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The emergence of the BTK inhibitor ibrutinib and PI3K inhibitor idelalisib represented a revolution in the therapy of B cell malignancies. In some of these malignancies, they became the primary therapeutic strategy. However „BCR inhibitors" function by a more complex mechanism than anticipated. The evolution of point mutations, chromosomal aberrations and changes in the physiology of malignant B cells leads to resistance in some patients treated with „BCR inhibitors". The most commonly described aberration is the mutation in PLCγ bypassing BCR signalosome or the mutation in BTK preventing the covalent binding of ibrutinib. However, additional mutations leading to resistance are still being described. Furthermore, relative resistance to „BCR inhibitors" can be caused by non-genetic adaptive mechanisms leading to activation of alternative pathways and „compensation" of kinase inhibition. For instance, PI3K-Akt and NFκB activation or BCL2 upregulation lead to B cell survival even after BTK inhibition. This suggests some potentially effective therapeutic combinations of BTK/PI3K inhibitors together with other targeted inhibitors for clinical trials. Alternatively, drugs mimicking the BTK/PI3K inhibition effect can be used to prevent adhesion and migration of malignant B cells (chemokine and integrin pathway inhibition) or to block the pro-proliferative signals from the microenvironment such as IL4 (STAT inhibitors). [ABSTRACT FROM AUTHOR]

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We performed the genetic analysis of Rasopathy syndromes in patients from Central European by direct sequencing followed by next generation sequencing of genes associated with Rasopathies. All 51 patients harboured the typical features of Rasopathy syndromes. Thirty-five mutations were identified in the examined patients (22 in PTPN11, two in SOS1, one in RIT1, one in SHOC2, two in HRAS, three in BRAF, two in MAP2K1 and two in the NF1 gene). Two of them (p.Gly392Glu in the BRAF gene and p.Gln164Lys in the MAP2K1 gene) were novel with a potentially pathogenic effect on the structure of these proteins. Statistically significant differences in the presence of pulmonary stenosis (63.64% vs. 23.81%, P = 0.013897) and cryptorchidism (76.47% vs. 30%, P = 0.040224) were identified as the result of comparison of the prevalence of phenotypic features in patients with the phenotype of Noonan syndrome and mutation in the PTPN11 gene, with the prevalence of the same features in patients without PTPN11 mutation. Cryptorchidism as a statistically significant feature in our patients with PTPN11 mutation was not reported as significant in other European countries (Germany, Italy and Greece). The majority of mutations were clustered in exons 3 (45.45%), 8 (22.73%), and 13 (22.73%) of the PTPN11 gene. [ABSTRACT FROM AUTHOR]

Introduction: Rickets is a failure of enchondral mineralisation of new formed bone in a growing persons. There are three groups of causes of rickets - the failure of bone mineralisation, disorders of phosphate homeostasis, and disorders related to vitamin D. The Vitamin D aquires its biological activity after the activation in two steps. The microsomal 25-hydroxylase provides course of first step in liver. The deficiency of this enzyme causes vitamin D dependent rickets type 1B with low serum level of 25-hydroxyvitamin D and with normal serum level of 1,25(OH)2D. The rate-limiting step of biological activation of vitamin D is the reaction catalysed by the mitochondrial 1a-hydroxylase in kidney. Mutations of CYP27B1 (gene for 1a-hydroxylase) causing deficiency of 1a-hydroxylase enzymatic activity lead to decreased serum level of biological active form of vitamin D (with normal serum level of recirculated form of the vitamin D - 25OHvitD) and cause the vitamin D dependent rickets type 1A. The defect of nuclear receptor for vitamin D (VDR) or the defect of another member of nuclear hormonal receptors family (retinoid X receptor) forming heterodimer with VDR cause the vitamin D dependent rickets type 2. This type is associated with increased level of serum 1,25(OH)2D. Case report: We present the case of a 2 yrs old girl with the diagnosis of vitamin D dependent rickets type 1A. She had typical clinical features (dental problems, caput quadratum, rachitic rosary, widening of wrist, bowed legs, bone pain, muscle weakness, retardation of growth), and the following laboratory findings: hypocalcemia, hypophosphatemia, elevation of serum alkaline phosphatese and parathyroid hormone. Radiografic findings showed skeletal deformities, cupping and fraying of metaphyseal region. Material and metods: The DNA was isolated from periferal blood leukocytes and all exons of CYP27B1 gene were analysed by DNA sequencing. Results: The mutation c.1166G>A (p.Arg389His) was detected in homozygous state in our patient. Conclusion: The molecular analysis of rickets helps to determine the precise type of the vitamin D dependent rickets and to start the treatment in childhood early. [ABSTRACT FROM AUTHOR]

