ResearchPad - clinical-report https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Expansion of the phenotype of lateral meningocele syndrome]]> https://www.researchpad.co/article/elastic_article_8284 Lateral meningocele syndrome (LMS) is due to specific pathogenic variants in the last exon of NOTCH3 gene. Besides the lateral meningoceles, this condition presents with dysmorphic features, short stature, congenital heart defects, and feeding difficulties. Here, we report a girl with neurosensorial hearing loss, severe gastroesophageal reflux disease, congenital heart defects, multiple renal cysts, kyphosis and left‐convex scoliosis, dysmorphic features, and mild developmental delay. Exome sequencing detected the previously unreported de novo loss‐of‐function variant in exon 33 of NOTCH3 p.(Lys2137fs). Following the identification of the gene defect, MRI of the brain and spine revealed temporal encephaloceles, inner ears anomalies, multiple spinal lateral meningoceles, and intra‐ and extra‐dural arachnoid spinal cysts. This case illustrates the power of reverse phenotyping to establish clinical diagnosis and expands the spectrum of clinical manifestations related to LMS to include inner ear abnormalities and multi‐cystic kidney disease.

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<![CDATA[Paternal mosaicism for a novel <i>PBX1</i> mutation associated with recurrent perinatal death: Phenotypic expansion of the <i>PBX1</i>‐related syndrome]]> https://www.researchpad.co/article/elastic_article_7108 Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra‐renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one‐day‐old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post‐zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow‐up studies for presumed de novo and low‐level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.

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<![CDATA[Novel compound heterozygous stop‐gain mutations of <i>LRBA</i> in a Vietnamese patient with Common Variable Immune Deficiency]]> https://www.researchpad.co/article/elastic_article_6649 We describe the clinical, immunological, and genetic analyses of a Vietnamese patient presenting with typical and atypical symptoms of common variable immune deficiency. Whole exome sequencing revealed novel compound stop‐gain mutations of LRBA. Our findings also expand the already broad range of known CVID clinical phenotypes and contribute to the understanding of phenotype–genotype correlation in LRBA deficiency.

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<![CDATA[Clinical and genetic data of 22 new patients with <i>SMAD3</i> pathogenic variants and review of the literature]]> https://www.researchpad.co/article/elastic_article_6643 Pathogenic SMAD3 variants are responsible for a cardiovascular phenotype, mainly thoracic aortic aneurysms and dissections, with variable expressivity and incomplete penetrance. To investigate the clinical variability observed within SMAD3 patients, we reviewed the data of 22 new patients from our Centre and of 133 patients reported in the literature. We first aimed to delineate an estimated frequency of the main clinical signs associated with SMAD3 pathogenic variants and, then, to look for genotype‐phenotype correlations. We showed herein the absence of correlation between the SMAD3 variant type and the occurrence of an aortic phenotype in patients. This report brings additional data for the genotype‐phenotype correlations of SMAD3 variants and the need to explore in more detail the effects of genetic modifiers that could influence the phenotype.

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<![CDATA[Profound intellectual disability caused by homozygous TRAPPC9 pathogenic variant in a man from Malta]]> https://www.researchpad.co/article/elastic_article_6639 A man previously diagnosed with autism spectrum disorder secondary to intellectual disability, absent speech and repetitive behaviors was found to have homozygous pathogenic variants in TRAPPC9. In the context of the currently reported 48 known cases of TRAPPC9 pathogenic variants, his phenotype is consistent with previously reported phenotypes. Interestingly, it is found that, although the known pathogenic variants do not cluster in respect to location within the gene, the known cases all appears to be from a localized geographic area.

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<![CDATA[A preliminary computational outputs versus experimental results: Application of sTRAP, a biophysical tool for the analysis of SNPs of transcription factor‐binding sites]]> https://www.researchpad.co/article/elastic_article_6626 We tested sTRAP to do some analysis on DNA variations in the cognate binding sites of specific transcription factors, for which there were the results of the experimental approaches, in the literature. At the same time, we compared the results of both of the procedures with the data of another bioinformatics model RAVEN, as an alternative one.

