Cytoarchitectonically Defined Volumes of Early Extrastriate Visual Cortex in Unmedicated Adults With Body Dysmorphic Disorder.

BACKGROUND: Individuals with body dysmorphic disorder (BDD) misperceive that they have prominent defects in their appearance, resulting in preoccupations, time-consuming rituals, and distress. Previous neuroimaging studies have found abnormal activation patterns in the extrastriate visual cortex, which may underlie experiences of distorted perception of appearance. Correspondingly, we investigated gray matter volumes in individuals with BDD in the early extrastriate visual cortex using cytoarchitectonically defined maps that were previously derived from postmortem brains. METHODS: We analyzed T1-weighted magnetic resonance imaging data from 133 unmedicated male and female participants (BDD: n = 65; healthy control subjects: n = 68). We used cytoarchitectonically defined probability maps for the early extrastriate cortex, consisting of areas corresponding to V2, V3d, V3v/VP, V3a, and V4v. Gray matter volumes were compared between groups, supplemented by testing associations with clinical symptoms. RESULTS: The BDD group exhibited significantly larger gray matter volumes in the left and right early extrastriate cortex. Region-specific follow-up analyses revealed multiple subregions showing larger volumes in BDD, significant in the left V4v. There were no significant associations after corrections for multiple comparisons between gray matter volumes in early extrastriate cortex and BDD symptoms, comorbid symptoms, or duration of illness. CONCLUSIONS: Greater volumes of the early extrastriate visual cortex were evident in those with BDD, which aligns with outcomes of prior studies revealing BDD-specific functional abnormalities in these regions. Enlarged volumes of the extrastriate cortex in BDD might manifest during neurodevelopment, which could predispose individuals to aberrant visual perception and contribute to the core phenotype of distortion of perception for appearance.

Whole Exome Sequencing Reveals a Novel AUTS2 In-Frame Deletion in a Boy with Global Developmental Delay, Absent Speech, Dysmorphic Features, and Cerebral Anomalies.

Neurodevelopmental disorders (NDDs) are a group of highly prevalent, clinically and genetically heterogeneous pediatric disorders comprising, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V), intellectual disability, developmental delay, autism spectrum disorders, and other neurological and cognitive disorders manifesting in the developmental age. To date, more than 1000 genes have been implicated in the etiopathogenesis of NNDs. Among them, AUTS2 (OMIM # 607270) encodes a protein involved in neural migration and neuritogenesis, and causes NNDs with different molecular mechanisms including copy number variations, single or multiple exonic deletion and single nucleotide variants. We describes a 9-year-old boy with global developmental delay, absent speech, minor craniofacial anomalies, hypoplasia of the cerebellar vermis and thinning of the corpus callosum, resulted carrier of the de novo AUTS2 c.1603_1626del deletion at whole exome sequencing (WES) predicted to cause the loss of eight amino acids [p.(His535_Thr542del)]. Notably, our patient is the first reported so far in medical literature carrying an in-frame deletion and the first in which absent language, hypoplasia of the cerebellar vermis and thinning of the corpus callosum has been observed thus useful to expand the molecular spectrum of AUTS2 pathogenic variants and to broaden our knowledge on the clinical phenotype associated.

Novel de novo TRIP12 mutation reveals variable phenotypic presentation while emphasizing core features of TRIP12 variations.

Intellectual disability (ID) is a complicated and multifactorial condition often with an unclear cause. Advancements in diagnostic techniques have identified genetic causes in a significant proportion. Pathogenic variants in TRIP12, encoding for an E3 ligand in the ubiquitin-protease pathway, have previously been identified as a cause of ID with autistic behavior and dysmorphic features. We report two unrelated patients with de novo mutations in TRIP12 and diagnoses of global developmental delay, autism spectrum disorder and dysmorphic features, as well as a range of other characteristics. Exome sequencing was utilized as part of an extensive genetic workup for both individuals. The genotypic and phenotypic data for both patients has been collated with previously reported data. Epilepsy was noted in about 20% published cases. One of our patents had epilepsy. These cases highlight the variable phenotypic presentations of TRIP12 variations while emphasizing the core features of ID and speech delay, with or without autistic features and epilepsy.

Brain white matter abnormalities associated with copy number variants.

White matter (WM) signal abnormalities are demonstrated in various neurodevelopmental disorders on brain magnetic resonance imaging (MRI). The pattern of WM abnormalities can aid in the diagnostic process. This study aims to characterize the WM changes found in microdeletion/microduplication syndromes. Thirteen patients with neurodevelopmental disorders due to copy number variations were collected from a cohort of children with evidence of WM abnormalities on brain MRI, in two medical centers. A pediatric neuroradiologist blindly interpreted the MRI scans. Clinical and genetic findings were retrospectively extracted from the medical records. WM changes included: multifocal (10/13) periventricular (12/13) and subcortical (5/13) signal abnormalities and WM volume loss (6/13). Dysgenesis of the corpus callosum was depicted in 12/13. The main clinical features were: global developmental delay (13/13), hypotonia (11/13), epilepsy (10/13), dysmorphic features (9/13), microcephaly (6/13), short stature (6/13), and systemic involvement (6/13). We showed that different chromosomal micro-rearrangement syndromes share similar MRI patterns of nonspecific multifocal predominantly periventricular WM changes associated with corpus callosum dysgenesis with or without WM and gray matter loss. Hence, the association of these features in a patient evaluated for global developmental delay/intellectual disability suggests a chromosomal micro-rearrangement syndrome, and a chromosomal microarray analysis should be performed.

De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia.

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.

Parameters of visual processing abnormalities in adults with body image concerns.

Body dysmorphic disorder (BDD), at the extreme end of the body image concern (BIC) spectrum, is thought to be associated with a local (detail-focussed) visual processing bias. Given that the inversion of a stimulus disrupts holistic processing and demands detail-specific attention, this perceptual bias is characterised by superior processing of such inverted stimuli. This study examined the processing bias, via a body-inversion discrimination task, of 26 participants with non-clinical, high-BIC (Dysmophic Concern Questionnaire (DCQ) scores between 11-19) and 26 participants with low-BIC (DCQ scores between 0-4). This study also explored the impact of varying stimuli presentation durations and discrimination difficulties during the inversion task on visual processing. As hypothesised, compared to those with low-BIC, participants with high-BIC demonstrated superior accuracy when discriminating between images of inverted bodies, indicating a local processing bias. Also as hypothesised, this local processing bias selectively manifested only when stimuli were presented for longer durations and at higher discrimination difficulties, revealing the parameters of this, potentially conscious, processing tendency. Consistent with previous research, this study identified a local processing bias in those with high BIC, which may be a predisposing factor for developing BDD. In turn, identifying the parameters (stimulus exposure and stimulus complexity) in which the local bias manifests has implications for future interventions aiming to reverse this perceptual abnormality.

A novel FBXO28 frameshift mutation in a child with developmental delay, dysmorphic features, and intractable epilepsy: A second gene that may contribute to the 1q41-q42 deletion phenotype.

Chromosome 1q41-q42 deletions have recently been associated with a recognizable neurodevelopmental syndrome of early childhood (OMIM 612530). Within this group, a predominant phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, distinct dysmorphology, and brain anomalies on magnetic resonance imaging/computed tomography has emerged. Previous reports of patients with de novo deletions at 1q41-q42 have led to the identification of an evolving smallest region of overlap which has included several potentially causal genes including DISP1, TP53BP2, and FBXO28. In a recent report, a cohort of patients with de novo mutations in WDR26 was described that shared many of the clinical features originally described in the 1q41-q42 microdeletion syndrome (MDS). Here, we describe a novel germline FBXO28 frameshift mutation in a 3-year-old girl with intractable epilepsy, ID, DD, and other features which overlap those of the 1q41-q42 MDS. Through a familial whole-exome sequencing study, we identified a de novo FBXO28 c.972_973delACinsG (p.Arg325GlufsX3) frameshift mutation in the proband. The frameshift and resulting premature nonsense mutation have not been reported in any genomic database. This child does not have a large 1q41-q42 deletion, nor does she harbor a WDR26 mutation. Our case joins a previously reported patient also in whom FBXO28 was affected but WDR26 was not. These findings support the idea that FBXO28 is a monogenic disease gene and contributes to the complex neurodevelopmental phenotype of the 1q41-q42 gene deletion syndrome.

[Body image disorder in 100 Tunisian female breast cancer patients]. / Le trouble de l'image du corps chez 100 femmes tunisiennes atteintes d'un cancer du sein.

