[Wiskott-Aldrich syndrome with platelets of normal size and c.295C>T mutation of the WAS gene. Case report]. / Síndrome de Wiskott-Aldrich con plaquetas de tamaño normal y mutación c.295C>T en el gen WAS. Informe de caso.

BACKGROUND: Wiskott-Aldrich syndrome is an Inborn Error of Immunity characterized by thrombocytopenia, small platelets, severe eczema, recurrent infections, tendency to autoimmune diseases and neoplasms. The diagnosis of the syndrome can be difficult, especially when platelets are of normal size. CASE REPORT: A three-year-old male patient was referred to a specialized sector of university hospital for presenting acute otitis media that progressed to sepsis by Haemophilus influenzae. At one month of age, he had been diagnosed with autoimmune thrombocytopenia, and splenectomy was performed at two years of age. During follow-up, three hospitalizations were necessary: an infection by Streptococcus pneumoniae, which progressed to sepsis; one due to exacerbation of eczema, isolating S. epidermidis; another due to fever of undetermined origin. The tests showed normal number of platelets after splenectomy, platelets always with normal size. At age four, tests were performed: IgE 3128 Ku/L; IgA, IgG, and normal anti-polysaccharide antibodies; decreased IgM; decrease CD19, TCD4, naïve T and B; increased TCD8; normal NK. A diagnostic hypothesis of "probable" WAS was made. Genetic research has identified the c.295C>T mutation in the WAS gene. CONCLUSIONS: The case reported expressed a new mutation in the SWA gene, characterized by clinical manifestations of the mild phenotype of Wiskott-Aldrich syndrome, with thrombocytopenia, platelets of normal size, and X-linked inheritance. It is important to establish the early diagnosis and treatment to offer a better quality of life in these patients.

ANTECEDENTES: El síndrome de Wiskott-Aldrich es un error innato de la inmunidad, distinguido por trombocitopenia, plaquetas pequeñas, eccema severo, infecciones recurrentes, y susceptibilidad a enfermedades autoinmunes y neoplasias. El diagnóstico es difícil de establecer, especialmente cuando las plaquetas son de tamaño normal. REPORTE DE CASO: Paciente masculino de 3 años, enviado al Hospital Universitario da Santa Casa de São Paulo, Brasil, por otitis media aguda, con evolución a sepsis por Haemophilus influenzae. Al mes de edad fue diagnosticado con trombocitopenia autoinmune, y a los 2 años se llevó a cabo explenectomía. Durante el seguimiento requirió tres hospitalizaciones: una por infección por Streptococcus pneumoniae, que evolucionó a sepsis; otra por exacerbación de eccema, aislándose S. epidermidis, y la última por fiebre de origen indeterminado. Las pruebas de laboratorio informaron: concentración de plaquetas dentro de los valores de referencia después de la esplenectomía, y de tamaño normal. A los 4 años se efectuaron nuevas pruebas, que reportaron: IgE 3128 kU/L; IgA, IgG y anticuerpos anti-polisacáridos normales; disminución de IgM y de CD19, TCD4, T y B vírgenes; aumento de TCD8; NK normales. Se sospechó el diagnóstico de síndrome de Wiskott-Aldrich. Mediante estudios de genética se identificó la mutación c.295C>T en el gen WAS. CONCLUSIONES: El caso aquí expuesto expresó una nueva mutación en el gen SWA, caracterizado por manifestaciones clínicas de fenotipo leve del síndrome de Wiskott-Aldrich, con trombocitopenia, plaquetas de tamaño normal y herencia ligada al cromosoma X. Es importante establecer el diagnóstico y tratamiento oportunos para ofrecer una mejor calidad de vida en estos pacientes.

The surgical management of a patient with chronic renal failure and macrothrombocytopenia related to the MYH9 gene mutation: A case report.

MYH9 disease is a rare genetic disorder in which there is a mutation in the gene for the non-muscle myosin heavy chain IIA. It initially causes macrothrombocytopenia followed by other clinical manifestations. When the patient reaches adulthood, he can develop chronic kidney failure. Thus, the risk of suffering a hemorrhage, difficulty in repairing and, infections increases in individuals with this disease. In addition, the use of drugs in these patients should be carefully evaluated. An adult patient sought dental care with a complaint associated with a tooth with advanced dental caries. He had severe thrombocytopenia (7000 platelets/mm3 ), hearing loss, and chronic kidney failure. The diagnosis of MYH9 disease was confirmed through genotyping. After clinical examination, extraction was planned. Local and systemic procedures were used to prevent hemorrhage, especially postoperatively. Although the patient had an infection at the surgical wound site and no episode of postoperative bleeding, the repair process occurred normally. The purpose of this article is to report the surgical management of a patient with MYH9 disease.

