Utility of Basophil Activation Test for monitoring the acquisition of clinical tolerance after oral desensitization to cow's milk: Pilot study

Objective: The quantification of basophil activation by flow cytometry is a useful tool for the assessment of immediate-type responses to food allergens and the prediction of clinical tolerance in food allergy patients. The aim of this study is to investigate how the analysis of allergen-induced CD63 up-regulation by flow cytometry can be effective in monitoring the acquisition of clinical tolerance by specific oral desensitization in food allergy. To our knowledge, this is the first study to examine this topic. Materials and methods: Three male patients affected by cow’s milk allergy underwent successful oral desensitization to cow’s milk. In order to monitor the acquired clinical tolerance that occurred after treatment, we performed laboratory tests for total and specific IgE, specific IgG4 and the Basophil Activation Test (BAT) both at baseline and at the end of the desensitization protocol. Results: Using a fluorescent enzyme immunoassay, the comparison of specific cow’s milk antibodies before and after treatment showed a decrease of specific IgE levels, without reaching normal values, and an increase of specific IgG4 levels. A complete suppression of cow’s milk proteins (a-lactoalbumin, b-lactoglobulin and casein) induced CD63 regulation was observed in all three reported cases. Conclusions: Using flow cytometry, food allergen-specific basophil responses could be monitored in order to identify an acquired tolerance induced by desensitization treatment. Although further studies are needed to develop this important new topic, it was interesting to note that the BAT seemed to be more sensitive and characterized by a close correlation with clinical tolerance

DeepGestalt analysis of the SETD5-associated intellectual disability syndrome

Aim: This is the first computer-assisted study focused on the craniofacial features of the intellectual disability (ID)/developmental delay (DD) syndrome related to haploinsufficiency of the SETD5 gene (SET domain-containing protein 5, MIM#615743), which is a chromatin regulator. The purpose of this novel research is to better delineate the facial phenotype of this condition and identify the associated dysmorphic features to consider for clinical diagnosis.Methods: A total of 18 2D frontal images of previously published pediatric individuals (aged 1-14 years, Caucasian ethnicity) with SETD5 mutations (SETD5, cohort 1) were uploaded to the RESEARCH application of the Face2Gene online platform (V.19.1.3) (FDNA Inc., Boston, MA, USA). Images from this group of patients were compared with 36 photos of individuals with two other known chromatin disorders, specifically KBG (KBGS, cohort 2, 18 images) and Koolen-de Vries syndromes (KdVS, cohort 3, 18 images), which share with the SETD5-related ID syndrome a very similar facial gestalt and peculiar dysmorphisms. An additional cohort of 18 unaffected controls that were matched for age and ethnicity (Ctrl., controls, cohort 4) was also included in the comparison experiment.Results: Results obtained from the binary comparison analysis were expressed in terms of Area Under the Curve and its Receiver Operating Characteristic curve for aggregated splits. A high facial overlap between the SETD5-related phenotype and KBGS was demonstrated. Other conditions considered for the study were well recognized by the system and differentiated using the unaffected controls.Conclusion: This study confirms the presence of distinctive dysmorphic features that characterize the SETD5-related facial phenotype, providing observations about its possible role in facial morphogenesis

Clinical and genetic study of two patients with Zimmermann-Laband syndrome and literature review

Zimmermann-Laband syndrome (ZLS) is a rare MCA/MR condition mainly characterized by gingival hypertrophy, hypo/aplastic nails and distal phalanges, hypertrichosis and intellectual disability. The molecular basis of ZLS is unknown. Most patients are sporadic, although familial aggregation is also observed with different inheritance patterns. We report on two unrelated children with full-blown characteristics of ZLS. Remarkable variability in expression included severity of neurocognitive involvement and extent of appendicular and facial features. In both, comparative genome hybridization array at a similar to 75 Mb resolution resulted negative, while aminoacid metabolic screening revealed high plasma levels of hypoxanthine and xanthine in one. Literature review identified 50 previously published patients (27 females, 23 males), including 14 familial, clustered in four pedigrees, and 37 sporadic. Tabulation of clinical features confirmed the core phenotype and identified developmental delay as the unique major clinical problem (occurring in 40% of the cases) with a moderately high risk of epilepsy (13%). Segregation analysis in the 20 sporadic patients with available data on healthy sibs and a single pedigree with affected sibs was significantly in contrast with an autosomal recessive mutation. An autosomal dominant mutation with high mutation rate and rare instances of germinal mosaicism seems the most likely inheritance pattern. This work may represent a starting point for future molecular studies aimed at identifying the molecular basis of ZLS. (C) 2013 Elsevier Masson SAS. All rights reserved

Helsmoortel-Van der Aa Syndrome as emerging clinical diagnosis in intellectually disabled children with autistic traits and ocular involvement

A recent syndromic condition with craniofacial dysmorphisms, comprising congenital ocular defect and neurodevelopmental delay named Helsmoortel-Van der Aa Syndrome (HVDAS) (OMIM#615873), has been described and molecularly defined, identifying pathogenic mutations in the ADNP gene (OMIM#611386) as biological cause. We report on two children, displaying intellectual disability (ID) and peculiar congenital eyes anomalies, both carrying a de novo nonsense mutation in the ADNP gene. The review of present and literature reports, suggests that the diagnosis of HVDAS should be suspected in patients with ID accompanied by behavioral features in the Autism Spectrum Disorder and distinctive craniofacial phenotype. Among dysmorphisms due to malformation of the periorbital region, ptosis appears to be particularly recurrent in HVDAS. Furthermore, the present patients could support the inclusion of the HVDAS associated with specific mutations clustering within a small ADNP genomic region among clinical conditions reminiscent of the blepharophimosis/mental retardation syndromes (BMRS)

Autism Spectrum Disorder in a patient with a genomic rearrangement that only involves the EPHA5 gene

About one child in 68 is affected by the Autism Spectrum Disorder (ASD), one of the most common brain development dysfunction linked with intellectual disability, especially in males. The ASD biological basis are not yet fully known but they are considered to be multifactorial. A large number of genes and genomic loci hav been proposed as possibily associated with this condition and some of them could represent major genetic putative determinants. In this report we describe the case of a 14-yearold female Italian proband affected by ASD, carrying an undescribed ~270 Kb interstitial microduplication, localized to the distal portion of the 4q13.1 region. The aberration resulted inherited from a mild symptomatic father. This chromosome structural anomaly resulted to include a large part of a single gene, that is EPHA5, a receptor tyrosine kinase involved in neural development already indicated to be connected with ASD by previous Genome Wide Association Studies (GWAS). Considering the very reduced size of the novel disclosed duplication embedding the sole EPHA5 gene, we could hypothesize that this gene duplication may result deleterious for its expression and then that it could be anyway involved in the determinism of the patient autistic phenotype