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Unmasking Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS): diagnostic pitfalls of de novo mutations.

First author: Yixiang Yves-Jean Zhu

Journal: The Journal of Allergy and Clinical Immunology: In Practice


Unmasking Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS): diagnostic pitfalls of de novo mutations

Tumor necrosis factor receptor–associated periodic syndrome (TRAPS) is a rare genetic autoinflammatory disease associated with pathogenic variants in the TNFRSF1A gene. It usually runs in families through autosomal dominant inheritance, but can also appear sporadically when a de novo vriant occurs. We report 14 cases of TRAPS due to de novo variants, including 2 new French patients and 12 previously published cases. These patients faced a median diagnostic delay of 13 years, with recurrent flares lasting around 11 days, typically involving fever, abdominal pain, and joint pain. None presented with migratory myalgias or periorbital edema. The rarity of the disease, the nonspecific symptoms, and the absence of family history make the diagnosis particularly challenging. Clinicians should be aware that long-lasting unexplained inflammatory flares point to TRAPS, even in patients without a family history.



 
 
 

Living with Familial Mediterranean Fever (FMF): what helps you cope better?

Article title: The effects of self-efficacy in managing the disease and disease adaptation levels of Familial Mediterranean

Fever (fmf) patients on satisfaction with life: a web-based cross-sectional study

First author: Demir RN

Journal: Orphanet Journal of Rare Diseases

Author of the abstract: Rim BOURGUIBA


L’impact de la confiance en soi sur la qualité de vie des personnes atteintes de Fièvre Méditerranéenne Familiale

Abstract

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease in the world. It is characterized by recurrent inflammatory episodes of fever, abdominal pain, chest pain, and joint pain. Treatment is based on colchicine as first-line therapy, with biotherapy sometimes necessary. In addition to medical management, patients' ability to adapt to chronic disease and their sense of self-efficacy, defined as their feeling of personal effectiveness in managing the disease, can influence their quality of life. The objective of this study was to evaluate the impact of self-efficacy in FMF management and levels of adaptation to the disease on the satisfaction/quality of life of patients with FMF.


Methods:

A cross-sectional observational study was conducted using an online questionnaire distributed on Facebook and Instagram (FMF patient groups) between February and April 2024. The authors included adult Turkish patients (≥18 years old) who had been diagnosed at least one year prior.


The assessment tools used were:

- Self-Efficacy Scale for Chronic Disease (6 items).

- Adaptation to Chronic Illness Scale (25 items: physical, psychological, and social adaptation).

- Satisfaction With Life Scale.


Results

In this study of 423 adult Turkish patients with FMF, there was a predominance of females (73.8%), with ages ranging from 32 to 45 years. A disease duration of 21 years or more was reported in 38.3% of patients. The average self-efficacy score in disease management was relatively high (4.67/10). Adaptation to the disease was moderate overall (3.10/5), with better physical adaptation (3.36), followed by psychological adaptation (2.92) and social adaptation (2.87). Life satisfaction was below average (2.68/5). The correlation study revealed positive and significant associations between self-efficacy and adaptation (r = 0.532), between self-efficacy and life satisfaction (r = 0.417), and between adaptation and life satisfaction (r = 0.564) (Table 1). Regression analysis showed that self-efficacy explained 17.4% of the variance in life satisfaction, while adaptation to the disease explained 31.8%, confirming their decisive role in the self-management of FMF on quality of life (Table 2).


Conclusion

This study shows that in patients with FMF, self-efficacy and adaptation to the disease directly influence the overall low quality of life in this population. Strengthening therapeutic education and psychosocial support appears essential to improving the quality of life of adult patients with FMF.



Table 1: Correlation study between self-efficacy and quality of life in FMF patients

Étude de corrélation entre l’auto-efficacité et la qualité de vie chez les patients FMF

Table 2: Regression analysis of self-efficacy on quality of life and disease management

Analyse de régression de l’auto-efficacité sur la qualité de vie et la gestion de la maladie

 
 
 

New variants of the MRTFA gene broaden the spectrum of actinopathy with low white blood cell counts and inflammation

Article title: Des nouveaux variants de MRTFA expandent le phénotype de cette actinopathie avec neutropénie et manifestations autoinflammatoires
First author: Wendao Li
Journal: Pediatric Allergy and Immunology
Author of the abstract: Philippe Mertz

De nouvelles variantes du gène MRTFA élargissent le spectre d’une actinopathie avec baisse des globules blancs et inflammation

Three key points to remember:


  1. MKL1 deficiency was known to cause major disruption of the actin cytoskeleton and severe primary immunodeficiency with phagocyte defects.

