Immune deficiency, autoimmune disease and intellectual disability: A pleiotropic disorder caused by biallelic variants in the TPP2 gene.

Four individuals from two families presented with a multisystemic condition of suspected genetic origin that was diagnosed only after genome analysis. The main phenotypic features were immune system dysregulation (severe immunodeficiency with autoimmunity) and intellectual disability. The four individuals were found to be homozygous for a 4.4 Kb deletion removing exons 20-23 (NM_003291.4) of the TPP2 gene, predicting a frameshift with premature termination of the protein. The deletion was located on a shared chromosome 13 haplotype indicating a Swiss founder mutation. Tripeptidyl peptidase 2 (TPP2) is a protease involved in HLA/antigen complex processing and amino acid homeostasis. Biallelic variants in TPP2 have been described in 10 individuals with variable features including immune deficiency, autoimmune cytopenias, and intellectual disability or chronic sterile brain inflammation mimicking multiple sclerosis. Our observations further delineate this severe condition not yet included in the OMIM catalog. Timely recognition of TPP2 deficiency is crucial since (1) immune surveillance is needed and hematopoietic stem cell transplantation may be necessary, and (2) for provision of genetic counselling. Additionally, enzyme replacement therapy, as already established for TPP1 deficiency, might be an option in the future.

[Newborn screening for severe T and B lymphocyte deficiencies in Switzerland]. / Pédiatrie - Dépistage des nouveau-nés en Suisse pour les déficiences sévères à lymphocytes T et B.

Severe Combined Immunodeficiency (SCID) is one of the most severe forms of Primary Immunodeficiencies (PID) and leads to a potentially fatal course of disease without early and definitive treatment. Adequate management, from the first days of life, can improve the survival and outcome of patients with SCID. This can be achieved through newborn screening (NBS) based on the measurement of T-cell receptor excision circles (TREC). Already present in many countries, this NBS test was introduced in Switzerland in January 2019 on a pilot phase. In addition to the assessment of TRECs, the measurement of kappa recombinant excision circles (KREC) has also been introduced at the same time and allows the identification of severe forms of PID characterized by profound B cell lymphopenia.

Le déficit immunitaire combiné sévère (DICS) fait partie des formes sévères d'immunodéficience primaire (IDP) avec un tableau clinique fatal sans traitement précoce et définitif, comme la transplantation des cellules souches hématopoïétiques. Une prise en charge adéquate dès les premiers jours de vie va permettre d'améliorer le devenir des patients avec DICS. Une meilleure prise en charge est devenue possible grâce au dépistage néonatal basé sur la mesure des cercles d'excision des récepteurs des cellules T. Ce test a été introduit en Suisse dans une phase pilote à partir de janvier 2019, avec un dépistage supplémentaire via le dosage des cercles d'excision des recombinants Kappa, qui permet d'identifier des formes graves d'IDP se manifestant surtout par une lymphopénie B profonde.

Prevalence of tuberculosis in migrant children in Switzerland and relevance of current screening guidelines.

AIMS: Since 2016, Swiss guidelines recommend screening of all migrant children <5 years of age for tuberculosis (TB) and to screen older children only if they have risk factors for TB. Our goals were to describe the epidemiology of latent tuberculosis (LTBI) in migrant children at the Lausanne University Hospital, to identify determinants of LTBI and tuberculosis disease (TBD), and to evaluate the risk of a false-positive tuberculin skin test (TST) when using a positivity limit of 5 mm. METHODS: Newly arrived migrant children 0–18 years of age were prospectively enrolled from 31 August 2015 to 31 August 2017. Every migrant child was assessed for the risk of TB exposure and TBD and was administered a TST. A TB-spot test was performed in children ≥5 years of age when the TST was positive. Children with clinical and/or radiological signs of TBD were further investigated. Children ≥5 years of age with a positive TB-spot test and children <5 years of age with a positive TST, without clinico-radiological signs of TBD received a diagnosis of LTBI. A false-positive TST result was diagnosed in children ≥5 years of age when the TB-spot test was negative. Potential determinants of TB (LTBI and TBD) and of false-positive TSTs were identified. Student’s t-test or the Kruskal-Wallis test were used for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. All variables with a p-value <0.05 were included in a multivariate logistic regression model. RESULTS: Two hundred and fifty-three patients were eligible for the study. The median age of the patients was 8.1 years (interquartile range [IQR] 4.5–12.8) and 104 (41%) were female. Twenty-four percent of the patients (62/253) came from a country with a moderate–high incidence of TBD (≥80 cases per 100,000 individuals). Twenty-eight patients (11%) had positive TSTs, and TB was confirmed in 17 (6.7%) of these patients (16 with LTBI and 1 with TBD). On multivariate analysis, moderate–high incidence of TBD in the country of origin (adjusted odds ratio [aOR] 18.8, 95% confidence interval [CI] 5.1–68.6; p <0.001), older age (aOR 1.1, 95% CI 1.0–1.3; p = 0.025), and contact with a TBD patient (aOR 8, 95% CI 1.8–36.2; p = 0.007) were associated with a diagnosis of TB. Among the 23 children over 5 years of age who had a positive TST with measurement available, a measure between 5–9 mm was more frequent in case of a false-positive TST (5/9, 56% vs 0/14, 0%, p = 0.002). BCG vaccination was the only predictor of a false-positive TST (p = 0.03). CONCLUSION: Screening migrant children ≥5 years of age for TB could confer a public health benefit even in the absence of other risk factors. The limit of TST positivity could be raised from ≥5 mm to ≥10 mm to decrease the rate of false-positive results. A national assessment of migrant children between the ages of 5 and 15 should be carried out to confirm our findings.

Case Report: Case Series of Children With Multisystem Inflammatory Syndrome Following SARS-CoV-2 Infection in Switzerland.

Since the beginning of the severe SARS-CoV-2 pandemic, an increasing number of countries reported cases of a systemic hyperinflammatory condition defined as multi-system inflammatory syndrome in children (MIS-C). The clinical features of MIS-C can be an overlap of Kawasaki Disease (KD), Toxic Shock Syndrome (TSS), Macrophage Activation Syndrome (MAS), or have often an acute abdominal presentation. Intravenous immunoglobulin (IVIG) is recommended as first line therapy in KD. Recent evidence suggests intravenous immunoglobulins (IVIG) resistance in some cases of SARS-CoV-2 related MIS-C, thereby questioning the benefit of immunomodulators such as IL-1 or IL-6 blocking agents. We report on a cohort of 6 Swiss children with SARS-CoV2 related MIS-C presenting with clinical features compatible with Incomplete KD and Toxic Shock Syndrome associated to a cytokine storm. Serum cytokine profile investigations showed increased IL1RA levels (8 to 22-fold) in 5 of the 6 patients (one patient had not been tested), whereas, IL-6 serum levels were increased only in the 3 patients of the 6 who were tested. With exception of one patient who had only benefited by Anakinra, all patients received at least one dose of IVIG. One patient has only received Anakinra with favorable evolution, and three patients had also a steroid treatment. In addition to all this anti-inflammatory medication two patients have also received one dose of anti-IL6. In conclusion, our case series reports on clinical and laboratory findings of most of Swiss cases with MIS-C and suggests the use of Anakinra as an alternative to steroids in these children, most of whom presented with high IL-1RA levels.