Twins with Craniosynostosis: An Unidentified Variant/Twin Research: Kangaroo Care for Premature Twins; Developmental Delay in MZ Twins; Osteosarcoma in One Identical Twin; Controversies in Twin Pregnancy Management/Media Reports: Twin and Triplet Olympians; Twin’s Rescue from a Crocodile; Twin Pandas in Japan; Twin Surrogacy; Identical Twins in Pennsylvania

Craniosynostosis involves the early closure of one or more joints connecting the bones of an infant’s skull. A case of young monozygotic (MZ) male twins with an unidentified variant of this condition is described, followed by a summary of relevant published reports. This overview is followed by descriptions of a kangaroo care program for premature twins, developmental delay in an MZ twin pair, osteosarcoma in one MZ twin and controversial issues in the management of multiple pregnancies. Media reports of twin and triplet Olympic athletes, a twin’s rescue from a crocodile, the birth of twin pandas in Japan, a case of twin surrogacy and the birth of identical triplets are also presented.

Reduced Brain Connectivity in Clinical and Dimensional Autism Phenotypes Beyond Familial Confounding – A Twin Study

BackgroundPrevious studies on brain connectivity in clinical and dimensional autism have largely focused on selective connections and yielded inconsistent results. This study aimed to overcome these limitations. Global fiber tracking allowed a more unbiased assessment of white matter connectivity and utilizing a within-twin pair design introduced implicit control for genetic and environmental factors shared by twins and allowed conclusions regarding their impact. MethodsThe study examined the within-twin pair associations between structural brain connectivity of anatomically defined brain regions and both clinical autism spectrum diagnoses and dimensional autistic traits in 85 twin pairs (n=170; 56% monozygotic; 25 individuals with autism spectrum diagnosis). Structural connectivity was estimated using diffusion tensor imaging and linear regression models were fit, adjusted for IQ, other neurodevelopmental and psychiatric conditions and multiple testing. ResultsOverall, both clinical and dimensional autism phenotypes were associated with localized reductions in structural connectivity, despite comprehensively controlling for possible confounders, including all factors shared by twins. Twins fulfilling autism spectrum diagnostic criteria showed decreased brainstem-cuneus connectivity compared to their co-twins without the diagnosis. Further, twins with higher autistic traits showed decreased connectivity of the left hippocampus with the left fusiform and parahippocampal areas. These associations pointed into the same direction in mono- and dizygotic sub-cohorts, but were only significant in dizygotic twins.LimitationsThe recruitment approach of selecting primarily twin pairs discordant for autistic traits prevented a quantitative estimation of genetic and environmental contributions to brain correlates of clinical and dimensional autism. Further, assessing twins and excluding individuals with an IQ below 75 limited the generalizability of the findings. The statistical power allowed detecting medium-size or larger effects of dimensional autism. Finally, due the relatively small number of twin pairs discordant for a clinical autism, the results for clinical autism need to be interpreted with caution.ConclusionsReduced brainstem-cuneus connectivity might point towards alterations in low-level visual processing in clinical autism while reduced connectivity in networks crucial for visual and especially face processing seem to be more associated with dimensional aspects of autism. The results further suggest that the observed associations were potentially influenced by both genes and environment.

The Roles of Genetic and Early-Life Environmental Factors in the Association Between Overweight or Obesity and Hypertension: A Population-Based Twin Study

Aims/HypothesisWe aimed to explore whether and to what extent overweight or obesity could increase the risk of hypertension, and further to estimate the roles of genetic and early-life familial environmental factors in their association.MethodsThis prospective twin study was based on the Chinese National Twin Registry (CNTR), which collected information from self-report questionnaires. We conducted unmatched case-control analysis to examine the association between overweight or obesity and hypertension. And further to explore whether genetics and familiar environments shared within a twin pair, accounted for their association via co-twin matched case-control design. Generalized estimating equation (GEE) models and conditional logistic regressions were used in the unmatched and matched analyses, respectively. Then, we used logistic regressions to test the difference in odds ratios (ORs) between the unmatched and matched analyses. Finally, through bivariate twin model, the roles of genetic and environmental factors in the body mass index (BMI)- hypertension association were estimated.ResultsOverall, we included a total of 30,617 twin individuals, of which 7533 (24.6%) twin participants were overweight or obesity and 757 (2.5%) developed hypertension during a median follow-up time of 4.4 years. In the GEE model, overweight or obesity was associated with a 94% increased risk of hypertension (OR=1.94, 95% confidence interval (CI): 1.64~2.30). In the conditional logistic regression, the multi-adjusted OR was 1.80 (95% CI: 1.18~2.74). The difference in OR between unmatched and matched analyses was significant (P=0.016). Specifically, overweight or obesity was not associated with hypertension risk in the co-twin design when we full controlled genetic and familiar environmental factors (OR=0.89, 95 CI: 0.46~1.72). After controlling for age and sex, we found the positive BMI-hypertension association was mainly explained by a genetic correlation between them (rA= 0.59, 95% CI: 0.44~1.00).Conclusions/InterpretationGenetics and early-life environments shared by participants within a twin pair appear to account for the association between overweight or obesity and hypertension risk.

