• MeSH
• dítě MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• peritoneální fibróza * etiologie   diagnóza   MeSH
• rizikové faktory MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• membránové proteiny MeSH

Salt-losing tubulopathies are well-recognised diseases predisposing to metabolic disturbances in affected patients. One of the most severe complications can be life-threatening arrhythmias causing sudden cardiac arrest. We present here the first case of a pediatric patient with Gitelman syndrome associated sudden cardiac arrest without precipitating event. A 10-year-old boy collapsed due to ventricular fibrillation in the Prague tram. Lay cardiopulmonary resuscitation was initiated and external defibrillation restored sinus rhythm within minutes. Initial laboratory examination revealed severe hypokalemia requiring large amounts of electrolyte supplementation. Genetic testing focused to tubulopathies was performed and the diagnosis of Gitelman syndrome was made following the identification of two pathogenic variants in SLC12A3 gene (c.2633 + 1G>A and c.2221G>A). Implantable cardioverter-defibrillator was implanted to prevent sudden cardiac death. The patient was in a good clinical condition with satisfactory electrolyte serum levels at the last follow-up. Causes of electrolyte abnormalities in children should be identified early to prevent the development of rare but potentially fatal complications.

• Klíčová slova
• Gitelman syndrome, arrhythmia, hypokalemia, hypomagnesemia, sudden cardiac arrest,
• Publikační typ
• kazuistiky MeSH

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.

• MeSH
• dasatinib MeSH
• endoteliální buňky * metabolismus   MeSH
• fosforylace MeSH
• lidé MeSH
• neutrofily metabolismus   MeSH
• skupina kinas odvozených od src-genu * genetika   metabolismus   MeSH
• vaskulitida * genetika   MeSH
• zánět metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• dasatinib MeSH
• lyn protein-tyrosine kinase MeSH Prohlížeč
• skupina kinas odvozených od src-genu * MeSH

Fetal intracranial hemorrhage represents a rare event with an estimated prevalence of 1:10 000 pregnancies. We report a patient diagnosed prenatally with intracranial hemorrhage and ventriculomegaly carrying a novel, previously unreported, likely pathogenic variant in COL4A1. At the gestational age of 27 weeks, dilation of lateral ventricles was detected during a routine prenatal ultrasound scan, confirmed by prenatal MRI at 30 + 3 weeks of gestation. Prenatal examinations included amniocentesis with conventional G-band karyotyping and arrayCGH, and maternal testing for TORCH and parvovirus B19 infections. Virtual gene panel based on whole-exome sequencing data was performed postnatally. At the age of 2.5 months, the patient manifested epileptic seizures that remain difficult to control. Postnatal MRI showed partial thalamic fusion and polymicrogyria, in addition to severe enlargement of lateral ventricles, multiple deposits of hemosiderin in cerebral and cerebellar hemispheres, and thin optic nerve and chiasma. Virtual gene panel based on whole-exome sequencing data led to a detection of a de novo previously unreported in-frame deletion NM_001845.5:c.4688_4711del in COL4A1 located in the highly conserved NC1 domain initiating collagen helix assembly. The presented case lies one a more severe end of the COL4A1 mutation-related disease spectrum, manifesting as fetal intracranial bleeding, malformation of cortical development, drug-resistant epilepsy, and developmental delay.

• Klíčová slova
• COL4A1, COL4A1 mutation-related disorders, intracranial hemorrhage, malformation of cortical development, polymicrogyria,
• MeSH
• hydrocefalus * MeSH
• intrakraniální krvácení MeSH
• kojenec MeSH
• kolagen typu IV genetika   MeSH
• lidé MeSH
• mutace MeSH
• plod MeSH
• polymikrogyrie * genetika   MeSH
• těhotenství MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• COL4A1 protein, human MeSH Prohlížeč
• kolagen typu IV MeSH

BACKGROUND: Schimke immunoosseous dysplasia (SIOD) is an ultra-rare inherited disease affecting many organ systems. Spondyloepiphyseal dysplasia, T-cell immunodeficiency and steroid resistant nephrotic syndrome are the main symptoms of this disease. CASE PRESENTATION: We aimed to characterize the clinical, pathological and genetic features of SIOD patients received at tertiary Pediatric Nephrology Center, University Hospital Motol, Prague, Czech Republic during the period 2001-2021. The mean age at diagnosis was 21 months (range 18-48 months). All patients presented with growth failure, nephropathy and immunodeficiency. Infections and neurologic complications were present in most of the affected children during the course of the disease. CONCLUSIONS: Although SIOD is a disease characterized by specific features, the individual phenotype may differ. Neurologic signs can severely affect the quality of life; the view on the management of SIOD is not uniform. Currently, new therapeutic methods are required.