Involvement of von Willebrand factor and botrocetin in the thrombocytopenia induced by Bothrops jararaca snake venom.

Patients bitten by snakes consistently manifest a bleeding tendency, in which thrombocytopenia, consumption coagulopathy, mucous bleeding, and, more rarely, thrombotic microangiopathy, are observed. Von Willebrand factor (VWF) is required for primary hemostasis, and some venom proteins, such as botrocetin (a C-type lectin-like protein) and snake venom metalloproteinases (SVMP), disturb the normal interaction between platelets and VWF, possibly contributing to snakebite-induced bleedings. To understand the relationship among plasma VWF, platelets, botrocetin and SVMP from Bothrops jararaca snake venom (BjV) in the development of thrombocytopenia, we used (a) Wistar rats injected s.c. with BjV preincubated with anti-botrocetin antibodies (ABA) and/or Na2-EDTA (a SVMP inhibitor), and (b) VWF knockout mice (Vwf-/-) injected with BjV. Under all conditions, BjV induced a rapid and intense thrombocytopenia. In rats, BjV alone reduced the levels of VWF:Ag, VWF:CB, high molecular weight multimers of VWF, ADAMTS13 activity, and factor VIII. Moreover, VWF:Ag levels in rats that received BjV preincubated with Na2-EDTA and/or ABA tended to recover faster. In mice, BjV caused thrombocytopenia in both Vwf-/- and C57BL/6 (background control) strains, and VWF:Ag levels tended to decrease in C57BL/6, demonstrating that thrombocytopenia was independent of the presence of plasma VWF. These findings showed that botrocetin present in BjV failed to affect the extent or the time course of thrombocytopenia induced by envenomation, but it contributed to decrease the levels and function of plasma VWF. Thus, VWF alterations during B. jararaca envenomation are an ancillary event, and not the main mechanism leading to decreased platelet counts.

Rare inherited kidney diseases: an evolving field in Nephrology.

There are more than 150 different rare genetic kidney diseases. They can be classified according to diagnostic findings as (i) disorders of growth and structure, (ii) glomerular diseases, (iii) tubular, and (iv) metabolic diseases. In recent years, there has been a shift of paradigm in this field. Molecular testing has become more accessible, our understanding of the underlying pathophysiologic mechanisms of these diseases has evolved, and new therapeutic strategies have become more available. Therefore, the role of nephrologists has progressively shifted from a mere spectator to an active player, part of a multidisciplinary team in the diagnosis and treatment of these disorders. This article provides an overview of the recent advances in rare hereditary kidney disorders by discussing the genetic aspects, clinical manifestations, diagnostic, and therapeutic approaches of some of these disorders, named familial focal and segmental glomerulosclerosis, tuberous sclerosis complex, Fabry nephropathy, and MYH-9 related disorder.

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)

Nonalcoholic Fatty Liver Disease and Thrombocytopenia III: Its Association With Insulin Resistance.

Thrombocytopenia (less than 100 × 109/L platelets) presents in around one quarter of patients with nonalcoholic fatty liver disease (NAFLD), the hepatic component of insulin resistance (IR). It is unknown whether IR, by itself, associates with thrombocytopenia. Persons with NAFLD and/or IR were prospectively accrued in the study after February 2018. Insulin resistance was defined by assessing α hydroxybutyrate, lynoleoyl glycerolphosphocoline, oleic acid, and insulin (Quantose IR), whereas the presence of NAFLD was defined by serologic determinations (Fibromax) and liver transient elastography (Fibroscan). In 78 patients with NAFLD, thrombocytopenia was identified in 22 (28%), whereas in 19 persons with IR, 14 (73%) were found to have NAFLD. In persons with IR + NAFLD, thrombocytopenia presented in 9 (64%). In the subset of patients with IR, the prevalence of thrombocytopenia was 52%. There was only 1 patient with IR/without NAFLD who displayed thrombocytopenia. Significant statistical association between NAFLD and thrombocytopenia was found (odds ratio [OR]: = 13, confidence interval [CI]: 1.5-162, P = .05), whereas there was no association between IR and thrombocytopenia (OR = 0.38, CI: 0.06-2.3, P = .61). Insulin resistance, by itself, was not found to be associated with diminished platelet counts. The presence of NAFLD, one of the consequences of IR, seems to be required to lead into thrombocytopenia.