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<![CDATA[Novel compound heterozygous pathogenic variants in <i>ASCC1</i> in a Chinese patient with spinal muscular atrophy with congenital bone fractures 2 : Evidence supporting a "Definitive" gene‐disease relationship]]> https://www.researchpad.co/article/elastic_article_6622 Spinal muscular atrophy with congenital bone fractures 2.

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<![CDATA[Rapid detection by <i>hydrops panel</i> of Noonan syndrome with <i>PTPN11</i> mutation (p.Thr73Ile) and persistent thrombocytopenia]]> https://www.researchpad.co/article/elastic_article_6615 Nonimmunological hydrops fetalis (NIHF) is still a challenging diagnosis. The success of identifying a cause depends on the thoroughness of efforts to establish a diagnosis. We report a premature with NIHF. The hydrops panel revealed Noonan syndrome (NS) with a mutation in PTPN11 c.218C>T (p.Thr73Ile). The variant of c.218C>T (p.Thr73Ile) has not yet been described in literature relating to NIHF. Only a few case reports of this variant are known.

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<![CDATA[Isoflurane Sedation in Patients Undergoing Venoarterial Extracorporeal Membrane Oxygenation Treatment for Cardiogenic Shock—An Observational Propensity-Matched Study]]> https://www.researchpad.co/article/N9104cd1c-2cd8-4a43-9b14-23baf30f292c

Objectives:

The feasibility and hemodynamic effects of isoflurane sedation in cardiogenic shock in the presence of venoarterial extracorporeal membrane oxygenation treatment are currently unknown.

Design:

Retrospective single-center study.

Setting:

Cardiac ICU of Munich university hospital.

Patients/Subjects:

Cardiogenic shock patients with venoarterial extracorporeal membrane oxygenation treatment under sedation with volatile isoflurane between November 2018 and October 2019 have been enrolled in this study and were matched by propensity score in a 1:1 ratio with IV sedated patients treated between January 2013 and November 2018 from the cardiogenic shock registry of the university hospital of Munich.

Measurements and Main Results:

Isoflurane sedation was used in 32 patients with cardiogenic shock and venoarterial extracorporeal membrane oxygenation treatment. The mean age of conventionally sedated patients was 58.4 ± 13.8 years and 56.3 ± 11.5 years for patients with isoflurane sedation (p = 0.51). Administration of isoflurane was associated with lower IV sedative drug use during venoarterial extracorporeal membrane oxygenation treatment (86% vs 32%; p = 0.01). Mean systolic arterial pressure was similar (94.3 ± 12.6 vs 92.9 ± 10.5 mm Hg; p = 0.65), but mean heart rate was significantly higher in the conventional sedation group, when compared with the isoflurane group (85.2 ± 20.5 vs 74.7 ± 15.0 beats/min; p = 0.02). Catecholamine doses, venoarterial extracorporeal membrane oxygenation blood and gas flow, ventilation time (304 ± 143 vs 398 ± 272 hr; p = 0.16), bleeding complications bleeding academic research consortium 3a or higher (59.3% vs 65.3%; p = 0.76), and 30-day mortality (59.2% vs 63.4%, p = 0.80) were similar in both groups. The overall sedation costs per patient were significantly lower in the conventional group, when compared with the isoflurane group (537 ± 624 vs 1280 ± 837 €; p < 0.001).

Conclusions:

Volatile sedation with isoflurane is feasible—albeit at higher costs—in patients with cardiogenic shock and venoarterial extracorporeal membrane oxygenation treatment and was not associated with higher catecholamine dosage or extracorporeal membrane oxygenation flow rate compared with IV sedation.

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<![CDATA[Effect of Flumazenil on Hypoactive Delirium in the ICU: A Double-Blind, Placebo-Controlled Pilot Study]]> https://www.researchpad.co/article/N53f49160-8a46-4e98-8abd-6fc0cc19ed10

Supplemental Digital Content is available in the text.

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<![CDATA[A Syrian patient with Steel syndrome due to compound heterozygous COL27A1 mutations with colobomata of the eye]]> https://www.researchpad.co/article/Na7068733-8a24-4fe8-a99d-b515021d59c7

Abstract

The joint occurrence of short stature, congenital dislocation of the hip, carpal coalition, dislocation of the radial head, cavus deformity, scoliosis, and vertebral anomalies was first described in 1993 by Steel et al. (OMIM #615155) in 23 children from Puerto Rico. The condition is caused by a deficient matrix protein, collagen type XXVII alpha 1 chain, due to bi‐allelic loss of function mutations in the gene COL27A1. Outside of Puerto Rico, only four families have been described, in three of which the patients also had hearing loss. However, structural eye defects have not yet been reported in conjunction with this rare autosomal recessive syndrome. Here, we describe a 9‐year‐old girl born to nonconsanguineous Syrian parents with the characteristic features of Steel syndrome, including short stature, massive malalignment of large joints, kyphoscoliosis, hearing loss, and typical facial dysmorphism. However, she was also born with bilateral colobomata of the irides and choroido‐retinae with unilateral affection of the macula. Whole exome sequencing identified two pathogenic compound heterozygous variants in COL27A1: c.93del, p.(Phe32Leufs*71) and c.3075del, p.(Lys1026Argfs*33). There was no discernible alternative cause for the colobomata. Our findings might indicate an association of this exceptionally rare disorder caused by COL27A1 mutations with developmental defects of the eye from the anophthalmia/microphthalmia/coloboma spectrum.

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<![CDATA[Possible mitochondrial dysfunction in a patient with deafness, dystonia, and cerebral hypomyelination (DDCH) due to BCAP31 Mutation]]> https://www.researchpad.co/article/Ne0d84645-73e1-4368-a9b6-b5dfcde0024a

Abstract

Background

Deafness, dystonia, and cerebral hypomyelination (DDCH) is an X‐linked disorder due to hemizygous mutations of BCAP31.

Methods

We report an 8‐year‐old boy with DDCH who possibly accompanied mitochondrial dysfunction. Clinical evaluation, respiratory chain enzyme assay, and whole exome sequencing analysis were performed.

Results

Mitochondrial dysfunction was suspected by respiratory chain enzyme assay on his cultured skin fibroblasts which showed significantly decreased complex I enzyme activity. Whole exome sequencing analysis revealed a recurrent BCAP31 mutation (c.97C>T:p.Gln33*) which confirmed the diagnosis of DDCH for the patient.

Conclusion

We speculate that mitochondrial dysfunction may be a feature in patients with DDCH.

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<![CDATA[MeCP2_e2 partially compensates for lack of MeCP2_e1: A male case of Rett syndrome]]> https://www.researchpad.co/article/N063677fe-31a0-4e55-8cd1-c2a62a069201

Abstract

Background

Rett syndrome (RTT) is a neurodevelopmental disorder that predominantly affects girls. Its causative gene is the X‐linked MECP2 encoding the methyl‐CpG‐binding protein 2 (MeCP2). The gene comprises four exons and generates two isoforms, namely MECP2_e1 and MECP2_e2. However, it remains unclear whether both MeCP2 isoforms have similar function in the brain.

Methods

We report a case of a boy with typical RTT. Male cases with MECP2 variants have been considered inviable, but somatic mosaicism of the variants can cause RTT in males. Whole‐exome sequencing was performed to search for the genetic background.

Results

A novel nonsense and mosaic variant was identified in exon 1 of MECP2, and the variant allele fraction (VAF) was 28%. Our patient had the same level of VAF as that in reported male cases with mosaic variants in MECP2 exon 3 or 4, but manifested RTT symptoms that were milder in severity compared to those in these patients.

Conclusion

This is probably because the variants in MECP2 exon 3 or 4 disrupt both isoforms of MeCP2, whereas the variant in exon 1, as presented in this study, disrupts only MeCP2_e1 but not MeCP2_e2. Therefore, our findings indicate that MeCP2_e2 may partially compensate for a deficiency in MeCP2_e1.