• Klíčová slova
• Case series, Chronic kidney disease, Nephropathy, Schimke immunoosseous dysplasia, Transient ischemic attacks, Transplantation,
• MeSH
• centra terciární péče MeSH
• kvalita života MeSH
• lidé MeSH
• nefrotický syndrom * diagnóza   genetika   komplikace   MeSH
• osteochondrodysplazie * diagnóza   genetika   terapie   MeSH
• syndromy imunologické nedostatečnosti * diagnóza   genetika   komplikace   MeSH
• vzácné nemoci MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND AND OBJECTIVES: Malformations of cortical development (MCD), though individually rare, constitute a significant burden of disease. The diagnostic yield of next-generation sequencing (NGS) in these patients varies across studies and methods, and novel genes and variants continue to emerge. METHODS: Patients (n = 123) with a definite radiologic or histopathologic diagnosis of MCD, with or without epilepsy were included in this study. They underwent NGS-based targeted gene panel (TGP) testing, whole-exome sequencing (WES), or WES-based virtual panel testing. Selected patients who underwent epilepsy surgery (n = 69) also had somatic gene testing of brain tissue-derived DNA. We analyzed predictors of positive germline genetic finding and diagnostic yield of respective methods. RESULTS: Pathogenic or likely pathogenic germline genetic variants were detected in 21% of patients (26/123). In the surgical subgroup (69/123), we performed somatic sequencing in 40% of cases (28/69) and detected causal variants in 18% (5/28). Diagnostic yield did not differ between TGP, WES-based virtual gene panel, and open WES (p = 0.69). Diagnosis of focal cortical dysplasia type 2A, epilepsy, and intellectual disability were associated with positive results of germline testing. We report previously unpublished variants in 16/26 patients and 4 cases of MCD with likely pathogenic variants in non-MCD genes. DISCUSSION: In this study, we are reporting genetic findings of a large cohort of MCD patients with epilepsy or potentially epileptogenic MCD. We determine predictors of successful ascertainment of a genetic diagnosis in real-life setting and report novel, likely pathogenic variants in MCD and non-MCD genes alike.

• Publikační typ
• časopisecké články MeSH

We report the clinical findings of 26 individuals from 16 unrelated families carrying variants in the COL2A1 or COL11A1 genes. Using Sanger and next-generation sequencing, 11 different COL2A1 variants (seven novel), were identified in 13 families (19 affected individuals), all diagnosed with Stickler syndrome (STL) type 1. In nine families, the COL2A1 disease-causing variant arose de novo. Phenotypically, we observed myopia (95%) and retinal detachment (47%), joint hyperflexibility (92%), midface retrusion (84%), cleft palate (53%), and various degrees of hearing impairment (50%). One patient had a splenic artery aneurysm. One affected individual carrying pathogenic variant in COL2A1 showed no ocular signs including no evidence of membranous vitreous anomaly. In three families (seven affected individuals), three novel COL11A1 variants were found. The propositus with a de novo variant showed an ultrarare Marshall/STL overlap. In the second family, the only common clinical sign was postlingual progressive sensorineural hearing impairment (DFNA37). Affected individuals from the third family had typical STL2 signs. The spectrum of disease phenotypes associated with COL2A1 or COL11A1 variants continues to expand and includes typical STL and various bone dysplasias, but also nonsyndromic hearing impairment, isolated myopia with or without retinal detachment, and STL phenotype without clinically detectable ocular pathology.

• Klíčová slova
• COL11A1, COL2A1, Marshall syndrome, Stickler syndrome, myopia, nonsyndromic hearing loss, retinal detachment,
• MeSH
• artritida genetika   MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• kojenec MeSH
• kolagen typ II genetika   MeSH
• kolagen typ XI genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutační analýza DNA MeSH
• nemoci pojiva genetika   MeSH
• odchlípení sítnice genetika   MeSH
• percepční nedoslýchavost genetika   MeSH
• předškolní dítě MeSH
• rodokmen MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• COL11A1 protein, human MeSH Prohlížeč
• COL2A1 protein, human MeSH Prohlížeč
• kolagen typ II MeSH
• kolagen typ XI MeSH

BACKGROUND: In cystic fibrosis newborn screening (CFNBS), immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) can be used as screening parameters. We evaluated the IRT×PAP product as second-tier parameter in CFNBS in newborns with elevated IRT. METHODS: Data on 410,111 screened newborns including 78 patients with classical cystic fibrosis (CF) from two European centers were retrospectively analyzed by discrimination analysis to identify a screening protocol with optimal cutoffs. We also studied differences in PAP measurement methods and the association of IRT and PAP with age. RESULTS: PAP values differed systematically between fluorometric and photometric assays. The IRT×PAP product showed better discrimination for classical CF than PAP only as second-tier screening parameter (p<0.001). In CF patients, IRT decreased while PAP values remained high over years. In newborns without CF, IRT decreased after birth over weeks while PAP increased within days. CONCLUSIONS: The IRT×PAP product performs well as second-tier cutoff parameter for CFNBS. Screening quality parameters depend on the analytic method and on age at blood collection.

• Klíčová slova
• Cutoff, Cystic fibrosis, Immunoreactive trypsinogen, Newborn screening, Pancreatitis-associated protein,
• MeSH
• chemické techniky analytické MeSH
• cystická fibróza * krev   diagnóza   MeSH
• lidé MeSH
• novorozenec MeSH
• novorozenecký screening metody   MeSH
• proteiny asociované s pankreatitidou analýza   MeSH
• retrospektivní studie MeSH
• senzitivita a specificita MeSH
• trypsinogen * analýza   imunologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• proteiny asociované s pankreatitidou MeSH
• trypsinogen * MeSH

BACKGROUND: In recent years different IRT/PAP protocols have been evaluated, but the individual performance remains unclear. To optimize the IRT/PAP strategy we compared protocols from three regional CF newborn screening centers (Heidelberg, Dresden, and Prague). METHODS: We evaluated the effect of elevating the IRT-cut-off from 50 to 65 μg/l (~97.5th to ~99.0th percentile), the need of a failsafe protocol (FS, IRT ≥ 99.9th percentile) and the relative performance using either two IRT-dependent PAP-cut-offs or one PAP-cut-off. FINDINGS: Elevation of the IRT cut-off to 65 μg/l (~99.0th percentile) increased the PPV significantly (Dresden: 0.065 vs. 0.080, p < 0.0001, Prague: 0.052 vs. 0.074, p < 0.0001) without reducing sensitivity. All three IRT/PAP protocols showed a trend towards a higher sensitivity with FS than without and when using one PAP-cut-off instead of two IRT-dependent PAP-cut-offs. CONCLUSIONS: For best performance we suggest an IRT/PAP protocol with an IRT-cut-off close to the 99.0th percentile, FS, and a single PAP-cut-off.

• Klíčová slova
• Biochemical screening, CF, CFNBS, Cystic fibrosis, DBS, FS, IRT, Immunoreactive trypsinogen, MI, NBS, Newborn screening, PAP, PI, PS, Pancreatitis associated protein, cystic fibrosis, cystic fibrosis newborn screening, dried blot spot, failsafe strategy, immunoreactive trypsinogen, meconium ileus, newborn screening, pancreatic insufficient, pancreatic sufficient, pancreatitis associated protein,
• MeSH
• antigeny nádorové analýza   krev   genetika   MeSH
• cystická fibróza krev   diagnóza   genetika   MeSH
• genetické testování metody   normy   MeSH
• klinická chemie metody   normy   MeSH
• lektiny typu C analýza   krev   genetika   MeSH
• lidé MeSH
• nádorové biomarkery analýza   krev   genetika   MeSH
• novorozenec MeSH
• novorozenecký screening metody   normy   MeSH
• prospektivní studie MeSH
• protein CFTR genetika   MeSH
• proteiny asociované s pankreatitidou MeSH
• retrospektivní studie MeSH
• senzitivita a specificita MeSH
• test suché kapky krve metody   normy   MeSH
• trypsinogen analýza   krev   genetika   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• antigeny nádorové MeSH
• CFTR protein, human MeSH Prohlížeč
• lektiny typu C MeSH
• nádorové biomarkery MeSH
• protein CFTR MeSH
• proteiny asociované s pankreatitidou MeSH
• REG3A protein, human MeSH Prohlížeč
• trypsinogen MeSH

BACKGROUND: This two decade long study presents a comprehensive overview of the CFTR mutation distribution in a representative cohort of 600 Czech CF patients derived from all regions of the Czech Republic. METHODS: We examined the most common CF-causing mutations using the Elucigene CF-EU2v1™ assay, followed by MLPA, mutation scanning and/or sequencing of the entire CFTR coding region and splice site junctions. RESULTS: We identified 99.5% of all mutations (1194/1200 CFTR alleles) in the Czech CF population. Altogether 91 different CFTR mutations, of which 20 were novel, were detected. One case of de novo mutation and a novel polymorphism was revealed. CONCLUSION: The commercial assay achieved 90.7%, the MLPA added 1.0% and sequencing increased the detection rate by 7.8%. These comprehensive data provide a basis for the improvement of CF DNA diagnostics and/or newborn screening in our country. In addition, they are relevant to related Central European populations with lower mutation detection rates, as well as to the sizeable North American "Bohemian diaspora".

• Klíčová slova
• AT, Austrian/Austria, CE, CF, CFTR, CZ, Central Europe, Cystic Fibrosis, Cystic fibrosis, Czech Republic, Czech Republic/Czech, DE, De novo CFTR mutation, German/Germany, HU, Hungarian/Hungary, MLPA, NBS, Newborn screening, PL, Polish/Poland, SK, Slovak/Slovakia, UK, USA, United Kingdom, United States of America, cystic fibrosis transmembrane conductance regulator gene, multiplex ligation-dependent probe amplification, newborn screening,
• MeSH
• alely MeSH
• dítě MeSH
• klinické laboratorní techniky MeSH
• lidé MeSH
• mutace MeSH
• předškolní dítě MeSH
• protein CFTR genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• protein CFTR MeSH