Investigations of an individual with a Marfanoid habitus, mild intellectual disability, and severe social anxiety identifies PCDHGA5 as a candidate neurodevelopmental disorder gene.

Marfanoid habitus and intellectual disability (MHID) co-occur in multiple neurodevelopmental disorders (NDD). Among those, Lujan-Fryns, an X-linked genetic disorder associated with variants in MED12 was the first such syndrome identified. Accurate molecular diagnosis for these MHID syndromes remains a challenge due to significant clinical and genetic heterogeneity. We present a case report of a 20-year-old male patient with MHID and severe social anxiety. A comprehensive clinical evaluation, including morphotype assessment, cognitive, and psychometric and genetic testing, was conducted to provide a detailed understanding of the patient's complex clinical presentation. Psychometric assessments revealed severe social anxiety and various cognitive and emotional challenges. Despite some autism-like symptoms, the patient's clinical presentation was more aligned with mild intellectual disability. Exome sequencing was inconclusive but identified a heterozygous de novo missense variant in the PCDHGA5 gene. This gene is not known in human pathology yet, but we also report a second patient with a syndromic neurodevelopmental disorder and a rare de novo variant which leads us to propose this as a candidate gene. Our findings emphasize the importance of multidisciplinary approach in the diagnosis and management of MHID. This case report underscores the need for objective clinical evaluations and standardized tools to better understand the complex clinical profiles of patients with NDDs. The identification of novel PCDHGA5 gene variants adds this gene's candidacy to the genetic landscape of MHID-NDD, warranting further investigation to determine its potential contribution.

Steroid hormone pathways, vitamin D and autism: a systematic review.

The origins of the male preponderance in autism incidence remain unclear. The idea that perinatal factors associated with sex differentiation (e.g., steroid hormone pathways) may increase the possibility of the emergence of autism is complementary to the hypothesis that female individuals are intrinsically less likely to develop autism. Empirical evidence for the mechanistic roles of in utero steroid hormones in autism etiology is accumulating but inconsistent. We conducted a systematic review using rigorous criteria for the measurements of steroids and vitamin D exposure, to summarize the potential contributing roles of prenatal and early postnatal steroids and vitamin D alterations to the emergence of autism. We searched PubMed, PsychInfo, Scopus, and included 22 studies for qualitative synthesis. Among them, six studies examined the association of autism diagnoses in offspring and levels of steroids and precursor steroid hormones in the fetal environment, eight studies examined the associations between autism and maternal and fetal blood vitamin D levels during pregnancy and at birth, and eight studies examined the associations between offspring autism diagnoses and maternal hyperandrogenemia diagnosed before pregnancy. We identified promising and complex results regarding the relations between steroid metabolism and autism. The interpretation of findings was limited by the mostly observational study designs, insufficient investigation of the effects of offspring sex, confounders and their cumulative effects on the development of the child, and unclear impact of the timing of steroids exposure and their effects on fetal neurodevelopment.

The Current View on the Paradox of Pain in Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, which affects 1 in 44 children and may cause severe disabilities. Besides socio-communicational difficulties and repetitive behaviors, ASD also presents as atypical sensorimotor function and pain reactivity. While chronic pain is a frequent co-morbidity in autism, pain management in this population is often insufficient because of difficulties in pain evaluation, worsening their prognosis and perhaps driving higher mortality rates. Previous observations have tended to oversimplify the experience of pain in autism as being insensitive to painful stimuli. Various findings in the past 15 years have challenged and complicated this dogma. However, a relatively small number of studies investigates the physiological correlates of pain reactivity in ASD. We explore the possibility that atypical pain perception in people with ASD is mediated by alterations in pain perception, transmission, expression and modulation, and through interactions between these processes. These complex interactions may account for the great variability and sometimes contradictory findings from the studies. A growing body of evidence is challenging the idea of alterations in pain processing in ASD due to a single factor, and calls for an integrative view. We propose a model of the pain cycle that includes the interplay between the molecular and neurophysiological pathways of pain processing and it conscious appraisal that may interfere with pain reactivity and coping in autism. The role of social factors in pain-induced response is also discussed. Pain assessment in clinical care is mostly based on subjective rather than objective measures. This review clarifies the strong need for a consistent methodology, and describes innovative tools to cope with the heterogeneity of pain expression in ASD, enabling individualized assessment. Multiple measures, including self-reporting, informant reporting, clinician-assessed, and purely physiological metrics may provide more consistent results. An integrative view on the regulation of the pain cycle offers a more robust framework to characterize the experience of pain in autism.

