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2.
BMJ Case Rep ; 17(3)2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38453218

RESUMO

A late adolescent primigravida was found to have a fetus with a cystic hygroma and significant shortening of the limbs on first-trimester ultrasound. She underwent chorionic villus sampling with normal microarray result. In the early second trimester, the fetus was found to have the absence of all four limbs and a thorough skeletal dysplasia workup was pursued, identifying a variant in the FLNB gene (c.62C>G). The patient underwent termination of pregnancy. The care of this patient was expedited by first-trimester sonographic evidence of limb abnormalities enabling timely clinical management.


Assuntos
Doenças Fetais , Linfangioma Cístico , Osteocondrodisplasias , Gravidez , Feminino , Adolescente , Humanos , Doenças Fetais/genética , Primeiro Trimestre da Gravidez , Ultrassonografia , Mutação , Ultrassonografia Pré-Natal , Filaminas/genética
3.
Hum Genomics ; 18(1): 23, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38448978

RESUMO

BACKGROUND/OBJECTIVES: Rare genetic disorders causing specific congenital developmental abnormalities often manifest in single families. Investigation of disease-causing molecular features are most times lacking, although these investigations may open novel therapeutic options for patients. In this study, we aimed to identify the genetic cause in an Iranian patient with severe skeletal dysplasia and to model its molecular function in zebrafish embryos. RESULTS: The proband displays short stature and multiple skeletal abnormalities, including mesomelic dysplasia of the arms with complete humero-radio-ulna synostosis, arched clavicles, pelvic dysplasia, short and thin fibulae, proportionally short vertebrae, hyperlordosis and mild kyphosis. Exome sequencing of the patient revealed a novel homozygous c.374G > T, p.(Arg125Leu) missense variant in MSGN1 (NM_001105569). MSGN1, a basic-Helix-Loop-Helix transcription factor, plays a crucial role in formation of presomitic mesoderm progenitor cells/mesodermal stem cells during early developmental processes in vertebrates. Initial in vitro experiments show protein stability and correct intracellular localization of the novel variant in the nucleus and imply retained transcription factor function. To test the pathogenicity of the detected variant, we overexpressed wild-type and mutant msgn1 mRNA in zebrafish embryos and analyzed tbxta (T/brachyury/ntl). Overexpression of wild-type or mutant msgn1 mRNA significantly reduces tbxta expression in the tailbud compared to control embryos. Mutant msgn1 mRNA injected embryos depict a more severe effect, implying a gain-of-function mechanism. In vivo analysis on embryonic development was performed by clonal msgn1 overexpression in zebrafish embryos further demonstrated altered cell compartments in the presomitic mesoderm, notochord and pectoral fin buds. Detection of ectopic tbx6 and bmp2 expression in these embryos hint to affected downstream signals due to Msgn1 gain-of-function. CONCLUSION: In contrast to loss-of-function effects described in animal knockdown models, gain-of-function of MSGN1 explains the only mildly affected axial skeleton of the proband and rather normal vertebrae. In this context we observed notochord bending and potentially disruption of pectoral fin buds/upper extremity after overexpression of msgn1 in zebrafish embryos. The latter might result from Msgn1 function on mesenchymal stem cells or on chondrogenesis in these regions. In addition, we detected ectopic tbx6 and bmp2a expression after gain of Msgn1 function in zebrafish, which are interconnected to short stature, congenital scoliosis, limb shortening and prominent skeletal malformations in patients. Our findings highlight a rare, so far undescribed skeletal dysplasia syndrome associated with a gain-of-function mutation in MSGN1 and hint to its molecular downstream effectors.


