Connective Tissue Abnormalities Research Articles

Hyper IgE Syndromes.

The Hyper IgE Syndromes are rare primary immunodeficiencies characterized by eczema, recurrent skin and respiratory infections and elevated serum IgE levels. Nowadays a geneticmolecular characterization is possible and allows the distinction in various monogenic pathologies, which share some clinical characteristics but also important differences. In addition to long-known STAT3 and DOCK8 gene mutations, in fact, also ZNF341, CARD11, ERBB2IP, IL6R and IL6ST genes mutations can cause the disease. The main clinical manifestations are represented by newborn rash, eczema similar to atopic dermatitis, bacterial and viral skin infections, cold abscesses, respiratory infections with possible pulmonary complications, allergies, gastrointestinal manifestations, malignancies and connective tissue abnormalities. Diagnosis is still a challenge because, especially in the early stages of life, it is difficult to distinguish from other pathologies characterized by eczema and high IgE, such as atopic dermatitis. Several scores and diagnostic pathways have been developed, but it is essential to seek a genetic diagnosis. Treatment is based on prevention and early treatment of infections, meticulous skincare, intravenous immunoglobulins and HSCT, which, in some HIES subtypes, can modify the prognosis. Prognosis is related to the affected gene, but also to early diagnosis, timely treatment of infections and early HSCT.

Hypermobile Ehlers-Danlos syndrome and spontaneous CSF leaks: the connective tissue conundrum.

Collagen, the most abundant protein in the body, is a key component of the extracellular matrix (ECM), which plays a crucial role in the structure and support of connective tissues. Abnormalities in collagen associated with connective tissue disorders (CTD) can lead to neuroinflammation and weaken the integrity of the blood-brain barrier (BBB), a semi-permeable membrane that separates the brain's extracellular fluid from the bloodstream. This compromise in the BBB can result from disruptions in ECM components, leading to neuroinflammatory responses, neuronal damage, and increased risks of neurological disorders. These changes impact central nervous system homeostasis and may exacerbate neurological conditions linked to CTD, manifesting as cognitive impairment, sensory disturbances, headaches, sleep issues, and psychiatric symptoms. The Ehlers-Danlos syndromes (EDS) are a group of heritable CTDs that result from varying defects in collagen and the ECM. The most prevalent subtype, hypermobile EDS (hEDS), involves clinical manifestations that include joint hypermobility, skin hyperextensibility, autonomic dysfunction, mast cell activation, chronic pain, as well as neurological manifestations like chronic headaches and cerebrospinal fluid (CSF) leaks. Understanding the connections between collagen, CSF, inflammation, and the BBB could provide insights into neurological diseases associated with connective tissue abnormalities and guide future research.

АНАЛИЗ УРОВНЯ И СТРУКТУРЫ ПАТОЛОГИЧЕСКОЙ ПОРАЖЕННОСТИ ПОДРОСТКОВ РЕСПУБЛИКИ БЕЛАРУСЬ

Background. Assessment of the health indicators of adolescents, among which morbidity indicators occupy a leading place, makes it possible to determine the need of this age group for preventive measures, as well as to evaluate their effectiveness. Objective. To study the level and etiological structure of pathologies among adolescents residing in the Republic of Belarus. Material and methods. A sample of 1118 people aged 10-18 years was studied. The data was obtained by extracting information from primary medical documentation. Results. It was established that the prevalence of pathologies in the general group of adolescents is 1568.87 [1488.45; 1649.30] cases per 1000 people. The main factors aggravating the health status of adolescents are such classes of diseases and pathological conditions as eye diseases (in the vast majority, myopia), diseases of the musculoskeletal system and connective tissue (primarily postural disorders and flat feet), congenital malformations, deformations and chromosomal abnormalities (in 88.59% cases – congenital anomalies of the circulatory system), diseases of the digestive system (in a quarter of cases – gastritis, duodenitis). The main contributors to these pathologies are schoolrelated ones. It was revealed that less than 20% of 10-18-year-olds are absolutely healthy, almost 2/3 of the surveyed have risk factors for the development of diseases and almost one out of six has a chronic pathology in the compensation stage. Conclusions. The results obtained indicate the need to improve preventive measures aimed to minimize pathologies caused by learning, the need to introduce targeted prevention programs, as well as to improve medical and psychological-pedagogical support for students.

