regulatory disorders
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Author(s):  
Holly Wobma ◽  
Ryan Perkins ◽  
Lisa Bartnikas ◽  
Fatma Dedeoglu ◽  
Janet Chou ◽  
...  

In recent years, a number of monogenic disorders have been described that are characterized by immune dysregulation. A subset of these ‘primary immune regulatory disorders’ can cause severe interstitial lung disease, often recognized in late childhood or adolescence. Patients presenting to pulmonary clinic may have long and complex medical histories but lack a unifying genetic diagnosis. It is crucial for pulmonologists to recognize features suggestive of multisystem immune dysregulation and to initiate genetic workup, since targeted therapies based on underlying genetics may halt or even reverese pulmonary disease progression. Through such an approach, our center has been able to diagnose and treat a cohort of patients with interstitial lung disease from gene defects that affect immune regulation. Here we present representative cases related to pathogenic mutations in three distinct pathways and summarize disease manifestations and treatment approaches. We conclude with a discussion of our perspective on the outstanding challenges for diagnosing and managing these complex life-threatening and chronic disorders.


2021 ◽  
Vol 12 ◽  
Author(s):  
Marta López-Nevado ◽  
Luis I. González-Granado ◽  
Raquel Ruiz-García ◽  
Daniel Pleguezuelo ◽  
Oscar Cabrera-Marante ◽  
...  

Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (NRAS, KRAS), susceptibility to EBV (MAGT1, PRKCD, XIAP, SH2D1A, RASGRP1, TNFRSF9), antibody deficiency (PIK3CD gain of function (GOF), PIK3R1 loss of function (LOF), CARD11 GOF), regulatory T-cells defects (CTLA4, LRBA, STAT3 GOF, IL2RA, IL2RB, DEF6), combined immunodeficiencies (ITK, STK4), defects in intrinsic and innate immunity and predisposition to infection (STAT1 GOF, IL12RB1) and autoimmunity/autoinflammation (ADA2, TNFAIP3,TPP2, TET2). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare in other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life.


2021 ◽  
Vol 12 ◽  
Author(s):  
Anna K. Georg ◽  
Paul Schröder-Pfeifer ◽  
Manfred Cierpka ◽  
Svenja Taubner

Objective: Early regulatory disorders (ERD) in infancy are typically associated with high parenting stress (PS). Theoretical and empirical literature suggests a wide range of factors that may contribute to PS related to ERD. The aim of this study was to identify key predictors of maternal PS within a large predictor data set in a sample of N = 135 mothers of infants diagnosed with ERD.Methods: We used machine learning to identify relevant predictors. Maternal PS was assessed with the Parenting Stress Index. The multivariate dataset assessed cross-sectionally consisted of 464 self-reported and clinically rated variables covering mother-reported psychological distress, maternal self-efficacy, parental reflective functioning, socio-demographics, each parent's history of illness, recent significant life events, former miscarriage/abortion, pregnancy, obstetric history, infants' medical history, development, and social environment. Variables were drawn from behavioral diaries on regulatory symptoms and parental co-regulative behavior as well as a clinical interview which was utilized to diagnose ERD and to assess clinically rated regulatory symptoms, quality of parent–infant relationship, organic/biological and psychosocial risks, and social–emotional functioning.Results: The final prediction model identified 11 important variables summing up to the areas maternal self-efficacy, psychological distress (particularly depression and anger-hostility), infant regulatory symptoms (particularly duration of fussing/crying), and age-appropriate physical development. The RMSE (i.e., prediction accuracy) of the final model applied to the test set was 21.72 (R2 = 0.58).Conclusions: This study suggests that among behavioral, environmental, developmental, parent–infant relationship, and mental health variables, a mother's higher self-efficacy, psychological distress symptoms particularly depression and anger symptoms, symptoms in the child particularly fussing/crying symptoms, and age-inappropriate physical development are associated with higher maternal PS. With these factors identified, clinicians may more efficiently assess a mother's PS related to ERD in a low-risk help-seeking sample.


2021 ◽  
Vol 12 ◽  
Author(s):  
Danielle E. Arnold ◽  
Deepak Chellapandian ◽  
Jennifer W. Leiding

Recently, primary immune regulatory disorders have been described as a subset of inborn errors of immunity that are dominated by immune mediated pathology. As the pathophysiology of disease is elucidated, use of biologic modifiers have been increasingly used successfully to treat disease mediated clinical manifestations. Hematopoietic cell transplant (HCT) has also provided definitive therapy in several PIRDs. Although biologic modifiers have been largely successful at treating disease related manifestations, data are lacking regarding long term efficacy, safety, and their use as a bridge to HCT. This review highlights biologic modifiers in the treatment of several PIRDs and there use as a therapeutic bridge to HCT.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mona Katharina Sprengeler ◽  
Janna Mattheß ◽  
Melanie Eckert ◽  
Katharina Richter ◽  
Gabriele Koch ◽  
...  

