Non-deflating balloon during pulmonary valvuloplasty.

A 3-year-old, 4.8 kg, male intact, mixed breed dog was referred for balloon pulmonary valvuloplasty (BPV). Echocardiography was consistent with severe type A pulmonic stenosis and BPV was recommended. During BPV, the balloon catheter failed to deflate despite multiple attempts at repositioning and the use of different deflation syringes. After approximately two minutes of cardiopulmonary arrest, forceful retrograde traction resulted in removal of the fully inflated balloon. Cardiopulmonary resuscitation was unsuccessful. Post-mortem evaluation by a board-certified pathologist identified rupture of the cranial vena cava and hemothorax, suspected to be secondary to forceful removal of the fully inflated balloon. Manufacturer's evaluation of the balloon catheter used in the procedure identified multiple kinks and a segment of stretched catheter shaft suspected to be the cause for the inability to deflate. A manufacturing defect present prior to use or predisposing to stretching of the catheter segment could not be ruled out. Kinking and/or stretching of the catheter during BPV were possible causes as well. Although the inability to deflate a balloon catheter seems to be a very rare occurrence, it should be considered as a potential complication of BPV.

Cri-du-Chat Syndrome: Revealing a Familial Atypical Deletion in 5p.

Introduction: Cri-du-chat syndrome is generally diagnosed when patients present a high-pitched cry at birth, microcephaly, ocular hypertelorism, and prominent nasal bridge. The karyotype is useful to confirm deletions in the short arm of chromosome 5 (5p-) greater than 10 Mb. In cases of smaller deletions, it is necessary to resort to other molecular techniques such as fluorescence in situ hybridization, multiplex ligation-dependent probe amplification (MLPA) or genomic array. Case Presentation: We report a family with an atypical deletion in 5p (mother and 2 children) and variable phenotypes compared with the literature. We applied a P064 MLPA kit to evaluate 5p- in the mother and the 2 children, and we used the Infinium CytoSNP-850K BeadChip genomic array to evaluate the siblings, an 11-year-old boy and a 13-year-old girl, to better define the 5p breakpoints. Both children presented a high-pitched cry at birth, but they did not present any of the typical physical features of 5p- syndrome. The MLPA technique with 5 probes for the 5p region revealed that the patients and their mother presented an atypical deletion with only 4 probes deleted (TERT_ex2, TERT_ex13, CLPTM1L, and IRX4). The genomic array performed in the siblings' samples revealed a 6.2-Mb terminal deletion in 5p15.33p15.32, which was likely inherited from their mother, who presented similar molecular features, seen in MLPA. Discussion: The sparing of the CTNND2 gene, which is associated with cerebral development, in both siblings may explain why these 2 patients had features such as better communication skills which most patients with larger 5p deletions usually do not present. In addition, both patients had smaller deletions than those found in patients with a typical 5p- phenotype. This report demonstrates the utility of genomic arrays as a diagnostic tool to better characterize atypical deletions in known syndromes such as 5p- syndrome, which will allow a better understanding of the genotype-phenotype correlations.

Heart rate distribution in dogs with third degree atrioventricular block and rate responsive pacemakers.

INTRODUCTION: In dogs, single lead ventricular pacing, ventricular sensing, inhibition response, rate adaptive (VVIR) pacemakers are routinely used to treat third degree atrioventricular block. The objectives of this study were to investigate the heart rate distribution in dogs with VVIR pacemakers, and report changes when activity settings were adjusted. ANIMALS: Eighteen client-owned dogs with VVIR pacemakers for third degree atrioventricular block. MATERIALS AND METHODS: This observational study consisted of a review of medical records of dogs with VVIR pacemakers. For dogs with >50% of paced beats at the lower pacing rate, the activity daily living (ADL) and exertion responses were increased. Re-evaluations were performed after 6-12 months. RESULTS: Heart rate distribution similar to healthy dogs was absent for all dogs. In nine dogs, the ADL and exertion responses were increased to the highest level. Of these, three dogs showed no improvement in heart rate distribution; for two dogs, one with an epicardial pacemaker, several activity settings were adjusted and pacing at higher heart rates was observed at re-evaluation. Four dogs died or were lost to follow-up. Clinical signs had resolved for all dogs after pacemaker implantation. CONCLUSION: Default activity settings of VVIR pacemakers do not result in heart rate distribution equivalent to healthy dogs. Increasing the ADL and exertion response settings to the highest levels did not improve the pacemaker rate response. Further investigations into the role of dog size, generator positioning, pacemaker settings, and whether rate responsiveness is required for dogs' quality and quantity of life are warranted.