Assuntos
Anormalidades Múltiplas , Nanismo , Osteocondrodisplasias , Animais , Feminino , Humanos , Gravidez , Mutação com Ganho de Função , Irã (Geográfico) , RNA Mensageiro , Proteínas com Domínio T/genética , Fatores de Transcrição , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
4.
Iran J Allergy Asthma Immunol ; 23(1): 115-121, 2024 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-38485906

RESUMO

Sanjad Sakati Syndrome (SSS) is categorized as a neuroendocrine-related disease due to disorders of the nervous and hormonal systems. Since hormonal changes in these patients may affect the nature and function of the immune system. Thus, in this study, cell count and phagocytotic function of neutrophils were evaluated which may be influenced by changes in the hormonal rate and growth factors. In this study, the neutrophil count value and the oxidative burst were evaluated in six patients diagnosed with SSS and six healthy individuals. There was a significant reduction in the neutrophil count observed in SSS patients compared to healthy controls (37.41±7.93 percent vs. 66.5±6.8 percent). However, there was no significant difference in neutrophil oxidative index between patients with SSS and control subjects (172.33±55.08 vs. 217.00±77.38). We concluded that in patients with SSS, the phagocytic activity of neutrophils was not affected by hormonal changes, while the number of neutrophils and neutrophil-to-lymphocyte ratio (NLR) index were decreased.


Assuntos
Anormalidades Múltiplas , Acrocefalossindactilia , Transtornos do Crescimento , Hipoparatireoidismo , Deficiência Intelectual , Neutrófilos , Osteocondrodisplasias , Convulsões , Humanos , Neutrófilos/fisiologia , Explosão Respiratória , Deficiência Intelectual/diagnóstico , Contagem de Leucócitos , Contagem de Linfócitos
5.
Eur J Med Genet ; 68: 104930, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428804

RESUMO

Achondroplasia (ACH), the most common form of skeletal dysplasia, is characterized by severe disproportionate short stature, rhizomelia, exaggerated lumbar lordosis, brachydactyly, macrocephaly with frontal bossing and midface hypoplasia. Ligamentous laxity has been reported as a striking feature of ACH, but its prevalence and characteristics have not been systematically evaluated yet. There is growing evidence that ligamentous laxity can be associated with chronic musculoskeletal problems and may affect motor development leading to abnormal developmental trajectories. This study aimed to assess the prevalence of ligamentous laxity in children with ACH through standardized tools, the Beighton scale and its modified version for preschool-age children. A total of 33 children (mean age 6.4 ± 3.2 years; age range 1-12.5 years) diagnosed with ACH by the demonstration of a pathogenic variant in the FGFR3 gene and 33 age- and sex-matched healthy controls were included in the study. Both ligamentous laxity assessment and neurological examinations were performed; medical history was also collected from caregivers. Children with ACH showed a 2 times higher risk of ligamentous laxity than the group without skeletal dysplasia (OR = 2.2; 95% CI = 1.0 to 4.7), with 55% of children meeting the diagnostic criteria for hypermobility. No significant difference in ligamentous laxity was observed between males and females. Joint involvement analysis revealed characteristic patterns, with knee hypermobility observed in 67% of patients, while rare was elbow hypermobility. Longitudinal assessments indicated a decreasing trend in ligamentous laxity scores over time, suggesting a potential decrease in hypermobility issues during adulthood. The findings of this study provide valuable insights into the prevalence and characteristics of ligamentous laxity in ACH. Implementation of standardized ligamentous laxity assessments might guide patients' follow-up and facilitate early interventions, helping to prevent pain and improve outcomes and quality of life for such patients. Further prospective studies are needed to explore the natural history of ligamentous laxity in ACH and investigate the potential impact of emerging pharmacological treatments upon hypermobility.


Assuntos
Acondroplasia , Instabilidade Articular , Osteocondrodisplasias , Masculino , Criança , Pré-Escolar , Feminino , Humanos , Adulto , Lactente , Prevalência , Qualidade de Vida , Instabilidade Articular/epidemiologia , Acondroplasia/epidemiologia , Acondroplasia/genética , Estudos Prospectivos
7.
Org Lett ; 26(8): 1612-1617, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38377309

RESUMO

The biosynthetic gene cluster responsible for the production of C2-asymmetric 16-membered dilactones, including pyrenophorol and its derivatives, was discovered through genome mining of polyketides from a sponge-derived fungus. The biosynthetic pathway of the pyrenophorol dilactones was subsequently elucidated. A distinctive flavoenzyme PylE was identified to catalyze the isomerization of the 4-alcohol-2,3-unsaturated moiety within the dilactone scaffold, resulting in the formation of a 1,4-diketone. Further insights into the catalytic mechanism of PylE were obtained through mutagenesis experiments combined with molecular docking.