Harmonizing Motherhood: Navigating Pregnancy Outcomes in Connective Tissue Disorders.

Background Connective tissue disorders encompass a diverse array of autoimmune and hereditary conditions, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and antiphospholipid antibody syndrome. These disorders present unique challenges during pregnancy due to their complex pathophysiology and potential complications. Understanding their impact on pregnancy outcomes is vital for optimizing maternal and fetal health. Objective To investigate the burden, complications, maternal and fetal outcomes, and prognosis of connective tissue disorders in pregnancy. Methods The study was conducted over one year and six months at Saveetha Medical College and Hospital, Chennai, India, involving 45 pregnant women diagnosed with connective tissue disorders. Standard antenatal investigations were conducted, and participants were monitored throughout the antenatal period. Maternal and fetal outcomes were meticulously evaluated. Results Baseline characteristics revealed a heterogeneous distribution of age and parity among participants, reflecting the diverse nature of connective tissue disorders in pregnancy. Maternal medical outcomes, such as gestational hypertension (GHTN) and gestational diabetes mellitus (GDM), were prevalent, highlighting the necessity of close monitoring. Obstetric outcomes included spontaneous abortion and preterm delivery, indicating elevated risks in this population. Fetal outcomes, including fetal growth restriction and admission to the neonatal intensive care unit, underscored the impact of these disorders on fetal health. Conclusion This study examines pregnant connective tissue disorder burden, complications, maternal and fetal outcomes, and prognosis. The complicated relationship between these illnesses, and pregnancy requires specialist care and close monitoring. The participants' baseline features represent connective tissue condition heterogeneity, affecting clinical practice. Among the study subjects, 40% had RA and 20% had SLE, the most common connective tissue illness. Adverse maternal medical outcomes, like GHTN (27.27% of antiphospholipid syndrome (APS) patients and 22.22% of SLE patients) and GDM (18.18% of APS patients and 11.11% of SLE patients), highlight the need for close maternal health monitoring and management during pregnancy. Overall, this study sheds light on connective tissue abnormalities and pregnancy outcomes. Healthcare providers can improve reproductive health and well-being for various illnesses by knowing these relationships.

<i>De novo</i> <i>AHDC1</i> Deletions Identified by Genome Sequencing in Two Individuals with Xia-Gibbs Syndrome

<b><i>Introduction:</i></b> Xia-Gibbs syndrome (XGS) is a rare syndromic disorder characterized by developmental delay with intellectual disability, muscular hypotonia, brain anomalies, and nonspecific dysmorphic features. Different heterozygous variants in <i>AHDC1</i> have been reported as causal for XGS, comprising mainly <i>de novo</i> stop-gain and frameshift events, but also missense variants, deletions, and a duplication of the locus. <b><i>Case Presentation:</i></b> We hereby report 2 patients with clinical features of XGS. In the first patient, a <i>de novo</i> interstitial deletion in 1p36.11p35.3 encompassing the entire coding region of <i>AHDC1</i> was initially suspected by trio exome sequencing and subsequently confirmed by shallow genome sequencing. In the second patient, a <i>de novo</i> deletion comprising most of the 5′ untranslated region of <i>AHDC1</i> was detected by genome sequencing. <b><i>Conclusion:</i></b> We identified the smallest deletion comprising <i>AHDC1</i> reported so far by shallow genome sequencing as well as another small <i>AHDC1</i> deletion by genome sequencing. These methods represent useful techniques for the identification and confirmation of small deletions and structural variants. Furthermore, our data provide additional evidence of <i>AHDC1</i> haploinsufficiency as a disease mechanism in XGS. Clinically, foot deformity, skin and connective tissue abnormalities observed in one of the patients are consistent with other reported cases of XGS. These findings suggest that these manifestations could be considered as more prevalent characteristics, underscoring the importance of in-depth phenotyping.

