinary system (22.22 versus 0.00, P = 0.004), whereas significant differences were not found for the genital organs or musculoskeletal system. CONCLUSIONS: Monozygotic twins had higher concordance rates than DZ twins only in specific organ systems. It may be speculated that nervous system, circulatory system, cleft lip/palate and urinary system are primarily genetically affected. TWEETABLE ABSTRACT: Monozygotic twins had higher concordance rates than dizygotic twins only in specific organ systems.

Outcomes of Monochorionic, Diamniotic Twin Pregnancies with Prenatally Diagnosed Intertwin Weight Discordance.

OBJECTIVE: Monochorionic, diamniotic (MCDA) twin pairs are predisposed to various pregnancy complications due to the unique placental angioarchitecture of monochorionicity. Few studies have evaluated the outcomes of weight-discordant MCDA pairs without selective fetal growth restriction (SFGR) or the risk factors for development of SFGR. This study aims to describe the natural history of expectant, noninvasive management of weight-discordant MCDA twins and to evaluate risk factors associated with progression to SFGR. STUDY DESIGN: This was a retrospective cohort study at a single, tertiary care center in the United States. All MCDA twins with isolated intertwin weight discordance (ITWD) ≥ 20% diagnosed before 26 weeks' gestational age (GA) were included. The primary outcome of descriptive analyses was overall pregnancy outcome, incorporating both survival to delivery and GA at delivery, as defined by the North American Fetal Therapy Network. The secondary outcome was SFGR in one twin (defined as estimated fetal weight < 10% for GA) and factors associated with this progression. Only those with fetal ultrasound (US) within 4 weeks of delivery were included in this secondary analysis. RESULTS: Among 73 MCDA pairs with ITWD, 73% had a good pregnancy outcome, with dual live delivery at a median GA of 33 weeks. Among the 34 pairs with adequate US follow-up, 56% developed SFGR. There were no differences in GA at delivery or discordance at birth between those who did and those who did not develop SFGR. There was a nonsignificant association between increasing ITWD at diagnosis and subsequent development of SFGR. CONCLUSION: Expectant, noninvasive management can be considered in MCDA twin pregnancies with ITWD ≥ 20% diagnosed before 26 weeks. This approach is associated with a good pregnancy outcome in the majority of cases, even after the development of SFGR in the smaller twin. KEY POINTS: · Nearly 75% of weight-discordant mo/di twins have a good pregnancy outcome.. · Weight-discordant mo/di twins deliver at a mean gestational age of 33 weeks without invasive therapy.. · Noninvasive management should be considered for weight-discordant mo/di twins..

Predicting Adverse Outcomes in Monochorionic-Diamniotic Twins: The Role of Intertwin Discrepancy in Middle Cerebral Artery Doppler Measurements and the Cerebroplacental Ratio.

OBJECTIVE: This study was aimed to evaluate the role of intertwin discrepancy in middle cerebral artery peak systolic velocity (MCA-PSV) and cerebroplacental ratio (CPR) for the prediction of adverse outcomes in monochorionic-diamniotic (MCDA) twin pregnancies. STUDY DESIGN: A retrospective cohort study of MCDA pregnancies that underwent ultrasound surveillance at a perinatal referral center from 2007 to 2017. Intertwin MCA-PSV discrepancy (MCA-ΔPSV-MoM) was defined as the absolute difference of MCA-PSV multiple of the median (MoM) for gestational age between twins. Intertwin CPR discrepancy (CPR-Δ) was defined as the absolute difference of CPR between twins. The maximum MCA-ΔPSV-MoM and CPR-Δ before and after 26 weeks of gestation were assessed as predictors of pregnancy and neonatal outcomes through simple logistic regression models and Pearson's correlation coefficients. Receiver operating characteristic (ROC) curves were generated to determine the predictive value of maximum MCA-ΔPSV-MoM and CPR-Δ. RESULTS: A total of 143 MCDA pregnancies met inclusion criteria. There was a significant association between MCA-ΔPSV-MoM at <26 weeks and the development of twin anemia-polycythemia sequence (TAPS; p = 0.007), intrauterine fetal demise (IUFD; p = 0.009), and neonatal intensive care unit (NICU) admission (p < 0.05). MCA-ΔPSV-MoM at ≥26 weeks was associated with the development of TAPS (p < 0.001). CPR-Δ at <26 weeks was associated with the development of twin-twin transfusion syndrome (TTTS; p = 0.03) and NICU admission (p = 0.02). MCA-ΔPSV-MoM at ≥26 weeks was highly predictive of TAPS (area under curve [AUC] = 0.92). A cut-off of 0.44 would identify TAPS with 100% sensitivity and 73% specificity. CONCLUSION: In MCDA pregnancies, intertwin MCA and CPR discrepancies are associated with adverse pregnancy and neonatal outcomes, including TAPS, TTTS, IUFD, and NICU admission. Evaluation of intertwin MCA and CPR differences demonstrated the potential for clinical predictive utility in the surveillance of MCDA twin pregnancies. KEY POINTS: · Intertwin discrepancy of MCA-PSV and CPR is associated with adverse pregnancy outcomes.. · Intertwin differences in Doppler ultrasound may occur prior to meeting diagnostic criteria for TTTS or TAPS.. · There is potential clinical predictive utility in MCA and CPR surveillance of MCDA twin pregnancies..