Assuntos
Compostos Heterocíclicos , Isomerismo , Cetonas , Osteocondrodisplasias , Simulação de Acoplamento Molecular , Catálise
8.
Genes (Basel) ; 15(2)2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38397214

RESUMO

Skeletal dysplasia, also called osteochondrodysplasia, is a category of disorders affecting bone development and children's growth. Up to 552 genes, including fibroblast growth factor receptor 3 (FGFR3), have been implicated by pathogenic variations in its genesis. Frequently identified causal mutations in osteochondrodysplasia arise in the coding sequences of the FGFR3 gene: c.1138G>A and c.1138G>C in achondroplasia and c.1620C>A and c.1620C>G in hypochondroplasia. However, in some cases, the diagnostic investigations undertaken thus far have failed to identify the causal anomaly, which strengthens the relevance of the diagnostic strategies being further refined. We observed a Caucasian adult with clinical and radiographic features of achondroplasia, with no common pathogenic variant. Exome sequencing detected an FGFR3(NM_000142.4):c.1075+95C>G heterozygous intronic variation. In vitro studies showed that this variant results in the aberrant exonization of a 90-nucleotide 5' segment of intron 8, resulting in the substitution of the alanine (Ala359) for a glycine (Gly) and the in-frame insertion of 30 amino acids. This change may alter FGFR3's function. Our report provides the first clinical description of an adult carrying this variant, which completes the phenotype description previously provided in children and confirms the recurrence, the autosomal-dominant pathogenicity, and the diagnostic relevance of this FGFR3 intronic variant. We support its inclusion in routinely used diagnostic tests for osteochondrodysplasia. This may increase the detection rate of causal variants and therefore could have a positive impact on patient management. Finally, FGFR3 alteration via non-coding sequence exonization should be considered a recurrent disease mechanism to be taken into account for new drug design and clinical trial strategies.


Assuntos
Acondroplasia , Osteocondrodisplasias , Criança , Adulto , Humanos , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Acondroplasia/diagnóstico , Acondroplasia/genética , Acondroplasia/patologia , Mutação , Éxons , Fenótipo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética
9.
A A Pract ; 18(3): e01759, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38411585

RESUMO

Spondylometaphyseal dysplasia (SMD) is a rare genetic disorder affecting skeletal growth and development presenting anesthesiologists with many perioperative challenges. We present a case of a patient found to have multilevel tracheal stenosis due to twisting and folding of his trachea. This was discovered on imaging during a research review of SMD cases at our institution. Structural and functional abnormalities of the trachea have not been reported in SMD. This is the first description of a patient with SMD with severe multilevel tracheal disease requiring tracheal reconstructive surgery.


Assuntos
Osteocondrodisplasias , Estenose Traqueal , Humanos , Estenose Traqueal/cirurgia , Osteocondrodisplasias/complicações , Osteocondrodisplasias/cirurgia , Traqueia , Anestesiologistas
10.
Mol Biol Rep ; 51(1): 274, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38305850