Abstract 2056: Impaired Cellular Metabolic Adaptations In Autosomal-Dominant Hyper-IgE Syndrome: Possible Implications To Deficient Angiogenesis And Wound Healing

Background: Autosomal dominant Hyper-IgE syndrome (AD-HIES; Job’s syndrome) is caused by dominant negative mutations in signal transducer and activator of transcription 3 (STAT3). Patients present with immunodeficiency accompanied by severe non-immunological features including poor post infection lung healing, subsequent pulmonary failure, and skeletal, connective tissue, and vascular abnormalities including arterial tortuosity and aneurisms which can lead to myocardial infarction and subarachnoid hemorrhage. HIF1a-dependent deficient angiogenesis has been implicated in the abnormal wound healing response of AD-HIES. Both STAT3 and HIF1a are major regulators of cellular metabolism. In this study we are testing the hypothesis that dysregulation of cellular metabolic pathways may contribute to AD-HIES pathophysiology. Methods: We used skin fibroblasts (SF) from 4 AD-HIES patients and 4 normal volunteers. To investigate ability of the cells to adapt and function in nutrient-deficient conditions (to model tissue damages disrupting normal tissue perfusion) we exposed them to a culture media lacking glucose, pyruvate and glutamine (deficient media). We used a live imaging approach (IncucyteS3 System, Sartorius) to analyze cell proliferation, reactive oxygen species (ROS), cell death, and wound closing ability (scratch-wound assay). Results: In deficient media, both AD-HIES and control SF decreased their proliferation rate. While control SF adapted, AD-HIES SF showed decreased survival after prolong nutrient deprivation. Level of ROS, measured at 12, 24, 48h in deficient media was 25% higher in AD-HIES SF (n=8, P=0.003). We used a scratch-wound assay to assess the ability of fibroblasts to migrate and close the wound after 48h of adaptation to deficient media. In full media, both control and AD-HIES fibroblast completely closed the wound within 36h. In deficient media, wound closure was delayed to much higher degree by AD-HIES fibroblasts (60±14% closure by control SF vs 18±9% by AD-HIES SF, n=4, P=0.016). Conclusions: Adaptive remodeling of cellular metabolism is impaired in AD-HIES SF that may contribute to deficient angiogenesis and poor wound healing, suggesting possible therapeutic targets within cellular metabolic pathways.

Investigating the role connective tissue fibroblasts play in the altered muscle anatomy associated with the limb abnormality, Radial Dysplasia.

Radial dysplasia (RD) is a congenital upper limb birth defect that presents with changes to the upper limb anatomy, including a shortened or absent radius, bowed ulna, thumb malformations, a radially deviated hand and a range of muscle and tendon malformations, including absent or abnormally shaped muscle bundles. Current treatments to address wrist instability caused by a shortened or absent radius frequently require an initial soft tissue distraction intervention followed by a wrist stabilisation procedure. Following these surgical interventions, however, recurrence of the wrist deviation remains a common, long-term problem following treatment. The impact of the abnormal soft connective tissue (muscle and tendon) anatomy on the clinical presentation of RD and the complications following surgery are not understood. To address this, we have examined the muscle, fascia and the fascial irregular connective tissue (ICT) fibroblasts found within soft connective tissues, from RD patients. We show that ICT fibroblasts isolated from RD patients are functionally abnormal when compared to the same cells isolated from control patients and secrete a relatively disordered extracellular matrix (ECM). Furthermore, we show that ICT fibroblast dysfunction is a unifying feature found in RD patients, even when the RD clinical presentation is caused by distinct genetic syndromes.

A new conceptual model for anorexia nervosa: A role for connective tissue?

The etiology of anorexia nervosa (AN) remains to be fully elucidated, and current theories also fail to account for the direct effect of starvation on the health of the organs and tissues, specifically the connective tissue present in most organs of the body. Individuals with hereditary disorders of connective tissue manifest with clinical symptoms that overlap with AN, as the abnormal connective tissue also contributes to many of the other extra-articular manifestations of these hereditary disorders. This article hypothesizes that a similar pathophysiology may also contribute to the clinical presentation of AN. Therefore, a better understanding is needed to elucidate: (1) the relationship between abnormal connective tissue and AN, (2) the impact of starvation toward the development of abnormal connective tissue and how this manifests clinically, (3) the etiology of autonomic nervous system changes contributing to the dysautonomia in AN, and (4) how the sensory signals sent from potentially abnormal connective tissue to the central nervous system impact interoception in AN. A conceptual model incorporating abnormal connective tissue is provided. PUBLIC SIGNIFICANCE: The etiology of AN remains poorly understood and current theories fail to account for the direct impact of starvation on the health of the organs and tissues of the body. There is significant clinical overlap between AN and hereditary connective tissue disorders. This paper attempts to provide a new conceptual model for AN in which abnormal connective tissue contributes to the underlying pathogenesis.