Diagnostic Process for Autism Spectrum Disorder: A Meta-Analysis of Worldwide Clinical Practice Guidelines for the Initial Somatic Assessment.

(1) Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is highly associated with various somatic conditions that can be masked by the core symptoms of ASD and thus complicate the diagnosis. Identifying co-occurring somatic disorders is critical for providing effective healthcare and social services for ASD populations and influences their long-term outcomes. A systematic assessment of co-occurring somatic conditions is essential during this ASD diagnostic process. Therefore, this study aimed to identify the organization and content of the initial somatic assessment (ISA). (2) Methods: We conducted a systematic review of the clinical practice guidelines (CPG) for the ASD diagnostic process published between January 2005 and December 2019 in English and French and performed an appraisal following the Appraisal of Guidelines Research and Evaluation, second edition (AGREE-II). (3) Results: We selected 14 CPGs that were heterogeneous in quality, with methodological scores between 32.3 and 91.9. Clinical examinations are the first step in the ISA, and the participation of pediatric, neuropediatric, and genetic specialists was highly recommended by the majority of the CPGs. The recommendations included hearing screening tests (10/14), visual examinations (8/14), and systematic genetic investigations (4/14). The CPGs also described additional investigations that should be conducted based on numerous warning signs. (4) Conclusions: Screening for consensual international warning signs is necessary to perform a comprehensive and systematic ISA during the ASD diagnostic process. A "referral form" could be used to guide clinicians and improve the coordination process. This tool may reinforce epidemiological data on co-occurring somatic disorders in patients with ASD.

New Technologies as Promising Tools for Assessing Facial Emotion Expressions Impairments in ASD: A Systematic Review.

The ability to recognize and express emotions from facial expressions are essential for successful social interactions. Facial Emotion Recognition (FER) and Facial Emotion Expressions (FEEs), both of which seem to be impaired in Autism Spectrum Disorders (ASD) and contribute to socio-communicative difficulties, participate in the diagnostic criteria for ASD. Only a few studies have focused on FEEs processing and the rare behavioral studies of FEEs in ASD have yielded mixed results. Here, we review studies comparing the production of FEEs between participants with ASD and non-ASD control subjects, with a particular focus on the use of automatic facial expression analysis software. A systematic literature search in accordance with the PRISMA statement identified 20 reports published up to August 2020 concerning the use of new technologies to evaluate both spontaneous and voluntary FEEs in participants with ASD. Overall, the results highlight the importance of considering socio-demographic factors and psychiatric co-morbidities which may explain the previous inconsistent findings, particularly regarding quantitative data on spontaneous facial expressions. There is also reported evidence for an inadequacy of FEEs in individuals with ASD in relation to expected emotion, with a lower quality and coordination of facial muscular movements. Spatial and kinematic approaches to characterizing the synchrony, symmetry and complexity of facial muscle movements thus offer clues to identifying and exploring promising new diagnostic targets. These findings have allowed hypothesizing that there may be mismatches between mental representations and the production of FEEs themselves in ASD. Such considerations are in line with the Facial Feedback Hypothesis deficit in ASD as part of the Broken Mirror Theory, with the results suggesting impairments of neural sensory-motor systems involved in processing emotional information and ensuring embodied representations of emotions, which are the basis of human empathy. In conclusion, new technologies are promising tools for evaluating the production of FEEs in individuals with ASD, and controlled studies involving larger samples of patients and where possible confounding factors are considered, should be conducted in order to better understand and counter the difficulties in global emotional processing in ASD.