Total bilirubin is an independent predictor of death in dogs with degenerative valvular disease and dilated cardiomyopathy.

INTRODUCTION: There is little published regarding the association between canine cardiovascular disease and the hepatic system. The objective of the study was to evaluate the relationship between hepatic parameters, survival, and disease stages of dogs with either dilated cardiomyopathy (DCM) or degenerative valvular disease (DVD). ANIMALS, MATERIALS, AND METHODS: Retrospective study analyzing hepatic parameters in dogs with DVD or DCM in American College of Veterinary Internal Medicine stage B or C and healthy control dogs. Associations between liver parameters, type and stage of disease, and survival were investigated. RESULTS: Ninety-nine dogs were included in the study: 61 DVD, 22 DCM, and 16 controls. Differences in liver parameter concentrations between DCM, DVD, and disease stages were found. Univariate analysis identified alanine aminotransferase (P < 0.001), aspartate aminotransferase (P = 0.02), and total bilirubin (P = 0.005) as predictors of mortality. In the multivariate analysis, total bilirubin remained an independent predictor of mortality. CONCLUSIONS: The observed differences between DCM, DVD, and disease stages are likely consistent with disease-specific hemodynamics and progression of disease. This and the role of total bilirubin as an independent predictor for mortality indicate that in dogs with DVD and DCM the cardiovascular-hepatic interaction might be of relevance for disease progression and outcome, as reported for humans with cardiac disease. Further studies into the role of hepatic function in canine cardiac disease are required.

Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.

Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.

Impact of achondroplasia on Latin American patients: a systematic review and meta-analysis of observational studies.

BACKGROUND: Achondroplasia (ACH), the most common form of disproportionate short stature, is caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene. Recent advances in drug therapy for ACH have highlighted the importance of elucidating the natural history and socioeconomic burden of this condition. Recognition that there are many potential issues for the patient with ACH is the first step in planning cost-effective interventions in Latin America (LATAM), a vast geographic territory comprising countries with multicultural characteristics and wide socioeconomic differences. We conducted a systematic literature review to characterize the impact of ACH on affected individuals and on healthcare resources in LATAM countries. METHODS: Searches of the global medical literature as well as regional and local medical literature up to August 2020. Observational studies on patients with ACH from any LATAM country. Pairs of reviewers independently screened eligible articles, extracted data from included studies, and assessed their risk of bias. RESULTS: Fifty-three unique studies (28 case series and cross-sectional studies and 25 case reports) including data on 1604 patients were eligible. Of these studies, 11 had data available for meta-analysis. Both premature mortality and all-cause mortality in the pooled studies was 15% [95% Confidence Interval (CI) 1.0E-3 to 0.47; I2 = 82.9%, p = 0.0029; three studies, n = 99 patients]. Frequency of cardio-respiratory-metabolic disorders was 17% [95% CI 0.04-0.37; I2 = 90.3%, p < 0.0001; four studies, n = 230 patients]; nervous system disorders was 18% [95% CI 0.07-0.33; I2 = 84.6%, p < 0.0001; six studies, n = 262 patients]; ear, nose, throat and speech disorders was 32% [95% CI 0.18-0.48; I2 = 73.4%, p = 0.0046; five studies, n = 183 patients]; and spinal issues including stenosis, compression and associated pain was 24% [95% CI 0.07-0.47; I2 = 91.3%, p < 0.0001; five studies, n = 235 patients]. CONCLUSIONS: There is currently evidence of high clinical burden in ACH patients in LATAM countries. Establishing the impact of ACH provides the necessary foundation for planning tailored and effective public health interventions.

Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface.

The goal of this study was to perform a clinical and molecular investigation in an eight-year-old female child diagnosed with hypophosphatasia (HPP). The proband and her family were evaluated by medical and dental histories, biochemical analyses, radiographic imaging, and genetic analysis of the tissue-nonspecific alkaline phosphatase (ALPL) gene. A bioinformatic analysis was performed to predict the structural and functional impact of the point mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) molecule and to define their potential contribution to the phenotype. We identified a novel combination of heterozygous ALPL missense variants in the proband, p.Ala33Val and p.Asn47His, compatible with an autosomal recessive mode of inheritance and resulting in skeletal and dental phenotypes. Computational modeling showed that the affected Asn47 residue is located in the coil structure close to the N-terminal α-helix, whereas the affected Ala33 residue is localized in the N-terminal α-helix. Both affected residues are located close to the homodimer interface, suggesting they may impair TNSALP dimer formation and stability. Clinical and biochemical follow-up revealed improvements after six years of ERT. Reporting this novel combination of ALPL variants in childhood HPP provides new insights into genotype-phenotype associations for HPP and specific sites within the TNSALP molecule potentially related to a childhood-onset HPP and skeletal and dental manifestations. Beneficial effects of ERT are implicated in skeletal and dental tissues.