Loose anagen syndrome in one identical twin girl.

Loose anagen syndrome (LAS) is a hair disorder involving insufficient anchoring of the hair follicle to the scalp owing to an autosomal dominant or sporadic mutation in the gene encoding keratin 6. There are three phenotypes of LAS, including type B, which presents in young, light-haired girls as unruly, uncombable hair with diminished growth. We present a 2-year-old girl with LAS type B whose identical twin sister was unaffected. The diagnosis was confirmed with a painless hair pull test proven to contain anagen hairs with ruffled cuticles on trichoscopy, preventing the need for unnecessary referrals and diagnostic tests.

Early- and late-onset selective fetal growth restriction in monochorionic diamniotic twin pregnancy: natural history and diagnostic criteria.

OBJECTIVES: To evaluate the natural history and outcome of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancy, according to gestational age at onset and various reported diagnostic criteria, and to quantify the risk of superimposed twin-to-twin transfusion syndrome (TTTS). METHODS: This was a cohort study of MCDA twin pregnancies that had their routine antenatal care from the first trimester at St George's Hospital, London, UK. Pregnancies had ultrasound examinations every 2 weeks at 16-24 weeks and then every 2-3 weeks until delivery. The diagnostic criteria for sFGR were estimated fetal weight (EFW) of one twin < 10th centile and intertwin EFW discordance ≥ 25%. We also applied other diagnostic criteria reported in a recent Delphi consensus. Pregnancies in which the diagnosis of TTTS was made before that of sFGR were not included in the analysis. Pregnancies that underwent fetal intervention for sFGR were excluded. The incidence of sFGR was compared between the different diagnostic criteria, overall and according to gestational age at onset. In all subsequent analyses, cases of sFGR included those diagnosed according to any of the criteria. The Gratacós classification of sFGR was applied (Type I, II or III). Pregnancy outcomes included miscarriage, intrauterine death, neonatal death and admission to the neonatal unit. Comparisons between groups were carried out using the Mann-Whitney U-test for continuous variables and the chi-square or Fisher's exact test for categorical variables. RESULTS: The analysis included 287 MCDA twin pregnancies. According to the International Society of Ultrasound in Obstetrics and Gynecology diagnostic criteria, the incidence of early (< 24 weeks) sFGR was 4.9%, while that of late sFGR was 3.8%. When applying the various diagnostic criteria, the incidence of early sFGR varied from 1.7% to 9.1% and that of late sFGR varied from 1.1% to 5.9%. In early-onset cases, the incidence of Type I sFGR was 80.8%, that of Type II was 15.4% and that of Type III was 3.8%. The corresponding figures in late-onset cases were 94.4%, 5.6% and 0%. The incidence of superimposed TTTS was 26.9% in cases affected by early-onset sFGR and 5.6% in those affected by late-onset sFGR. The incidence of perinatal death was 8.0% in early-onset sFGR and 5.6% in late-onset sFGR (P = 0.661). Admission to the neonatal unit occurred in 61.0% and 52.9% of cases, respectively (P = 0.484). CONCLUSIONS: In MCDA twin pregnancies, early-onset sFGR is slightly more common than is late-onset sFGR, although this difference was not significant, and is associated with worse perinatal outcome. The incidence of Types II and III sFGR is higher in early-onset sFGR. The incidence also varies according to the diagnostic criteria used, which supports the use of standardized international diagnostic criteria. Superimposed TTTS is more common in early- than in late-onset sFGR. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Gender-Discordant Monochorionic-Diamniotic Twins Both With 45,X/46,X, Idic(Y) Mosaicism and a Novel Deletion Within the TBC1D5 Gene.