RESUMO

BACKGROUND: Spondyloepimetaphyseal dysplasia with joint laxity type 3 (SEMDJL3) is a rare skeletal dysplasia associated with EXOC6B, a component of the exocyst complex, involved in vesicle tethering and exocytosis at the plasma membrane. So far, EXOC6B and the pathomechanisms underlying SEMDJL3 remain obscure. METHODS AND RESULTS: Exoc6b was detected largely at the perinuclear regions and the primary cilia base in ATDC5 prechondrocytes. Its shRNA lentiviral knockdown impeded primary ciliogenesis. In Exoc6b silenced prechondrocytes, Hedgehog signaling was attenuated, including when stimulated with Smoothened agonist. Exoc6b knockdown deregulated the mRNA and protein levels of Col2a1, a marker of chondrocyte proliferation at 7- and 14-days following differentiation. It led to the upregulation of Ihh another marker of proliferative chondrocytes. The levels of Col10a1, a marker of chondrocyte hypertrophy was enhanced at 14 days of differentiation. Congruently, Axin2, a canonical Wnt pathway modulator that inhibits chondrocyte hypertrophy was repressed. The expression of Mmp13 and Adamts4 that are terminal chondrocyte hypertrophy markers involved in extracellular matrix (ECM) remodelling were downregulated at 7 and 14 days of chondrogenesis. Bglap that encodes for the most abundant non-collagenous bone matrix constituent and promotes ECM calcification was suppressed at 14 days of chondrocyte differentiation. ECM mineralization was assessed by Alizarin Red staining. Gene expression and ciliogenesis were investigated by reverse transcription quantitative real-time PCR, immunoblotting, and immunocytochemistry. CONCLUSIONS: These findings provide initial insights into the potential role of Exoc6b in primary ciliogenesis and chondrogenic differentiation, contributing towards a preliminary understanding of the molecular pathomechanisms underlying SEMDJL3.


Assuntos
Condrogênese , Proteínas Hedgehog , Instabilidade Articular , Osteocondrodisplasias , Diferenciação Celular/genética , Células Cultivadas , Condrogênese/genética , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Hipertrofia , Via de Sinalização Wnt
11.
Eur J Med Genet ; 68: 104924, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38355094

RESUMO

Diaphanospondylodysostosis is a rare genetic skeletal disorder caused by biallelic variants in the BMPER gene. The term, diaphanospondylodysostosis, includes ischiospinal dysotosis, which was previously known as a distinct entity with milder clinical features. The clinical phenotype of diaphanospondylodysostosis is quite variable with mortality in early postnatal life in some patients. Main clinical and radiographic features are narrow thorax, vertebral segmentation defects, rib anomalies, ossification defects of vertebrae, ischium and sacrum, and renal cysts. In this study, we report on a 14-year-old girl patient with diaphanospondylodysostosis harbouring a novel BMPER mutation. The patient presented with severe scoliosis and severely hypoplastic/aplastic distal phalanges of the fingers and toes, findings yet hitherto not described in this syndrome.


Assuntos
Anormalidades Craniofaciais , Disostoses , Osteocondrodisplasias , Costelas/anormalidades , Escoliose , Coluna Vertebral/anormalidades , Feminino , Humanos , Adolescente , Escoliose/diagnóstico por imagem , Escoliose/genética , Coluna Vertebral/diagnóstico por imagem , Disostoses/diagnóstico por imagem , Disostoses/genética , Costelas/diagnóstico por imagem , Proteínas de Transporte
12.
Poult Sci ; 103(4): 103534, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38401226

RESUMO

The poultry skeletal system serves multiple functions, not only providing structural integrity but also maintaining the balance of essential minerals such as calcium and phosphorus. However, in recent years, the consideration of skeletal traits has been overlooked in the selective breeding of broilers, resulting in an inadequate adaptation of the skeletal system to cope with the rapid increase in body weight. Consequently, this leads to lameness and bone diseases such as tibial dyschondroplasia (TD), which significantly impact the production performance of broilers. Accumulating evidence has shown that microRNAs (miRNA) play a crucial role in the differentiation, formation, and disease of cartilage. However, the miRNA-mediated molecular mechanism underlying chicken TD formation is still poorly understood. The objective of this study was to investigate the biological function and regulatory mechanism of miRNA in chicken TD formation. Based on transcriptome sequencing of tibial cartilage in the healthy group and TD group, miR-206a-3p was found to be highly expressed in TD cartilage. The function of miR-206a-3p was explored through the transfection test of miR-206a-3p mimics and miR-206a-3p inhibitor. In this study, we utilized qRT-PCR, CCK-8, EdU, western blot, and flow cytometry to detect the proliferation, differentiation, and apoptosis of chondrocytes. The results revealed that miR-206a-3p suppressed the proliferation and differentiation of TD chondrocytes while promoting their programmed cell death. Furthermore, through biosynthesis and dual luciferase assays, it was determined that BMP6 was the direct target gene of miR-206a-3p. This finding was further supported by rescue experiments which confirmed the involvement of BMP6 in the regulatory pathway governed by miR-206a-3p. Our results suggest that miR-206a-3p can inhibits the proliferation and differentiation promote apoptosis through the target gene BMP-6 and suppressing the Smad2/3 signaling pathway in chicken TD chondrocytes.


