In the last decade, undiagnosed disease programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases. In our single-center study, we have launched a pilot program for pediatric patients with undiagnosed diseases in the second-largest university hospital in the Czech Republic. This study was prospectively conducted at the Department of Pediatrics at University Hospital Brno between 2020 and 2023. A total of 58 Czech patients with undiagnosed diseases were enrolled in the study. All children underwent singleton WES with targeted phenotype-driven analysis. We identified 28 variants, including 11 pathogenic, 13 likely pathogenic, and 4 VUS according to ACMG guidelines, as diagnostic of genetic diseases in 25 patients, resulting in an overall diagnostic yield of 43%. Eleven variants were novel and had not been previously reported in any public database. The overall clinical utility (actionability) enabling at least one type of change in the medical care of the patient was 76%, whereas the average number of clinical implications to individual patient care was two. Singleton WES facilitated the diagnostic process in the Czech undiagnosed pediatric population. We believe it is an effective approach to enable appropriate counseling, surveillance, and personalized clinical management.

• Klíčová slova
• Rare genetic diseases, Undiagnosed patients, Whole-exome sequencing,
• MeSH
• dítě MeSH
• genetické testování metody   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• nediagnostikované nemoci * genetika   diagnóza   epidemiologie   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• sekvenování exomu * metody   MeSH
• vzácné nemoci * genetika   diagnóza   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

INTRODUCTION: Sepsis is one of the most common causes of death in patients admitted to intensive care units (ICUs). The development of sepsis is significantly influenced by genetic predisposition. In this study, we highlight a potential association between a variant of the fat mass and obesity-associated (FTO) gene and risk of sepsis in children and adolescents. METHODS: We investigated a first-intron tagging FTO polymorphism (rs17817449) by comparing a severe condition (SC) group, comprising 598 paediatric patients (ages 0-19 years) admitted to an ICU with fever, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, or multiple organ dysfunction syndrome (MODS), with a control group consisting of 616 healthy young adults. RESULTS: We observed a lower prevalence (p < 0.01; OR = 0.59, 95% CI = 0.39-0.87) of the FTO TT genotype in febrile and SIRS patients compared to patients with severe illness. There was a borderline trend towards a lower prevalence of the FTO TT genotype in the control group compared to the SC group (p < 0.09, OR = 0.81, 95% CI = 0.62-1.06). CONCLUSIONS: Our findings suggest that rs17817449, a common FTO polymorphism, may be a predictor of sepsis in paediatric patients, and that higher body weight is protective against this clinical complication.

• Klíčová slova
• child, genetic predisposition to the disease, genotype, obesity, sepsis,
• MeSH
• dítě MeSH
• gen pro FTO * genetika   MeSH
• genetická predispozice k nemoci MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• multiorgánové selhání genetika   MeSH
• novorozenec MeSH
• polymorfismus genetický MeSH
• předškolní dítě MeSH
• sepse * genetika   MeSH
• studie případů a kontrol MeSH
• syndrom systémové zánětlivé reakce genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• FTO protein, human MeSH Prohlížeč
• gen pro FTO * MeSH

Our goal was to identify highly accurate empirical models for the prediction of the risk of febrile seizure (FS) and FS recurrence. In a prospective, three-arm, case-control study, we enrolled 162 children (age 25.8 ± 17.1 months old, 71 females). Participants formed one case group (patients with FS) and two control groups (febrile patients without seizures and healthy controls). The impact of blood iron status, peak body temperature, and participants' demographics on FS risk and recurrence was investigated with univariate and multivariate statistics. Serum iron concentration, iron saturation, and unsaturated iron-binding capacity differed between the three investigated groups (pFWE < 0.05). These serum analytes were key variables in the design of novel multivariate linear mixture models. The models classified FS risk with higher accuracy than univariate approaches. The designed bi-linear classifier achieved a sensitivity/specificity of 82%/89% and was closest to the gold-standard classifier. A multivariate model assessing FS recurrence provided a difference (pFWE < 0.05) with a separating sensitivity/specificity of 72%/69%. Iron deficiency, height percentile, and age were significant FS risk factors. In addition, height percentile and hemoglobin concentration were linked to FS recurrence. Novel multivariate models utilizing blood iron status and demographic variables predicted FS risk and recurrence among infants and young children with fever.

