RESUMO
Kidney failures in infants are mostly caused by congenital anomalies of the kidney and urinary tract (CAKUT), which are among the most common congenital birth disorders worldwide when paired with cardiac abnormalities. People with CAKUT often have severe kidney failure as a result of a wide range of abnormalities that can occur alone or in conjunction with other syndromic disorders. In this study, we aimed to investigate the expression pattern of CAKUT candidate genes alpha-8 integrin (ITGA8) and Van Gogh-like 2 (VANGL2) in fetal tissues of healthy and CAKUT-affected kidneys using immunohistochemistry and immunofluorescence. We found that under CAKUT circumstances, the expressions of ITGA8 and VANGL2 are changed. Additionally, we showed that VANGL2 expression is constant during fetal aging, but ITGA8 expression varies. Moreover, compared to normal healthy kidneys (CTRL), ITGA8 is poorly expressed in duplex kidneys (DKs) and dysplastic kidneys (DYS), whereas VANGL2 is substantially expressed in dysplastic kidneys (DYS) and poorly expressed in hypoplastic kidneys (HYP). These results point to VANGL2 and ITGA8 as potential prognostic indicators for CAKUT malformations. Further research is necessary to explore the molecular mechanisms underlying this differential expression of ITGA8 and VANGL2.
Assuntos
Cadeias alfa de Integrinas , Rim , Humanos , Rim/metabolismo , Rim/anormalidades , Cadeias alfa de Integrinas/metabolismo , Cadeias alfa de Integrinas/genética , Refluxo Vesicoureteral/metabolismo , Refluxo Vesicoureteral/genética , Anormalidades Urogenitais/metabolismo , Anormalidades Urogenitais/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Feminino , Sistema Urinário/metabolismo , Sistema Urinário/anormalidades , MasculinoRESUMO
Approximately half of the cases of chronic kidney disease (CKD) in childhood are caused by congenital anomalies of the kidney and urinary tract (CAKUT). Specific genes were identified as having significant importance in regard to the underlying genetic factors responsible for the CAKUT phenotype, and in our research, we focused on analyzing and comparing the expression levels of ectodysplasin A2 receptor (EDA2R), protocadherin9 (PCDH9), and TNF receptor-associated factor 7 (TRAF7) proteins in the cortex and medulla of healthy control kidneys during developmental phases 2, 3, and 4. We also performed an analysis of the area percentages of the mentioned proteins in the cortical and medullary sections of healthy embryonic and fetal kidneys compared to those affected by CAKUT, including duplex kidneys (DK), horseshoe kidneys (HK), hypoplastic kidneys (HYP), and dysplastic kidneys (DYS). We found that the CAKUT candidate gene proteins EDA2R, PCDH9, and TRAF7 are all expressed during normal human kidney development stages. In DYS, the expression of EDA2R was higher than in normal kidneys, likely due to EDA2R's role in apoptosis, which was upregulated in specific cases and could possibly contribute to the formation of DYS. The expression of PCDH9 was lower in HK, which can be attributed to the possible role of PCDH9 in cell migration suppression. Decreased PCDH9 expression is linked to increased cell migration, potentially contributing to the development of HK. The level of TRAF7 expression was reduced in all examined kidney disorders compared to normal kidneys, suggesting that this reduction might be attributed to the crucial role of TRAF7 in the formation of endothelium and ciliogenesis, both of which are essential for normal kidney development. Further research is required to ascertain the function of these proteins in both the typical development of the kidney and in CAKUT.
Assuntos
Caderinas , Rim , Anormalidades Urogenitais , Refluxo Vesicoureteral , Humanos , Caderinas/genética , Caderinas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Rim/metabolismo , Rim/anormalidades , Rim/crescimento & desenvolvimento , Rim/embriologia , Protocaderinas , Sistema Urinário/anormalidades , Sistema Urinário/metabolismo , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/patologia , Refluxo Vesicoureteral/genética , Refluxo Vesicoureteral/patologiaRESUMO
Gestational diabetes mellitus (GDM) presents a substantial population health concern. Previous studies have revealed that GDM can ultimately influence nephron endowment. In this study, we established a GDM mouse model to investigate the embryological alterations and molecular mechanisms underlying the development of congenital anomalies of the kidney and urinary tract (CAKUT) affected by GDM. Our study highlights that GDM could contribute to the manifestation of CAKUT, with prevalent phenotypes characterized by isolated hydronephrosis and duplex kidney complicated with hydronephrosis in mice. Ectopic ureteric buds (UBs) and extended length of common nephric ducts (CNDs) were noted in the metanephric development stage. The expression of Ret and downstream p-ERK activity were enhanced in UBs, which indicated the alteration of RET/MAPK/ERK pathway may be one of the mechanisms contributing to the increased occurrence of CAKUT associated with GDM.
Assuntos
Diabetes Gestacional , Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas c-ret , Anormalidades Urogenitais , Refluxo Vesicoureteral , Animais , Feminino , Camundongos , Gravidez , Diabetes Gestacional/metabolismo , Rim/anormalidades , Rim/metabolismo , Rim/embriologia , Proteínas Proto-Oncogênicas c-ret/metabolismo , Proteínas Proto-Oncogênicas c-ret/genética , Sistema Urinário/anormalidades , Sistema Urinário/embriologia , Anormalidades Urogenitais/etiologia , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/patologiaRESUMO
We present three new and six published infants with overlapping features of LUMBAR syndrome (lower body hemangioma, urogenital anomalies, spinal cord malformations, bony deformities, anorectal/arterial anomalies and renal anomalies) and OEIS complex (omphalocele, exstrophy, imperforate anus, and spinal defects), also known as cloacal exstrophy. OEIS is included under the recently proposed umbrella coined recurrent constellations of embryonic malformations (RCEMs). The RCEMs represent a phenotypically overlapping spectrum of rare disorders of caudal dysgenesis with unknown cause but likely shared pathogenesis. It has recently been proposed that LUMBAR be considered an RCEM. This report of infants with combined features of OEIS and LUMBAR is the first to demonstrate an overlap between LUMBAR and another RCEM, which supports LUMBAR's inclusion within the RCEM spectrum.
Assuntos
Anormalidades Múltiplas , Anus Imperfurado , Humanos , Anus Imperfurado/genética , Anus Imperfurado/patologia , Anus Imperfurado/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/diagnóstico , Feminino , Masculino , Recém-Nascido , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/patologia , Hérnia Umbilical/diagnóstico , Hérnia Umbilical/patologia , Lactente , Síndrome , Cloaca/anormalidades , Cloaca/patologia , Hemangioma/patologia , Hemangioma/diagnóstico , Hemangioma/genética , Fenótipo , Coluna Vertebral/anormalidades , Coluna Vertebral/patologia , Coluna Vertebral/diagnóstico por imagem , EscolioseRESUMO
Renal coloboma syndrome (RCS) and dominant optic atrophy are mainly caused by heterozygous mutations in PAX2 and OPA1, respectively. We describe a patient with digenic mutations in PAX2 and OPA1. A female infant was born without perinatal abnormalities. Magnetic resonance imaging at 4 months of age showed bilateral microphthalmia and optic nerve hypoplasia. Appropriate body size was present at 2 years of age, and mental development was favorable. Color fundus photography revealed severe retinal atrophy in both eyes. Electroretinography showed slight responses in the right eye, but no responses in the left eye, suggesting a high risk of blindness. Urinalysis results were normal, creatinine-based estimated glomerular filtration rate was 63.5 mL/min/1.73 m2, and ultrasonography showed bilateral hypoplastic kidneys. Whole exome sequencing revealed de novo frameshift mutations in PAX2 and OPA1. Both variants were classified as pathogenic (PVS1, PS2, PM2) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Genetic testing for ocular diseases should be considered for patients with suspected RCS and a high risk of total blindness.
