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Klinefelter syndrome (KS) (47, XXY) is the most common sex chromosome disorder, with a prevalence of 1 in every 660 newborn males. Despite the profound adverse effects of anxiety and depression, and their greater prevalence in KS populations, no research has been conducted to date to identify the determinants of anxiety and depression among patients with KS. We examined the relationships between personality traits, social engagement, and anxiety and depression symptoms among KS patients (n = 69) and a group of male controls (n = 69) matched for age and years of education. KS patients experienced more anxiety and depression symptoms than control participants. Neuroticism was the strongest and most consistent mediator between KS and both anxiety and depression symptoms. This research suggests that neuroticism may play a central role in attention switching, anxiety and depression among patients with Klinefelter syndrome. The central role of neuroticism suggests that it may be used to help identify and treat KS patients at particularly high-risk for attention-switching deficits, anxiety and depression.

Background Marfan syndrome is a genetic disorder with considerable morbidity and mortality. Presently, clinicians use the 2010 revised Ghent nosology, which includes optional genetic sequencing of the FBN1 gene, to diagnose patients. So far, only a few studies based on older diagnostic criteria have reported a wide range of prevalence and incidence. Our aim was to study prevalence, incidence, and age at diagnosis in patients with Marfan syndrome. Method Using unique Danish patient-registries, we identified all possible Marfan syndrome patients recorded by the Danish healthcare system (1977–2014). Following, we confirmed or rejected the diagnosis according to the 2010 revised Ghent nosology. Results We identified a total of 1628 persons with possible Marfan syndrome. We confirmed the diagnosis in 412, whereof 46 were deceased, yielding a maximum prevalence of 6.5/100,000 at the end of 2014. The annual median incidence was 0.19/100,000 (range: 0.0–0.7) which increased significantly with an incidence rate ratio of 1.03 (95 % CI: 1.02–1.04, p  < 0.001). We found a median age at diagnose of 19.0 years (range: 0.0–74). The age at diagnosis increased during the study period, uninfluenced by the changes in diagnostic criteria. We found no gender differences. Conclusion The increasing prevalence of Marfan syndrome during the study period is possibly due to build-up of a registry. Since early diagnosis is essential in preventing aortic events, diagnosing Marfan syndrome remains a task for both pediatricians and physicians caring for adults.

Klinefelter syndrome (KS) has a prevalence ranging from 85 to 250 per 100.000 newborn boys making it the most frequent sex chromosome aneuploidy in the general population. The molecular basis for the phenotypic traits and morbidity in KS are not clarified. We performed genome-wide DNA methylation profiling of leucocytes from peripheral blood samples from 67 KS patients, 67 male controls and 33 female controls, in addition to genome-wide RNA-sequencing profiling in a subset of 9 KS patients, 9 control males and 13 female controls. Characterization of the methylome as well as the transcriptome of both coding and non-coding genes identified a unique epigenetic and genetic landscape of both autosomal chromosomes as well as the X chromosome in KS. A subset of genes show significant correlation between methylation values and expression values. Gene set enrichment analysis of differentially methylated positions yielded terms associated with well-known comorbidities seen in KS. In addition, differentially expressed genes revealed enrichment for genes involved in the immune system, wnt-signaling pathway and neuron development. Based on our data we point towards new candidate genes, which may be implicated in the phenotype and further point towards non-coding genes, which may be involved in X chromosome inactivation in KS.

Background Neurofibromatosis type 1 (NF1) is a genetic condition characterized by various somatic manifestations and cognitive impairments, but the latter are sparsely described in adults. This study aimed at characterizing potential impairments of neurocognitive functions using neuropsychological tests as well as a self-report questionnaire. Methods In a nationwide, population-based study including 103 adults with NF1 and 38 age- and gender-matched NF1-free comparisons, we used a comprehensive neurocognitive test battery to assess intelligence and visual short-term memory, immediate visuospatial recall, reaction time, sustained attention, motor speed, planning, planning time, working memory as well as multitasking and a questionnaire to assess executive functions. Descriptive statistics, multivariate analysis of variance (MANOVA), and general linear models with repeated measure analysis of variance (ANOVA) were used. Results We observed a statistically significant difference in overall performance-based cognitive functioning. Adults with NF1 showed significant, moderate-to-severe impairments in intelligence, visual short-term memory, immediate visuospatial recall, sustained attention ( p  < 0.0001–0.002), and some executive functions ( p  = 0.008 − 0.001), whereas other cognitive functions (multitasking, reaction time, motor speed, spatial working memory, planning time, and planning efficacy as well as some self-reported executive functions) were unimpaired. Conclusions This is the first study with a population-based sample of persons with NF1 and the results show impairments of intelligence and other cognitive functions. The pattern of both significant cognitive impairments and non-significantly different cognitive functions suggests a cognitive profile of selective rather than generalized cognitive deficits in NF1.