• MeSH
• deficit železa * MeSH
• febrilní křeče * diagnóza   etiologie   MeSH
• horečka komplikace   MeSH
• kojenec MeSH
• lidé MeSH
• předškolní dítě MeSH
• studie případů a kontrol MeSH
• železo MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• železo MeSH

BACKGROUND: Cardiac-urogenital syndrome [MIM # 618280] is a newly described very rare syndrome associated with pathogenic variants in the myelin regulatory factor (MYRF) gene that leads to loss of protein function. MYRF is a transcription factor previously associated only with the control of myelin-related gene expression. However, it is also highly expressed in other tissues and associated with various organ anomalies. The clinical picture is primarily dominated by complex congenital cardiac developmental defects, pulmonary hypoplasia, congenital diaphragmatic hernia, and urogenital malformations. CASE PRESENTATION: We present case reports of two siblings of unrelated parents in whom whole-exome sequencing was indicated due to familial occurrence of extensive developmental defects. A new, previously undescribed splicing pathogenic variant c.1388+2T>G in the MYRF gene has been identified in both patients. Both parents are unaffected, tested negative, and have another healthy daughter. The identical de novo event in siblings suggests gonadal mosaicism, which can mimic recessive inheritance. CONCLUSIONS: To our knowledge, this is the first published case of familial cardiac-urogenital syndrome indicating gonadal mosaicism.

• Klíčová slova
• MYRF gene, Scimitar syndrome, cardiac-urogenital syndrome, familiar occurrence, whole-exome sequencing,
• MeSH
• lidé MeSH
• mozaicismus * MeSH
• sekvenování exomu MeSH
• sourozenci * MeSH
• syndrom MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Myrf protein, human MeSH Prohlížeč
• transkripční faktory MeSH

Paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS) is a new disease in children and adolescents that occurs after often asymptomatic or mild COVID-19. It can be manifested by different clinical symptomatology and varying severity of disease based on multisystemic inflammation. The aim of this retrospective cohort trial was to describe the initial clinical presentation, diagnostics, therapy and clinical outcome of paediatric patients with a diagnosis of PIMS-TS admitted to one of the 3 PICUs. All paediatric patients who were admitted to the hospital with a diagnosis of paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) during the study period were enrolled in the study. A total of 180 patients were analysed. The most common symptoms upon admission were fever (81.6%, n = 147), rash (70.6%, n = 127), conjunctivitis (68.9%, n = 124) and abdominal pain (51.1%, n = 92). Acute respiratory failure occurred in 21.1% of patients (n = 38). Vasopressor support was used in 20.6% (n = 37) of cases. Overall, 96.7% of patients (n = 174) initially tested positive for SARS-CoV-2 IgG antibodies. Almost all patients received antibiotics during in-hospital stays. No patient died during the hospital stay or after 28 days of follow-up. Initial clinical presentation and organ system involvement of PIMS-TS including laboratory manifestations and treatment were identified in this trial. Early identification of PIMS-TS manifestation is essential for early treatment and proper management of patients.