Preventive education on adolescent idiopathic scoliosis in junior high school students at Surakarta

Adolescent idiopathic scoliosis (AIS) is a structural disorder of the vertebrae characterized by vertebral curvature exceeding 10°, commonly identified in children aged 10-18 years. Several contributing factors for AIS include genetic factors, abnormalities in connective tissue and skeletal muscles, biomechanical factors, and the use of school bags with associated weight. The primary issue identified from the preliminary study is the relatively high AIS rate, reaching 10.2%, with no previous preventive education programs implemented for students. The targeted participants for this program are students from Muhammadiyah Middle School 5 and Muhammadiyah Middle School 7 in Surakarta. The team conducted AIS prevention health education sessions in April-May 2023 for students aged 12-15 years. The educational activities involved the use of informative materials such as pocket books and videos, covering topics like the definition of Adolescent Idiopathic Scoliosis, physical examination methods for AIS, and preventive measures through posture correction exercises and the proper use of school bags.Results from the influence test, employing the Paired Sample T-Test, indicate a Sig. (2-tailed) value of 0.023. This implies a significant difference in the average knowledge level before and after receiving education on AIS prevention.

A successful case of deceased-donor liver transplantation from a donor with Marfan syndrome: a case report

BackgroundLiver transplantation is the definitive therapy for patients with decompensated cirrhosis. Marfan syndrome is a systemic inheritable connective tissue disease associated with fibrillin-1 gene mutations, which cause abnormalities in connective tissue. Vascular changes due to Marfan syndrome occur mostly in the main vessels due to the high amount of connective tissue within the vessel wall and the high pressure and blood flow to which they are exposed. The incidence of changes in visceral arteries is about 0.42% and usually presents with cystic medial necrosis. This report is the first deceased-donor liver transplantation with a donor with Marfan syndrome with a history of abdominal surgery.Case presentationA patient in his 50s underwent liver transplantation for decompensated alcoholic cirrhosis. The donor, a 50s male with Marfan syndrome, was diagnosed with brain-death due to a cerebral hemorrhage caused by a cerebral aneurysm. The donor’s clinical presentation as Marfan syndrome was aortic dissection, with multiple surgical procedures performed from the aortic root to the abdominal aorta. An intraoperative biopsy of the hepatic artery showed no abnormality, so this organ was considered appropriate. The surgery was completed without any problems of the arterial anastomosis. The patient’s postoperative course was uneventful, and he was transferred to a hospital for recuperation on the 18th postoperative day. One year after the surgery, the patient is still alive without any complications from the transplantation or arterial problems.ConclusionsEven if the patient had a history of surgery for vascular anomalies extending to the abdominal aorta due to Marfan syndrome, the patient can be a donor for liver transplantation under appropriate judgment, including intraoperative biopsy.

Diagnosis and treatment of cardiovascular disease in patients with heritable connective tissue disorders or heritable thoracic aortic diseases.

Patients with heritable connective tissue disorders (HCTDs), represented by Marfan syndrome, can develop fatal aortic and/or arterial complications before age 50. Therefore, accurate diagnosis, appropriate medical treatment, and early prophylactic surgical treatment of aortic and arterial lesions are essential to improve prognosis. Patients with HCTDs generally present with specific physical features due to connective tissue abnormalities, while some patients with heritable thoracic aortic diseases (HTADs) have few distinctive physical characteristics. The development of genetic testing has made it possible to provide accurate diagnoses for patients with HCTDs/HTADs. This review provides an overview of the diagnosis and treatment of HCTDs/HTADs, including current evidence on cardiovascular interventions for this population.