Hidatidosis múltiple: un desafío diagnóstico y terapéutico. Reporte de un caso clínico en el estado Monagas. / Multiple hydatid disease: a diagnostic and therapeutic challenge. Clinical case report in Monagas

Introducción: La hidatidosis, conocida también como equinococosis quística (EQ), es una zoonosis poco frecuente causada por el parásito Echinococcus, de la clase de los céstodos, del filio platelmintos. Se han descrito cuatro especies, los de importancia médica en humanos son: el Echinococcus multilocularis, Echinococcus vogeli y Echinococcus granulosus , este último responsable del 95% de los casos reportados de hidatidosis humana. Frecuentemente afectan la cavidad abdominal ubicándose en hígado, bazo, riñón, músculo y es poco común en retroperitoneo. Caso clínico : se trata de paciente masculino de 30 años, presentando dolor abdominal en hemiabdomen derecho, con limitación funcional de la marcha y estreñimiento, posterior a estudios de imágenes, se confirma patología compatible con hidatidosis abdominal en retroperitoneo derecho, se inicia tratamiento médico antiparasitario por un mes y luego se realiza resolución quirúrgica para resección de quiste retroperitoneal derecho, con buenos resultados. Conclusión : Este reporte debe su importancia a la escasa frecuencia con que se ha documentado esta patología en el país, sobre todo en la región oriental(AU)

Introduction: Hydatid disease, also knowns as echinococcosis, is an uncommon zoonosis frequently caused by the Echinococcus parasite, class cestodes, and phylum flatworms. Four species have been described, the ones with human medical relevance are multilocularis echuinococcus, vogeli echinococcus y granulosus echinococcus, last one being responsible for 95% of the human hydatidosis cases reported. They frequently affect the abdominal cavity, are located in the liver, spleen, kidney, and muscle, and rarely in the retroperitoneum.Clinical case : it is about a male patient, 30 years old, with symptoms for 3 years, feeling abdominal pain in right hemi-abdomen, ambulation disturbance, and constipation; after imaging tests is confirmed pathology compatible with Hydatid disease in right hemi-abdomen, Antiparasitic medical treatment was started for a month and then open surgical resolution was performed by resection of the right retroperitoneal cyst, with good results.Conclusion : This report owes its importance to the limited documented cases in the country, especially in the eastern region. It is also relevant because of the little-known special surgical technique used and the constant influx of foreigners in the country with unusual epidemiological pathologies that require treatment during their stay(AU)

Human genomics of the humoral immune response against polyomaviruses.

Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. To identify human genetic determinants of the humoral immune response against polyomaviruses, we performed genome-wide association studies and meta-analyses of qualitative and quantitative immunoglobulin G responses against BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), Merkel cellpolyomavirus (MCPyV), WU polyomavirus (WUPyV), and human polyomavirus 6 (HPyV6) in 15,660 individuals of European ancestry from three independent studies. We observed significant associations for all tested viruses: JCPyV, HPyV6, and MCPyV associated with human leukocyte antigen class II variation, BKPyV and JCPyV with variants in FUT2, responsible for secretor status, MCPyV with variants in STING1, involved in interferon induction, and WUPyV with a functional variant in MUC1, previously associated with risk for gastric cancer. These results provide insights into the genetic control of a family of very prevalent human viruses, highlighting genes and pathways that play a modulating role in human humoral immunity.

Targeted massively parallel sequencing for congenital generalized lipodystrophy.

OBJECTIVE: Our aim is to establish genetic diagnosis of congenital generalized lipodystrophy (CGL) using targeted massively parallel sequencing (MPS), also known as next-generation sequencing (NGS). METHODS: Nine unrelated individuals with a clinical diagnosis of CGL were recruited. We used a customized panel to capture genes related to genetic lipodystrophies. DNA libraries were generated, sequenced using the Illumina MiSeq, and bioinformatics analysis was performed. RESULTS: An accurate genetic diagnosis was stated for all nine patients. Four had pathogenic variants in AGPAT2 and three in BSCL2. Three large homozygous deletions in AGPAT2 were identified by copy-number variant analysis. CONCLUSION: Although we have found allelic variants in only 2 genes related to CGL, the panel was able to identify different variants including deletions that would have been missed by Sanger sequencing. We believe that MPS is a valuable tool for the genetic diagnosis of multi-genes related diseases, including CGL.