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.

[Hereditary thrombocytopenia associated with a mutation in the MYH-9 gene. Report of one case]. / Trombocitopenia hereditaria relacionada a gen MYH-9: Primera familia reportada en Chile con diagnóstico molecular. Caso clínico.

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.

Intermittent low platelet counts hampering diagnosis of X-linked thrombocytopenia in children: report of two unrelated cases and a novel mutation in the gene coding for the Wiskott-Aldrich syndrome protein.

BACKGROUND: Thrombocytopenia can occur in different circumstances during childhood and although immune thrombocytopenia is its most frequent cause, it is important to consider other conditions, especially when there is a persistent or recurrent low platelet count. We report two cases of intermittent thrombocytopenia, previously misdiagnosed as immune thrombocytopenia. CASES PRESENTATION: Both cases described were boys who presented with an intermittent pattern of thrombocytopenia, with a persistently low mean platelet volume. In both patients, peripheral blood smear revealed small platelets and flow cytometry showed low expression of Wiskott-Aldrich syndrome protein (WASP) in leucocytes. Molecular analysis of the first case identified a mutation in exon 2 of the gene coding for WASP, leading to a p.Thr45Met amino acid change and confirming the diagnosis of X-linked thrombocytopenia. In the second case, a novel missense mutation in exon 2 of the gene coding for WASP was detected, which resulted in a p.Pro58Leu amino acid change. CONCLUSION: These two rare presentations of thrombocytopenia highlight the importance of evaluating the peripheral blood smear in the presence of recurrent or persistent thrombocytopenia and show that failing to do so can lead to misdiagnoses. Since thrombocytopenia may be found in pediatric outpatient clinic, increased awareness among general pediatricians will help to improve the differential diagnosis of this condition.

Differential expression of SDF-1 receptor CXCR4 in molecularly defined forms of inherited thrombocytopenias.

The SDF-1-CXCR4 axis plays an essential role in the regulation of platelet production, by directing megakaryocyte (MK) migration toward the vascular niche, thus allowing terminal maturation and proplatelet formation, and also regulates platelet function in an autocrine manner. Inherited thrombocytopenias (IT) comprise a spectrum of diverse clinical conditions caused by mutations in genes involved in platelet production and function. We assessed CXCR4 expression and SDF-1 levels in a panel of well-characterized forms of IT. Decreased surface CXCR4 levels were found in 8 of 27 (29.6%) IT patients by flow cytometry, including 4 of 6 patients with ANKRD26-RT, 3 of 3 patients with GPS and 1 of 6 patients with FPD/AML. Low CXCR4 levels were associated with impaired SDF-1-triggered platelet aggregation, indicating that this decrease is functionally relevant, whereas a normal platelet response was shown in patients harbouring preserved membrane CXCR4. Reduced CXCR4 was not due to decreased gene expression, as platelet RNA levels were normal or increased, suggesting a post-transcriptional defect. Increased ligand-induced receptor internalization was ruled out, as circulating SDF-1 levels were similar to controls. MK CXCR4 expression was normal, indicating that the defect in CXCR4 arises after the step of platelet biogenesis. In conclusion, the finding of defective CXCR4 expression specifically associated with certain IT disorders highlights the fact that abnormalities in several megakaryocytic regulators underlie IT pathogenesis and further reveal the heterogeneous nature of these conditions.

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)

Genotyping of Human Platelet Antigens by BeadChip Microarray Technology.

Human platelet antigen (HPA) typing plays a critical role in the diagnosis of fetal/neonatal alloimmune thrombocytopenia, and the prevention of posttransfusion purpura and refractoriness to platelet transfusions. The recent development of high-throughput genotyping methods, allowing simultaneous genotyping of as many as 17 HPAs, is of utmost interest for saving time and money. Here, we describe a microarray technology named "BeadChip," designed for HPA-1 to -9, -11, and -15 genotyping of up to 96 individuals, in approximately 5 h. This technology was used to study allele frequencies in Brazilian blood donors, considering the heterogeneous ethnic composition.

Proteins of the mitotic checkpoint and spindle are related to chromosomal instability and unfavourable prognosis in patients with myelodysplastic syndrome.

