Next-generation sequencing profiling of miRNAs in individuals with 22q11.2 deletion syndrome revealed altered expression of miR-185-5p.

BACKGROUND: The 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with highly variable phenotypic manifestations, even though most patients present the typical 3 Mb microdeletion, usually affecting the same ~ 106 genes. One of the genes affected by this deletion is DGCR8, which plays a crucial role in miRNA biogenesis. Therefore, the haploinsufficiency of DGCR8 due to this microdeletion can alter the modulation of the expression of several miRNAs involved in a range of biological processes. RESULTS: In this study, we used next-generation sequencing to evaluate the miRNAs profiles in the peripheral blood of 12 individuals with typical 22q11DS compared to 12 healthy matched controls. We used the DESeq2 package for differential gene expression analysis and the DIANA-miTED dataset to verify the expression of differentially expressed miRNAs in other tissues. We used miRWalk to predict the target genes of differentially expressed miRNAs. Here, we described two differentially expressed miRNAs in patients compared to controls: hsa-miR-1304-3p, located outside the 22q11.2 region, upregulated in patients, and hsa-miR-185-5p, located in the 22q11.2 region, which showed downregulation. Expression of miR-185-5p is observed in tissues frequently affected in patients with 22q11DS, and previous studies have reported its downregulation in individuals with 22q11DS. hsa-miR-1304-3p has low expression in blood and, thus, needs more validation, though using a sensitive technology allowed us to identify differences in expression between patients and controls. CONCLUSIONS: Thus, lower expression of miR-185-5p can be related to the 22q11.2 deletion and DGCR8 haploinsufficiency, leading to phenotypic consequences in 22q11.2DS patients, while higher expression of hsa-miR-1304-3p might be related to individual genomic variances due to the heterogeneous background of the Brazilian population.

Leucemia mieloide aguda congénita con aplasia del timo / Congenital acute myeloid leukemia with thymic aplasia

La leucemia congénita es una entidad rara que se diagnostica entre el momento del nacimiento y los primeros 30 días de vida. Menos del 1 % de las leucemias de la infancia se diagnostican en el neonato. La hipoplasia severa o aplasia del timo se observa en el síndrome de Di George, que incluye varias malformaciones congénitas y déficit inmunológico, principalmente de células T por hipoplasia del timo, aunque se puede observar aplasia del timo en pacientes sin diagnóstico de Di George. Se presenta un caso diagnosticado como leucemia mieloide aguda congénita. En el momento del nacimiento presentó palidez mucocutánea intensa, petequias, equímosis generalizadas y hepatoesplenomegalia. El diagnóstico se confirmó por la presencia de blastos mieloides en periferia y médula ósea y por la caracterización inmunofenotípica de estas células. La necropsia confirmó la aplasia del timo.

Congenital leukemia is a rare disease in which a leukemic process is presented at birth or during the first 30 days of life. Less than 1 % of childhood leukemia is diagnosed in newborns. The severe hypoplasia or total thymic aplasia is seen at Di George syndrome which includes several birth defects and immune deficit, mainly of T cells by thymic hypoplasia; nevertheless, severe thymic hypoplasia can be observed in patients without diagnosis of Di George. We report a case of congenital acute myeloid leukemia who presented intense paleness generalized petechiae and ecchymoses as well as hepatosplenomegaly. The diagnosis was confirmed by the presence of blasts in peripheral blood smear and bone marrow aspirate. Immunophenotyping was performed and contributed to a definitive diagnosis. The autopsy confirmed the thymic aplasia.

DiGeorge Syndrome: a not so rare disease.

INTRODUCTION: The DiGeorge Syndrome was first described in 1968 as a primary immunodeficiency resulting from the abnormal development of the third and fourth pharyngeal pouches during embryonic life. It is characterized by hypocalcemia due to hypoparathyroidism, heart defects, and thymic hypoplasia or aplasia. Its incidence is 1:3000 live births and, despite its high frequency, little is known about its natural history and progression. ←This is probably due to diagnostic difficulties and the great variety of names used to describe it, such as velocardiofacial, Shprintzen, DiGeorge, and CATCH 22 Syndromes, as well as conotruncal facial anomaly. All represent the same genetic condition, chromosome 22q11.2 deletion, which might have several clinical expressions. OBJECTIVES: To describe clinical and laboratorial data and phenotypic characteristics of patients with DiGeorge Syndrome. METHODS: Patients underwent standard clinical and epidemiological protocol and tests to detect heart diseases, facial abnormalities, dimorphisms, neurological or behavioral disorders, recurrent infections and other comorbidities. RESULTS: Of 14 patients (8m - 18y11m), only one did not have 22q11.2 deletion detected. The main findings were: conotruncal malformation (n = 12), facial abnormalities (n = 11), hypocalcemia (n = 5) and low lymphocyte count (n=2). CONCLUSION: The authors pointed out the necessity of DGS suspicion in all patient presenting with heart defects, facial abnormalities (associated or not with hypocalcemia), and immunological disorders because although frequency of DGS is high, few patients with a confirmed diagnosis are followed up.