Assuntos
MicroRNAs , Osteocondrodisplasias , Animais , Condrócitos/fisiologia , Galinhas/genética , Galinhas/metabolismo , Osteocondrodisplasias/genética , Osteocondrodisplasias/veterinária , Proteína Morfogenética Óssea 6/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proliferação de Células , Apoptose
13.
BMC Musculoskelet Disord ; 25(1): 133, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38347477

RESUMO

OBJECTIVE: The aim of the study was to investigate the 3.0 Tesla magnetic resonance imaging (MRI) features of Madelung's deformity. MATERIALS AND METHODS: The wrist MRI scans of 19 patients clinically diagnosed with Madelung's deformity and 20 patients without deformity were consecutively selected from Beijing Jishuitan Hospital between April 2019 and December 2022 for observation, in the case group and control group, respectively. Multiple linear regression was used to analyze the factors affecting tilting angle and width of central disc (CD, also termed as triangular fibrocartilage, the main component of triangular fibrocartilage complex), while the chi-square test was used to compare the occurrences of CD (radial) attachment displacement, VL, and RTL. p < 0.05 indicated statistical significance. RESULTS: Madelung's deformity significantly contributed to the tilting and thickening of the CD. In the case group, the tilting angle and thickness of CD were (51.46 ± 1.33)° and (0.23 ± 0.01) cm, respectively, which was statistically significant (p < 0.05); the radial attachment of the CD significantly shifted away from the distal articular surface level (χ2 = 39.00, p < 0.001), with a mean displacement of (0.97 ± 0.38) cm. Furthermore, the cases demonstrated abnormally developed Vickers ligament (χ2 = 35.19, p < 0.001) and radiotriquetral ligament (χ2 = 25.66, p < 0.001). CONCLUSION: MRI provides a notable advantage in diagnosing Madelung's deformity. Compared with the control group, patients with Madelung's deformity exhibited tilting and thickening of the CD. Additionally, the radial attachment of the CD was significantly shifted proximally with abnormal development of Vickers and radiotriquetral ligaments.


Assuntos
Transtornos do Crescimento , Osteocondrodisplasias , Rádio (Anatomia) , Ulna , Humanos , Radiografia , Imageamento por Ressonância Magnética , Articulação do Punho/diagnóstico por imagem
14.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(2): 244-249, 2024 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-38311568

RESUMO

OBJECTIVE: To analyze the clinical phenotype and genetic basis for a child featuring familial short stature. METHODS: A child who was admitted to Huzhou Maternal and Child Health Care Hospital on October 7, 2021 for growth retardation and pectus carinatum was selected as the study subject. Physical exam and medical imaging was performed. The child was subjected to whole exome sequencing, and candidate variants were verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a 1-year-old male, had manifested with slightly short stature (Z = -2.03), midfacial dysplasia, and multiple skeletal dysplasia such as pectus carinatum, irregular vertebral morphology, and defect of lumbar anterior bones. His mother, maternal grandmother and great-maternal grandfather also had short stature. WES revealed that the child has harbored a heterozygous c.2858dupA (p.Asp953GlufsTer476) frameshifting variant of the ACAN gene, which was inherited from his mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2858dup (p.Sp953Glufster476) variant was classified as likely pathogenic (PVS1+PM2_Supporting). The patient has shown marked improved height after receiving 11 months of treatment with human recombinant growth hormone (supplemental dose) starting from 20 months of age. CONCLUSION: The ACAN: c.2858dup (p.Asp953GlufsTer476) variant probably underlay the pathogenesis of short stature in this child.