INTRODUCTION: This study aimed at tracking the prevalence of body image disorder in a population of Tunisian women followed for breast cancer and the factors associated with it. PATIENTS END METHODS: The cross-sectional study was conducted at Salah-Azaiez Institute in Tunis, over a period of four months. One hundred outpatients followed for confirmed breast cancer were recruited. The questionnaire targeted the women's sexuality and their couple relationships, along with their socio-demographic, clinical, and therapeutic characteristics. The scales used were BIS, HADS, and FSFI. RESULTS: The prevalence of body image disorder according to BIS was 45% with an average of 11.5±11.2 among the interrogated patients, 24.7% of which reported an alteration in their couple relationships and 47% in their sexual relations. In univariate analysis, body image disorder was associated with family support, change in couple relationship, depression and anxiety. Body image disorder and sexual dysfunction were interrelated: each of them fostered the prevalence of the other. Multivariate analysis showed that occupational activity was an independent predictor and the absence of anxiety an independent protective factor. Body image disorder was an independent predictive factor of depression and anxiety. DISCUSSION: The quality of couple relation and sexuality, along with the impact of the patient's surrounding are decisive for the protection or alteration of her body image.

The neurobiology of body dysmorphic disorder: A systematic review and theoretical model.

There has been an increase in neuroimaging research in body dysmorphic disorder (BDD), yet little is known about the underlying neurobiological basis of the disorder. We aimed to provide a systematic overview of the literature on the neurobiology of BDD. Two reviewers undertook a search of three electronic research databases: PubMed, PsycINFO, and Google Scholar. The search consisted of synonyms commonly associated with BDD and methods to evaluate brain structure, function, and network organisation. Out of an initial yield of 175 articles, 19 fulfilled inclusion criteria and were reviewed. We identified differences in brain activity, structure, and connectivity in BDD participants in frontostriatal, limbic, and visual system regions when compared to healthy control and other clinical groups. We put forth a neurobiological model of BDD pathophysiology that involves wide-spread disorganisation in neural networks involved in cognitive control and the interpretation of visual and emotional information. This review considers how this model might aid in the development of future research and understanding of BDD.

Prevalência do transtorno dismórfico corporal em pacientes candidatos e/ou submetidos a procedimentos estéticos na especialidade da cirurgia plástica: uma revisão sistemática com meta-análise / Prevalence of body dysmorphic disorder in patients who are candidates and/or are submitted to aesthetic procedures in the specialty of plastic surgery: a systematic review with meta-analysis

Este estudo objetivou verificar, por meio de uma revisão sistemática da literatura e da realização de uma meta-análise, a prevalência do transtorno dismórfico corporal em pacientes candidatos e/ou submetidos a procedimentos estéticos na especialidade da Cirurgia Plástica. Para cumprir com o objetivo proposto, foram analisados os mais relevantes estudos publicados originalmente em qualquer idioma, porém, que estivessem indexados às bases de dados National Library of Medicine (MEDLINE), Cochrane e Scielo, nas quais as buscas foram realizadas, por meio do uso de descritores associados ao tema e de critérios de inclusão e exclusão. Sendo assim, a amostra final deste estudo foi composta por 15 publicações, as quais foram submetidas a uma meta-análise, podendo-se verificar que 12,5% dos pacientes que são candidatos/submetidos a procedimentos estéticos na especialidade da Cirurgia Plástica possuem transtorno dismórfico corporal. Destes, a maioria é do gênero feminino (75,7%) e possui média de idade de 30 (± 10,5) anos. Devido ao alto índice de pacientes com transtorno dismórfico corporal atendidos na especialidade, ressalta-se a importância de os cirurgiões plásticos atentarem-se para o adequado atendimento dos pacientes, com vistas à identificação dos indivíduos potencialmente portadores desse transtorno e, consequentemente, à solicitação de um acompanhamento interdisciplinar com a participação de psicólogos e psiquiatras.

This study aimed at showing the prevalence of body dysmorphic disorder (BDD) in patients who are candidates and/or are submitted to aesthetic procedures in the specialty of plastic surgery via a systematic review of the literature and a meta-analysis. To comply with the proposed objective, we analyzed the most relevant studies originally published in any language that were available in the National Library of Medicine (MEDLINE), Cochrane, and SciELO databases. Searches were performed using keywords associated with the theme and inclusion and exclusion criteria. Thus, the final sample of this study was composed of 15 publications, which were submitted to a meta-analysis. It can be confirmed that 12.5% of the patients who were candidates/submitted to aesthetic procedures in the specialty of plastic surgery had BDD. Of these, the majority were women (75.7%) with a mean age of 30 (± 10.5) years. Given the high number of patients with BDD attended to in the specialty, it is important that plastic surgeons focus on providing patients with adequate care to identify individuals who potentially have BDD and consequently conduct an interdisciplinary follow-up with the participation of psychologists and psychiatrists.

