BACKGROUND: Glucocorticoids are commonly used in children with different chronic diseases. Growth failure represents a so far untreatable undesired side-effect. As lithium chloride (LiCl) is known to induce cell renewal in various tissues, we hypothesized that LiCl may prevent glucocorticoid-induced growth failure. METHODS: We monitored growth of fetal rat metatarsals cultured ex-vivo with dexamethasone and/or LiCl, while molecular mechanisms were explored through RNA sequencing by implementing the differential gene expression and gene set analysis. Quantification of β-catenin in human growth plate cartilage cultured with dexamethasone and/or LiCl was added for verification. RESULTS: After 14 days of culture, the length of dexamethasone-treated fetal rat metatarsals increased by 1.4 ± 0.2 mm compared to 2.4 ± 0.3 mm in control bones (p < 0.001). The combination of LiCl and dexamethasone led to bone length increase of 1.9 ± 0.3 mm (p < 0.001 vs. dexamethasone alone). By adding lithium, genes for cell cycle and Wnt/β-catenin, Hedgehog and Notch signaling, were upregulated compared to dexamethasone alone group. CONCLUSIONS: LiCl has the potential to partially rescue from dexamethasone-induced bone growth impairment in an ex vivo model. Transcriptomics identified cell renewal and proliferation as candidates for the underlying mechanisms. Our observations may open up the development of a new treatment strategy for bone growth disorders. IMPACT: LiCl is capable to prevent glucocorticoid-induced growth failure in rat metatarsals in vitro. The accompanying drug-induced transcriptomic changes suggested cell renewal and proliferation as candidate underlying mechanisms. Wnt/beta-catenin pathway could be one of those novel mechanisms.
- MeSH
- beta-katenin * metabolismus MeSH
- chlorid lithný * farmakologie MeSH
- dexamethason * farmakologie MeSH
- glukokortikoidy farmakologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- metatarzální kosti * účinky léků MeSH
- potkani Sprague-Dawley MeSH
- proliferace buněk účinky léků MeSH
- růstová ploténka účinky léků metabolismus MeSH
- signální dráha Wnt účinky léků MeSH
- vývoj kostí účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Genetic nephrotic syndrome is caused by pathogenic variants in genes encoding proteins necessary for the stability and functionality of the glomerular filtration barrier. To date, more than 70 genes associated with steroid-resistant nephrotic syndrome have been identified. We review the clinical and molecular aspects of genetic nephrotic syndrome with a particular focus on genes associated with slit membrane and podocyte cytoskeleton defects. Sanger sequencing and next-generation sequencing are widely used in the identification of novel gene variants and help us gain a better understanding of the disease. Despite these findings, therapy is mainly supportive and focused on the reduction of proteinuria and management of chronic kidney disease with an unfavorable outcome for a significant proportion of cases. Positive therapeutic effects of immunosuppressive drugs have been reported in some patients; however, their long-time administration cannot be generally recommended. CONCLUSION: Personalized treatment based on understanding the distinct disease pathogenesis is needed. With this, it will be possible to avoid harmful immunosuppressive therapy and improve outcomes and quality of life for pediatric patients suffering from genetic nephrotic syndrome.
- MeSH
- cytoskelet metabolismus patologie MeSH
- dítě MeSH
- glomerulus patologie MeSH
- kvalita života MeSH
- lidé MeSH
- nefrotický syndrom * etiologie MeSH
- nemoci ledvin * patologie MeSH
- podocyty * metabolismus MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy 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.
- 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
Approximately one third of children with steroid-resistant nephrotic syndrome (SRNS) carry pathogenic variants in one of the many associated genes. The WT1 gene coding for the WT1 transcription factor is among the most frequently affected genes. Cases from the Czech national SRNS database were sequenced for exons 8 and 9 of the WT1 gene. Eight distinct exonic WT1 variants in nine children were found. Three children presented with isolated SRNS, while the other six manifested with additional features. To analyze the impact of WT1 genetic variants, wild type and mutant WT1 proteins were prepared and the DNA-binding affinity of these proteins to the target EGR1 sequence was measured by microscale thermophoresis. Three WT1 mutants showed significantly decreased DNA-binding affinity (p.Arg439Pro, p.His450Arg and p.Arg463Ter), another three mutants showed significantly increased binding affinity (p.Gln447Pro, p.Asp469Asn and p.His474Arg), and the two remaining mutants (p.Cys433Tyr and p.Arg467Trp) showed no change of DNA-binding affinity. The protein products of WT1 pathogenic variants had variable DNA-binding affinity, and no clear correlation with the clinical symptoms of the patients. Further research is needed to clarify the mechanisms of action of the distinct WT1 mutants; this could potentially lead to individualized treatment of a so far unfavourable disease.
