CNKSR2 mutation causes the X-linked epilepsy-aphasia syndrome:A case report and review of literature

The mutation in CNKSR2 leads to a broad spectrum of phenotypic variability and manifests as an X-linked intellectual disability. However, we reported that the male patient in this study not only had intellectual disability but also epileptic seizures. In addition, there were progressive language impairment, attention deficit hype-ractivity disorder and autism. Electroencephalograms showed continuous spike-and-wave during sleep. Genetic testing revealed a de novo mutation of the CNKSR2 gene(c.2185C >T, p.Arg729Ter) in the child that was not detected in the parents. Therefore, the child was diagnosed with X-linked epilepsy aphasia syndrome. Deletion of the CNKSR2 gene has been rarely reported in epilepsy aphasia syndrome, but no de novo mutation has been found in this gene. This report not only adds to the spectrum of epilepsy aphasia syndrome but also helps clinicians in diagnosis and genetic counseling.

X-linked recessive Kallmann syndrome:A case report

BACKGROUND Kallmann syndrome(KS),also known as hypogonadotropic hypogonadism(HH)or olfactory-gonadal dysplasia,is a genetic condition in which the primary symptom is a failure to begin puberty or a failure to fully complete it.It occurs in both males and females and has the additional symptoms of hypogonadism and almost invariably infertility.The condition has a low prevalence that is estimated to be 1 in 4000 for male HH cases overall and 1:50000 for KS.It is three to five times more common in males than females.Whether this is a true sex imbalance or a reflection of how difficult KS/HH is to diagnose correctly in males vs females has yet to be fully established.CASE SUMMARY This article reports a 26-year-old male presenting with delayed puberty.The synthetic decapeptide luteinizing hormone-releasing hormone stimulation test showed that the secretion levels of follicle-stimulating hormone and luteinizing hormone were delayed.The eigengenes commonly associated with idiopathic HH(IHH)were screened,and an X-linked recessive(KAL-1)mutation was found.His gonadotropin and testosterone levels increased significantly after pulsatile gonadotropin-releasing hormone(GnRH)subcutaneous therapy by pump.A relevant literature review on the recent advances in the diagnosis and treatment of KS and genetic counseling was conducted.CONCLUSION KS is caused by a KAL-1 mutation that follows an X-linked recessive inheritance pattern.Pulsatile GnRH subcutaneous therapy by pump was effective in this patient.

Early-onset refractory diarrhea due to immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome associated with a novel mutation in the FOXP3 gene: A case report

BACKGROUND Immune dysregulation,polyendocrinopthy,enteropathy,X-linked(IPEX)syndrome is a rare X-linked recessive disease caused by mutations in the forkhead box protein 3(FOXP3)gene,which is a master transcriptional regulator for the development and function of CD4+CD25+regulatory T(Treg)cells.The dysfunction of these cells leads to multiple system autoimmune diseases.We present a case of IPEX due to a mutation not reported in the literature before.CASE SUMMARY We report a male patient with IPEX syndrome who presented with refractory diarrhea and malabsorption leading to failure to thrive,as well as with hypothyroidism and nephrotic syndrome.Laboratory investigation showed increased total IgE and Treg cells,decreased free triiodothyronine(FT3)and free thyroxine(FT4),and proteinuria.Multiple dietary and supportive treatments were introduced but did not improve the diarrhea during his hospital stay.Ultimately,whole exome sequencing revealed that the patient was hemizygous for the exon 5,c.542G>A(p.Ser181Asn)mutation of the FOXP3 gene,which has not been previously reported.The patient remains on prednisone and euthyrox while awaiting hematopoietic stem cell transplantation at the time of the compilation of this case report.CONCLUSION We report a novel FOXP3 gene mutation involved in IPEX.A high level of suspicion should be maintained in an early-onset refractory diarrhea patient.

X-linked Charcot-Marie-Tooth disease after SARS-CoV-2 vaccination mimicked stroke-like episodes: A case report

BACKGROUND Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) vaccinations have been administered worldwide, with occasional reports of associated neurological complications. Specifically, the impact of vaccinations on individuals with Xlinked Charcot-Marie-Tooth disease type 1(CMTX1) is unclear. Patients with CMTX1 can have stroke-like episodes with posterior reversible encephalopathy syndrome on magnetic resonance imaging(MRI), although this is rare.CASE SUMMARY A 39-year-old man was admitted with episodic aphasia and dysphagia for 2 d. He received SARS-CoV-2 vaccination 39 d before admission. Physical examination showed pes cavus and reduced tendon reflexes. Brain MRI showed bilateral, symmetrical, restricted diffusion with T2 hyperintensities in the cerebral hemispheres. Nerve conduction studies revealed peripheral nerve damage. He was diagnosed with Charcot-Marie-Tooth disease, and a hemizygous mutation in the GJB1 gene on the X chromosome, known to be pathogenic for CMTX1, was identified. Initially, we suspected transient ischemic attack or demyelinating leukoencephalopathy. We initiated treatment with antithrombotic therapy and immunotherapy. At 1.5 mo after discharge, brain MRI showed complete resolution of lesions, with no recurrence.CONCLUSION SARS-CoV-2 vaccination could be a predisposing factor for CMTX1 and trigger a sudden presentation.