AIMS: To study the immunoexpression of proteins related to the mitotic checkpoint (cell division cycle 20 (CDC20), mitotic arrest deficient 2 (MAD2)) and the mitotic spindle (Aurora-B) in patients with myelodysplastic syndrome (MDS). METHODS: Protein expression was analysed in bone marrow tissue samples from 40 patients with MDS using immunohistochemistry. Prognostic markers (transfusion dependency, depth of cytopenias, chromosomal abnormalities and survival) were also studied. RESULTS: Higher MAD2 expression was observed among patients with platelets <50×10(9)/L than among patients with platelets ≥50×10(9)/L (42.6±22.8% vs 22.7±19.1%, respectively). Higher CDC20 expression was identified among patients with three dysplasias compared with patients who presented with one or two dysplasias (33.9±24.1% vs 10.5±5.7% vs 12.8±7.8%, respectively), among patients who exhibited a complex versus non-complex karyotype (50.0±30.2% vs 18.4±14%, respectively) and among patients with platelets <50×10(9)/L vs platelets ≥50×10(9)/L (38.2±26.2% vs 16.1±12.4%, respectively). Higher Aurora-B expression was found in patients with an abnormal versus normal karyotype (21.2±13.2% vs 7.5±5.0%, respectively). High expression of MAD2 and CDC20 (≥50%) was associated with severe thrombocytopenia. We also found statistically significant differences in the overall survival rate when comparing different degrees of CDC20, MAD2 and Aurora-B protein expression. CONCLUSIONS: To the best of our knowledge, this is the first report to demonstrate that these proteins are associated with chromosomal abnormalities and poor prognosis in patients with MDS.

Disruption of hSWI/SNF complexes in T cells by WAS mutations distinguishes X-linked thrombocytopenia from Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS), an immunodeficiency disorder, and X-linked thrombocytopenia (XLT), a bleeding disorder, both arise from nonsynonymous mutations in WAS, which encodes a hematopoietic-specific WASp. Intriguingly, XLT evolves into WAS in some patients but not in others; yet the biological basis for this cross-phenotype (CP) effect remains unclear. Using human T-helper (TH) cells expressing different disease-causing WAS mutations, we demonstrated that hSWI/SNF-like complexes require nuclear-WASp to execute their chromatin-remodeling activity at promoters of WASp-target, immune function genes during TH1 differentiation. Hot-spot WAS mutations Thr45Met and Arg86Cys, which result in XLT-to-WAS disease progression, impair recruitment of hBRM- but not BRG1-enriched BAF complexes to IFNG and TBX21 promoters. Moreover, promoter enrichment of histone H2A.Z and its catalyzing enzyme EP400 are both impaired. Consequently, activation of Notch signaling, a hBRM-regulated event, and its downstream effector NF-κB are both compromised, along with decreased accessibility of nucleosomal DNA and inefficient transcription-elongation of WASp-target TH1 genes. In contrast, patient mutations Ala236Gly and Arg477Lys that manifest in XLT without progressing to WAS do not disrupt chromatin remodeling or transcriptional reprogramming of TH1 genes. Our study defines an indispensable relationship between nuclear-WASp- and hSWI/SNF-complexes in gene activation and reveals molecular distinctions in TH cells that might contribute to disease severity in the XLT/WAS clinical spectrum.

The presence of -308A TNFα is associated with anemia and thrombocytopenia in patients with myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematological diseases characterized by refractory cytopenia(s). MDS patients show increased levels of tumor necrosis factor alpha (TNFα) which is a multifunctional proinflammatory cytokine. The aim of this work is to examine the presence of -308A/G TNFα variants and to analyze whether it is associated with clinical parameters in a cohort of 101 Argentinean de novo MDS patients. The A/A+A/G genotype at TNFα -308 was overrepresented 2-fold in our population (p=0.0499, odds ratio-OR: 2.107) and these differences were more evident in RA-FAB subtype (p=0.0424, OR: 2.502). The presence of the high expressing -308A allele was associated with lower hemoglobin level (8.3 vs 9.9g/dL; p=0.0206), reduced platelet counts (89,000 vs 130,000/µL; p=0.0381) and younger age (59 vs 68years; p=0.0122) at diagnosis. Also, these patients showed 3.8-fold higher risk of transfusion requirement (76% vs 46%, p=0.0105) during the follow up. In conclusion, the presence of an inherited -308A TNFα, which increases its transcription level, was associated with the MDS phenotype in our cohort of Argentine MDS patients. Also, an overexpression of TNFα may promote an underlying proinflammatory state that cooperates with intrinsic defects within MDS progenitors to increase the severity of certain phenotypic features of the disease.

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(AU)

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(AU)

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