Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

Effect of fractional exhaled nitric oxide (FENO)-based asthma management during pregnancy versus usual care on infant development, temperament, sensory function and autism signs.

Asthma during pregnancy is associated with a range of adverse perinatal outcomes. It is also linked to increased rates of neurodevelopmental conditions in the offspring. We aimed to assess whether fractional exhaled nitric oxide (FENO)-based asthma management during pregnancy improves child developmental and behavioural outcomes compared to usual care. The Breathing for Life Trial was a randomised controlled trial that compared FENO-based asthma management during pregnancy to usual care. Participants were invited to the developmental follow-up, the Breathing for Life Trial - Infant Development study, which followed up infants at 6 weeks, 6 months and 12 months. The primary outcomes were measured in infants at 12 months using the Bayley-III: Cognitive, Language and Motor composite scores. Secondary outcomes included Bayley-III social-emotional and adaptive behaviour scores, autism likelihood and sensory and temperament outcomes. The exposure of interest was the randomised intervention group. Two hundred and twenty-two infants and their 217 participating mothers were recruited to the follow-up; 107 mothers were in the intervention group and 113 were in the control group. There was no evidence of an intervention effect for the primary outcomes: Bayley-III cognitive (mean = 108.9 control, 108.5 intervention, p = 0.93), language (mean = 95.9 control, 95.6 intervention, p = 0.87) and motor composite scores (mean = 97.2 control, 97.9 intervention, p = 0.25). Mean scores for secondary outcomes were also similar among infants born to control and FENO group mothers, with few results reaching p < 0.05. CONCLUSION:  In this sample, FENO-guided asthma treatment during pregnancy did not improve infant developmental outcomes in the first year of life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ACTRN12613000202763. WHAT IS KNOWN: • Maternal asthma during pregnancy has been associated with increased rates of neurodevelopmental conditions in offspring, including intellectual disability and autism. WHAT IS NEW: • This is the first study to examine how managing asthma during pregnancy via a FENO-guided algorithm or usual care affects infant developmental and behavioural outcomes. While the results of the study showed no impact of the intervention, and therefore do not support the integration of FENO-based management of asthma in antenatal settings for optimal infant development, they do send a positive message about the implications of active asthma management during pregnancy on infant developmental outcomes.

Parenting stress in mothers with asthma during the postpartum period.

OBJECTIVE: Maternal asthma often complicates pregnancy and is linked with poorer quality of life. Additionally, individuals with asthma are at an increased risk of depression and anxiety. We examined whether asthma during pregnancy is related to parenting stress in the first year postpartum and if this relationship varies with level of asthma control. METHODS: This cohort survey-based study included mothers with (n = 157) and without (n = 79) asthma. Mothers with asthma participated in this study following participation in a randomized controlled trial of a novel asthma management strategy during pregnancy. Mothers completed the Parenting Stress Index - Short Form during the first 12 months postpartum. Mothers with asthma also completed the Asthma Control Questionnaire. RESULTS: Parenting stress did not differ between mothers with and without asthma. Additionally, for mothers with asthma, there were no differences in levels of parenting stress based on asthma control. CONCLUSIONS: This study suggests that mothers with asthma are not at an increased risk for excessive parenting stress. However, due to response and sampling bias, levels of parenting stress in asthmatic mothers may be underreported in our sample.

Domains and measures of social cognition in acquired brain injury: A scoping review.

In acquired brain injury (ABI), social cognition is a contributing factor to the changes observed in functional outcomes. However, progress in assessing and understanding social cognitive impairments is limited by a lack of consistency in terminology and the proliferation in assessment tools, leading to a lack of consensus on what should be assessed and how. This review aims to examine the domains of social cognition commonly assessed in ABI, the assessment tools used, and the appropriateness of these tools for researchers and clinicians. Using the Arksey and O'Malley scoping review methodology, 367 articles reporting results from 10,930 people with an ABI met our inclusion criteria. The five most commonly assessed domains of social cognition were emotion perception, theory of mind, social communication, identity recognition and empathy. The most commonly used measure of these domains included: the Ekman and Friesen photo series, Faux Pas Recognition Test, La Trobe Communication Questionnaire, Benton Facial Recognition Test and the Interpersonal Reactivity Index. There are well-validated measures readily available that are underused in favour of non-standardized measures clinically or the development of one's own measure in research. The appropriateness of the identified measure for research and clinical use was discussed, including suggestions for future research.

Experiences of non-invasive prenatal screening: A survey study.