Introduction: Thyroid cancer in children is a hot topic because of the large clinical heterogeneity and the risk of severe complications. We aimed to study 1. The frequency, 2. Etiology, and 3. Risk factors of post-surgery complications of thyroid cancer., Material and Methods: A retrospective analysis including risk factors for post-surgery complications of patients treated for thyroid malignancies in years 2006-2018 was performed., Results: Over a period of 12 years 22 patients with thyroid malignancy (68% female; 12.6 ± 4.0 years of age, median follow-up 6 years) were identified. Histologically, 12 (55%) patients had papillary carcinoma. Six patients (27.3%) had multiple endocrine neoplasia type 2 (MEN2) syndrome, 3 (13.7%) patients had medullary carcinoma and 1 patient had follicular carcinoma. Neck lymph node metastases were diagnosed in 8 (36.4%), distant metastases in 6 (27.3%), and both locations were involved in 4 (18.2%) patients. Six (27.3%) children had surgical complications: 1 child had unilateral vocal cord paralysis and transient hypoparathyroidism and 5 had transient hypoparathyroidism. The higher risk of surgery complications in forward stepwise logistic regression was associated in with distant metastases (R2 = 0.584, OR 52.63, p = 0.010)., Conclusions: Postoperative complications were significantly associated with presence of distant metastases. Favorable results were observed in with children with MEN2 syndrome., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Unlabelled: Familial neurohypophyseal diabetes insipidus (FNDI) is a rare hereditary disorder with unknown prevalence characterized by arginine-vasopressin hormone (AVP) deficiency resulting in polyuria and polydipsia from early childhood. We report the clinical manifestation and genetic test results in seven unrelated kindreds of Czech or Slovak origin with FNDI phenotype. The age of the sign outset ranged from 2 to 17 years with remarkable interfamilial and intrafamilial variability. Inconclusive result of the fluid deprivation test in three children aged 7 and 17 years old might cause misdiagnosis; however, the AVP gene analysis confirmed the FNDI. The seven families segregated together five different mutations, two of them were novel (c.164C > A, c.298G > C). In addition, DNA analysis proved mutation carrier status in one asymptomatic 1-year-old infant., Conclusions: The present study together with previously published data identified 38 individuals with FNDI in the studied population of 16 million which predicts a disease prevalence of 1:450,000 for the Central European region. The paper underscores that diagnostic water deprivation test may be inconclusive in polyuric children with partial diabetes insipidus and points to the clinical importance and feasibility of molecular genetic testing for AVP gene mutations in the proband and her/his first degree relatives., What Is Known: • At least 70 different mutations were reported to date in about 100 families with neurohypophyseal diabetes insipidus (FNDI), and new mutations appear sporadically. What is New: • Two novel mutations of the AVP gene are reported • The importance of molecular testing in children with polyuria and inconclusive water deprivation test is emphasized.

Melanocortin-4 receptor (MC4R) deficiency is the most frequent monogenic form of obesity. The contribution of MC4R mutations to the Slovak population has not been investigated as yet. We screened the coding sequence of the MC4R gene in a cohort of 210 Slovak obese children and adolescents. We identified four different mutations in four patients, giving a mutation detection rate of 0.95%. Of these, three were missense mutations previously identified and characterized by other research groups (p.R7C, p.S127L and p. R305W, respectively). One was a novel nonsense mutation p.W174* detected in a severely obese 7-year-old boy. This mutation was further analyzed in family segregation analysis and exhibited variable penetrance. Two known amino acid polymorphisms (p.V103I and p.I251L) were also identified in seven subjects of our cohort group. We also performed multifactorial statistical analysis to determine the influence of genotypes on standard biochemical blood markers. No significant influence was observed in carriers of DNA variants on tested parameters. We conclude that rare heterozygous MC4R mutations contribute to the onset of obesity only in a few cases in the Slovak population.