The occurrence of monochorionic diamniotic twins with sex discordance is a very rare phenomenon. We present a case of spontaneously conceived gender-discordant monochorionic diamniotic twins born to a 23-year-old female, both twins demonstrating similar blood karyotype 45,X/46,X, idic(Y) and a novel 99 kb mutation at 3p24.3 involving exons 15-16 of transcript NM_001134381.1 of the Tre-2/Bub2/Cdc16 Domain Family Member 5 (TBC1D5) gene. The male twin showed no anatomic abnormalities and pelvic ultrasound revealed descended gonads. The female twin had a horseshoe-shaped kidney, normal uterus, and intra-abdominal gonads. The blood karyotype and microarray studies revealed similar distribution of X and isodicentric Y chromosome along with a novel genetic mutation which has not been previously reported. Our case findings not only report Turner syndrome mosaicism with a novel genetic mutation but also stress the importance of clinical follow-up of twins in order to evaluate the functional abnormalities associated with isodicentric Y chromosomes including germ cell tumors.

Intrafetal laser for midtrimester TRAP sequence-experience from a single center.

OBJECTIVE: To report our experience and evaluate outcomes in monochorionic pregnancies with Twin Reversed Arterial Perfusion sequence with intrafetal laser therapy. METHODS: Retrospective review of records of all pregnancies with TRAP sequence treated by intrafetal laser therapy between 2011 January and 2015 December that were retrieved and analysed. RESULTS: Electronic search of the scan database retrieved 57 cases of TRAP sequence during the study period, 7 triplets and 50 monochorionic twins. Intrafetal laser was done in 27 cases, 22 cases of twins and 5 cases of triplets. In the twins group, median gestational age at intervention was 22.5 weeks, the earliest done at 16.3 weeks. The median gestational age at delivery and birth weight was 37 weeks and 2.5 Kgs. The median procedure and delivery interval was 14 weeks. Live birth rate was 17/22 (77%) the pump survival rate was 16/22 (73%). Pregnancies with non-surviving pump were 5 in numbers (5/22). A repeat procedure was warranted in one case. In the triplet group, median gestational age at intervention, delivery and procedure delivery interval was 18, 35 and 17 weeks. CONCLUSION: Intrafetal laser is simple, effective and the treatment of choice to interrupt the vascular supply to acardiac twin.

Concomitant hypertriglyceridemia-induced pancreatitis in pregnant monozygotic twin siblings.

Hypertriglyceridemia-induced pancreatitis (HTIP) is the third most common cause of pancreatitis. Hypertriglyceridemia shows familial transition and pregnancy increases the risk of HTIP. The treatment of HTIP is initiated with supportive treatment and continues with specific treatments including plasmapheresis, insulin, heparin infusion, and hemofiltration. The current study reports monozygotic twins who are pregnant at the same time having concurrent HTIP attack.

A Population-Based Twin Study of Childhood Irritability and Internalizing Syndromes.

Childhood irritability exhibits significant theoretical and empirical associations with depression and anxiety syndromes. The current study used the twin design to parse genetic and environmental contributions to these relationships. Children ages 9-14 from 374 twin pairs were assessed for irritability and symptoms of depression, generalized anxiety, panic, social phobia, and separation anxiety using dimensional self-report instruments. Multivariate structural equation modeling decomposed the correlations between these syndromes into genetic and environmental components to examine shared and specific risk domains. Irritability had significant associations with each internalizing symptom domain. Genetic contributions to irritability are moderately correlated with genetic risk for symptoms of depression, generalized anxiety, and separation anxiety with weaker overlap with the other anxiety syndromes. Familial and specific environmental risk factors explained covariation among syndromes and indicated potential syndrome-specific risk. There is substantial overlap among the genetic and environmental factors that influence individual differences in irritability and those that increase liability for depression and anxiety symptoms in children. These findings deepen the current understanding of childhood internalizing risk factors and provide important implications for syndrome prediction and susceptibility gene discovery efforts.

COL4A1 Mutation as a Cause of Familial Recurrent Intracerebral Hemorrhage.