Abstract Background The first years of life are a significant period for child development, when children are particularly sensitive and prone to crises. This early phase lays the foundation for healthy growth. Clinical assessment of psychological symptoms in early infancy and adequate treatment are both important in improving the diagnostic outcome and preventing later long-term developmental consequences. The most common psychological problems in the first 3 years of life are regulatory disorders. The aim of this trial is to investigate the efficacy of Parent-Infant Psychotherapy (PIP) for infants and young children (aged 0–36 months, diagnosed with at least one regulatory disorder) and their mothers, compared to care as usual (CAU). Methods In this open multicentre randomised controlled trial, 160 mother-infant dyads are randomised to receive PIP or CAU for 6 weeks of intervention in clinical or outpatient (including home treatment) settings. The primary outcome is the maternal sensitivity (sensitivity scale of the Emotional Availability Scales (EAS)) after 6 weeks. Secondary outcomes include assessment of interaction, mental health problems, attachment, development, psychological factors, treatment adherence, health care system utilisation, and costs, after 6 weeks and 12 months. Discussion This study will evaluate whether a manualised focus-based short-term psychodynamic psychotherapeutic intervention in mother-child dyads improves the care situation for families of children diagnosed with regulatory disorders, and helps prevent long-term psychopathologies. Assessment of the intervention in different settings will support the development of more tailored interventions for affected infants and their mothers. Trial registration German Clinical Trial Register, ID: DRKS00017008. Registered 03/20/2019.


2021 ◽  
Vol 11 ◽  
Author(s):  
Sara Ciullini Mannurita ◽  
Rayan Goda ◽  
Ebe Schiavo ◽  
Maria Luisa Coniglio ◽  
Annachiara Azzali ◽  
...  

STAT3 gain-of-function (GOF) mutations can be responsible for an incomplete phenotype mainly characterized by hematological autoimmunity, even in the absence of other organ autoimmunity, growth impairment, or severe infections. We hereby report a case with an incomplete form of STAT3 GOF intensified by a concomitant hereditary hematological disease, which misleads the diagnosis. The patient presented with lymphadenopathy, splenomegaly, hypogammaglobulinemia, and severe autoimmune hemolytic anemia (AIHA) with critical complications, including stroke. A Primary Immune Regulatory Disorders (PIRD) was suspected, and molecular analysis revealed a de novo STAT3 gain-of-function mutation. The response to multiple immune suppressive treatments was ineffective, and further investigations revealed a spectrin deficiency. Ultimately, hematopoietic stem cell transplantation from a matched unrelated donor was able to cure the patient. Our case shows an atypical presentation of STAT3 GOF associated with hereditary spherocytosis, and how achievement of a good long-term outcome depends on a strict clinical and laboratory monitoring, as well as on prompt therapeutic intervention.


Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 673-679
Author(s):  
Markus G. Seidel

Abstract Severe immune cytopenias (SICs) are rare acquired conditions characterized by immune-mediated blood cell destruction. They may necessitate emergency medical management and long-term immunosuppressive therapy, strongly compromising the quality of life. The initial diagnostic workup involves excluding malignancies, congenital cytopenias, bone marrow failure syndromes, infections, and rheumatologic diseases such as systemic lupus erythematosus. Causal factors for SIC such as primary immunodeficiencies or immune regulatory disorders, which are referred to as inborn errors of immunity (IEIs), should be diagnosed as early as possible to allow the initiation of a targeted therapy and avoid multiple lines of ineffective treatment. Ideally, this therapy is directed against an overexpressed or overactive gene product or substitutes a defective protein, restoring the impaired pathway; it can also act indirectly, enhancing a countermechanism against the disease-causing defect. Ultimately, the diagnosis of an underling IEI in patients with refractory SIC may lead to evaluation for hematopoietic stem cell transplantation or gene therapy as a definitive treatment. Interdisciplinary care is highly recommended in this complex patient cohort. This case-based educational review supports decision making for patients with immune-mediated cytopenias and suspected inborn errors of immunity.


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