Background A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene BMPR2 in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years. Methods Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4.These were extended by the three genes ATP13A3, AQP1 and SOX17 from March 2018 onwards following the genes’ discovery. Results A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene BMPR2 while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes AQP1, KCNK3 and SOX17 in families with at least two PAH patients. Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH. Conclusions Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes.

BackgroundInborn errors of immunity (IEI) present with a large phenotypic spectrum of disease, which can pose diagnostic and therapeutic challenges. Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling, and has recently been associated with a novel IEI. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has a pleiotropic effect in humans.ObjectiveWe sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency.MethodsWe assessed impacts of reduced SOCS1 expression across multiple immune cell pathways utilizing patient cells and CRISPR/Cas9 edited primary human T cells.ResultsSOCS1 haploinsufficiency phenotypes straddled across the International Union of Immunological Societies classifications of IEI. We found that reduced SOCS1 expression led to dysregulation of multiple intracellular pathways in immune cells. STAT1 phosphorylation is enhanced, comparably with STAT1 gain-of-function mutations, and STAT3 phosphorylation is similarly reduced with concurrent reduction of Th17 cells. Furthermore, reduced SOCS1 E3 ligase function was associated with increased FAK1 in immune cells, and increased AKT and p70 ribosomal protein S6 kinase phosphorylation. We also found Toll-like receptor responses are increased in SOCS1 haploinsufficiency patients.ConclusionsSOCS1 haploinsufficiency is a pleiotropic monogenic IEI. Dysregulation of multiple immune cell pathways may explain the variable clinical phenotype associated with this new condition. Knowledge of these additional dysregulated immune pathways is important when considering the optimum management for SOCS1 haploinsufficient patients.

Background Although combination therapy is the gold standard for patients with pulmonary arterial hypertension (PAH), some of these patients are still being treated with monotherapy. Methods We conducted a retrospective analysis at four German PH centres to describe the prevalence and characteristics of patients receiving monotherapy. Results We identified 131 incident PAH patients, with a mean age of 64 ± 13.8 years and a varying prevalence of comorbidities, cardiovascular risk factors and targeted therapy. As in other studies, the extent of prescribed PAH therapy varied with age and coexisting diseases, and younger, so-called “typical” PAH patients were more commonly treated early with combination therapy (48% at 4–8 months). In contrast, patients with multiple comorbidities or cardiovascular risk factors were more often treated with monotherapy (69% at 4–8 months). Survival at 12 months was not significantly associated with the number of PAH drugs used (single, dual, triple therapy) and was not different between “atypical” and “typical” PAH patients (89% vs. 85%). Conclusion Although “atypical” PAH patients with comorbidities or a more advanced age are less aggressively treated with respect to combination therapy, the outcome of monotherapy in these patients appears to be comparable to that of dual or triple therapy in “typical” PAH patients.

ZusammenfassungEine CPAP-Therapie ist die häufigste Behandlungsform der obstruktiven Schlafapnoe.Schwerwiegende Komplikation dieser Behandlung sind sehr selten. Pneumothorax als Lungen-Barotrauma unter der CPAP-Therapie wird in Einzelfallberichten und ausschließlich bei vorbestehenden Lungen- und Thoraxerkrankungen beschrieben.Ein 68-jähriger, pulmonal nicht vorerkrankter Schlafapnoe-Patient mit einer langjährig etablierten CPAP-Therapie wird nach einem heftigen thorakalen Schmerzereignis mit anhaltender Luftnotsymptomatik stationär aufgenommen. Radiologisch und computertomografisch bestand ein ausgedehnter rechtsseitiger Pneumothorax mit rechts basal betontem bullösem Emphysem. Nach operativer Versorgung des sekundären Spontanpneumothorax konnte am 3. postoperativen Tag die nächtliche Überdruckatmung unter reduziertem CPAP-Druck mit zufriedenstellendem Schlafapnoe-Befund und ohne Pneumothorax-Rezidiv im Verlauf wiederaufgenommen werden.Als mögliche Pneumothorax-Ursache bei dem Patienten können alveoläre entzündliche Veränderungen infolge von Überdehnung und Drucksteigerung in Alveolen, die unter jahrelanger CPAP-Behandlung mit schrittweiser Drucksteigerung entstanden sind und folglich zu ausgedehnten Lungenveränderung mit Ruptur geführt haben, angenommen werden.Zusammenfassend und schlussfolgernd soll bei Patienten, die aufgrund einer Schlafapnoe über Jahre mittels Überdruckatmung behandelt werden, bei plötzlich einsetzenden thorakalen Schmerzen mit einer Luftnotsymptomatik an einen möglichen Spontanpneumothorax gedacht werden.