The COL4A1 mutation is a very rare monogenic cause of small vessel disease related to recurrent intracerebral hemorrhage. We report a family in which the index case presented with two intracerebral hemorrhages in the basal ganglia with severe periventricular leukoaraiosis and a cataract and vascular tortuosity in the ophthalmological study. His twin brother also had severe leukoaraiosis and multiple subcortical microhemorrhages as well as a congenital cataract and vascular tortuosity in the retina. The older sister had a porencephalic cyst and involvement of the periventricular white matter and intracerebral hemorrhage. In single-gene testing, all three were found to have the same COL4A1 mutation. Intracerebral subcortical hemorrhages or microhemorrhages and severe subcortical leukoaraiosis in familial cases may be related to COL4 mutations.

Contribution of Genome-Wide Significant Single Nucleotide Polymorphisms in Myopia Prediction: Findings from a 10-year Cohort of Chinese Twin Children.

PURPOSE: To determine the added predictive ability of genome-wide significant single nucleotide polymorphisms (SNPs) in refraction prediction in children and investigate the earliest age threshold for an accurate prediction of high myopia. DESIGN: Prospective longitudinal study. PARTICIPANTS: A total of 1063 first-born twins followed annually between 2006 and 2015 in China. The exposures were genetic factors (parental myopia, SNPs) and environmental factors (near work, outdoor activity). METHODS: Five linear mixed-effect models, consisting of different combinations of age, gender, genetic, and environmental factors, were built to predict myopia development. All predictions were performed on the basis of spherical equivalent (SE) at baseline and the measurements on the second and third visits. MAIN OUTCOME MEASURES: The primary outcome measure was SE at the last visit among all subjects, and the secondary outcome measure was the presence of high myopia at the age of 18 years. RESULTS: Mean age of the study population was 10.5±2.2 years (range, 7-15 years) at baseline, and 48.6% were male. In linear mixed-effect models, age, age square, gender, paternal SE, maternal SE, and genetic risk scores (GRSs) showed a significant fixed effect, whereas outdoor and near-work time were not significant to SE at the last visit. Incorporating more follow-up data into the model showed better performance across all models. In the prediction of the presence of high myopia at 18 years of age, the model consisting of only age and gender showed a good performance (area under the curve [AUC] = 0.95), whereas the addition of SNPs did not enhance the model performance significantly. The AUC for predicting high myopia was >0.95 after the age of 13 years for participants with a single visit and after the age of 12 years for those with 1 more visit data. CONCLUSIONS: A simple model incorporating age, sex, and relevant refraction data is sufficient to accurately predict high myopia; there was limited improvement in the prediction model after adding genetic information. Furthermore, this prediction on the outcome at 18 years is possible when the child is aged 12 to 13 years.

Genetic influences on the onset of obstructive sleep apnoea and daytime sleepiness: a twin study.

BACKGROUND: Obstructive sleep apnoea (OSA) is one of the major sources of the excessive daily sleepiness, cognitive dysfunction, and it increases cardiovascular morbidity and mortality. Previous studies suggested a possible genetic influence, based on questionnaires but no objective genetic study was conducted to understand the exact variance underpinned by genetic factors. METHODS: Seventy-one Hungarian twin pairs involved from the Hungarian Twin Registry (48 monozygotic, MZ and 23 dizygotic, DZ pairs, mean age 51 ± 15 years) underwent overnight polysomnography (Somnoscreen Plus Tele PSG, Somnomedics GMBH, Germany). Apnoea hypopnea index (AHI), respiratory disturbance index (RDI) and oxygen desaturation index (ODI) were registered. Daytime sleepiness was measured with the Epworth Sleepiness Scale (ESS). Bivariate heritability analysis was applied. RESULTS: The prevalence of OSA was 41% in our study population. The heritability of the AHI, ODI and RDI ranged between 69% and 83%, while the OSA, defined by an AHI ≥5/h, was itself 73% heritable. The unshared environmental component explained the rest of the variance between 17% and 31%. Daytime sleepiness was mostly determined by the environment, and the variance was influenced in 34% by the additive genetic factors. These associations were present after additional adjustment for body mass index. CONCLUSION: OSA and the indices of OSA severity are heritable, while daytime sleepiness is mostly influenced by environmental factors. Further studies should elucidate whether close relatives of patients with OSA may benefit from early family risk based screening.