Successful Use of Dupilumab in the Treatment of Acquired Perforating Dermatosis Associated with Atopic Dermatitis

Acquired reactive perforating collagenosis is a rare cutaneous disorder characterised by the extrusion of abnormal connective tissue trough epidermidis and/or follicular units. Reactive perforating collagenosis is often associated with systemic diseases in which pruritus is a common symptom (e.g., diabetes and chronic kidney disease). Less commonly, it has been associated with chronic inflammatory dermatoses, including atopic dermatitis, as in this case. In this report, we describe the exceptional case of a 35‐year‐old man affected by acquired reactive perforating collagenosis associated with atopic dermatitis who was resistant to conventional topical and systemic treatment and experienced complete resolution of clinical signs and symptoms after 12 weeks of treatment with dupilumab. In our patient, the severe pruritus induced by atopic dermatitis likely contributed to the development of acquired perforating collagenosis lesions, which are thought to be a reactive response to chronic scratching and repetitive injury to the skin. Chronic pruritus in atopic dermatitis is known to be driven by type 2 cytokines, including IL‐4 and IL‐13, and dupilumab, a monoclonal antibody inhibiting IL‐4 and IL‐13 signalling, has been shown to be effective in the treatment of moderate to severe atopic dermatitis as well as other type 2‐driven pruritic dermatological conditions. This case supports the potential use of dupilumab for the treatment of reactive perforating dermatosis.

Connective tissue involvement in an m.10191 T > C carrier with Leigh-like syndrome

BackgroundConnective tissue involvement in a mitochondrial disorder has been only rarely reported.Case presentationA 32-year-old female with Leigh-like syndrome extending into adulthood due to the mtDNA variant m.10191 T > C developed various connective tissue abnormalities, which manifested as hyperlaxity of joints, decreased clivo-axial angle, subluxations of various joints, scoliosis, hyperextensibility of skin (stretchy skin), easy tearing, papyraceous scarring, frequent petechiae, very easy bruising, impaired wound healing, blood pooling in feet, and tiny veins. She received symptomatic treatment and physiotherapy, which provided some sort of relief.ConclusionsThe phenotypic spectrum of the m.10191 T > C variant is broader than previously anticipated.

Corneal structural alterations in autism spectrum disorder: An in vivo confocal microscopy study.

Individuals with autism spectrum disorder (ASD) often exhibit joint hypermobility and connective tissue disorders. However, it remains unclear if ASD individuals also have structural alterations in the connective tissue of the cornea. This study aims to determine whether the Kobayashi structure (K-structure) characteristics differ between adults with ASD and typically developing controls (TDC) and explore the clinical correlates of the K-structure abnormality. We recruited 30 ASD adults and 35 TDC. Corneal structures, particularly the K-structure in the Bowman's layer, of the participants were examined using in vivo confocal microscopy (IVCM), and a K-grading ranging from 1 to 4 was given to each eye based on the level of morphological mosaicism. The ASD participants' eyes received a significantly higher single-eye K-grading than that of the TDC eyes (p < 0.001), and the medians [25th, 75th percentile] of bilateral-eye summed K-grading were 8 [7, 8] and 5 [4, 6] in ASD and TDC, respectively (p < 0.001). A significantly higher K-grading in the ASD participants' eyes was still observed after adjusting for the within-subject inter-eye correlation (p < 0.001). Youden Index showed the optimal cutoffs to differentiate ASD from TDC by bilateral-eye summed K-grading and single-eye K-grading was >6 and >3, respectively. Additionally, a higher K-grading was associated with fewer visual sensation seeking in ASD (Spearman's correlation coefficient ρ = -0.518, p = 0.008) and low visual registration (i.e., higher sensory threshold) in TDC (ρ = 0.446, p = 0.023). This study provided novel evidence of corneal structural alterations in ASD by IVCM. Our findings may not only support the prior hypothesis of the association between ASD and connective tissue abnormalities but also shed light on the relationship between connective tissue disorder and neurodevelopmental disorders.

SLIT3-mediated fibroblast signaling: a promising target for antifibrotic therapies.

The SLIT family (SLIT1-3) of highly conserved glycoproteins was originally identified as ligands for the Roundabout (ROBO) family of single-pass transmembrane receptors, serving to provide repulsive axon guidance cues in the nervous system. Intriguingly, studies involving SLIT3 mutant mice suggest that SLIT3 might have crucial biological functions outside the neural context. Although these mutant mice display no noticeable neurological abnormalities, they present pronounced connective tissue defects, including congenital central diaphragmatic hernia, membranous ventricular septal defect, and osteopenia. We recently hypothesized that the phenotype observed in SLIT3-deficient mice may be tied to abnormalities in fibrillar collagen-rich connective tissue. Further research by our group indicates that both SLIT3 and its primary receptor, ROBO1, are expressed in fibrillar collagen-producing cells across various nonneural tissues. Global and constitutive SLIT3 deficiency not only reduces the synthesis and content of fibrillar collagen in various organs but also alleviates pressure overload-induced fibrosis in both the left and right ventricles. This review delves into the known phenotypes of SLIT3 mutants and the debated role of SLIT3 in vasculature and bone. Present evidence hints at SLIT3 acting as an autocrine regulator of fibrillar collagen synthesis, suggesting it as a potential antifibrotic treatment. However, the precise pathway and mechanisms through which SLIT3 regulates fibrillar collagen synthesis remain uncertain, presenting an intriguing avenue for future research.