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<![CDATA[Expression of programmed death ligand-1 and programmed death-1 in samples of invasive ductal carcinoma of the breast and its correlation with prognosis]]> https://www.researchpad.co/article/5c0dcd4ad5eed0c484d00c94

The aim of the current study is to investigate programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) expressions and to analyze the relationship between the expression of PD-L1 and PD-1 proteins and the molecular type, clinicopathological factors, and prognosis of invasive ductal carcinoma. We enrolled 136 patients with invasive ductal carcinoma of the breast. The expression of PD-L1 in tumor cells and that of PD-1 on paratumor-infiltrating immune cells was detected by immunohistochemistry, and the data were analyzed using SPSS software. The positive expression rates of PD-L1 and PD-1 in triple-negative breast cancer (TNBC) were 47.8 and 43.5%, which were higher than those of other subtypes (P<0.05). The expression of PD-L1 in tumor cells was correlated with the expression of estrogen receptor, progesterone receptor, and Ki-67 (P<0.05). The expression of PD-1 in the tumor-infiltrating immune cells was correlated with the expression of estrogen receptor, progesterone receptor, and Ki-67 and the histological grade (P<0.05). The expression of PD-L1 in tumor cells was correlated with the expression of PD-1 in paratumor-infiltrating immune cells (P<0.001). The expression of PD-L1 in tumor cells was found to be an independent prognostic risk factor with the progression-free survival rate for breast invasive ductal carcinoma (P=0.003). These results indicate that PD-L1 and PD-1 were highly expressed in TNBC which suggests that patients with TNBC may benefit from targeted immune therapies to a greater degree than patients with other subtypes. PD-L1 expression is an independent risk factor for breast invasive ductal carcinoma and expression of PD-L1 is expected to be a prognostic factor for breast cancer.

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<![CDATA[Scarf pin-related hijab syndrome: A new name for an unusual type of foreign body aspiration]]> https://www.researchpad.co/article/5b4ad38d463d7e6c275999f5

Background

Foreign body aspiration refers to the inhalation of an object into the respiratory system and is a serious and potentially fatal event. A distinct group of patients has recently been recognized among Muslim nations. These patients include women who wear headscarves and place the safety pin in their mouth prior to securing the veils, leading to accidental foreign body aspiration. The aim of this study was to analyze the main presentation, diagnosis, treatment, and outcome of patients with scarf pin aspiration.

Methods

This prospective study involved patients with a history of scarf pin aspiration admitted to a single center during an 18-month period. Their main presentation, diagnosis, treatment, and outcome were analyzed.

Results

In total, 27 patients were included. The needle was extracted by flexible bronchoscopy in 12 (44.4%) patients, rigid bronchoscopy in 13 (48.1%), and thoracotomy in 2 (74%). One patient died during rigid bronchoscopy. All remaining 26 patients were satisfied with the postsurgical outcome at a mean follow-up of 1 week.

Conclusions

Scarf pin aspiration differs from other types of foreign body aspiration considering the specific population affected, and its management algorithm may thus differ from that of other foreign bodies. The left main bronchus is the most common site of pin impaction. Rigid bronchoscopy is the most commonly performed procedure for successful retrieval.

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<![CDATA[Dyssegmental dysplasia, Silverman‐Handmaker type: A challenging antenatal diagnosis in a dizygotic twin pregnancy]]> https://www.researchpad.co/article/5b5b78fc463d7e1e0134c315

Abstract

Background

Dyssegmental dysplasia Silverman‐Handmaker (DDSH; MIM 224410) type is an extremely rare skeletal dysplasia caused by functional null mutations in the perlecan gene. Less than forty cases are reported in the literature, of which only four were prenatally detected.

Methods

We report on a dizygotic twin pregnancy from consanguineous parents for which one of the twins presented prenatally with severe micromelia, limb bowing and scoliosis, and postnatally with clinical and radiological features compatible with a diagnosis of dyssegmental dysplasia. Molecular studies were undertaken to confirm the clinical diagnosis of DDSH.

Results

Molecular analysis results revealed a novel homozygous variant in the HSPG2 gene (MIM 142461), NM_005529.6(HSPG2):c.4029 + 1G>A, consistent with a diagnosis of DDSH.

Conclusion

To the best of our knowledge, the current report is only the seventh molecularly confirmed case of DDSH.