Genetic and Epigenetic Characterization of a Discordant KMT2A/AFF1-Rearranged Infant Monozygotic Twin Pair

The KMT2A/AFF1 rearrangement is associated with an unfavorable prognosis in infant acute lymphocytic leukemia (ALL). Discordant ALL in monozygotic twins is uncommon and represents an attractive resource to evaluate intrauterine environment–genetic interplay in ALL. Mutational and epigenetic profiles were characterized for a discordant KMT2A/AFF1-rearranged infant monozygotic twin pair and their parents, and they were compared to three independent KMT2A/AFF1-positive ALL infants, in which the DNA methylation and gene expression profiles were investigated. A de novo Q61H NRAS mutation was detected in the affected twin at diagnosis and backtracked in both twins at birth. The KMT2A/AFF1 rearrangement was absent at birth in both twins. Genetic analyses conducted at birth gave more insights into the timing of the mutation hit. We identified correlations between DNA methylation and gene expression changes for 32 genes in the three independent affected versus remitted patients. The strongest correlations were observed for the RAB32, PDK4, CXCL3, RANBP17, and MACROD2 genes. This epigenetic signature could be a putative target for the development of novel epigenetic-based therapies and could help in explaining the molecular mechanisms characterizing ALL infants with KMT2A/AFF1 fusions.

1254Comorbidity of atopic diseases and gastroesophageal reflux in adults: a co-twin control study

Background Gastroesophageal reflux disease (GERD) is the most common non-allergic comorbidity in adults with asthma, however comorbidity with other atopic diseases such as eczema and hayfever is unclear. The objective was to assess the comorbidity of GERD with atopic diseases in adults, and to investigate possible mechanisms including genetic and affective factors. Methods A co-twin control study harnessing 46 583 adult Swedish twins. Questionnaires on health status were linked to national patient and prescribed drug register data. Within twin-pair comparisons were made between unpaired, monozygotic (MZ) and dizygotic (DZ) twins to assess common genetic liability. Affective traits (depression, anxiety and neuroticism) were added to models to assess their role in comorbidity. Results The risk of GERD in those with asthma was OR1.52 (95% CI 1.38, 1.68); hayfever OR1.22 (95%CI 1.12, 1.34); and eczema OR1.23 (95%CI 1.10, 1.38). Within twin-pair associations attenuated in decreasing order of shared genetics for all atopic diseases e.g. self-report asthma with GERD: DZ twins adjOR1.41 (95%CI 0.96, 2.08), MZ twins adjOR1.24 (95%CI 0.82, 1.87). Adjusting for affective traits only slightly attenuated the comorbidity associations. Conclusions GERD is a common comorbidity in adults with asthma, hayfever and/or eczema. We found evidence for shared genetic factors but not for affective traits. Key messages GERD is a common comorbidity not only in adults with asthma, but also in adults with eczema or hayfever. Twin research has revealed evidence for a common genetic liability to explain comorbidity.

Whole-genome analysis of monozygotic twins discordant for type 1 narcolepsy

Narcolepsy type 1 (NT1) is a rare and chronic neurological disease characterized by sudden sleep attacks, overwhelming daytime drowsiness, and cataplexy. To contribute to the understanding of NT1 genetic causes, here we describe a whole-genome analysis of a monozygotic twin pair discordant for NT1. Our study revealed that although both twins have the same pathogenic mutations in NT1 associated genes (such as HLA-DQB1*06:02:01, HLA-DRB1*11:01:02/*15:03:01) the unaffected twin has mutations in genes outside the HLA loci that could be suppressing the NT1 phenotype. These results support the notion that NT1 has an immunological basis but that protective mutations in non-HLA might interfere with the clinical manifestation of the disease.

Twins Separated at Birth: Across a Country and Around the World/Twin Research: Memorial Tribute to Isaac Blickstein, MD; Infanticide and Sacrifice of Archaic-Aged Twins and Triplets; Prehistoric Twin Burials; Highlights from a Conference on Three Identical Strangers/Media Reports: An Atypical Twin Father; An Actor’s Twin Brother; Twin Link to Tulsa, Oklahoma Massacre; Superfetated Twins; Twin Comedians and Script Writers; Indian Twins’ Loss to COVID-19

Every reared-apart monozygotic (MZ) twin pair offers a fresh perspective on human developmental questions. This is true regardless of whether the co-twins were raised in the same country or across the globe. The members of two pairs of separated MZ female twins have recently come to attention. In one case the twins were raised by different families in Argentina; in the other case the twins were raised by different families in Sweden and Vietnam. The perceptions and perspectives of these twins are insightful. The twin research section that follows begins with a tribute to our late esteemed colleague, Dr Isaac Blickstein (1953−2020). Research concerning the infanticide and sacrifice of Archaic-aged twins and triplets and prehistoric twin burials is reviewed next. Highlights from a conference focused on the 2018 film Three Identical Strangers are also included in this portion. The final section of this article includes media reports of an atypical twin father, an actor’s twin brother, a twin link to the 1921 Tulsa, Oklahoma massacre, the birth of superfetated twins, twin comedians and script writers and Indian twins’ tragic loss to COVID-19.