Background Little is known about employment status, occupation, and disposable income in adults with NF1. Methods From the Danish National Patient Registry and database of two national Centers for Rare Diseases, we identified 1469 adults with NF1, who were matched to 11,991 randomly selected population comparisons on sex and birth year and month. Annual information on employment, occupation and disposable income was ascertained from national registries in 1980–2019. Results Adults with NF1 had a lower odds ratio (OR) for employment [OR 0.71, 95% confidence interval (CI) 0.61–0.83] and higher OR for health-related unemployment (OR 2.94, 95% CI 2.16–3.96) at age 30 years than population comparisons, which persisted at age 40 and 50 years. Somatic diagnoses were associated with a higher OR for health-related unemployment in adults with NF1 than in the population comparisons. Adults with NF1 had a slightly lower disposable income, with a 14% (0.82–0.89) reduction observed among the youngest birth cohort. Furthermore, adults with NF1 were less likely to be in a high skilled occupation at ages 30, 40 and 50 years. Conclusion Adults with NF1 have a lower employment rate, which was mainly due to health-related reasons and a slightly lower disposable income than adults without NF1. Thus, anticipation guidance for employment should be part of the management of NF1 families.

Background Marfan syndrome is associated with morbidity and mortality due to aortic dilatation and dissection. Preventive aortic root replacement has been the standard treatment in Marfan syndrome patients with aortic dilatation. In this study, we present aortic event data from a nationwide Marfan syndrome cohort. Method The nationwide cohort of Danish Marfan syndrome patients was established from the Danish National Patient Registry and the Cause of Death Register, where we retrieved information about aortic surgery and dissections. We associated aortic events with age, sex, and Marfan syndrome diagnosis prior or after the first aortic event. Results From the total cohort of 412 patients, 150 (36.4 %) had an aortic event. Fifty percent were event free at age 49.6. Eighty patients (53.3 %) had prophylactic surgery and seventy patients (46.7 %) a dissection. The yearly event rate was 0.02 events/year/patient in the period 1994–2014. Male patients had a significant higher risk of an aortic event at a younger age with a hazard ratio of 1.75 (CI 1.26–2.42, p  = 0.001) compared with women. Fifty-three patients (12.9 %) were diagnosed with MFS after their first aortic event which primarily was aortic dissection [ n  = 44 (83.0 %)]. Conclusion More than a third of MFS patients experienced an aortic event and male patients had significantly more aortic events than females. More than half of the total number of dissections was in patients undiagnosed with MFS at the time of their event. This emphasizes that diagnosing MFS is lifesaving and improves mortality risk by reducing the risk of aorta dissection.

Children with neurofibromatosis 1 (NF1) may have a high burden of somatic disease and cognitive impairments, which can lead to poor academic performance. We evaluated school grades from exams ending mandatory schooling (usually around age 15 or 16 years) of children with NF1 in a population-based registry study using a within-school matched design. The study included 285 children with NF1 and 12,000 NF1-free peers who graduated from the same school and year during 2002–2015. We estimated overall and gender-specific grades by subject and compared the grades of children with NF1 with those of NF1-free peers in linear regression models. We also examined the effect of social and socioeconomic factors (immigration status and parental education, income and civil status) on grades and age at finalizing ninth grade. School grades varied considerably by socioeconomic stratum for all children; however, children with NF1 had lower grades by an average of 11–12% points in all subjects. In the adjusted models, children with NF1 had significantly lower grades than their NF1-free peers, with largest negative differences in grades observed for girls with NF1. Finally, children with NF1 were 0.2 (CI 0.1–0.2) years older than their peers on graduating from ninth grade, but only maternal educational modified the age at graduating. In conclusion, students with NF1 perform more poorly than their peers in all major school subjects. Gender had a strong effect on the association between NF1 and school grades; however, socioeconomic factors had a similar effect on grades for children with NF1 and their peers.