Diagnosis and management of the phenotypic spectrum of twins with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with a heterogeneous phenotypic spectrum. There is an increased prevalence of monozygotic twinning in BWS. Given the epigenetic nature and phenotypic spectrum that defines BWS, twins are often discordant for clinical features, and clinicians are faced with the challenge of diagnosing and managing these twins. We present a cohort of multiple pregnancies in which one or more child from each pregnancy was diagnosed with BWS. We conducted a chart review of monochorionic and dichorionic gestations. Clinical scores for monochorionic twins demonstrated phenotypic discordance between the proband and twin. Based on linear regression analysis, a higher clinical score in the proband correlated with larger phenotypic discordance between twin siblings. Despite phenotypic discordance, however, we observed a consistent additive clinical score for a pregnancy (proband's plus twin's scores from a pregnancy). This idea of a finite degree of affectedness for a pregnancy implies a finite number of epigenetically affected cells. This further corroborates the idea that timing of monozygotic monochorionic twinning correlates with the disruption of establishment and/or maintenance of imprinting. The difference in clinical score between a proband and their twin may be due to diffused mosaicism, whereby there is an asymmetric distribution of affected cells among the multiple fetuses in a monozygotic monochorionic pregnancy, leading to a spectrum of variably affected phenotypes. Based on these findings, we recommend an algorithm for a conservative approach to clinically evaluate all children in a monozygotic multiple gestation affected by BWS.

Myocardial Infarction in the Neonate Without Coronary Artery Occlusion and Structurally Normal Heart: A Report of 2 Cases in Twin Pregnancies and Review of the Literature.

Myocardial infarction (MI) is a common diagnosis in the adult population and is associated with coronary artery atherosclerosis. However, it is an unusual diagnosis in the pediatric population, especially in the neonatal period. The authors present 2 autopsy cases of MI in newborn babies of twin pregnancies with normal heart and coronary arteries. The first case is that of a 10-day-old female, monochorionic-diamniotic, twin B born at 29 weeks' gestation. The autopsy revealed diffuse subacute MI in both ventricles, which was compatible with a global hypoxic event during perinatal period. The hypoxic insult was likely caused by maternal HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome as evident in the placental examination, which showed placental infarct and decidual arteriopathy. The second case is that of a 2-day-old term male, dichorionic-diamniotic, twin A with an antenatal history of prolonged rupture of membranes. The hospital course was complicated by neonatal sepsis. The autopsy showed diffuse hemorrhage in the internal organs including the heart, along with myocyte necrosis. The overall findings were consistent with multiorgan dysfunction syndrome resulting from sepsis. Previous reported cases of MI in neonates without coronary artery occlusion were also reviewed and portrayed.

The development of a brief screener for autism using item response theory.

BACKGROUND: Brief screening instruments focusing on autism spectrum disorder (ASD) that can be administered in primary care are scarce; there is a need for shorter and more precise instruments. The Autism-Tics, AD/HD and other Comorbidities inventory (A-TAC) has previously been validated for ASD reporting excellent validity. This study aims to determine the psychometric properties of each item in the ASD domain (17 items) in the A-TAC using item response theory (IRT), and thereby construct and validate a short form that could be used as a screening instrument in the general population. METHODS: Since 2004, parents of all 9-year-old Swedish twins have been invited to participate in a telephone interview in the Child and Adolescent Twin Study in Sweden (CATSS). The CATSS is linked to the National Patient Register (NPR), which includes data from in- and outpatient care. Data on ASD (A-TAC) collected in CATSS were compared with diagnoses from the NPR. Diagnoses that had been made both before (previous validity) and after (predictive validity) the interviews were included. The sample was divided into a developmental sample and a validation sample. An IRT model was fitted to the developmental sample and item parameters were used to select a subset of items for the short form. The performance of the proposed short form was examined in the validation sample by the use of receiver operation characteristic curves. RESULTS: Four items which were able to discriminate among individuals with more autism traits were deemed sufficient for use in the short form. The values of the area under the receiver operating characteristic curve for a clinical diagnosis of ASD was .95 (previous validity) and .72 (predictive validity). CONCLUSIONS: The proposed short form with 4 out of the original 17 items from A-TAC, showed excellent previous validity while the predictive validity was fair. The validity of the short form was in agreement with previous validations of the full ASD domain. The short form can be a valuable screening instrument in primary care settings in order to identify individuals in need for further assessment and for use in epidemiological studies.