Assuntos
Nanismo , Osteocondrodisplasias , Pectus Carinatum , Humanos , Lactente , Masculino , Biologia Computacional , Nanismo/genética , Mães , Mutação , Osteocondrodisplasias/genética , Fenótipo
15.
Int J Mol Sci ; 25(2)2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38256186

RESUMO

Mucopolysaccharidoses (MPSs) are a group of inborn errors of the metabolism caused by a deficiency in the lysosomal enzymes required to break down molecules called glycosaminoglycans (GAGs). These GAGs accumulate over time in various tissues and disrupt multiple biological systems, including catabolism of other substances, autophagy, and mitochondrial function. These pathological changes ultimately increase oxidative stress and activate innate immunity and inflammation. We have described the pathophysiology of MPS and activated inflammation in this paper, starting with accumulating the primary storage materials, GAGs. At the initial stage of GAG accumulation, affected tissues/cells are reversibly affected but progress irreversibly to: (1) disruption of substrate degradation with pathogenic changes in lysosomal function, (2) cellular dysfunction, secondary/tertiary accumulation (toxins such as GM2 or GM3 ganglioside, etc.), and inflammatory process, and (3) progressive tissue/organ damage and cell death (e.g., skeletal dysplasia, CNS impairment, etc.). For current and future treatment, several potential treatments for MPS that can penetrate the blood-brain barrier and bone have been proposed and/or are in clinical trials, including targeting peptides and molecular Trojan horses such as monoclonal antibodies attached to enzymes via receptor-mediated transport. Gene therapy trials with AAV, ex vivo LV, and Sleeping Beauty transposon system for MPS are proposed and/or underway as innovative therapeutic options. In addition, possible immunomodulatory reagents that can suppress MPS symptoms have been summarized in this review.


Assuntos
Mucopolissacaridoses , Osteocondrodisplasias , Humanos , Terapias em Estudo , Mucopolissacaridoses/genética , Mucopolissacaridoses/terapia , Anticorpos Monoclonais , Glicosaminoglicanos , Inflamação
16.
Pathol Res Pract ; 254: 155092, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38218042

RESUMO

Schimke immuno-osseous dysplasia (SIOD) is a rare multi-system condition caused by biallelic loss-of-function mutations in the SMARCAL1 gene. This disorder is characterized by disproportionate growth failure, T-cell deficiency, and renal dysfunction. Pathogenic variants in the SMARCAL1 gene have been reported in only approximately half of SIOD-affected individuals. Among these alterations, nonsense and frameshift mutations generally lead to a severe phenotype with early onset. In this study, we identified novel mutations in an Iranian patient with SIOD. A 4-year-old girl with developmental delay and facial dysmorphism was referred to our center for molecular diagnosis. We applied whole-exome and Sanger sequencing for co-segregation analysis. Subsequently, bioinformatic analysis was performed to assess the pathogenic effects of the variants and their post-transcriptional effects. We discovered two novel mutations (c.2281delT and c.2283delA) in exon 15 of the SMARCAL1 gene, resulting in a truncated protein with a loss of 193 amino acids (p.S761Rfs*1). Variant effect predictors indicated that these variants are pathogenic, and multi-sequence alignments revealed high conservation of this region among different species. Given that our patient exhibited severe a phenotype and passed away soon after receiving a definitive molecular diagnosis, we propose that the loss of the helicase C-terminal domain in the deleted part of SMARCAL1 may lead to the severe form of SIOD. Besides, the combination of growth retardation and bone abnormalities also plays a crucial role in the early diagnosis of the disease.


