Genetic analysis of a child with atypical Hemolytic uremic syndrome and nephrotic-range proteinuria / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic etiology for a child with atypical Hemolytic uremic syndrome (aHUS) in conjunct with nephrotic level proteinuria.@*METHODS@#A child patient who had visited the Affiliated Hospital of Qingdao University on June 25, 2020 was selected as the study subject. Clinical data of the patient was collected. Whole exome sequencing (WES) was carried out for the child, and candidate variant was verified by Sanger sequencing of the child and his parents.@*RESULTS@#The child, an 8-month-old male, had presented mainly with edema, oliguria, hematuria, nephrotic level proteinuria, anemia, thrombocytopenia, increased creatinine and urea, hypercholesterolemia but normal complement levels. Genetic testing revealed that he has harbored compound heterozygous variants of the DGKE gene, namely c.12_18dupGAGGCGG (p.P7fs*37) and c.1042G>T (p.D348Y), which were respectively inherited from his father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were classified as likely pathogenic and variant of uncertain significance, respectively. By combining his clinical manifestations and results of genetic testing, the child was diagnosed with aHUS with nephrotic level proteinuria.@*CONCLUSION@#For infants and young children with aHUS in conjunct with nephrotic level proteinuria, variants of the DGKE gene should be screened. Above finding has expanded the mutational spectrum of the DGKE gene.

Aspectos genéticos moleculares del síndrome de trombocitopenia con ausencia de radios / Molecular genetic aspects of the thrombocytopenia syndrome with absent radii

Introducción: La trombocitopenia con ausencia de radios es un síndrome genético poco frecuente. Se caracteriza por la ausencia bilateral de radios con presencia de ambos pulgares y trombocitopenia. Pueden estar presentes, además, malformaciones en miembros inferiores, cardiovasculares, gastrointestinales, neurológicas y vasculares. Objetivo: Analizar los aspectos genéticos moleculares más recientes del síndrome de trombocitopenia. Métodos: Se realizó una revisión de la literatura en inglés y español, a través del sitio web PubMed y el motor de búsqueda Google académico, de artículos publicados en los últimos 10 años. Se hizo un análisis y resumen de la bibliografía revisada. Análisis y síntesis de la información: El patrón de herencia de la enfermedad es autosómico recesivo, un heterocigótico compuesto por un alelo nulo del gen RBM8A, localizado en el locus 1q21.1 y la presencia de un polimorfismo de simple nucleótido en regiones no codificantes en el otro alelo. Este gen codifica la proteína Y14, la cual es uno de los cuatro componentes del complejo de unión de exones, complejo multiproteico que se une al ARNm y que, una vez finalizado el empalme, interviene en la eficiencia de la traducción y la degradación del ARNm que presenten codones de terminación prematura. Conclusiones: La trombocitopenia es la primera enfermedad en el humano en la que se describe un defecto en una subunidad del complejo de unión de exones. A pesar del avance en los últimos años en el conocimiento de las bases moleculares de la enfermedad, aún son necesarias nuevas investigaciones para explicar la relación entre el gen RBM8 y las manifestaciones esqueléticas(AU)

Introduction: Thrombocytopenia with absent radii is a rare genetic syndrome, characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia. In addition, malformations may be present, involving the lower limbs, as well as the cardiovascular, gastrointestinal, neurological, and vascular systems. Objective: To analyze the most recent molecular genetic aspects of thrombocytopenia syndrome. Methods: A review of the literature in English and in Spanish was carried out, in the PubMed website and using the search engine of Google Scholar, for articles published in the last ten years. We performed analysis and summary of the reviewed bibliography. Information analysis and synthesis: The disease has an autosomal recessive inheritance pattern, a heterozygote composed of a null allele of the RBM8A gene, located at the 1q21.1 locus and the presence of a single nucleotide polymorphism in non-coding regions in the other allele. This gene encodes the Y14 protein, which is one of the four components of the exon-binding complex, a multiprotein complex that binds to mRNA and that, once splicing is complete, intervenes in the efficiency of translation and degradation of mRNA that have premature termination condons. Conclusions: Thrombocytopenia is the first disease in humans in which a defect in a subunit of the exon binding complex was described. Despite the advance in recent years in understanding the molecular basis of the disease, new research is still necessary to explain the relationship between the RBM8 gene and skeletal manifestations(AU)