DiGeorge Syndrome: a not so rare disease

INTRODUCTION: The DiGeorge Syndrome was first described in 1968 as a primary immunodeficiency resulting from the abnormal development of the third and fourth pharyngeal pouches during embryonic life. It is characterized by hypocalcemia due to hypoparathyroidism, heart defects, and thymic hypoplasia or aplasia. Its incidence is 1:3000 live births and, despite its high frequency, little is known about its natural history and progression. ←This is probably due to diagnostic difficulties and the great variety of names used to describe it, such as velocardiofacial, Shprintzen, DiGeorge, and CATCH 22 Syndromes, as well as conotruncal facial anomaly. All represent the same genetic condition, chromosome 22q11.2 deletion, which might have several clinical expressions. OBJECTIVES: To describe clinical and laboratorial data and phenotypic characteristics of patients with DiGeorge Syndrome. METHODS: Patients underwent standard clinical and epidemiological protocol and tests to detect heart diseases, facial abnormalities, dimorphisms, neurological or behavioral disorders, recurrent infections and other comorbidities. RESULTS: Of 14 patients (8m - 18y11m), only one did not have 22q11.2 deletion detected. The main findings were: conotruncal malformation (n = 12), facial abnormalities (n = 11), hypocalcemia (n = 5) and low lymphocyte count (n=2). CONCLUSION: The authors pointed out the necessity of DGS suspicion in all patient presenting with heart defects, facial abnormalities (associated or not with hypocalcemia), and immunological disorders because although frequency of DGS is high, few patients with a confirmed diagnosis are followed up.

Corpus callosum morphology and ventricular size in chromosome 22q11.2 deletion syndrome.

In this paper, novel methods were used to map the corpus callosum morphology of children with chromosome 22q11.2 deletion syndrome in order to further investigate changes to that structure and to examine their possible effects on cognitive function. The callosal profiles were extracted from the centermost MRI midsagittal slice by supervised thresholding and the structure's boundary and midline were computed automatically. Difference analysis was based on non-rigid registration, in which a template image is warped to conform to the shape of each corpus callosum in the sample. Boundaries and midlines were registered to a template and the results used to determine the average callosal shapes for children with the deletion and for controls. Pointwise registration also enabled the detailed evaluation of callosal curvature, width, area and length. Significant differences between the two groups were found in shape, size and bending angle. Results showed group differences that were concentrated in the anterior part of the structure, more specifically in the rostrum, which was larger and longer in the group with the syndrome. Correlation analyses showed that ventricular enlargement does not fully account for callosal morphology differences in children with the deletion. However, areal measurements did reveal important relationships between changes in callosal morphology and cognitive function. These novel findings reveal intricate relationships between genetic and disease-specific factors in the callosal anatomy and the potential impact of those changes on cognitive functions.

Infecciones asociadas a inmunodeficiencias primarias 1970-1994 servicio anatomía patológica Hospital Miguel Pérez Carreño / Infections associated immunodeficiency primary 1970-1994 service pathological anatomy Hospital Miguel Pérez Carreño

Las inmunodeficiencias primarias son un aspecto de la patología inmunitaria aún en estudio, de gran relevancia a lo que contribuye la serie estudiada de pacientes con inmunodeficiencias primarias. Se realizó un estudio restrospectivo en registros de patología del Hospital Miguel Pérez Carreño donde se encontraron 2.244 autopsias (período 1970-1994). De éstas 10(0,4 por ciento) correspondieron con inmunodeficiencias primarias. Con el fin de estudiar sus complicaciones infecciosas y aspectos clínicos patológicos, se revisaron las autopsias con el diagnóstico de inmunodeficiencias primarias, en relación a complicaciones infecciosas. El material fue procesado y evaluado conforme a técnicas estándar. Los resultados fueron expresados en términos absolutos, porcentuales y promediales, usando la prueba de T de Student (grado de confianza de 95 por ciento; p<0,05). Los casos de inmunodeficiencias primarias, todos presentaron alguna complicación infecciosa. La edad promedio fue de 6,4 ± 5,7 meses (70 por ciento lactantes menores (30 por ciento lactantes mayores) (p>0,05). Seis casos (60 por ciento) fueron masculinos y 4 (40 por ciento) femeninos (p<0,05). En relación con el tipo de inmunodeficiencia primaria, correspondieron principalmente con Sindrome de DiGeorge (40 por ciento) (p<0,005) e inmunodeficiencia combinada (20 por ciento). Se encontró que el 60 por ciento presentó infección respiratoria baja (p<0,05), 40 por ciento presentó enterocolitis bacteriana, en tanto que 30 por ciento tuvieron diarrea. Sería interesante concluir haciéndonos la interrogante de que, si las infecciones respiratorias y más aún las diarreas, dada su morbilidad en 5 años, cuantos casos que fallecen no se han llevado consigo como secreto un diagnóstico no realizado de una inmunodeficiencia primaria

The spectrum of the DiGeorge syndrome.

Clinical and autopsy data on 25 patients with DiGeorge syndrome and its variants are presented. Congenital heart disease was the most common presenting complaint; 15 patients came to medical attention in the first 48 hours of life because of cyanosis, cardiac murmurs, or tachycardia and tachypnea. Two unusual anomalies, interrupted aortic arch or truncus arteriosus, were seen in 17 patients. Clinically documented hypocalcemia associated with seizures was seen in ten patients, with a median age at onset of eight days. Fifteen of our 25 patients died at less than one month of age. Most of the patients surviving the first month of life developed purulent rhinitis, maculopapular rashes, failure to thrive, and developmental delay. Sixteen patients had major congenital anomalies not localized to the anterior neck and thorax; these anomalies included arhinencephaly, cleft lip, palate, or uvula, diaphragmatic abnormalities, hydronephrosis, malrotation of the gut and imperforate anus. The 24 autopsied cases constitute 0.7% of the 3,469 sequential postmortem studies done in the period 1950--1975 at The Children's Orthopedic Hospital and Medical Center.