FISH Diagnosis of 22q11.2 Deletion Syndrome

The 22q11.2 deletion syndrome is the most common microdeletion syndrome. Although once thought to be separate disorders, cardiac anomalies, abnormal face, thymic hypoplasia, cleft palate, hypocalcemia, and chromosome 22 deletions (CATCH 22); DiGeorge syndrome; velocardiofacial syndrome; and conotruncal anomaly face syndrome are now known to be part of the same 22q11.2 deletion syndrome. Diagnosis of this syndrome is extremely challenging because of wide variability in phenotypic presentations. When the deletion is suspected, genetic testing is typically ordered. Conventional karyotyping is only capable of detecting a small percentage of chromosome deletions. However, fluorescence in situ hybridization (FISH) is capable of detecting many deletions and microdeletions. This article discusses the pathophysiology and presentation of chromosome 22q11.2 deletion syndrome. The use of FISH as a diagnostic tool is also described, including the FISH process, its use, and its accuracy and reliability in the diagnosis of chromosome 22q11.2 deletion syndrome in the fetus and/or newborn.     

Allergy accelerates the disease progression of chronic rhinosinusitis

Background: The role of allergy in the development of chronic rhinosinusitis (CRS) in East Asians is not clear.

Aims/objectives: The aim was to investigate the impact of allergies in the clinical characteristics of chronic rhinosinusitis.

Material and methods: A total of 138 CRS patients who underwent endoscopic sinus surgery were included. A brief history of rhinosinusitis symptoms, blood eosinophil count, blood-specific allergen tests, computed tomography (CT) scan findings, Lund-Mackay (LM) CT scores, and Sino-Nasal Outcome Test (SNOT-22) Questionnaire scores, and sinoscopy findings at 3 and 6 months postoperatively.

Results: The ImmunoCAP test was positive in 71(51%) patients and negative in 67(49%) patients. The mean age of those who received endoscopic sinus surgery was 7-years younger in the allergic group compared with the non-allergic group (p?=?.008). The peripheral eosinophil count in the allergic group was higher than that of the non-allergic group (p?=?.008). The LM scores and SNOT-22 scores were not significantly different between the two groups. The recurrence rate of nasal polyps in the allergic group was higher but without statistical significance.

Conclusions and significance: Allergy may accelerate the disease progression of CRS. The presence of the serum-specific IgE was correlated with peripheral eosinophil percentage, especially in the CRSwNP patients.     

Interleukin‐21 receptor signalling is not critically required for imiquimod‐induced psoriasiform dermatitis in mice

Psoriasis is largely mediated by interleukin (IL)‐23/T helper (Th) 17 axis, and IL‐21 is a pleiotropic cytokine expressed by Th17 cells. Despite previously reported possible pathogenic roles of IL‐21 in human psoriasis, we found that IL‐21 receptor (IL‐21R) signalling was not crucial for imiquimod‐induced psoriatic inflammation, using IL‐21R^?/? mice. The severity of imiquimod‐induced psoriatic manifestation and pro‐inflammatory Th17 cytokine levels, IL‐17A‐producing γδ T cells and CD4+ T cells, and in vitro IL‐17A production by γδ T cells after IL‐23 stimulation was comparable between wild‐type and IL‐21R^?/? mice. Collectively, IL‐21R signalling was not critically involved in IMQ‐induced psoriatic inflammation despite an increased IL‐21 expression in the IMQ‐treated mouse skin. Our data may represent the significant differences between human psoriasis and murine psoriasis model, and further studies using other models will be required to elucidate the role of IL‐21 in psoriasis pathogenesis.     

Th1/Th17/Th22 immune response and their association with joint pain,imagenological bone loss,RANKL expression and osteoclast activity in temporomandibular joint osteoarthritis: A preliminary report

It is well accepted that the presence of cytokines belonging to the Th1/Th17/Th22 axis of immuno‐inflammatory response in the joint environment, such as IL‐1β, IL‐17 and IL‐22, respectively, are associated with pathogenesis of several synovial joint degenerative disorders. During temporomandibular joint osteoarthritis (TMJ‐OA), IL‐1β and IL‐17 have been implicated in the inflammation and resorption of sub‐chondral bone; however, the role of Th22 response in the TMJ‐OA pathophysiology has not been established. This study aimed to compare the expression of Th1/Th17/Th22‐type cytokines, chemokines and chemokine receptors in synovial fluid samples obtained from TMJ‐OA or disk displacement with reduction (DDWR) patients. In addition, it aimed to associate these levels with joint pain, imagenological signs of bone degeneration, RANKL production, osteoclastogenesis and osteoclast‐induced bone resorption. Higher levels of IL‐1β, IL‐17 and IL‐22 were expressed in TMJ‐OA compared with DDWR subjects, and these increased levels significantly correlated with RANKL expression, joint pain and articular bone degeneration. Higher levels of CCR5, CCR6 and CCR7, as well as their respective ligands CCL5 and CCL20, responsible for recruitment of IL‐1β, IL‐17 and IL‐22‐producing cells, were over‐expressed in TMJ‐OA compared with DDWR subjects. Osteoclastogenesis and osteoclast‐induced bone resorption were significantly greater in presence of synovial fluid from TMJ‐OA compared with DDWR subjects. These data demonstrate that cytokines, CCLs and CCRs associated with the Th1/Th17/Th22 axis of immuno‐inflammatory response are involved in TMJ‐OA pathogenesis. These findings suggest that IL‐22 is involved in the RANKL expression in TMJ‐OA, which in turn induces differentiation of osteoclasts and subsequent resorption of sub‐chondral bone.     