Long-term impact of early initiation of enzyme replacement therapy in 34 MPS VI patients: A resurvey study.

Patients with mucopolysaccharidosis type VI (MPS VI) present with a wide range of disease severity and clinical manifestations, with significant functional impairment and shortened lifespan. Enzyme replacement therapy (ERT) with galsulfase has been shown to improve clinical and biochemical parameters including patient survival, quality of life and growth. The present study is a resurvey of 34 Brazilian MPS VI patients with rapidly progressive disease (classical phenotype) who initiated ERT with galsulfase under five years of age and had been on ERT until data collection in 2019, with few exceptions (n = 4 patients who died before 2019). Anthropometric measures, urinary glycosaminoglycans, and data regarding cardiac, orthopedic, neurologic, sleep apnea, hearing and ophthalmologic outcomes were filled in by specialists. Pubertal development, clinical complications, hospitalizations, and surgeries were also assessed. In this resurvey study, treatment with galsulfase has shown to be safe and well tolerated in MPS VI patients who initiated ERT under the age of 5 years and who have been undergoing ERT for approximately 10 years. Mortality rate suggests that early initiation of ERT may have a positive impact on patients' survival, improving but not preventing disease progression and death. MPS VI patients on ERT also showed improved growth velocity and the pubertal development was normal in all surviving patients. Follow-up data on pneumonia and hospitalization suggest that early ERT may have a protective effect against major respiratory complications. Cardiac valve disease progressed since their prior evaluation and spinal cord compression was observed in a large number of patients, suggesting that these disease complications were not modified by ERT.

Phenotype-genotype analysis of 242 individuals with RASopathies: 18-year experience of a tertiary center in Brazil.

We report the clinical and molecular data of a large cohort comprising 242 individuals with RASopathies, from a single Tertiary Center in Brazil, the largest study from Latin America. Noonan syndrome represented 76% of the subjects, with heterozygous variants in nine different genes, mainly PTPN11, SOS1, RAF1, LZTR1, and RIT1, detected by Sanger and next-generation sequencing. The latter was applied to 126 individuals, with a positive yield of 63% in genes of the RAS/MAPK cascade. We present evidence that there are some allelic differences in PTPN11 across distinct populations. We highlight the clinical aspects that pose more medical concerns, such as the cardiac anomalies, bleeding diathesis and proliferative lesions. The genotype-phenotype analysis between the RASopathies showed statistically significant differences in some cardinal features, such as craniofacial and cardiac anomalies, the latter also statistically significant for different genes in Noonan syndrome. We present two individuals with a Noonan syndrome phenotype, one with an atypical, structural cardiac defect, harboring variants in genes mainly associated with isolated hypertrophic cardiomyopathy and discuss the role of these variants in their phenotype.

Targeted massively parallel sequencing for congenital generalized lipodystrophy

ABSTRACT Objective: Our aim is to establish genetic diagnosis of congenital generalized lipodystrophy (CGL) using targeted massively parallel sequencing (MPS), also known as next-generation sequencing (NGS). Subjects and methods: Nine unrelated individuals with a clinical diagnosis of CGL were recruited. We used a customized panel to capture genes related to genetic lipodystrophies. DNA libraries were generated, sequenced using the Illumina MiSeq, and bioinformatics analysis was performed. Results: An accurate genetic diagnosis was stated for all nine patients. Four had pathogenic variants in AGPAT2 and three in BSCL2. Three large homozygous deletions in AGPAT2 were identified by copy-number variant analysis. Conclusions: Although we have found allelic variants in only 2 genes related to CGL, the panel was able to identify different variants including deletions that would have been missed by Sanger sequencing. We believe that MPS is a valuable tool for the genetic diagnosis of multi-genes related diseases, including CGL.

Lymphoproliferative disorder with polyautoimmunity and hypogammaglobulinemia: An unusual presentation of 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) has a heterogeneous presentation that includes multiple congenital anomalies and immunodeficiency, one of the most striking features. Usually, it is characterized by T cell lymphopenia, B cell dysfunction and autoimmunity. Here, we describe an unusual case of 22q11.2DS in a patient with lymphoproliferative disorder, polyautoimmunity and hypogammaglobulinemia.

Determination of the nonradiative conversion efficiency of lead mixed-halide perovskites using optical and photothermal spectroscopy.

Mixed-halide organic-inorganic hybrid perovskites are considered promising light-absorbing materials in the development of solar cells related to the obtained high-power conversion efficiency. Current efforts are focused on the study of the energy-conversion mechanisms, where the nonradiative recombination pathway is the least explored. In this work, a combination of optical and photoacoustic spectroscopies is used to determine the visible spectral light-into-heat conversion efficiency of lead-based mixed-halide organic-inorganic hybrid perovskites in a semicomplete n-i-p mesoscopic perovskite solar cell (PSC). A remarkable average conversion efficiency of about 87% has been found for the nonradiative combination in the perovskite, with the estimated composition ${{\rm FA}_{0.71}}{{\rm MA}_{0.29}}{{\rm PbI}_{2.9}}{{\rm Br}_{0.1}}$FA0.71MA0.29PbI2.9Br0.1 in the wavelength range of 400 to 800 nm. As a result, 13% of the incident light is transformed in radiative recombination processes and/or photodegradation of the material. Furthermore, the extinction coefficient and refractive index of the material are reported, and it was found that the optical constants and the optical absorption in the short-wavelength range are significantly smaller than previously reported for${{\rm MAPbI}_3}$MAPbI3.

Gene expression profile suggesting immunological dysregulation in two Brazilian Bloom's syndrome cases.

BACKGROUND: Bloom syndrome (BS) is a rare autosomal recessive chromosome instability disorder. The main clinical manifestations are growth deficiency, telangiectasic facial erythema, immunodeficiency, and increased risk to develop neoplasias at early age. Cytogenetic test for sister chromatid exchanges (SCEs) is used as a diagnostic marker for BS. In addition, most patients also present mutations in the BLM gene, related to defects in the DNA repair mechanism. However, the molecular mechanism behind the pathogenicity of BS is still not completely understood. METHODS: We describe two patients confirmed with BS by SCE and molecular analysis. Also, we performed the gene expression profile by the RNA-seq methodology in mRNA transcripts for differential gene expression analysis using as a biological condition for comparison BS versus health controls. RESULTS: We detected 216 differentially expressed genes related to immunological pathways such as positive regulation and activation of B cells, immune effector process and absence of difference of DNA repair genes expression. In addition; we also observed differentially expressed genes associated with apoptosis control, such as BCL2L1, CASP7, CDKN1A, E2F2, ITPR, CD274, TNFAIP6, TNFRSF25, TNFRSF13C, and TNFRSF17. CONCLUSION: Our results suggest that the combination of altered expression of genes involved in signaling pathways of immune response and apoptosis control may contribute directly to the main characteristics observed in BS, such as recurrent infections, growth failure, and high risk of cancer. Transcriptome studies of other instability syndromes could allow a more accurate analysis of the relevant gene interactions associated with the destabilization of the genome. This is a first description of the profile of differential gene expression related to immunological aspects detected in patients with BS by RNA-seq.

Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus.

PURPOSE: TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum. METHODS: Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR. RESULTS: We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified. CONCLUSION: We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.

Breakpoint delineation in 5p- patients leads to new insights about microcephaly and the typical high-pitched cry.

BACKGROUND: Cri du chat syndrome (CdCS) is a rare syndrome caused by a partial or complete deletion of the short arm of chromosome 5 (5p-). The main clinical features include a high-pitched cry, facial asymmetry, microcephaly, round face at birth, epicanthal folds, hypotonia, delayed growth and development. METHODS: We studied 14 Brazilian patients with CdCS using genomic array in order to better define the 5p breakpoints and recognize copy number variations (CNVs) that contribute to clinical manifestations associated with the syndrome. RESULTS: Array confirmed terminal deletions in 13 patients and an interstitial deletion in one patient. It was also possible to map the breakpoints and associate a genomic region of 4.7 Mb to the development of head circumference and cat-like cry. We also found other CNVs concomitant to the 5p deletion including a 9p duplication, a 17q deletion, and a 22q deletion in three different patients. CONCLUSION: With advancements of molecular cytogenomic methods in the last two decades, it was possible to evidence cryptic alterations and improve the genotype-phenotype correlation. In this work, we describe a new genomic region associated with microcephaly and cat-like cry and highlight the importance of precise delineation of 5p deletion breakpoints and detection of other CNVs in CdCS patients to improve genotype-phenotype correlation to perform a complete clinical and molecular diagnosis.