Assuntos
Arteriosclerose , Síndromes de Imunodeficiência , Síndrome Nefrótica , Osteocondrodisplasias , Doenças da Imunodeficiência Primária , Embolia Pulmonar , Feminino , Humanos , Pré-Escolar , Irã (Geográfico) , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/complicações , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/metabolismo , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/genética , Síndrome Nefrótica/complicações , DNA Helicases/genética
17.
Liver Int ; 44(3): 811-822, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38230874

RESUMO

BACKGROUND AND AIMS: To systematically review the literature for reports on Wolcott-Rallison syndrome, focusing on the spectrum and natural history, genotype-phenotype correlations, patient and native liver survival, and long-term outcomes. METHODS: PubMed, Livio, Google Scholar, Scopus and Web of Science databases were searched. Data on genotype, phenotype, therapy, cause of death and follow-up were extracted. Survival and correlation analyses were performed. RESULTS: Sixty-two studies with 159 patients met the inclusion criteria and additional 30 WRS individuals were collected by personal contact. The median age of presentation was 2.5 months (IQR 2) and of death was 36 months (IQR 50.75). The most frequent clinical feature was neonatal diabetes in all patients, followed by liver impairment in 73%, impaired growth in 72%, skeletal abnormalities in 59.8%, the nervous system in 37.6%, the kidney in 35.4%, insufficient haematopoiesis in 34.4%, hypothyroidism in 14.8% and exocrine pancreas insufficiency in 10.6%. Episodes of acute liver failure were frequently reported. Liver transplantation was performed in six, combined liver-pancreas in one and combined liver-pancreas-kidney transplantation in two individuals. Patient survival was significantly better in the transplant cohort (p = .0057). One-, five- and ten-year patient survival rates were 89.4%, 65.5% and 53.1%, respectively. Liver failure was reported as the leading cause of death in 17.9% of cases. Overall survival was better in individuals with missense mutations (p = .013). CONCLUSION: Wolcott-Rallison syndrome has variable clinical courses. Overall survival is better in individuals with missense mutations. Liver- or multi-organ transplantation is a feasible treatment option to improve survival.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus , Epífises/anormalidades , Osteocondrodisplasias , Recém-Nascido , Humanos , Lactente , Seguimentos , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Osteocondrodisplasias/genética , eIF-2 Quinase/genética
18.
Int J Mol Sci ; 25(2)2024 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-38255821

RESUMO

Pulmonary hypertension (PH) with interstitial lung diseases (ILDs) often causes intractable conditions. CD26/Dipeptidyl peptidase-4 (DPP4) is expressed in lung constituent cells and may be related to the pathogenesis of various respiratory diseases. We aimed to clarify the functional roles of CD26/DPP4 in PH-ILD, paying particular attention to vascular smooth muscle cells (SMCs). Dpp4 knockout (Dpp4KO) and wild type (WT) mice were administered bleomycin (BLM) intraperitoneally to establish a PH-ILD model. The BLM-induced increase in the right ventricular systolic pressure and the right ventricular hypertrophy observed in WT mice were attenuated in Dpp4KO mice. The BLM-induced vascular muscularization in small pulmonary vessels in Dpp4KO mice was milder than that in WT mice. The viability of TGFß-stimulated human pulmonary artery SMCs (hPASMCs) was lowered due to the DPP4 knockdown with small interfering RNA. According to the results of the transcriptome analysis, upregulated genes in hPASMCs with TGFß treatment were related to pulmonary vascular SMC proliferation via the Notch, PI3K-Akt, and NFκB signaling pathways. Additionally, DPP4 knockdown in hPASMCs inhibited the pathways upregulated by TGFß treatment. These results suggest that genetic deficiency of Dpp4 protects against BLM-induced PH-ILD by alleviating vascular remodeling, potentially through the exertion of an antiproliferative effect via inhibition of the TGFß-related pathways in PASMCs.


Assuntos
Hipertensão Pulmonar , Doenças Pulmonares Intersticiais , Osteocondrodisplasias , Humanos , Animais , Camundongos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/genética , Dipeptidil Peptidase 4/genética , Fosfatidilinositol 3-Quinases , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/genética , Bleomicina/toxicidade , Camundongos Knockout , Fator de Crescimento Transformador beta/genética
19.
Orphanet J Rare Dis ; 19(1): 29, 2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38281003