Human Cytochrome P450 Family 4 Enzymes: Function,Genetic Variation and Regulation

The microsomal cytochrome P450 (CYP) family 4 monooxygenases are the major fatty acid ω-hydroxylases. These enzymes remove excess free fatty acids to prevent lipotoxicity, catabolize leukotrienes and prostanoids, and also produce bioactive metabolites from arachidonic acid ω-hydroxylation. In addition to endogenous substrates, recent evidence indicates that CYP4 monooxygenases can also metabolize xenobiotics, including therapeutic drugs. This review focuses on human CYP4 enzymes and updates current knowledge concerning catalytic activity profiles, genetic variation and regulation of expression. Comparative differences between the human and rodent CYP4 enzymes regarding catalytic function and conditional expression are also discussed.     

Characterizing regression in Phelan McDermid Syndrome (22q13 deletion syndrome)

PurposeTo describe the frequency and characteristics of developmental regression in a sample of 50 patients with Phelan McDermid Syndrome (PMS) and investigate the possibility of association between regression, epilepsy, and electroencephalogram (EEG) abnormalities and deletion size.MethodsThe Autism Diagnostic Interview-Revised (ADI-R) was used to evaluate regression in patients with a confirmed diagnosis of PMS. Information on seizure history and EEGs was obtained from medical record review. Deletion size was determined by DNA microarray.ResultsA history of regression at any age was present in 43% of all patients. Among those exhibiting regression, 67% had onset after the age of 30 months, affecting primarily motor and self-help skills. In 63% of all patients there was a history of seizures and a history of abnormal EEG was also present in 71%. No significant associations were found between regression and seizures or EEG abnormalities. Deletion size was significantly associated with EEG abnormalities, but not with regression or seizures.ConclusionThis study found a high rate of regression in PMS. In contrast to regression in autism, that often occurs earlier in development and affects language and social skills, we found regression in PMS most frequently has an onset in mid-childhood, affecting motor and self-help skills. We also found high rates of seizures and abnormal EEGs in patients with PMS. However, a history of abnormal EEG and seizures was not associated with an increased risk of regression. Larger deletion sizes were found to be significantly associated with a history of abnormal EEG.     

Extending the communication phenotype associatedwith 22q11.2 Microdeletion Syndrome

This paper has three aims. The first is to describe and critically evaluate two recent studies from the authors' centre. Study one is a retrospective, consecutive series case note audit of 76 children aged 3.01 – 9.11 years of age, aimed at examining the age at which children with 22q11 deletion syndrome (22q11DS) are able to achieve oral pressure in their speech, and providing an overview of presentation. Study two is a pilot study to investigate the prevalence of dyspraxic features in a consecutive series of 21 school age children with 22q11DS, aged 4.0 – 8.11 years of age. The second aim is to discuss these studies within the context of a critical review of the current knowledge about 22q11 deletion syndrome. The third aim is to challenge some common thinking around the management of velopharyngeal dysfunction ( VPD) in 22q11DS. This discussion highlights that it is sometimes possible to investigate and treat palate function with good outcomes in the preschool years based on limited speech and language and investigations. Areas for future research are discussed. This paper further underlines the complexity of the communication profile in this population, with confirmation of the unique speech and language phenotype.     

The potential of PTPN22 as a therapeutic target for rheumatoid arthritis

ABSTRACT

Introduction: PTPN22 encodes a lymphoid-specific tyrosine phosphatase (LYP) that is a master regulator of the immune response. This gene is a major susceptibility factor for a wide range of autoimmune conditions, including rheumatoid arthritis (RA) for which it represents the strongest non-HLA contributor to disease risk. A missense PTPN22 allele (R620W) affecting the protein-protein interaction of LYP with other relevant players was described as the functional variant of the association. This review will focus on the role of PTPN22 in the pathogenic mechanisms underlying RA predisposition and discuss the possibility of developing LYP-based treatment strategies with a potential application in clinical practice.

Areas covered: This review covers the literature showing how PTPN22 is implicated in signalling pathways involved in the autoimmune and autoinflammatory processes underlying RA. Insights obtained from studies aimed at developing novel selective LYP suppressors for treating RA are summarized.

Expert opinion: Targeting key risk factors during the early steps of the disease may represent a good strategy to accomplish complete disease remission. As cumulating evidences suggest that PTPN22 R620W is a gain-of-function variant, a growing interest in developing LYP inhibitors has arisen. The potential efficacy and possible application of such compounds are discussed.