BACKGROUND: In Australia, using non-invasive prenatal testing (NIPT) to screen for fetal abnormalities is becoming more commonplace. However, there is a lack of standardised procedures surrounding pre-test counselling. This holds the potential for variability in pregnant people's experiences when undergoing NIPT, which subsequently may impact their ability to make informed decisions surrounding NIPT results. AIM: This study sought to characterise the experiences of Australian women undergoing NIPT, including perceptions of informed choice, counselling experiences and decision to undergo NIPT. MATERIALS AND METHODS: Australian women who had been recently pregnant (n = 94) completed an online survey which assessed: their knowledge of and attitude toward NIPT; satisfaction with counselling; satisfaction with their decision; and decisional conflict to undergo NIPT. The survey also allowed participants to provide qualitative information about their counselling experience and reasons for undergoing NIPT. RESULTS: Overall, participants had good knowledge of and positive attitudes toward NIPT, experienced low decisional conflict and were overall satisfied with their counselling experience and decision to undergo NIPT. However, some participants expressed dissatisfaction with the lack of information provided, and biased language, by counselling providers. The desire to be informed was the most frequent reason for undergoing NIPT. CONCLUSION: The provision of accurate and objective information in pre-test counselling is important to reduce decisional conflict and improve satisfaction with the decision to undergo NIPT. It is recommended counselling providers present pregnant people with neutral, objective, and accurate information at the time of pre-test counselling.

Altered white matter microstructure in 22q11.2 deletion syndrome: a multisite diffusion tensor imaging study.

22q11.2 deletion syndrome (22q11DS)-a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22-is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6-52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen's d's ranging from -0.9 to -1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers.

Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size.

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen's d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = -1.01/-1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

What parents want to know in the first postnatal year: A Delphi consensus study.

BACKGROUND: Early postnatal psychoeducation intervention programmes can support new parents in the adjustment to parenthood. However, most psychoeducation programmes focus on pregnancy and the birth and fail to deliver relevant and age-specific information to new parents about what to expect in the postpartum period. Learning more about this intense period in a new parent's life will facilitate a healthy transition to parenthood. Considering the needs of time-poor but tech-savvy new parents, it is also necessary to rethink the delivery methods of such information to maximize impact. METHOD: Two panels of experts in perinatal mental health (eight professionals and eight parents with lived experience) participated in a Delphi consensus study to establish what topics of information are most important for parents in the first postnatal year. RESULTS: A total of 89 topics of information were endorsed by at least 80% of both panels as Essential or Good to Know information for new parents. The topics were grouped under the following themes: sleep, attachment, co-parenting, parental mental health, developmental milestones, feeding, social and community support, safety and health. CONCLUSIONS: This study established consensus between perinatal experts and parents with lived experience in order to produce relevant m-health psychoeducation for parents in the first postnatal year. The study findings will inform the development of perinatal m-health psychoeducation programmes.

Observational study of mental health in asthmatic women during the prenatal and postnatal periods.

Objective: We aimed to examine the prevalence and severity of psychological distress of women with asthma in both the prenatal and postnatal periods, and to determine whether asthmatic women with and without mental health problems differ in self-management, medications knowledge, and asthma symptoms.Methods: We assessed spirometry performance and asthma symptoms in 120 women (mean age 29.8 years) before 23 weeks gestation, as part of the Breathing for Life Trial (Trial ID: ACTRN12613000202763). Prenatal depression data was obtained from medical records. At 6 weeks postpartum, we assessed general health, self-reported asthma control, depression symptoms (with the Edinburgh Postnatal Depression Scale) and adaptive functioning (with the Achenbach System of Empirically Based Assessment scales).Results: Twenty percent of our sample reported having a current mental health diagnosis, 14% reported currently receiving mental health care, while 47% reported having received mental health care in the past (and may/may not have received a diagnosis). The sample scored high on the Aggressive Behavior, Avoidant Personality, and Attention Deficit/Hyperactivity scales. Poorer self-reported postnatal asthma control was strongly correlated with elevated somatic complaints, externalizing problems, antisocial personality problems, and greater withdrawal. Prenatal spirometry or asthma severity and control were largely not associated with measures of psychopathology.Conclusions: These findings indicate that pregnant women with asthma frequently report issues with psychopathology during the prenatal and postnatal periods, and that the subjective perception of asthma control may be more related to psychopathology than objective asthma measures. However, due to sample bias, these findings are likely to be understated.

"She'll be able to live independently as long as I'm around": The "lived" experience of parenting a child with 22q11.2 deletion syndrome in the transition to adulthood.

BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome. Parents of emerging adults with 22q11DS have an intense and ongoing involvement in their child's life. This study explores the lived experience of parents in relation to their child becoming independent and establishing intimate relationships. METHOD: Interpretative phenomenological analysis was used to explore the positive and negative experiences of five parents of emerging adults with 22q11DS. RESULTS: Supervised independence overarched four subordinate themes. These themes highlighted the difficulties experienced by parents attempting to relinquish control whilst still experiencing a need to keep their child safe as their child negotiated a complex stage of life. Parents waited for "signs" from their child before initiating conversations about intimate relationships. CONCLUSIONS: These findings provide insight into the lived experience of parenting a child through the transition into adulthood, providing a catalyst for further research with the aim of facilitating better services for families.

The effects of maternal asthma during pregnancy on child cognitive and behavioral development: A systematic review.

OBJECTIVE: Maternal asthma during pregnancy is associated with a higher risk of negative perinatal outcomes. However, little is known about the direct effects of maternal asthma on infant cognitive development. We examined the evidence for an impact of maternal asthma during pregnancy on cognitive and behavioral development of the child. DATA SOURCES: We conducted a MEDLINE, PsychINFO, and manual search of the databases for all available studies until January 9th, 2018. STUDY SELECTIONS: Studies were deemed relevant if they included child cognitive and behavioral development as the outcome, with maternal asthma as the determinant of interest. RESULTS: Ten articles matched selection criteria. Some studies report that maternal asthma is associated with increased risk for autism and intellectual disability in children. However, these effects are small and are often eliminated when controlling for confounding variables. Other studies have found no association. The only prospective study found that well-managed asthma during pregnancy was not associated with negative developmental outcomes in children. CONCLUSIONS: The evidence suggests that the relationship between maternal asthma during pregnancy and poor developmental and behavioral outcomes of children is weak. Children of mothers with well-managed asthma during pregnancy have similar developmental trajectories to those born to healthy mothers. Prospective, longitudinal studies are needed to confirm these conclusions. Optimal asthma management is important in pregnancy as it may have longer term benefits for the health of the offspring. As the rate of asthma increases in the population, the implications of maternal asthma on child development will be of greater importance.

Cardiovascular disease lifestyle risk factors in people with psychosis: a cross-sectional study.

BACKGROUND: People with psychosis die on average 25 years earlier than those in the general population, with cardiovascular disease (CVD) contributing to much of the excess mortality. This cross-sectional study aimed to identify the relationship between lifestyle risk factors for CVD - poor nutrition, smoking and low physical activity levels - and dyslipidaemia, hypertension and hyperglycaemia while controlling for potential confounders in 1825 people from the Survey of High Impact Psychosis (SHIP) in Australia. We also aimed to identify clustering patterns of lifestyle risk factors and associated demographic variables. METHODS: Three logistic regressions were used to predict the effect of nutrition, smoking and physical activity on dyslipidaemia, hypertension and hyperglycaemia while controlling for clozapine use, sex and age. Clustering patterns of nutrition, smoking and physical activity were examined using the two-step cluster method which is based on hierarchical cluster analysis. Demographic variables associated with different clusters were identified using measures of association. RESULTS: Smoking status had a positive association with dyslipidaemia (adjusted odds ratio = 0.50; 95% confidence interval = 0.32-0.78; p = 0.002). Other cardiovascular disease lifestyle risk factors did not have a significant relationship with dyslipidaemia, hypertension and hyperglycaemia. Clustering patterns of lifestyle risk factors showed that younger men, with low education levels, and relying on a government pension, were most likely to display the poorest lifestyle risk behaviours. The largest cluster (42%) of participants was characterised by a mixed demographic profile and were most likely to display poor nutrition and low physical activity levels but less likely to smoke. CONCLUSIONS: Only smoking status had a significant positive association with dyslipidaemia which could indicate that there are additional factors affecting the relationship between other cardiovascular lifestyle risk factors and dyslipidaemia, hypertension and hyperglycaemia in people with psychosis. Unknown confounders and traditional lifestyle risk factors may explain the high rates of CVD in this group. Clustering of lifestyle risk factors and their demographic profiles could help the design of intervention programs in people with psychosis.

Severity of illness and adaptive functioning predict quality of care of children among parents with psychosis: A confirmatory factor analysis.