Some anti-epileptic drugs (AED) have well-known teratogenic effects. The aim of the present study was to elucidate the effect of prenatal exposure to AED and the risk of enamel defects in the primary and permanent dentition. A total of 38 exposed and 129 non-exposed children, 6-10 years of age, were recruited from the Aarhus Birth Cohort and the Department of Neurology, Viborg Regional Hospital, Denmark. Medication during pregnancy was confirmed by the Danish Prescription Database. All children had their teeth examined and outcomes in terms of enamel opacities and enamel hypoplasia were recorded. Children prenatally exposed to AED have an increased prevalence of enamel hypoplasia (11% vs. 4%, odds ratio (OR) = 3.6 [95% confidence interval (CI): 0.9 to 15.4]), diffuse opacities (18% vs. 7%, OR = 3.0; [95% CI: 1.0 to 8.7, p<0.05]), and numerous (>3) white opacities (18% vs. 10%, OR = 2.2; [95% CI: 0.8 to 6.1]) in the primary dentition. In the permanent dentition, an increased risk of numerous (>3) white opacities (34% vs. 12%, OR = 3.3; [95% CI: 1.3 to 8.4]) was found. The present study shows that children prenatally exposed to AED have an increased risk of developing numerous teeth with white opacities in their primary and permanent dentition. In addition, they also have an increased risk of developing diffuse opacities and enamel hypoplasia in their primary teeth.

BackgroundThe probability of a pregnancy, live birth, stillbirth and abortion has never been assessed in women with neurofibromatosis 1 (NF1) in a large population-based study.MethodsWe included 1006 women (15–49 years) registered with NF1 in the Danish National Patient Registry or followed in two national Centers for Rare Diseases and 10 020 women from the Danish population. Information on pregnancy outcomes was ascertained from health registries. Cumulative incidence, mean cumulative count, hazard ratios (HRs) and proportion ratios (PRs) with 95% CIs were calculated.ResultsThe cumulative incidence of a first pregnancy at age 50 years was slightly lower in women with NF1 (74%; 95% CI 70 to 77) than in population comparisons (78%; 95% CI 77 to 79). When all pregnancies were included, two pregnancies were expected per woman at age of 50 years, irrespective of a NF1 diagnosis. The hazard of a pregnancy did not differ between women with NF1 (HR 1.03; 95% CI 0.95 to 1.11) and the comparisons after adjustment for somatic and psychiatric disease. The proportion of pregnancies that resulted in a live birth was 63% (783/1252) among women NF1 and 68% (8432/12 465) among the comparisons, yielding a PR of 0.95 (95% CI 0.90 to 1.00). The proportions of stillbirths (PR 2.83; 95% CI 1.63 to 4.93) and spontaneous abortions (PR 1.40; 95% CI 1.09 to 1.79) were increased in women with NF1.ConclusionsA similar hazard for pregnancy was observed for women with NF1 and population comparisons after adjustment for potential medical consequences of NF1. However, women with NF1 experienced more spontaneous abortions and stillbirths.

PurposeThe Danish neurofibromatosis 1 (NF1) cohort was initiated to study health-related, socioeconomic and psychological consequences of living with the monogenetic disorder NF1 using a nationwide and population-based approach.ParticipantsThe cohort includes all 2467 individuals in Denmark who were hospitalised with or due to NF1 from 1977 to 2013 or registered in the RAREDIS Database (1995–2013), a national clinical database for rare diseases, or both. A comparison cohort matched to individuals with NF1 on sex and date of birth was identified in the Civil Registration System (n=20 132).Findings to dateAll cohort members were linked to the unique Danish registries to obtain information on hospital contacts, birth outcomes, education and partnership. A questionnaire was completed by 244 of the 629 adult cohort members with NF1 registered in the RAREDIS Database to evaluate the psychosocial and emotional burden. Further, neuropsychological tests were performed on 103 adult cohort members with NF1 and 38 adult population comparisons. To date, six studies have been published. Individuals with NF1 had an increased risk for (1) hospitalisation for disorders affecting all organ systems of the body throughout all decades of life, (2) psychiatric disorders, (3) attaining a short or medium long education and (4) not forming a life partner. Women with NF1 had an increased risk for spontaneous abortions and stillbirths. Finally, adults with NF1 had an impaired quality of life and a high need for professional support for physical, psychological and work-related problems, which was partly associated with disease severity and visibility.Future plansThe cohort will regularly be updated with newly diagnosed patients in the RAREDIS Database as well as with outcome information in the Danish registries. New studies are in progress to assess other medical and socioeconomic dimensions of living with NF1.