- MeSH
- dítě MeSH
- DNA terapeutické užití MeSH
- léková rezistence MeSH
- lidé MeSH
- mutace MeSH
- nefrotický syndrom * farmakoterapie genetika metabolismus MeSH
- proteiny WT1 * genetika metabolismus MeSH
- steroidy farmakologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Monogenic nephrotic syndrome (NS) is associated with a resistance to initial glucocorticoid therapy and causative variants, which may be found in several genes influencing podocyte stability and kidney development. The TTC21B gene, which encodes the retrograde intraflagellar transport protein IFT139, is found mostly in association with ciliopathies in humans. The role of this protein in podocyte cytoskeleton stability was confirmed later and the mutated TTC21B also may be associated with proteinuric diseases, such as nephrotic syndrome. Our patient manifested as an infant with brachydactyly, nephrotic-range proteinuria, and renal tubular acidosis, and a kidney biopsy revealed focal segmental glomerulosclerosis (FSGS). Multiple phalangeal cone-shaped epiphyses of the hand were seen on X-ray. Next-generation sequencing revealed the well-described p.Pro209Leu heterozygous variant and a novel heterozygous p.Cys14Arg variant in the TTC21B gene. Our finding confirmed that the causative variants in the TTC21B gene may contribute to a spectrum of clinical features, such as glomerular proteinuric disease with tubulointerstitial involvement and skeletal abnormalities.
- Publikační typ
- kazuistiky MeSH
BACKGROUND: Familial non-autoimmune hyperthyroidism is a rare disease caused by germline activating variants in the thyroid-stimulating hormone receptor (TSHR) gene. The c.1856A > G (p.Asp619Gly) pathogenic variant has been described in cases of toxic adenoma but never before, to our knowledge, in a case of familial non-autoimmune hyperthyroidism. PATIENT FINDINGS: A 3-year-old boy was admitted for acute gastroenteritis presenting with goiter and tall stature. Laboratory findings revealed peripheral hyperthyroidism and negativity for thyroid autoantibodies. Antithyroid drug treatment was effective, but relapses occurred shortly after attempts to decrease the drug dose. As the boy's father and paternal grandmother also experienced relapsing hyperthyroidism manifesting in early childhood, genetic testing of TSHR was indicated. The c.1856A > G (p.Asp619Gly) pathogenic variant was found in all three affected family members. Functional in vitro characterization of the variant verified that it enhances constitutional activation of the receptor, leading to increased production of cyclic adenosine monophosphate. Total thyroidectomy was indicated in the boy due to an unsatisfactory prognosis. Due to persistent positive thyroglobulin serum concentration, a diagnostic radioiodine scan was performed approximately 2 years later. Residual thyroid tissue was revealed; therefore, radioiodine ablative therapy was performed. Despite adequate thyroxine substitution over a long period of follow-up, TSH remained suppressed. CONCLUSIONS: Unlike Graves' disease, familial non-autoimmune hyperthyroidism cases present with antithyroid drug-dependence. Not ultrasound but positive thyroglobulin serum concentration indicated residual thyroid tissue. Early detection of residual thyroid tissue and radioiodine ablation prevented the subject from experiencing relapsing hyperthyroidism and undergoing unnecessary repeated surgery. Life-long hormone substitution should be adjusted to free thyroxine rather than TSH serum concentrations.
- MeSH
- Gravesova nemoc * MeSH
- hypertyreóza * genetika MeSH
- lidé MeSH
- lokální recidiva nádoru MeSH
- předškolní dítě MeSH
- radioizotopy jodu MeSH
- receptory thyreotropinu genetika metabolismus MeSH
- thyreoglobulin chemie MeSH
- thyreostatika farmakologie MeSH
- thyreotropin chemie MeSH
- thyroxin metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- přehledy MeSH
- Klíčová slova
- Denysův-Drashův syndrom,
- MeSH
- hypertenze diagnóza genetika terapie MeSH
- lidé MeSH
- novorozenec MeSH
- poruchy sexuálního vývoje s karyotypem 46, XY diagnóza genetika MeSH
- příčina smrti MeSH
- renální insuficience MeSH
- vrozené, dědičné a novorozenecké nemoci a abnormality MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- kazuistiky MeSH
Dent disease is an X-linked recessive renal tubular disorder characterized by proximal tubule dysfunction. Typical features include low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets, and chronic renal failure. We present a case of a 6-year-old boy with nephrotic proteinuria without hypoalbuminemia or edema. His renal biopsy revealed focal segmental glomerulosclerosis (FSGS), some of the glomeruli were globally sclerotic. Hypercalciuria was present intermittently and urine protein electrophoresis showed low molecular weight protein fraction of 50%. The next generation sequencing identified pathogenic variant in OCRL gene causing Dent disease type 2. We report an uncommon histologic finding of FSGS in Dent disease type 2 and highlight the importance of protein content examination and genetic analysis for the proper diagnosis in these complicated cases.
- Publikační typ
- kazuistiky MeSH
- MeSH
- biologické markery metabolismus MeSH
- kojenec MeSH
- lidé MeSH
- nefrotický syndrom farmakoterapie genetika MeSH
- ubichinon analogy a deriváty metabolismus terapeutické užití MeSH
- vitaminy terapeutické užití MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- kazuistiky MeSH