“Monozygotic twins discordant for severe clinical recurrence of COVID-19 show drastically distinct T cell responses to SARS-Cov-2”

ABSTRACTBackgroundClinical recurrence of COVID-19 in convalescent patients has been reported, which immune mechanisms have not been thoroughly investigated. Presence of neutralizing antibodies suggests other types of immune response are involved.MethodsWe assessed the innate type I/III IFN response, T cell responses to SARS-CoV-2 with IFNγ ELISPOT, binding and neutralizing antibody assays, in two monozygotic twin pairs with one COVID-19 recurrence case.ResultsIn pair 1, four months after a first mild episode of infection for both siblings, one displayed severe clinical recurrence of COVID-19. Twin pair 2 of siblings underwent non-recurring asymptomatic infection. All fours individuals presented similar overall responses, except for remarkably difference found in specific cellular responses. Recurring sibling presented a reduced number of recognized T cell epitopes as compared to the other three including her non-recurring sibling.ConclusionsOur results suggest that an effective SARS-CoV-2-specific T cell immune response is key for complete viral control and avoidance of clinical recurrence of COVID-19. Besides, adaptive immunity can be distinct in MZ twins. Given the rising concern about SARS-CoV-2 variants that evade neutralizing antibodies elicited by vaccination or infection, our study stresses the importance of T cell responses in protection against recurrence/reinfection.Key pointsImmune parameters leading to COVID-19 recurrence/reinfection are incompletely understood. A COVID-19 recurrence case in a monozygotic twin pair is described with an intact antibody and innate type I/III Interferon response and drastically reduced number of recognized SARS-CoV-2 T cell epitopes.

Twin Anemia Polycythemia Sequence in a Dichorionic Twin Pregnancy Leading to Severe Cerebral Injury in the Recipient

Twin anemia polycythemia sequence (TAPS) is a form of chronic imbalanced feto-fetal transfusion through minuscule placental anastomoses leading to anemia in the TAPS donor and polycythemia in the TAPS recipient and has been reported only in monochorionic twins. We report a very unusual case of TAPS which developed in a dichorionic twin pair, born at a gestational age of 33⁺². Twin 1 (recipient) was polycythemic and had a hemoglobin value of 22.4 g/dL, whereas twin 2 (donor) was anemic with a hemoglobin value of 9.8 g/dL and an increased reticulocyte count (72‰). Color dye injection of the placenta revealed the presence of a deep-hidden small veno-venous anastomosis. Dichorionicity was confirmed on histologic examination. Aside from respiratory distress syndrome, the donor twin had an uncomplicated neonatal course. The recipient twin developed a post-hemorrhagic ventricular dilatation requiring treatment with a ventriculoperitoneal shunt and Rickham reservoir. This report shows that in dichorionic twins, placental anastomoses can be present, which can lead to the development of TAPS with severe consequences. Therefore, when a pale and plethoric dichorionic twin pair is born, a complete diagnostic work-up is required, including a full blood count with reticulocytes and placental injection, to investigate the presence and nature of potential underlying feto-fetal transfusion. Once the diagnosis of TAPS has been established, cerebral ultrasound, hearing screening, and long-term follow-up are strongly recommended as these twins have increased risk for severe cerebral injury, hearing loss, and long-term neurodevelopmental impairment.

Middle-age dementia risk scores and old-age cognition: a quasi-experimental population-based twin study with over 20-year follow-up

BackgroundMiddle-age risk scores predict cognitive impairment, but it is not known if these associations are evident when controlling for shared genetic and environmental factors. Using two risk scores, self-report educational-occupational score and Cardiovascular Risk Factors, Aging and Dementia (CAIDE), we investigated if twins with higher middle-age dementia risk have poorer old-age cognition compared with their co-twins with lower risk.MethodsWe used a population-based older Finnish Twin Cohort study with middle-age questionnaire data (n=15 169, mean age=52.0 years, SD=11.8) and old-age cognition measured via telephone interview (mean age=74.1, SD=4.1, n=4302). Between-family and within-family linear regression analyses were performed.ResultsIn between-family analyses (N=2359), higher educational-occupational score was related to better cognition (B=0.76, 95% CI 0.69 to 0.83) and higher CAIDE score was associated with poorer cognition (B=−0.73, 95% CI −0.82 to -0.65). Within twin-pair differences in educational-occupational score were significantly related to within twin-pair differences in cognition in dizygotic (DZ) pairs (B=0.78, 95% CI 0.25 to 1.31; N=338) but not in monozygotic (MZ) pairs (B=0.12, 95% CI −0.44 to 0.68; N=221). Within twin-pair differences in CAIDE score were not related to within twin-pair differences in cognition: DZ B=−0.38 (95% CI −0.90 to 0.14, N=343) and MZ B=−0.05 (95% CI −0.59 to 0.49; N=226).ConclusionMiddle-age dementia risk scores predicted old-age cognition, but within twin-pair analyses gave little support for associations independent of shared environmental and genetic factors. Understanding genetic underpinnings of risk score−cognition associations is important for early detection of dementia and designing intervention trials.