OBJECTIVE: Parenthood is central to the personal and social identity of many people. For individuals with psychotic disorders, parenthood is often associated with formidable challenges. We aimed to identify predictors of adequate parenting among parents with psychotic disorders. METHODS: Data pertaining to 234 parents with psychotic disorders living with dependent children were extracted from a population-based prevalence study, the 2010 second Australian national survey of psychosis, and analysed using confirmatory factor analysis. Parenting outcome was defined as quality of care of children, based on participant report and interviewer enquiry/exploration, and included level of participation, interest and competence in childcare during the last 12 months. RESULTS: Five hypothesis-driven latent variables were constructed and labelled psychosocial support, illness severity, substance abuse/dependence, adaptive functioning and parenting role. Importantly, 75% of participants were not identified to have any dysfunction in the quality of care provided to their child(ren). Severity of illness and adaptive functioning were reliably associated with quality of childcare. Psychosocial support, substance abuse/dependence and parenting role had an indirect relationship to the outcome variable via their association with either severity of illness and/or adaptive functioning. CONCLUSION: The majority of parents in the current sample provided adequate parenting. However, greater symptom severity and poorer adaptive functioning ultimately leave parents with significant difficulties and in need of assistance to manage their parenting obligations. As symptoms and functioning can change episodically for people with psychotic illness, provision of targeted and flexible support that can deliver temporary assistance during times of need is necessary. This would maximise the quality of care provided to vulnerable children, with potential long-term benefits.

Association between domestic water hardness, chlorine, and atopic dermatitis risk in early life: A population-based cross-sectional study.

BACKGROUND: Domestic water hardness and chlorine have been suggested as important risk factors for atopic dermatitis (AD). OBJECTIVE: We sought to examine the link between domestic water calcium carbonate (CaCO3) and chlorine concentrations, skin barrier dysfunction (increased transepidermal water loss), and AD in infancy. METHODS: We recruited 1303 three-month-old infants from the general population and gathered data on domestic water CaCO3 (in milligrams per liter) and chlorine (Cl2; in milligrams per liter) concentrations from local water suppliers. At enrollment, infants were examined for AD and screened for filaggrin (FLG) skin barrier gene mutation status. Transepidermal water loss was measured on unaffected forearm skin. RESULTS: CaCO3 and chlorine levels were strongly correlated. A hybrid variable of greater than and less than median levels of CaCO3 and total chlorine was constructed: a baseline group of low CaCO3/low total chlorine (CaL/ClL), high CaCO3/low total chlorine (CaH/ClL), low CaCO3/high total chlorine (CaL/ClH) and high CaCO3/high total chlorine (CaH/ClH). Visible AD was more common in all 3 groups versus the baseline group: adjusted odds ratio (AOR) of 1.87 (95% CI, 1.25-2.80; P = .002) for the CaH/ClL group, AOR of 1.46 (95% CI, 0.97-2.21; P = .07) for the CaL/ClH, and AOR of 1.61 (95% CI, 1.09-2.38; P = .02) for the CaH/ClH group. The effect estimates were greater in children carrying FLG mutations, but formal interaction testing between water quality groups and filaggrin status was not statistically significant. CONCLUSIONS: High domestic water CaCO3 levels are associated with an increased risk of AD in infancy. The influence of increased total chlorine levels remains uncertain. An intervention trial is required to see whether installation of a domestic device to decrease CaCO3 levels around the time of birth can reduce this risk.

Filaggrin-null mutations are associated with increased maturation markers on Langerhans cells.

BACKGROUND: Mutations in the gene encoding filaggrin (FLG), an epidermal structural protein, are the strongest risk factor identified for the development of atopic dermatitis (AD). Up to 50% of patients with moderate-to-severe AD in European populations have FLG-null alleles compared with a general population frequency of 7% to 10%. OBJECTIVE: This study aimed to investigate the relationship between FLG-null mutations and epidermal antigen-presenting cell (APC) maturation in subjects with and without AD. Additionally, we investigated whether the cis isomer of urocanic acid (UCA), a filaggrin breakdown product, exerts immunomodulatory effects on dendritic cells. METHODS: Epidermal APCs from nonlesional skin were assessed by using flow cytometry (n = 27) and confocal microscopy (n = 16). Monocyte-derived dendritic cells from healthy volunteers were used to assess the effects of cis- and trans-UCA on dendritic cell phenotype by using flow cytometry (n = 11). RESULTS: Epidermal APCs from FLG-null subjects had increased CD11c expression. Confocal microscopy confirmed this and additionally revealed an increased number of epidermal CD83(+) Langerhans cells in FLG-null subjects. In vitro differentiation in the presence of cis-UCA significantly reduced costimulatory molecule expression on monocyte-derived dendritic cells from healthy volunteers and increased their ability to induce a regulatory T-cell phenotype in mixed lymphocyte reactions. CONCLUSIONS: We show that subjects with FLG-null mutations have more mature Langerhans cells in nonlesional skin irrespective of whether they have AD. We also demonstrate that cis-UCA reduces maturation of dendritic cells and increases their capacity to induce regulatory T cells, suggesting a novel link between filaggrin deficiency and immune dysregulation.