ERBIN and phosphoglucomutase 3 deficiency.

ERBIN and phosphoglucomutase 3 (PGM3) mutations both lead to rare primary atopic disorders characterized by allergic disease and connective tissue abnormalities, though each disorder has its own rather unique pattern of multisystem presentations. Pathway studies show how ERBIN mutations allow for enhanced TGFb signaling, and prevent STAT3 from negative-regulating TGFb signaling. This likely explains many elements of clinical overlap between disorders of STAT3 and TGFb signaling. The excessive TGFb signaling leading to increased IL-4 receptor expression also provides the rationale for precision-based therapy blocking the IL-4 receptor to treat the atopic disease. The mechanism by which PGM3 deficiency leads to atopic phenotypes is not well understood, nor is the broad variability in disease penetrance and expressivity, though preliminary studies suggest an overlap with IL-6 receptor signaling defects.

Abstract P3026: Multimodal Imaging To Identify Pre-signals For Acute Aortic Dissection By Using Marfan Syndrome Model Mouse

Background: Marfan syndrome (MFS) is a genetic disorder caused by mutations in the gene encoding theextracellular matrix Fibrillin-1 (FBN1), resulting in systemic connective tissue abnormalities. The mostcommon life-threatening conditions are aortic rupture and/or dissection. Aortic dissections show a highmortality rate, but the details of molecular triggers are unknown, particularly in acute aortic dissection(AAD). Raman spectroscopy is a technique for analyzing molecular structures from Raman spectra. It hasrecently attracted attention in the biology field because it can non-invasively distinguish between diseaseand non-disease areas. Objectives: This study aimed to identify the signals that induce changes in the aortic wall prior to acuteaortic dissection using genetic analysis and Raman spectroscopy with preservation of positional information. Methods: An acute aortic dissection model was created by using MFS model mice (Fbn1 mgR/mgR ) byadministration of angiotensin II (AngII) via osmotic pump (Fbn1 mgR/mgR -AAD). Aortas from wild-type(WT), Fbn1 mgR/mgR and Fbn1 mgR/mgR -AAD mice were harvested, and frozen sections were prepared. Thevascular wall of each mouse was assessed histologically, followed by spatial transcriptomic analysis andRaman microscopy measurements. Multivariate data analysis was performed on the obtained Ramanspectra. Mass spectrometry (MS) imaging was utilized for lipidome analysis. Results: Label-free imaging of extracellular substrates (collagen fibres, elastic fibres, versican, andaggrecan), lipids, and cells was produced in WT, Fbn1 mgR/mgR and Fbn1 mgR/mgR - AAD aortic tissue. Spatialtranscriptomic analysis identified differentially expressed genes among these aortas. We identified markedlipid accumulations in the acute aortic dissection models with Raman and MS imaging.

Analysis of gut microbiota in patients with Williams–Beuren Syndrome reveals dysbiosis linked to clinical manifestations

Williams–Beuren syndrome (WBS) is a multisystem genetic disease caused by the deletion of a region of 1.5–1.8 Mb on chromosome 7q11.23. The elastin gene seems to account for several comorbidities and distinct clinical features such including cardiovascular disease, connective tissue abnormalities, growth retardation, and gastrointestinal (GI) symptoms. Increasing evidence points to alterations in gut microbiota composition as a primary or secondary cause of some GI or extra-intestinal characteristics. In this study, we performed the first exploratory analysis of gut microbiota in WBS patients compared to healthy subjects (CTRLs) using 16S rRNA amplicon sequencing, by investigating the gut dysbiosis in relation to diseases and comorbidities. We found that patients with WBS have significant dysbiosis compared to age-matched CTRLs, characterized by an increase in proinflammatory bacteria such as Pseudomonas, Gluconacetobacter and Eggerthella, and a reduction of anti-inflammatory bacteria including Akkermansia and Bifidobacterium. Microbial biomarkers associated with weight gain, GI symptoms and hypertension were identified. Gut microbiota profiling could represent a new tool that characterise intestinal dysbiosis to complement the clinical management of these patients. In particular, the administration of microbial-based treatments, alongside traditional therapies, could help in reducing or preventing the burden of these symptoms and improve the quality of life of these patients.