  2. The authors report here the first case of composite heterozygous variants in MRTFA, broadening the known phenotypic spectrum with major autoinflammatory manifestations and abnormalities in neutrophil number and function at the forefront.

  3. As illustrated here, the full phenotype of actinopathies remains to be discovered, highlighting the importance of accurate diagnosis and in-depth functional investigations.


The MRTFA gene encodes the Megakaryoblastic Leukemia 1 (MKL1) protein, a regulator of the SRF transcription factor that induces the transcription of genes involved in actin cytoskeleton homeostasis, cell migration, and adhesion in multiple cell types. Normally, G-actin polymerization releases MKL1, allowing it to enter the nucleus to coactivate SRF-targeted genes.

The MKL1 defect was initially described in 2015 in three patients who presented with a phenotype of actinopathy with combined immunodeficiency, including a defect in the number and function of phagocytes. These earlier cases, from consanguineous families, had homozygous variants leading to the complete absence of the MKL1 protein. The classic clinical picture included increased susceptibility to severe bacterial infections, poor wound healing, and thrombocytopenia.

This article reports the fourth patient with MKL1 deficiency and the first reported case associated with composite heterozygous variants in the MRTFA gene (NM_020831; p.Q377X/p.C684X). These two variants are located in critical domains of the MKL1 protein, resulting in the complete absence of the protein in PBMCs and neutrophils, and therefore of its function as a regulator of actin metabolism gene transcription factors.

The patient, aged 3 years and from a non-consanguineous family, presented her first symptoms at the age of 2 months. She suffered from early infections, intermittent neutropenia, and thrombocytopenia, with a nadir of 55 G/L. Unlike the cases initially described in the literature, the infections observed in this patient were relatively less severe. However, she had marked autoinflammatory manifestations, characterized by recurrent febrile episodes associated with multiple erythematous and papular skin lesions affecting the face and limbs, as well as swelling of the hands and feet. She also had intermittent bloody diarrhea, rectal ulcers, colitis, and colonic lymphoid follicular hyperplasia, as confirmed by endoscopy.


Multiple erythematous rashes on the patient's face and legs and swelling of the fee

Figure extraite de l’article

The authors conducted several functional explorations to understand the impact of these variants:


The absence of MKL1 caused marked dysfunction of the actin cytoskeleton, characteristic of actinopathies. A significant reduction in filamentous actin (F-actin) content was observed in neutrophils, monocytes, and, to a lesser extent, T and B lymphocytes. Similarly, F-actin polymerization in response to stimulation (fMLF) was reduced.


Major neutrophil dysfunction:

Migration: greatly reduced chemotactic response

ROS production and oxidative burst: The production of ROS (reactive oxygen species), whether intracellular or extracellular, and the production of H₂O₂ (assessed by DHR) were reduced in response to stimulation. This contrasts with previous reports that did not note any defects in ROS production.


NETs (Neutrophil Extracellular Traps): The formation of NETs, a crucial immune defense mechanism requiring intact actin cytoskeleton rearrangement, was impaired.

Transcriptomic analysis of neutrophils provided support for the clinical inflammatory observations, revealing downregulation of cytoskeletal genes but, concomitantly, upregulation of inflammatory pathways, including the NFkB pathway, TNFα, and a signature typical of inflammatory bowel disease (IBD). These results may partly explain the inflammatory manifestations observed in the patient.


In conclusion, the authors report here the first case of MKL1 deficiency associated with composite heterozygous variants, significantly broadening the known phenotypic spectrum. The association of a marked autoinflammatory phenotype with a less severe immune deficiency highlights the diversity and complexity of actinopathies. As illustrated here, the full phenotype of these diseases probably remains to be discovered, justifying further clinical and functional investigations.



 
 
 
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