The intense desire for healthy limb amputation: A dis-proprioceptive neuropsychiatric disorder.

BACKGROUND: The first mention of a condition in which apparently nonpsychotic individuals have a strong, unrelenting desire to amputate ≥1 of their healthy limbs was published nearly 4 decades ago. Once dismissed as a paraphilia, the condition in recent years has been re-investigated with neurologic testing and imaging, yielding evidence suggesting it may be attributable to a neuroanatomical anomaly. METHODS: A literature review of data was conducted of recently published studies with pinprick testing, magnetic resonance imaging (MRI)/functional MRI imaging, magnetoencephalography, and interviews of individuals with a desire for limb amputation. RESULTS: Published literature on this condition features studies with a limited number of participants. However, the results indicate that affected individuals predominantly desire amputation of the left lower limb, and correspondingly, usually have changes in cortical thickness in the right parietal lobe. CONCLUSIONS: Further investigation of this condition is warranted, particularly, more research into the precise nature of the anomalous neuroanatomy, biopsychosocial background of those with the condition, and longitudinal perspective of the childhood onset and evolution of symptoms. Large sample studies involving a collaborative effort across multiple sites are required.

Obsessive-compulsive skin disorders: a novel classification based on degree of insight.

Individuals with obsessive-compulsive features frequently visit dermatologists for complaints of the skin, hair or nails, and often progress towards a chronic relapsing course due to the challenge associated with accurate diagnosis and management of their psychiatric symptoms. The current DSM-5 formally recognizes body dysmorphic disorder, trichotillomania, neurotic excoriation and body focused repetitive behavior disorder as psychodermatological disorders belonging to the category of Obsessive-Compulsive and Related Disorders. However there is evidence that other relevant skin diseases such as delusions of parasitosis, dermatitis artefacta, contamination dermatitis, AIDS phobia, trichotemnomania and even lichen simplex chronicus possess prominent obsessive-compulsive characteristics that do not necessarily fit the full diagnostic criteria of the DSM-5. Therefore, to increase dermatologists' awareness of this unique group of skin disorders with OCD features, we propose a novel classification system called Obsessive-Compulsive Insight Continuum. Under this new classification system, obsessive-compulsive skin manifestations are categorized along a continuum based on degree of insight, from minimal insight with delusional obsessions to good insight with minimal obsessions. Understanding the level of insight is thus an important first step for clinicians who routinely interact with these patients.

Reduced cortical thickness in body dysmorphic disorder.

Recent neuroimaging studies in body dysmorphic disorder (BDD) have implicated abnormal structure and function of occipito-temporal and fronto-limbic regions in the potential pathophysiology of the disorder. To date, morphometric investigations have yielded inconsistent results, and have suggested that clinical symptoms may mediate structural brain abnormalities in BDD. We measured Grey Matter (GM) cortical thickness in 20 participants with BDD and 20 healthy control participants matched on age, gender, estimated IQ and handedness. We observed cortical thinning in BDD patients compared with healthy control participants within the left middle temporal and left inferior parietal gyrus. No significant relationships between cortical thickness and BDD symptom severity, insight, social anxiety and depression were observed within the BDD group. Thinning within left temporal and left inferior parietal regions supports the involvement of these regions in the pathophysiology of BDD.

Truncating de novo mutations in the Krüppel-type zinc-finger gene ZNF148 in patients with corpus callosum defects, developmental delay, short stature, and dysmorphisms.

BACKGROUND: Krüppel-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family. ZNF genes encode proteins that recognize specific DNA motifs in gene promotors. They act as transcriptional co-activators or -repressors via interaction with chromatin remodeling proteins and other transcription factors. Only few ZNF genes are currently linked to human disorders and identification of ZNF gene-associated human diseases may help understand their function. Here we provide genetic, statistical, and clinical evidence to support association of ZNF148 with a new intellectual disability (ID) syndrome disorder. METHODS: Routine diagnostic exome sequencing data were obtained from 2172 patients with ID and/or multiple congenital anomalies. RESULTS: In a cohort of 2172 patient-parent trios referred for routine diagnostic whole exome sequencing for ID and/or multiple congenital anomalies (MCA) in the period 2012-2016, four patients were identified who carried de novo heterozygous nonsense or frameshift mutations in the ZNF148 gene. This was the only ZNF gene with recurrent truncating de novo mutations in this cohort. All mutations resulted in premature termination codons in the last exon of ZNF148. The number of the de novo truncating mutations in the ZNF148 gene was significantly enriched (p = 5.42 × 10-3). The newly described ZNF148-associated syndrome is characterized by underdevelopment of the corpus callosum, mild to moderate developmental delay and ID, variable microcephaly or mild macrocephaly, short stature, feeding problems, facial dysmorphisms, and cardiac and renal malformations. CONCLUSIONS: We propose ZNF148 as a gene involved in a newly described ID syndrome with a recurrent phenotype and postulate that the ZNF148 is a hitherto unrecognized but crucial transcription factor in the development of the corpus callosum. Our study illustrates the advantage of whole exome sequencing in a large cohort using a parent-offspring trio approach for identifying novel genes involved in rare human diseases.

