[CF Lung Disease - a German S3 Guideline: Pseudomonas aeruginosa]. / S3-Leitlinie: Lungenerkrankung bei Mukoviszidose ­ Pseudomonas aeruginosa.

Cystic Fibrosis (CF) is the most common autosomal recessive genetic multisystemic disease. In Germany, it affects at least 8000 people. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the airway epithelial lining fluid which leads to reduction of the mucociliary clearance.Even if highly effective, CFTR modulator therapy has been available for some years and people with CF are getting much older than before, recurrent and chronic infections of the airways as well as pulmonary exacerbations still occur. In adult CF life, Pseudomonas aeruginosa (PA) is the most relevant pathogen in colonisation and chronic infection of the lung, leading to further loss of lung function. There are many possibilities to treat PA-infection.This is a S3-clinical guideline which implements a definition for chronic PA-infection and demonstrates evidence-based diagnostic methods and medical treatment in order to give guidance for individual treatment options.

Complete Tracheal Ring Deformity, Recurrent Pneumothoraces and Pleuropulmonary Blastoma in a Child: Coincidence or Common Genetic Cause?

Complete tracheal ring deformity (CTRD) is a rare abnormality of unknown etiology characterized by circumferentially continuous cartilaginous tracheal rings leading to variable degrees of tracheal stenosis with or without additional heart and lung malformations. Pleuropulmonary blastomas (PPB) are rare malignant mesenchymal tumors, which occur almost exclusively in young children. Pathogenic germline DICER1 variants are associated with PPB but also with other tumors like rhabdomyosarcoma or syndromic diseases like GLOW (Global developmental delay, lung cysts, overgrowth and Wilms tumor) syndrome. Here, we report a case with CTRD and recurrent pneumothoraces who additionally developed PPB on the genetic background of a pathogenic DICER1 variant.

Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma.

We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET < 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET > 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.

Infection prevention and control in patients with cystic fibrosis (CF): Results from a survey in 35 German CF treatment centers.

This survey evaluates whether the Cystic Fibrosis (CF)-specific infection prevention and control (IPC) recommendations released by the Commission for Hospital Hygiene and Infection Prevention (KRINKO) in 2012 have been implemented in specialized German CF facilities. Of 35 participating centers (response rate 32.7%), 37% care for more than 100 patients and 44% treat mainly adults. Clinics for adult CF patients report a shortage of qualified personnel for intensified environmental cleaning. Some hospitals struggle to provide single patient rooms with an adjacent sanitary area to segregate CF patients strictly. Most centers offer at least one decolonization cycle (including systemic and inhalative antibiotics) to patients colonized with MRSA. In CF centers in Germany, the KRINKO IPC recommendations are considered helpful by the attending physicians and thoroughly implemented. There is room for improvement concerning strict segregation of inpatients with CF in single patient rooms, in particular in large CF centers mainly caring for adults.

DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects.

RATIONALE: Primary ciliary dyskinesia (PCD) is characterized by recurrent airway infections and randomization of left-right body asymmetry. To date, autosomal recessive mutations have only been identified in a small number of patients involving DNAI1 and DNAH5, which encode outer dynein arm components. METHODS: We screened 109 white PCD families originating from Europe and North America for presence of DNAH5 mutations by haplotype analyses and/or sequencing. RESULTS: Haplotype analyses excluded linkage in 26 families. In 30 PCD families, we identified 33 novel (12 nonsense, 8 frameshift, 5 splicing, and 8 missense mutations) and two known DNAH5 mutations. We observed clustering of mutations within five exons harboring 27 mutant alleles (52%) of the 52 detected mutant alleles. Interestingly, 6 (32%) of 19 PCD families with DNAH5 mutations from North America carry the novel founder mutation 10815delT. Electron microscopic analyses in 22 patients with PCD with mutations invariably detected outer dynein arm ciliary defects. High-resolution immunofluorescence imaging of respiratory epithelial cells from eight patients with DNAH5 mutations showed mislocalization of mutant DNAH5 and accumulation at the microtubule organizing centers. Mutant DNAH5 was absent throughout the ciliary axoneme in seven patients and remained detectable in the proximal ciliary axoneme in one patient carrying compound heterozygous splicing mutations at the 3'-end (IVS75-2A>T, IVS76+5G>A). In a preselected subpopulation with documented outer dynein arm defects (n = 47), DNAH5 mutations were identified in 53% of patients. CONCLUSIONS: DNAH5 is frequently mutated in patients with PCD exhibiting outer dynein arm defects and mutations cluster in five exons.

Severe mucous membrane involvement in epidermolysis bullosa simplex with muscular dystrophy due to a novel plectin gene mutation.

UNLABELLED: Epidermolysis bullosa simplex with muscular dystrophy (OMIM 226670) is an autosomal recessive disorder caused by mutations of the human plectin gene on chromosome 8q24. Here, we report a 3-year-old girl, offspring of a consanguineous Lebanese family, who presented with skin blistering and recurrent episodes of severe respiratory distress necessitating tracheotomy at the age of 2 years. Repeated examination did not provide any evidence of muscle involvement. Indirect immunofluorescence analysis of a diagnostic skin biopsy with four different domain specific plectin antibodies showed a complete absence of plectin staining. Mutation analysis revealed a novel homozygous single guanine insertion mutation (5588insG/5588insG) residing in the N-terminal part of exon 31 of the plectin gene. CONCLUSION: The complete lack of protein expression, which may be attributed to a nonsense-mediated plectin mRNA decay, is likely to cause muscular dystrophy and other multisystem involvement later in life.