• Klíčová slova
• COVID-19, PIMS-TS, SARS-CoV-2, paediatric patient, post-COVID syndrome,
• Publikační typ
• časopisecké články MeSH

The worldwide outbreak of the novel 2019 coronavirus disease (COVID-19) has led to recognition of a new immunopathological condition: paediatric inflammatory multisystem syndrome (PIMS-TS). The Czech Republic (CZ) suffered from one of the highest incidences of individuals who tested positive during pandemic waves. The aim of this study was to analyse epidemiological, clinical, and laboratory characteristics of all cases of paediatric inflammatory multisystem syndrome (PIMS-TS) in the Czech Republic (CZ) and their predictors of severe course. We performed a retrospective-prospective nationwide observational study based on patients hospitalised with PIMS-TS in CZ between 1 November 2020 and 31 May 2021. The anonymised data of patients were abstracted from medical record review. Using the inclusion criteria according to World Health Organization definition, 207 patients with PIMS-TS were enrolled in this study. The incidence of PIMS-TS out of all SARS-CoV-2-positive children was 0.9:1,000. The estimated delay between the occurrence of PIMS-TS and the COVID-19 pandemic wave was 3 weeks. The significant initial predictors of myocardial dysfunction included mainly cardiovascular signs (hypotension, oedema, oliguria/anuria, and prolonged capillary refill). During follow-up, most patients (98.8%) had normal cardiac function, with no residual findings. No fatal cases were reported.Conclusions: A 3-week interval in combination with incidence of COVID-19 could help increase pre-test probability of PIMS-TS during pandemic waves in the suspected cases. Although the parameters of the models do not allow one to completely divide patients into high and low risk groups, knowing the most important predictors surely could help clinical management.

• Klíčová slova
• COVID-19, Incidence, MIS-C, Myocardial dysfunction, Predictors, Severe outcome,
• MeSH
• COVID-19 * komplikace   diagnóza   epidemiologie   MeSH
• dítě MeSH
• lidé MeSH
• pandemie MeSH
• prospektivní studie MeSH
• retrospektivní studie MeSH
• SARS-CoV-2 * MeSH
• syndrom systémové zánětlivé reakce MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH

BACKGROUND: Primary hypomagnesemia with secondary hypocalcemia (HSH) is a rare genetic disorder. Dysfunctional transient receptor potential melastatin 6 causes impaired intestinal absorption of magnesium, leading to low serum levels accompanied by hypocalcemia. Typical signs at initial manifestation are generalized seizures, tetany, and/or muscle spasms. CASE REPORT: We present a 5 w/o female manifesting tonic-clonic seizures. Laboratory tests detected severe hypomagnesemia and hypocalcemia. The molecular genetic analysis revealed two novel mutations within the TRPM6 gene c.3308dupC (p.Pro1104Thrfs*28) (p.P1104Tfs*28) and c.3958C>T (p.Gln1302*) (p.Q1302*) and the patient was successfully treated with Mg supplementation. CONCLUSION: Ion disbalance should be taken into account in the differential diagnosis of infantile seizures. Accurate diagnosis of HSH together with appropriate treatment are crucial to prevent irreversible neurological outcomes.

• Klíčová slova
• hypocalcemia, hypomagnesemia, infantile seizures, transient receptor potential melastatin 6,
• MeSH
• hořčík MeSH
• hyperkalciurie MeSH
• hypokalcemie * genetika   MeSH
• kationtové kanály TRPM * genetika   MeSH
• lidé MeSH
• mutace MeSH
• nedostatek hořčíku * vrozené   genetika   MeSH
• nefrokalcinóza MeSH
• vrozené poruchy tubulárního transportu MeSH
• záchvaty genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• hořčík MeSH
• kationtové kanály TRPM * MeSH
• TRPM6 protein, human MeSH Prohlížeč

