Spondylometepiphyseal dysplasia, Strudwick type

The clinical and radiographic observations in eight patients, radiographs on an additional six patients, and morphologic observations on chondro-osseous tissue from two of these 14 patients form the basis for delineating an entity distinct from the heterogeneous group of skeletal dysplasia involving spine and tubular bones, the spondyloepiphyseal, and spondylometaphyseal dysplasias. Disproportionately short limbs and delayed epiphyseal maturation are present at birth, and the entity is radiographically indistinguishable from spondyloepiphyseal dysplasia (SED) congenita during infancy. The metaphyseal change that allows identification of the entity described here develops during early childhood, and radiographically is seen as "dappling," ie, the mottled appearance of alternating zones of osteosclerosis and osteopenia. Severe scoliosis and cord compression may be important clinical problems related to the spine changes in adulthood. We have identified one family with two affected sibs and normal parents, suggesting autosomal recessive inheritance and distinguishing the entity from SED congenita that has autosomal dominant inheritance.     

Gene–Environment Interactions in Developmental Neurotoxicity: a Case Study of Synergy between Chlorpyrifos and CHD8 Knockout in Human BrainSpheres

Background: Autism spectrum disorder (ASD) is a major public health concern caused by complex genetic and environmental components. Mechanisms of gene–environment (G×E) interactions and reliable biomarkers associated with ASD are mostly unknown or controversial. Induced pluripotent stem cells (iPSCs) from patients or with clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9)-introduced mutations in candidate ASD genes provide an opportunity to study (G×E) interactions.Objectives: In this study, we aimed to identify a potential synergy between mutation in the high-risk autism gene encoding chromodomain helicase DNA binding protein 8 (CHD8) and environmental exposure to an organophosphate pesticide (chlorpyrifos; CPF) in an iPSC-derived human three-dimensional (3D) brain model.Methods: This study employed human iPSC-derived 3D brain organoids (BrainSpheres) carrying a heterozygote CRISPR/Cas9-introduced inactivating mutation in CHD8 and exposed to CPF or its oxon-metabolite (CPO). Neural differentiation, viability, oxidative stress, and neurite outgrowth were assessed, and levels of main neurotransmitters and selected metabolites were validated against human data on ASD metabolic derangements.Results: Expression of CHD8 protein was significantly lower in CHD8 heterozygous knockout (CHD8+/−) BrainSpheres compared with CHD8+/+ ones. Exposure to CPF/CPO treatment further reduced CHD8 protein levels, showing the potential (G×E) interaction synergy. A novel approach for validation of the model was chosen: from the literature, we identified a panel of metabolic biomarkers in patients and assessed them by targeted metabolomics in vitro. A synergistic effect was observed on the cholinergic system, S-adenosylmethionine, S-adenosylhomocysteine, lactic acid, tryptophan, kynurenic acid, and α-hydroxyglutaric acid levels. Neurite outgrowth was perturbed by CPF/CPO exposure. Heterozygous knockout of CHD8 in BrainSpheres led to an imbalance of excitatory/inhibitory neurotransmitters and lower levels of dopamine.Discussion: This study pioneered (G×E) interaction in iPSC-derived organoids. The experimental strategy enables biomonitoring and environmental risk assessment for ASD. Our findings reflected some metabolic perturbations and disruption of neurotransmitter systems involved in ASD. The increased susceptibility of CHD8+/− BrainSpheres to chemical insult establishes a possibly broader role of (G×E) interaction in ASD. https://doi.org/10.1289/EHP8580     

A phenotype intermediate between Desbuquois dysplasia and diastrophic dysplasia secondary to mutations in DTDST

We describe a child whose original clinical and radiologic manifestations led to a diagnosis of Desbuquois dysplasia. Subsequent development of features including cervical kyphosis and cystic ears caused us to reconsider the original diagnosis. The new complement of features in this patient fell in a range between Desbuquois dysplasia and diastrophic dysplasia. Molecular testing showed that she is a compound heterozygote for mutations in the diastrophic dysplasia sulfate transporter gene (DTDST). This finding confirms that there is locus heterogeneity in apparent Desbuquois dysplasia. It also expands the phenotypic spectrum of disorders caused by mutations in DTDST.     

Loneliness and depressive symptoms: the moderating role of the transition into retirement

Objectives: The transition to retirement implies significant changes in daily routine and in the social environment. More specifically, it requires more self-directed efforts in order to stay socially engaged. Hence, for those who suffer from loneliness, the transition to retirement could result in increased depressive symptoms due to the lack of structured daily routine.

Methods: We used two waves of the Health and Retirement Study, and tested whether the transition to retirement between the two waves moderates the effects of loneliness on depressive symptoms.

Results: The transition to retirement moderated the effect of loneliness in wave 1 on depressive symptoms in wave 2, such that for those who retired, the effect was stronger in comparison to those who stayed employed.

Conclusions: Although many manage to easily transition into retirement, lonely older workers are at increased risk for maladjustment and the experience of depressive symptoms following retirement. This group could perhaps benefit from interventions aimed at increasing daily social interactions and establishing a socially satisfying routine.