Trombocitopenia hereditaria relacionada a gen MYH-9: primera familia reportada en Chile con diagnóstico molecular: caso clínico / Hereditary thrombocytopenia associated with a mutation in the MYH-9 gene: report of one case

We report a 51-year-old female who had a first episode of thrombocytopenia at 23 years of age during a pregnancy. At the age of fifty, a hysterectomy was indicated due to a metrorrhagia: a platelet count of 21,000/ul was detected. She was treated with eltrombopag with a good response. The family history of the patient revealed the presence of thrombocytopenia in several family members. Suspecting a hereditary thrombocytopenia, a genetic study revealed a mutation in the MYH-9 gene. This mutation can be suspected when there is a family history of thrombocytopenia with autosomal dominant inheritance, macrothrombocytopenia and in this particular case, due to the response to thrombopoietin receptor agonist, eltrombopag.

Síndrome TAR en paciente adulto sin diagnóstico previo: presentación de un caso / TAR syndrome in an adult patient without previous diagnosis, a case report

El síndrome TAR (Thrombocytopenia with Absent Radius) es una patología congénita autosómica recesiva infrecuente, caracterizada por trombocitopenia con aplasia de radio bilateral. Incluye malformaciones esqueléticas, renales, hematológicas y cardíacas. Su base genética todavía no está clara. Presentamos el caso de una paciente sin diagnóstico previo de síndrome TAR que llega a la consulta, tras haber sido evaluada por varios profesionales médicos, para el diagnóstico y el tratamiento de trastornos hematológicos, que finalmente estuvieron asociados a su síndrome congénito. (AU)

Thrombocytopenia with Absent Radius (TAR) is a rare autosomic recessive disease characterized by thrombocytopenia and bilateral radial aplasia, which includes skeletal, hematologic, renal and cardiac abnormalities. The genetics bases of this syndrome remain unclear. We report here a patient without a previous diagnosis of TAR syndrome who was seen in the clinic, after being evaluated by several medical professionals for diagnosis and treatment of blood disorders, which eventually were associated with the congenital syndrome. (AU)

A Trp33Arg Mutation at Exon 1 of the MYH9 Gene in a Korean Patient with May-Hegglin Anomaly

In this report, we describe a Korean patient with May-Hegglin anomaly from a mutation of the MYH9 gene. The proband was a 21-year-old man with thrombocytopenia. He did not have a bleeding tendency. His neutrophil count was normal at 7490/mm3; however, the neutrophils contained abnormal basophilic inclusions in their cytoplasm. The platelet count was decreased at 15000/mm3 with giant platelets. Coagulation test results were not remarkable. Direct sequencing of MYH9 revealed that he was heterozygous for a mutation in exon 1, which was a 97T>A substitution mutation affecting codon 33, substituting tryptophan with arginine (Trp33Arg). Family study showed that both of his parents had normal phenotype and genotypes, indicating a de novo occurrence of the mutation in the proband.

Algunas consideraciones clínico-genéticas de la trombocitopenia con ausencia de radios / Some clinical-genetic considerations of the thrombocytopenia with lack of radios

La trombocitopenia con ausencia de radios (TAR) es un síndrome genético poco frecuente caracterizado por ausencia bilateral de radios con presencia de ambos pulgares y trombocitopenia. Suelen estar presentes, además, malformaciones en miembros inferiores, cardiovasculares, gastrointestinales, neurológicas y vasculares. El modo de herencia es autosómico recesivo, pero según evidencias encontradas en diferentes estudios, este no es el único patrón; existen familias donde se ha observado un patrón de herencia autosómico dominante con penetrancia reducida. Se han estudiado diferentes genes para tratar de explicar la mutación causante de este síndrome, entre ellos, los genes HOX, involucrados en la trombocitopenia amegacariocítica, pero no se ha encontrado relación con el síndrome TAR. Estudios moleculares revelan la presencia de una microdeleción intersticial a nivel del locus 1q21.1 como condición necesaria, pero no suficiente para que se desarrolle completamente el fenotipo TAR. En investigaciones recientes se ha demostrado la ausencia de expresión de la endoglina en las cÚlulas estromales de los pacientes con TAR. En ratones de laboratorio se ha observado que la inactivación genética de esta proteína transmembrana presente en las células endoteliales humanas está asociada con muertes fetales intraútero debido a anormalidades vasculares y cardíacas graves