Spindle cell hemangioma is a benign vascular tumor typically occurring in the dermis or subcutis of distal extremities as red-brown lesions that can grow in both size and number over time. They can be very painful and potentially disabling. A family history of cancer or previous history may be relevant and must be taken into consideration. Juxtaglomerular cell tumor (reninoma) is an extremely rare cause of secondary hypertension diagnosed mostly among adolescents and young adults. Excessive renin secretion results in secondary hyperaldosteronism. Subsequent hypokalemia and metabolic alkalosis, together with high blood pressure, are clues for clinical diagnosis. Histological examination of the excised tumor leads to a definitive diagnosis. Reninoma is found in subcapsular localization, in most cases as a solitary mass, in imaging studies of kidneys. Exceptionally, it can be located in another part of a kidney. Both spindle cell hemangioma and reninoma are extremely rare tumors in children and adolescents. Herein, the authors present a case report of a patient with hereditary BRCA1 interacting protein C-terminal helicase 1 (BRIP1) mutation, spindle cell hemangioma, and secondary hypertension caused by atypically localized reninoma.

• Klíčová slova
• children, hypertension, juxtaglomerular cell tumor, kidney, reninoma, spindle cell hemangioendothelioma,
• MeSH
• genetická predispozice k nemoci * MeSH
• hemangiom diagnóza   genetika   patologie   MeSH
• juxtaglomerulární aparát patologie   MeSH
• ledviny metabolismus   patologie   MeSH
• lidé MeSH
• proteiny FANC genetika   MeSH
• RNA-helikasy genetika   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BRIP1 protein, human MeSH Prohlížeč
• proteiny FANC MeSH
• RNA-helikasy MeSH

Congenital disorders of glycosylation (CDG) are a rapidly growing family of genetic diseases with the phosphomannomutase 2 (PMM2)-CDG being the most common form of CDG. Most of these monogenic diseases are autosomal recessive and have multi-systemic manifestations, mainly psychomotor retardation, facial dysmorphisms, characteristic distribution of the fat pads, and variable coagulation abnormalities. The association of fetal hydrops with CDG has been reported, and pericardial effusion was also rarely observed in patients with PMM2-CDG. Here we describe an infant boy with PMM2-CDG. The diagnosis was suspected based on inverted nipples, fat pads, and combined coagulopathy. However, the primary symptom was progressive pericardial effusion leading to patient death at the age of 3 months. Screening for CDG performed by the use of isoelectric focusing of serum transferrin showed a typical PMM2-CDG pattern. Exome sequencing revealed one common pathogenic variant (c.691G > A/p.Val231Met) and one novel variant (c.447 + 3dupA) in the PMM2 gene. Both PMM2 variants were further confirmed by Sanger sequencing in both the proband and the parents' DNA. The novel variant was predicted to result in loss of donor splice site, and the analysis at mRNA level confirmed that it leads to exon five skipping (r.348_447del) and causes premature termination of translation to the protein (p.G117Kfs∗4), therefore is classified as likely pathogenic. Although there is no curative therapy for the PMM2-CDG at the moment, the other supportive care options are available to be offered. The definite diagnosis of PMM2-CDG can also assist in the process of genetic counseling, family planning, and preimplantation genetic diagnosis.

• Klíčová slova
• PMM2-CDG, novel splicing variant, pericardial effusion, phosphomannomutase 2, whole exome sequencing,
• Publikační typ
• časopisecké články MeSH

Respiratory distress syndrome caused by a secondary surfactant deficiency is one of the most common diagnoses requiring admission to the Neonatal Intensive Care Unit. We illustrate the case of a term female newborn without prenatal and peripartal risks. There had been significant signs of respiratory distress 4 h after delivery. The condition gradually worsened to the point of needing oscillatory ventilation. The most common infectious and non-infectious causes were excluded. Considering the course of illness, a congenital surfactant deficiency was suspected. There nevertheless was no significant improvement after administration of surfactant. Following a short period of palliative care, the child died at 34 days of age due to respiratory failure. DNA diagnostics revealed compound heterozygosity of ABCA3 functional mutations leading to the p.Pro147Leu and p.Pro246Leu exchanges. The second identified mutation of ABCA3 c.737C>T had not to date been described in connection with primary surfactant deficiency.

• Klíčová slova
• ABCA3, children, respiratory distress syndrome, respiratory failure, surfactant,
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH