Autoimmune lymphoproliferative syndrome (ALPS) is a primary disorder of lymphocyte homeostasis, leading to chronic lymphoproliferation, autoimmune cytopenia, and increased risk of lymphoma. The genetic landscape of ALPS includes mutations in FAS, FASLG, and FADD, all associated with apoptosis deficiency, while the role of CASP10 defect in the disease remains debated. In this study, we aimed to assess the impact of CASP10 variants on ALPS pathogenesis. We benefit from thousands of genetic analysis datasets performed in our Institute\'s genetic platform to identify individuals carrying CASP10 variants previously suspected to be involved in ALPS outcome: p.C401LfsX15, p.V410I and p.Y446C, both at heterozygous and homozygous state. Clinical and laboratory features of the six included subjects were variable but not consistent with ALPS. Two individuals were healthy. Comprehensive analyses of CASP10 protein expression and FAS-mediated apoptosis were conducted and compared to healthy controls and ALPS patients with FAS mutations. Missense CASP10 variants (p.V410I and p.Y446C), which are common in the general population, did not disrupt CASP10 expression, nor FAS-mediated apoptosis. In contrast, homozygous p.C401LfsX15 CASP10 variant lead to a complete abolished CASP10 expression but had no impact on FAS-mediated apoptosis function. At heterozygous state, this p.C401LfsX15 variant lead to a reduced CASP10 protein levels but remained associated with a normal FAS-mediated apoptosis function. These findings demonstrate that CASPASE 10 is dispensable for FAS-mediated apoptosis. In consequences, CASP10 defect unlikely contribute to ALPS pathogenesis, since they did not result in an impairment of FAS-mediated apoptosis nor in clinical features of ALPS in human. Moreover, the absence of FAS expression up-regulation in subjects with CASP10 variants rule out any compensatory mechanisms possibly involved in the normal apoptosis function observed. In conclusion, this study challenges the notion that CASP10 variants contribute to the development of ALPS.

BACKGROUND: Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification.
METHODS: In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing.
RESULTS: We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5-13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses.
CONCLUSIONS: The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful to focus diagnostic and therapeutic efforts by triggering extended genetic analysis and consideration of targeted therapies, including in some children currently classified as having common variable immunodeficiency or Evans syndrome.
BACKGROUND: Deutsche Forschungsgemeinschaft under Germany\'s Excellence Strategy.
UNASSIGNED: For the German translation of the abstract see Supplementary Materials section.

Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disease caused germline mutation of FAS gene, gene encoding Fas ligand or Caspase 10 gene. However, in 20% of all ALPS patients, genetic defect is unknown. We presented a case of a 20-year-old male with a history of autoimmune lymphoproliferative syndrome (ALPS; confirmed by genetic study) who came to our medical center with a concern for malignancy. Although no malignancy was detected, his lack of IgA, very low level of IgG (requiring therapy with intravenous IgG) and highly elevated polyclonal IgM (hyperimmunoglobulin M syndrome) were unusual findings because ALPS patients with hypergammaglobulinemia usually demonstrate elevated IgA or IgG.

Fortunately, fatal accidents while high-altitude mountaineering have decreased in recent years, but the number of emergencies has increased. These nonfatal emergencies might represent situations where alpinists are stranded (emergencies in which alpinists are no longer able to continue their tour on their own because of, for example, exhaustion, equipment problems, or weather). We analyzed 4596 cases of high-altitude-mountaineering emergencies in the period 2009 to 2020 from the SAC (Swiss Alpine Club) emergency registry. In total, 1951 cases (41.6%) were due to being stranded, 1348 cases were due to falls (28.7%), and 352 cases were due to illness (7.5%); these were the three most common classes. In cases of being stranded, 90% of alpinists were uninjured or not seriously injured. In addition, we found only eight fatal cases. More than 50% of cases occurred while ascending a summit above 4000 m. The main causes of becoming stranded were exhaustion and weather changes. These findings suggest that alpinists contact rescue organizations before experiencing serious troubles; these situations thus present risks and dangers both to those stranded and to emergency services. Since exhaustion and weather changes are the two main causes, adequate preparation and tour planning may help prevent such emergencies.

Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.

Chronic immune thrombocytopenia (cITP) is often associated with an underlying predisposition towards autoimmunity, recognition of which is relevant to guide treatment. International recommendations on diagnostic steps and therapeutic measures of cITP in childhood exist. However, due to the low prevalence (1-2/100,000) and a variation of availability of immunological and hematological tests and treatments across pediatric units, we postulated that these guidelines are not uniformly adhered to and that immune dysregulation syndromes remained undiscovered. To delineate the current management of children and adolescents with cITP in Austria, we performed a nationwide cross-sectional study. Between 2011 and 2014, 81 children with cITP were seen at seven centers (median age 8.75 years; range 1-17; female:male ratio 47:34) at 641 visits during 180 patient years after diagnosis of cITP (>12 months ITP duration). Additional diagnoses were noted, most frequently immune or autoimmune disorders, hematologic diseases, or infections (in 37.3%, including Evans syndrome, autoimmune lymphoproliferative syndrome, systemic lupus erythematosus, and Fanconi anemia), or other symptoms like bi- or pancytopenia (n=9), lymphoproliferation or granulomatous inflammation (n = 3). Both decision to treat as well as choice of treatment varied: smaller centers tended to observe more frequently, larger centers applied a pattern of treatment modalities that appeared to depend less on bleeding tendency than on center policy. More than 50% of therapeutic interventions occurred in bleedings scores ≤2 (of 5), suggesting a strong psychosocial intention to treat. Platelet increment upon 479 therapeutic interventions of eight types was evaluated, with multiple treatment approaches being pursued sequentially in refractory patients. These data confirm the hypothesis of heterogeneous diagnostic and therapeutic management of cITP in Austrian children and corroborate the need for (1) a precise panel of parameters to exclude underlying disorders and (2) for biomarkers to predict treatment response.

Patients with autoimmune lymphoproliferative syndrome (ALPS), a disorder of impaired lymphocyte apoptosis, often undergo radiographic chest imaging to evaluate the presence and progression of lymphadenopathy. These images often lead to parenchymal and interstitial lung findings of unclear clinical significance.
To characterize the pulmonary findings associated with ALPS and to determine if lung abnormalities present on computed tomographic (CT) imaging of the chest correlate with infection or functional status.
Patients with lung abnormalities observed on chest CT scans were retrospectively identified from the largest known ALPS cohort. Lung computed tomography findings were characterized and correlated with medical records, bronchoalveolar lavage, biopsy, and lung function.
CT images of the chest were available for 234 (92%) of 255 of the patients with ALPS. Among patients with a chest CT scan, 18 (8%) had lung abnormalities on at least one CT scan. Fourteen (78%) of those 18 were classified as having ALPS with undetermined genetic defect. Most patients (n = 16 [89%]) with lung lesions were asymptomatic. However, two (11%) of them had associated dyspnea and/or desaturation on room air. Immunosuppressive treatment was administered for lung disease in nine (50%) cases, and all were followed for clinical outcomes.
Patients with ALPS can develop chest radiographic findings with protean manifestations that may mimic pulmonary infection. Management of patients with ALPS with incidental lung lesions identified by CT imaging should be guided by clinical correlation. Symptomatic patients may benefit from chest CT imaging and lesion biopsy to exclude infection and guide administration of immunosuppressive therapy.

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by dysregulation of the Fas apoptotic pathway. Clinical manifestations of ALPS include autoimmune cytopenias, organomegaly, and lymphadenopathy. These findings overlap with Evans syndrome (ES), defined by presence of at least 2 autoimmune cytopenias. We hypothesized a subset of patients with ES have ALPS and tested 45 children at 22 institutions, measuring peripheral blood double-negative T cells (DNTs) and Fas-mediated apoptosis. ALPS was diagnosed in 47% of patients tested. Markedly elevated DNTs (> or = 5%) were a strong predictor of ALPS (positive predictive value = 94%), whereas no patients with DNTs less than 2.5% had ALPS on apoptosis testing. Severity of cytopenias and elevated immunoglobulin levels also predicted ALPS. This is the largest published series describing children with ES and documents a high rate of ALPS among pediatric ES patients. These data suggest that children with ES should be screened for ALPS with DNTs.

BACKGROUND: Danazol is a drug most widely used for the prophylaxis of hereditary angioedema resulting from the deficiency of the C1-inhibitor. Potential hepatotoxic or liver tumor-inducing side effects of long-term danazol prophylaxis have been investigated during the follow-up of hereditary angioedema patients.
METHODS: Characteristic parameters of liver function (including bilirubin, GOT, GPT, gammaGT, total protein, ALP, LDH), as well as findings of viral serology screens and abdominal ultrasonography-determined during years 0 and 5 of follow-up of patient groups taking/not taking danazol-have been reviewed and analyzed comparatively.
RESULTS: From a population of 126 hereditary angioedema patients, 46 subjects taking danazol and another 46 not taking danazol fulfilled the inclusion criteria. Longitudinal follow-up did not reveal any clinically relevant difference between the liver function parameters determined in years 0 and 5 in the two groups. Abdominal ultrasound did not detect neoplastic or other potentially treatment-related alterations of the liver parenchyma. There were no discontinuations of treatment during the study.
CONCLUSIONS: Our results clearly suggest that, administered at the lowest effective dose, danazol does not induce liver injury in hereditary angioedema patients.