The thrombocytopenia with lack of radios (TLR) is uncommon genetic syndrome characterized by a bilateral lack of radios with presence of both thumbs and thrombocytopenia. Also, may to be present malformations of lower extremities, cardiovascular, gastrointestinal, neurological and vascular. The inheritance way is autosomal recessive, but according to the evidences founded in different studies, this is not the only pattern; there are families where there was an autosomal dominant pattern inheritance with reduced penetrance. Different genes have been studied to try to explain the mutation provoking this syndrome including the HOX genes involved in the megakaryocytic thrombocytopenia, but its relation with the TLR syndrome has been not found. Nuclear studies have demonstrated the presence of an interstitial microdeletion at level of 1q21.1 locus as a necessary condition but not enough for the complete development of the TLR phenotype. In recent researches has been demonstrated the lack of expression of endoglin in stromal cells of patients presenting with TLR. In laboratory mice it was noted that the trans-membrane genetic inactivation of this protein present in human endothelial cells is associated with intrauterine fetal deaths due to severe vascular and cardiac abnormalities

Fanconi's anemia in newborn.

Fanconi's anemia (FA) is a paradigm for congenital anomalies, aplastic anemia and predisposition to malignancies. Identification of the disease at birth is based on characteristic physical malformations, as hematologic manifestations at birth are extremely rare. We report a case of FA in a newborn who presented with anophthalmia, unilateral radial ray defect, hemivertebrae and thrombocytopenia.

Determining the mutation and the first reports of May Hegglin anomaly from Iran and the first homozygous E1841K mutations in the world

May-Hegglin anomaly [MHA] is a rare autosomal disorder which is characterized by triad of thrombocytopenia, giant platelets and Dohle like inclusion bodies in granulocytes. This is the first report of MHA and its mutation from Iran. The specimen of two patients [father 51 and son 15 y/o] collected with EDTA and tri-sodium citrate anticoagulants. CBC and peripheral blood smear studied by automatic cell counter and microscopic examination, respectively. Direct sequencing of extracted DNA of certain exons of MYH9 gene was performed. Both patients had demonstrated the diagnostic triad of MHA. Mutations showed homozygous and heterozygous pattern in the father and the son, respectively. This is the first report of MHA from Iran. The mutation of both patients was E1841K which is the most common type among MYH9 mutations in MHA. The most interesting finding was the homozygous mutation that did not entail any clinical severity

Síndrome de Wiskott Aldrich / The Wiskott-Aldrich syndrome

Introducción. El síndrome de Wiskott-Aldrich es un padecimiento recesivo ligado al cromosoma X, caracterizado por la triada de eccema, trombocitopenia e inmunodeficiencia variable, generalmente letal por la tendencia a infecciones graves. Caso clínico. Se describe el caso de lactante masculino de seis meses de edad quien manifestó inicialmente eccema a los 20 días de vida y cinco meses después se hicieron aparentes infecciones y petequias corroborándose trombocitopenia. Conclusiones. Tener presente esta posibilidad en el paciente varón con eccema, trombositopenia y tendencia a infecciones ya que se tiene la opción terepéutica del transplante de médula ósea

Síndrome de Tar: apresentaçäo de um caso / TAR's syndrome: report of a case

Os autores relatam um caso de um recém-nascido com trombocitopenia e ausência bilateral de rádio (TAR). Trata-se de uma síndrome autossômica recessiva, onde neste caso os pais näo eram co-sanguíneos e as manifestaçöes clínicas começaram com o aparecimento de hematemese, petéquias e hemorragia umbilical na idade de 10 dias. Além de ausência de rádio apresentava também anomalias esqueléticas

Trombocitopenia y aplasia radial (TAR) de curso benigno en gemelas univitelinas / Thrombocytopenia and radial aplasia of benign course in monozygotic twins

Se describen dos gemelas con síndrome de trombocitopenia asociada a aplasia radial (TAR) que fueron seguidas desde el nacimiento hasta los seis años de edad. Ambas tenían trombocitopenia, alteraciones esqueléticas típicas, reacción leucemoide inicial, eosinofilia medular y disminución de los megacariocitos medulares, pero a diferencia de otros pacientes presentaron una evolución más bien benigna. Los autores no encontraron referencias a este síndrome en gemelos univitelinos, hecho que aparece respaldar la tesis de que el TAR es un problema de origen genético