RESUMO

AIM: Achondroplasia is the most common of the skeletal dysplasias that cause fatal and disabling growth and developmental disorders in children, and is caused by a mutation in the fibroblast growth factor receptor, type 3 gene(FGFR3). This study aims to analyse the clinical characteristics and gene mutations of ACH to accurately determine whether a patient has ACH and to raise public awareness of the disease. METHODS: The database of Pubmed, Cochrane Library, Wanfang and CNKI were searched with terms of "Achondroplasias" or "Skeleton-Skin-Brain Syndrome" or "Skeleton Skin Brain Syndrome" or "ACH" and "Receptor, Fibroblast Growth Factor, Type 3" or "FGFR3". RESULTS: Finally, four hundred and sixty-seven patients with different FGFR3 mutations were enrolled. Of the 138 patients with available gender information, 55(55/138, 40%) were female and 83(83/138, 60%) were male. Among the patients with available family history, 47(47/385, 12%) had a family history and 338(338/385, 88%) patients were sporadic. The age of the patients ranged from newborn babies to 36 years old. The mean age of their fathers was 37 ± 7 years (range 31-53 years). Patients came from 12 countries and 2 continents, with the majority being Asian (383/432, 89%), followed by European (49/432, 11%). Short stature with shortened arms and legs was found in 112(112/112) patients, the abnormalities of macrocephaly in 94(94/112) patients, frontal bossing in 89(89/112) patients, genu valgum in 64(64/112) patients and trident hand were found in 51(51/112) patients. The most common mutation was p.Gly380Arg of the FGFR3 gene, which contained two different base changes, c.1138G > A and c.1138G > C. Ten rare pathogenic mutations were found, including c.831A > C, c.1031C > G, c.1043C > G, c.375G > T, c.1133A > G, c.1130T > G, c.833A > G, c.649A > T, c.1180A > T and c.970_971insTCTCCT. CONCLUSION: ACH was caused by FGFR3 gene mutation, and c.1138G > A was the most common mutation type. This study demonstrates the feasibility of molecular genetic testing for the early detection of ACH in adolescents with short stature, trident hand, frontal bossing, macrocephaly and genu valgum.


Assuntos
Acondroplasia , Geno Valgo , Megalencefalia , Osteocondrodisplasias , Criança , Recém-Nascido , Adolescente , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Acondroplasia/genética , Acondroplasia/patologia , Mutação/genética
20.
J Bronchology Interv Pulmonol ; 31(1): 57-62, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37249571

RESUMO

BACKGROUND: Tracheobronchopathia osteochondroplastica (TPO) is a rare idiopathic disease involving the tracheobronchial tree. It is mostly an incidental finding with non-specific clinical manifestations. It has typical bronchoscopic, radiological features and biopsy is usually considered non-essential. The study aimed to determine whether biopsy makes a difference in the management of patients. METHODS: All patients diagnosed with TPO in our institution over 15 years (2005 to 2020) were included in this study. Their medical records, chest computed tomography (CT), and bronchoscopy reports were retrospectively reviewed, and data were analysed. All the CT images were reviewed by a senior chest radiologist. RESULTS: From the 20,000 bronchoscopies and 260,000 CT thorax images obtained, 28 cases were diagnosed as TPO based on either bronchoscopy or radiology or both. Among the 19 cases diagnosed through bronchoscopy, 16 underwent a biopsy. In addition to TPO features, biopsy showed additional diagnoses in 6 cases. In 9 cases, TPO was not initially diagnosed by CT but by bronchoscopy. In 8 patients, TPO was diagnosed incidentally on CT performed for other reasons. On follow-up with the treatment of underlying/co-existing concomitant aetiologies, clinical improvement was noted in all patients. None of them progressed to respiratory failure or airway obstruction until the last follow-up. CONCLUSION: Among patients who underwent bronchoscopic biopsy of TPO lesions, 38% had biopsy results showing an alternative aetiology, which led to changes in the treatment plan for all these patients. Hence, a bronchoscopic biopsy of TPO lesions should be performed to rule out other aetiologies.


Assuntos
Osteocondrodisplasias , Doenças da Traqueia , Humanos , Doenças Raras/complicações , Estudos Retrospectivos , Doenças da Traqueia/diagnóstico por imagem , Doenças da Traqueia/complicações , Broncoscopia/métodos , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/complicações , Biópsia
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