Assuntos
Coloboma , GTP Fosfo-Hidrolases , Fator de Transcrição PAX2 , Refluxo Vesicoureteral , Humanos , Feminino , Fator de Transcrição PAX2/genética , GTP Fosfo-Hidrolases/genética , Coloboma/genética , Coloboma/diagnóstico , Refluxo Vesicoureteral/genética , Refluxo Vesicoureteral/diagnóstico , Atrofia Óptica Autossômica Dominante/genética , Atrofia Óptica Autossômica Dominante/diagnóstico , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/complicações , Mutação da Fase de Leitura , Sequenciamento do Exoma , Lactente , Pré-Escolar , Mutação , Insuficiência RenalRESUMO
OBJECTIVE: GREB1L has been linked prenatally to Potter's sequence, as well as less severe anomalies of the kidney, uterus, inner ear, and heart. The full phenotypic spectrum is unknown. The purpose of this study was to characterize known and novel pre- and postnatal phenotypes associated with GREB1L. METHODS: We solicited cases from the Fetal Sequencing Consortium, screened a population-based genomic database, and conducted a comprehensive literature search to identify disease cases associated with GREB1L. We present a detailed phenotypic spectrum and molecular changes. RESULTS: One hundred twenty-seven individuals with 51 unique pathogenic or likely pathogenic GREB1L variants were identified. 24 (47%) variants were associated with isolated kidney anomalies, 19 (37%) with anomalies of multiple systems, including one case of hypoplastic left heart syndrome, five (10%) with isolated sensorineural hearing loss, two (4%) with isolated uterine agenesis; and one (2%) with isolated tetralogy of Fallot. CONCLUSION: GREB1L may cause complex congenital heart disease (CHD) in humans. Clinicians should consider GREB1L testing in the setting of CHD, and cardiac screening in the setting of GREB1L variants.
Assuntos
Cardiopatias Congênitas , Nefropatias , Anormalidades Urogenitais , Feminino , Humanos , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Rim/anormalidades , Nefropatias/congênito , Proteínas de Neoplasias/genética , Anormalidades Urogenitais/genéticaRESUMO
Resumen: Introducción: Las anomalías congénitas del riñón y del tracto urinario se originan de alteraciones genéticas, en su mayoría desconocidas. Las mutaciones en el gen que codifica para el factor hepatocitario nuclear 1B (HNF1B), son la causa monogénica más frecuentemente descrita. Se desconocen datos en Chile y Latinoamérica. Objetivo: Determinar la presencia de variantes del gen HNF1B en niños chilenos con anomalías congénitas del riñón y/o tracto urinario y sus características clínicas. Pacientes y Mé todo: Estudio descriptivo con pacientes entre 10 meses y 17 años, consultantes en Unidad de Nefrología Hospital Luis Calvo Mackenna, período abril - diciembre 2016, portadores de displasia renal quística, displasia/hipoplasia renal no quística y/o riñón en herradura. Se determinaron variantes de HNF1B mediante secuenciación de exones 1, 2, 3 y 4; previa extracción y amplificación de DNA. Se utilizaron enzimas de restricción para definir si variantes eran homo o heterocigotas. Familiares di rectos de casos índices se estudiaron con secuenciación del exón afectado. Resultados: Se incluyeron 32 pacientes, 43,75% varones, mediana edad 11 años. El 65,6% displasia/hipoplasia renal no quística, 31,25% displasia renal quística y 3,15% riñón en herradura. En 2 pacientes (6,25%) se detectó una misma variante genética heterocigota en exón 4, posición 1027 (C1027T), no descrita anteriormente. El estudio de familiares determinó la variante en 3 de 5 individuos, todos sin anomalías nefrouro- lógicas congénitas. Conclusiones: Confirmamos la presencia de una variante genética heterocigota del gen HNF1B, no descrita previamente, dando inicio a la búsqueda de este tipo de mutaciones en nuestro medio, lo cual nos permite aproximarnos al conocimiento de causalidad, determinación de compromiso extrarrenal y consejo genético.
Abstract Introduction: Congenital anomalies of the kidney and urinary tract are caused by genetic alterations mostly unknown. Mutations in the gene that codes for hepatocyte nuclear factor 1B (HNF1B) are the most frequently described monogenic causes. Data are unknown in Chile and Latin America. Objective: To determine the presence of variants of the HNF1B gene in Chilean children with conge nital anomalies of the kidney and/or the urinary tract and their clinical characteristics. Patients and Method: Descriptive study with children aged 10 months to 17 years, patients of the Calvo Mackenna Hospital Nephrology Unit, with cystic renal dysplasia, non cystic renal dysplasia/hypoplasia, horses hoe kidney between April and December 2016. HNF1B variants were determined by sequencing of exons 1, 2, 3 and 4 after DNA extraction and amplification. Restriction enzymes were used to define if the variants were homo or heterozygous. Direct family members of index cases were studied with sequencing of the affected exon. Results: 32 patients were included, 43.75% males, median age 11 years. 65.6% of them had non-cystic renal dysplasia, 31.25% cystic renal dysplasia, and 3.15% hor seshoe kidney. In two patients (6.25%) the same heterozygous genetic variant was detected in exon 4, position 1027 (C1027T), not previously described. The study of relatives found the same variant in three out of five individuals, all without congenital nephro-urological anomalies. Conclusions: We confirmed the presence of a not previously described heterozygous genetic variant of the HNF1B gene. This work initiates the search for this type of mutations in our region which allows us to ap proach the knowledge of causality, determination of extrarenal involvement, and genetic counseling.
Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Anormalidades Urogenitais/genética , Doenças Urológicas/genética , Fator 1-beta Nuclear de Hepatócito/genética , Nefropatias/genética , Marcadores Genéticos , Chile , Estudos Prospectivos , Predisposição Genética para Doença , Heterozigoto , MutaçãoRESUMO
As anormalidades da diferenciação sexual são infrequentes na prática clínica. A caracterização de uma ampla variedade de síndromes tem sido muitas vezes confusa, necessitando, com relativa frequência, a consulta de múltiplos livros e uso constante de referências para uma correta compreensão. O presente artigo tem a proposta de revisar as entidades mais frequentes, seus métodos diagnósticos e sua conveniente orientação.(AU)
Abnormal sexual differentiation is not frequently seen in an individual clinician's practice. The categories of many syndromes in this area require special and constant references to review many papers and books to understand these abnormalities. In this paper, the most frequent syndromes are described, and their diagnostic methods and proposals for correct orientation are provided.(AU)
Assuntos
Humanos , Masculino , Feminino , Gravidez , Diferenciação Sexual/genética , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/etiologia , Anormalidades Urogenitais/genética , Transtornos do Desenvolvimento Sexual/embriologia , Útero/anormalidades , Vagina/anormalidades , Insuficiência Ovariana Primária , Desenvolvimento Sexual/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual , Transtorno 46,XY do Desenvolvimento Sexual , Disgenesia Gonadal/embriologia , Ductos Paramesonéfricos/anormalidadesRESUMO
A proposta deste estudo foi revisar os fatores genéticos e as anomalias cromossômicas passíveis de condicionarem anormalidades no aparelho genital feminino.
The aim of this study was to review the genetic factors and chromosomal abnormalities that can create Mullerian malformations in females' genital tract.
Assuntos
Humanos , Feminino , Anormalidades Congênitas/classificação , Anormalidades Congênitas/genética , Anormalidades Urogenitais/classificação , Anormalidades Urogenitais/genética , Aberrações Cromossômicas , Ductos Paramesonéfricos/anormalidades , Genética Médica , Genitália Feminina/anormalidades , Útero/anormalidades , Vagina/anormalidadesRESUMO
El síndrome de Beckwith-Wiedemann (SBW) es un desorden esporádico o heredado, infrecuente, que se caracteriza por peso elevado al nacimiento, macroglosia, defectos de la pared abdominal y menos frecuentemente hipoglucemia, hemihipertrofia y visceromegalia. Se presenta un paciente de sexo femenino de un mes de vida con antecedentes de nefromegalia evidenciada por ecografía prenatal con múltiples hemangiomas en tronco y labio superior. Al examen físico se evidenció notable macroglosia, hemihipertrofia con compromiso de genitales externos, onfalocele y percentilo de peso mayor a 90. El laboratorio demostró alfa fetoproteína de 608ng/ml. Se realizó diagnóstico de síndrome de Beckwith Wiedemann. El paciente evolucionó con aumento del número y tamaño de las lesiones hemangiomatosas, descenso de los niveles de alfa fetoproteína y su maduración psicomotriz fue adecuada a su edad. Presentamos un síndrome infrecuente en un paciente con hemangiomatosis neonatal benigna (HNB), asociación no descripta previamente en la literatura. Destacamos la importancia del examen físico en la consulta dermatológica como oportunidad diagnóstica.
Beckwith-Wiedemanns syndrome is a sporadic or hereditary rare disor-der characterized by macroglosia, omphalocele, visceromegalia, hypo-glycemia and hemihypertrophy.We report the case of a 1 month-old infant with a history of nephromegalia detected by prenatal ultrasound scan, who presented various generalized hemangiomas.On examination she had macroglosia, hemihypertrophy, omphalocele and high body weight. She also had alpha feto protein 608 ng/ml withno further abnormalities, leading us to diagnose Beckwith-Wiedemann ́s syndrome.The interest of this case is to report an infrecuent syndrome in a patient with diagnosis of neonatal hemangiomatosis. This association has not been previously reported in the literature. We wish to emphasize the importance of a thorough physical exam as part of the dermatologic consultation leading to the correct diagnosis.