Skin barrier dysfunction measured by transepidermal water loss at 2 days and 2 months predates and predicts atopic dermatitis at 1 year.

BACKGROUND: Loss-of-function mutations in the skin barrier protein filaggrin (FLG) are a major risk for atopic dermatitis (AD). The pathogenic sequence of disturbances in skin barrier function before or during the early development of AD is not fully understood. A more detailed understanding of these events is needed to develop a clearer picture of disease pathogenesis. A robust, noninvasive test to identify babies at high risk of AD would be important in planning early intervention and/or prevention studies. OBJECTIVES: To ascertain whether a noninvasive measurement of skin barrier function at day 2 after birth and at 2 months predicts the development of AD at 1 year. Furthermore, to determine whether increases in transepidermal water loss (TEWL) predate the development of clinical AD. METHODS: A total of 1903 infants were enrolled in the Cork Babies After Scope: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints Birth Cohort study from July 2009 to October 2011. Measurements of TEWL were made at birth (day 2) and at 2 and 6 months. The presence of AD was ascertained at 6 and 12 months, and disease severity was assessed by using the SCORing Atopic Dermatitis clinical tool at 6 months and by using both the SCORing Atopic Dermatitis clinical tool and Nottingham Severity Score at 12 months. A total of 1300 infants were genotyped for FLG mutations. RESULTS: At 6 months, 18.7% of the children had AD, and at 12 months, 15.53%. In a logistic regression model, day 2 upper quartile TEWL measurement was significantly predictive of AD at 12 months (area under the receiver operating characteristic curve, 0.81; P < .05). Lowest quartile day 2 TEWL was protective against AD at 12 months. An upper quartile 2 month TEWL was also strongly predictive of AD at 12 months (area under the receiver operating characteristic curve, 0.84; P < .05). At both ages, this effect was independent of parental atopy, FLG status, or report of an itchy flexural rash at 2 months. Associations were increased when parental atopy status or child FLG mutation status was added into the linear regression model. CONCLUSIONS: Impairment of skin barrier function at birth and at 2 months precedes clinical AD. In addition to providing important mechanistic insights into disease pathogenesis, these findings have implications for the optimal timing of interventions for the prevention of AD.

Filaggrin breakdown products determine corneocyte conformation in patients with atopic dermatitis.

BACKGROUND: Loss-of-function (LOF) mutations in the filaggrin gene (FLG) are a well-replicated risk factor for atopic dermatitis (AD) and are known to cause an epidermal barrier defect. The nature of this barrier defect is not fully understood. Patients with AD with FLG LOF mutations are known to have more persistent disease, more severe disease, and greater risk of food allergies and eczema herpeticum. Abnormalities in corneocyte morphology have been observed in patients with AD, including prominent villus-like projections (VP); however, these ultrastructural features have not been systematically studied in patients with AD in relation to FLG genotype and acute and convalescent status. OBJECTIVE: We sought to quantitatively explore the relationship between FLG genotype, filaggrin breakdown products (natural moisturizing factor [NMF]), and corneocyte morphology in patients with AD. METHODS: We studied 15 children at first presentation of AD and after 6 weeks of standard therapy. We applied atomic force microscopy to study corneocyte conformation in patients with AD stratified by FLG status and NMF level. By using a new quantitative methodology, the number of VPs per investigated corneocyte area was assessed and expressed as the Dermal Texture Index score. Corneocytes were also labeled with an anti-corneodesmosin antibody and visualized with scanning electron microscopy. RESULTS: We found a strong correlation between NMF levels and Dermal Texture Index scores in both acute and convalescent states (respective r = -0.80 and -0.75, P < .001 and P = .002). Most, but not all, VPs showed the presence of corneodesmosin abundantly all over the cell surface in homozygous/compound heterozygous FLG patients and, to a lesser extent, in heterozygous and wild-type patients. CONCLUSIONS: NMF levels are highly correlated with corneocyte morphology in patients with AD. These corneocyte conformational changes shed further insight into the filaggrin-deficient phenotype and help explain the barrier defect in patients with AD with FLG LOF mutations.

Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.

We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi2 test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.

Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.

Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of approximately 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.