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<![CDATA[Protein modeling and clinical description of a novel in‐frame GLB1 deletion causing GM1 gangliosidosis type II ]]> https://www.researchpad.co/article/5c368774d5eed0c4841feebd

Abstract

Background

Beta‐galactosidase‐1 ( GLB1) is a lysosomal hydrolase that is responsible for breaking down specific glycoconjugates, particularly GM1 (monosialotetrahexosylganglioside). Pathogenic variants in GLB1 cause two different lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB. In GM1 gangliosidosis, decreased β‐galactosidase‐1 enzymatic activity leads to the accumulation of GM1 gangliosides, predominantly within the CNS. We present a 22‐month‐old proband with GM1 gangliosidosis type II (late‐infantile form) in whom a novel homozygous in‐frame deletion (c.1468_1470delAAC, p.Asn490del) in GLB1 was detected.

Methods

We used an experimental protein structure of β‐galactosidase‐1 to generate a model of the p.Asn490del mutant and performed molecular dynamic simulations to determine whether this mutation leads to altered ligand positioning compared to the wild‐type protein. In addition, residual mutant enzyme activity in patient leukocytes was evaluated using a fluorometric assay.

Results

Molecular dynamics simulations showed the deletion to alter the catalytic site leading to misalignment of the catalytic residues and loss of collective motion within the model. We predict this misalignment will lead to impaired catalysis of β‐galactosidase‐1 substrates. Enzyme assays confirmed diminished GLB1 enzymatic activity (~3% of normal activity) in the proband.

Conclusions

We have described a novel, pathogenic in‐frame deletion of GLB1 in a patient with GM1 gangliosidosis type II.

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<![CDATA[Exome sequencing identifies NFS1 deficiency in a novel Fe-S cluster disease, infantile mitochondrial complex II/III deficiency]]> https://www.researchpad.co/article/5ad2047f463d7e2179a2c04a

Iron-sulfur (Fe-S) clusters are a class of highly conserved and ubiquitous prosthetic groups with unique chemical properties that allow the proteins that contain them, Fe-S proteins, to assist in various key biochemical pathways. Mutations in Fe-S proteins often disrupt Fe-S cluster assembly leading to a spectrum of severe disorders such as Friedreich's ataxia or iron-sulfur cluster assembly enzyme (ISCU) myopathy. Herein, we describe infantile mitochondrial complex II/III deficiency, a novel autosomal recessive mitochondrial disease characterized by lactic acidemia, hypotonia, respiratory chain complex II and III deficiency, multisystem organ failure and abnormal mitochondria. Through autozygosity mapping, exome sequencing, in silico analyses, population studies and functional tests, we identified c.215G>A, p.Arg72Gln in NFS1 as the likely causative mutation. We describe the first disease in man likely caused by deficiency in NFS1, a cysteine desulfurase that is implicated in respiratory chain function and iron maintenance by initiating Fe-S cluster biosynthesis. Our results further demonstrate the importance of sufficient NFS1 expression in human physiology.

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<![CDATA[Familial adenomatous polyposis in an adolescent with coexisting schizophrenia: treatment strategies and implications]]> https://www.researchpad.co/article/5af1cd5b463d7e767b7b0f57

Schizophrenia is associated with high mortality and morbidity. The etiology of schizophrenia remains unclear, studies implicate a multifactorial origin with genetic and environmental factors. The adenomatous polyposis coli (APC) gene has been associated with FAP (familial adenomatous polyposis), and studies have linked it to schizophrenia. However, there are few studies which examine the association between FAP and schizophrenia. Limited data exist regarding recommendations for genetic counseling of adolescents with comorbid psychiatric illness. A case of an adolescent with FAP who developed psychotic symptoms is presented. This case hopes to add to the literature about mental illness in those with FAP. A review of literature about the role of APC in schizophrenia as well as implications of genetic counseling on those who suffer with mental illness will be discussed.

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<![CDATA[Patent ductus arteriosus in a lamb: A case report]]> https://www.researchpad.co/article/5afdaaaa463d7e0aa444c39a

Patent ductus arteriosus (PDA) is a persistent patency of a vessel normally present in the fetus that connects the pulmonary arterial system to the aorta. The ductus arteriosus fails to close at birth when breathing commences and placental blood circulation is removed. Closure of the ductus arteriosus arises in response to decline pulmonary vascular resistance and increased systemic vascular resistance. This report describes a case of PDA in a two-month-old male lamb with clinical signs of machinery murmur, tachycardia, increase respiratory rate, weakness and ill thrift. Echocardiographic examination and necropsy finding confirmed PDA.

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