The Desire for Amputation or Paralyzation: Evidence for Structural Brain Anomalies in Body Integrity Identity Disorder (BIID).

BACKGROUND: Body Integrity Identity Disorder (BIID) is a condition in which individuals perceive a mismatch between their internal body scheme and physical body shape, resulting in an absolute desire to be either amputated or paralyzed. The condition is hypothesized to be of congenital nature, but evidence for a neuro-anatomical basis is sparse. METHODS: We collected T1-weighted structural magnetic resonance imaging scans on a 3T scanner in eight individuals with BIID and 24 matched healthy controls, and analyzed the data using voxel-based morphometry. RESULTS: The results showed reduced grey matter volume in the left dorsal and ventral premotor cortices and larger grey matter volume in the cerebellum (lobule VIIa) in individuals with BIID compared to controls. CONCLUSION: The premotor cortex and cerebellum are thought to be crucial for the experience of body-ownership and the integration of multisensory information. Our results suggest that BIID is associated with structural brain anomalies and might result from a dysfunction in the integration of multisensory information, leading to the feeling of disunity between the mental and physical body shape.

Shape alterations of basal ganglia and thalamus in xenomelia.

Xenomelia is a rare condition characterized by the persistent desire for the amputation of physically healthy limbs. Associations with morphological alterations such as reduced cortical thickness and surface area. Nothing is known, however, about the potential involvement of subcortical structures. The thalamus and basal ganglia process, relay, and integrate sensorimotor information and are involved in the preparation and execution of movements. Moreover, both of these structures house somatotopic representations of all body parts. We therefore investigated subcortical correlates of xenomelia by assessing basal ganglia and thalamus by means of vertex-wise shape analyses. For that purpose, we compared the shape of the thalamus, putamen, caudate nucleus, and the pallidum in 13 men suffering from xenomelia, all desiring a leg amputation, compared to 13 healthy control men. We hypothesised that the target leg is misrepresented in subcortical structures of individuals with xenomelia, especially in locations with a somatotopic representation. Shape analyses showed thinning of bilateral dorsomedial putamina, left ventromedial caudate nucleus and left medial pallidum associated with xenomelia. This was accompanied by thickening of bilateral lateral pallida and the left frontolateral thalamus. These shape differences were mainly located in sensorimotor areas of somatotopic leg representations. The present study provides strong evidence for shape differences in striatal, pallidal, and thalamic subregions housing subcortical body part representations. It adds to previously described neural correlates of a condition one can barely empathize with and invites future connectivity analyses in cortico-subcortical networks.

Novel COL4A1 mutation in an infant with severe dysmorphic syndrome with schizencephaly, periventricular calcifications, and cataract resembling congenital infection.

BACKGROUND: A clinical case is described of growth retardation, severe developmental delay, facial dysmorphic features with microcephaly, as well as congenital cataract, schizencephaly, periventricular calcifications, and epilepsy. METHODS: TORCH infection was suspected, but all tests for toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus were negative for the child and her mother; however, an increased level of antibodies against parvovirus B19 was detected in the proband. RESULTS: Chromosomal analysis and array-CGH showed no aberration. Target capture sequencing for COL4A1 and COL4A2 revealed a de novo COL4A1 mutation (c.2123G>T [p.Gly708Val]). The mutation occurred at a highly conserved Gly residue in the Gly-X-Y repeat of the collagen triple helical domain, suggesting that these mutations may alter the collagen IV α1α1α2 heterotrimers. The mutation was predicted to be damaging. CONCLUSION: We suggest that COL4A1 testing should be considered in patients with schizencephaly as well as with phenotype suggesting TORCH infection without any proven etiological factors.