Impact of Early Intervention for STAT3 Dominant-Negative Disease

IntroductionSTAT3 dominant negative disease (STAT3 DN) is characterized by elevated IgE, recurrent skin and lung infections, skeletal, connective tissue, and vascular abnormalities. Early genetic diagnosis, especially with familial disease, allows for early intervention, which may impact natural history through minimizing infectious complications. MethodsWe retrospectively reviewed medical records of 18 STAT3 DN pediatric patients born after 2007, when STAT3 genetic testing was available. Clinical features, laboratory results, infections and treatments were compared between those with STAT3 DN family history and probands. ResultsOur cohort included 8 patients with STAT3 DN diagnosed by family history (median age 9 years; range 4–14) and 10 probands (median age 13 years, range 5–14). For those with family history, one was diagnosed in utero, six by 6 months of age, and one at 2 years. Probands were diagnosed at a median age of 2 years (range 1–6 years). STAT3 mutation domains were similar between groups. Those with family history started antiseptic washes at a mean of 2.4 months and prophylactic antibiotics at 0.4 years, whereas probands initiated antiseptics at 4.5 years and prophylactic antibiotics at 3 years. Compared to probands, patients with STAT3 DN diagnosed by family history had significantly (p < 0.05) reduced rates of hospitalizations (mean 0.6 vs 6.2 times), bacterial pneumonias (13% vs 90%), >4 skin abscesses (25% vs 90%), other serious infections (0% vs 40%), recurrent ear infections and/or tympanostomy tube placement (0% vs 60%), and severe eczema (13% vs 60%). Significant differences were not seen in parenchymal lung abnormalities (13% vs 50%, p = 0.09) and non-immunologic features, such as fractures and joint hyperextensibility. Mean peak serum IgE and absolute eosinophil counts (AEC) were comparable (IgE 6,865 vs 13,317 IU/mL; AEC 1,023 vs 1,182 cells/uL in family history vs probands). Those with family history received less advanced therapies than probands, specifically immunoglobulin replacement (13% vs 60%), antifungals (25% vs 60%), and lung surgery (0% vs 40%). One proband received bone marrow transplantation. ConclusionEarly diagnosis and intervention positively impacts disease course and management with markedly reduced rates of infectious complications, which may decrease future morbidity and mortality in this vulnerable patient population.

Intrauterine adhesions: from pathogenesis to effective coping technologies

Intrauterine adhesions (IUDs) are one of the unresolved and unsolved problems of modern reproductive medicine worldwide. Adhesive lesions lead to partial or complete obliteration of the uterine cavity and/or cervical canal. The main clinical manifestations of IUDs are menstrual irregularities, cyclical pain, infertility and other various reproductive disorders. Reproductive outcomes in women with IUDs remain poorly understood and difficult to verify. At the same time, there is currently no understanding of the basic mechanisms of IUD development, including the processes explaining the failures of the above complications. The problem of overcoming IUD recurrences after adhesiolysis remains far from being finally resolved. The gold-standard treatment for IUD is hysteroscopic adhesiolysis, which, however, is associated with a high frequency of complications and relapses, highlighting the need for preventive approaches to the management of IUD. The drugs with enzymatic activity inhibiting abnormal connective tissue include bovhyaluronidase azoximer created by the Russian developers back in 2005. The drug consists of two components – hyaluronidase and azoximer bromide. The former is an enzyme, and the latter is a stabilizer that prolongs the action of hyaluronidase. Several studies have shown that bovhyaluronidase azoximer causes the destruction of intrauterine adhesions and restores the endometrium status in inflammatory pelvic diseases. Due to prolonged antifibrotic effect of bovhyaluronidase, azoximer can be used to treat women with IUDs to reduce the risk of the subsequent development of adhesive process in the uterine cavity.