Immunofluorescence study of type Ⅳ collagen α chains in epidermal base-ment membrane : application in diagnosis of X-linked Alport syndrome

Objective To detect the distribution of α5(Ⅳ) chain of collagen on the glomerular basement membrane (GBM) and epidermal basement membrane (EBM) in the Chinese Alport syndrome (AS) kindreds and to develop a simple diagnostic alternative method to electronic microscopy for diagnosis of AS. Methods Four male patients from 4 unrelated families manifested with hematuria, sensorineural hearing loss and had distinct family history. All patients had the characteristic AS pathologic changes by electron microscopy on their renal biopsy tissues. Three normal skin samples and 2 normal kidney samples were used as normal controls. Monoclonal antibody based IF test was performed to examine the α5(Ⅳ)NC1 domain in EBM of normal controls, X linked AS patients and their parents, and in GBM of normal controls and AS patients. Results In normal controls as well as the patients' fathers, all the monoclonal antibodies used in EBM and GBM staining showed positive reactions along basement membranes in a linear pattern. Characteristically, in AS patients there were negative reactions to monoclonal antibodies anti α5(Ⅳ)NC1 domain in EBM and anti α3 5(Ⅳ)NC1 domains in GBM. In patients' mothers, α5(Ⅳ) chain was distributed segmentally in EBM. Conclusion The staining of α5(Ⅳ) NC1 domain in EBM by IF can be used to diagnose patients and screen defect gene carriers of X linked AS.

Identification of a novel mutation in a Chinese family with Nance-Horan syndrome by whole exome sequencing

Objective： Nance-Horan syndrome （NHS） is a rare X-linked disorder characterized by congenital nuclear cataracts, dental anomalies, and craniofacial dysmorphisms. Mental retardation was present in about 30% of the reported cases. The purpose of this study was to investigate the genetic and clinical features of NHS in a Chinese family. Methods： Whole exome sequencing analysis was performed on DNA from an affected male to scan for can- didate mutations on the X-chromosome. Sanger sequencing was used to verify these candidate mutations in the whole family. Clinical and ophthalmological examinations were performed on all members of the family. Results： A combi- nation of exome sequencing and Sanger sequencing revealed a nonsense mutation c.322G〉T （E108X）in exon 1 of NHS gene, co-segregating with the disease in the family. The nonsense mutation led to the conversion of glutamic acid to a stop codon （E108X）, resulting in truncation of the NHS protein. Multiple sequence alignments showed that codon 108, where the mutation （c.322G〉T） occurred, was located within a phylogenetically conserved region. The clinical features in all affected males and female carriers are described in detail. Conclusions： We report a nonsense mutation c.322G〉T （E108X） in a Chinese family with NHS. Our findings broaden the spectrum of NHS mutations and provide molecular insight into future NHS clinical genetic diagnosis.

X linked recessive ichthyosis: Current concepts

In the present review, we describe the most importantaspects of the X-linked ichthyosis(XLI) and make a compilation of the some historic details of the disease. The aim of the present study is an update of the XLI. Historical, clinical, epidemiological, and molecular aspects are described through the text. Recessive XLI is a relatively common genodermatosis affecting different ethnic groups. With a high spectrum of the clinical manifestations due to environmental factors, the disease has a genetic heterogeneity that goes from a point mutation to a large deletion involving several genes to produce a contiguous gene syndrome. Most XLI patients harbor complete STS gene deletion and flanked sequences; seven intragenic deletions and 14 point mutations with a complete loss of the steroid sulfatase activity have been reported worldwide. In this study, we review current knowledge about the disease.

Deep Learning‑Assisted Quantitative Susceptibility Mapping as a Tool for Grading and Molecular Subtyping of Gliomas

This study aimed to explore the value of deep learning(DL)-assisted quantitative susceptibility mapping(QSM)in glioma grading and molecular subtyping.Forty-two patients with gliomas,who underwent preoperative T2 fluid-attenuated inversion recovery(T2 FLAIR),contrast-enhanced T1-weighted imaging(T1WI+C),and QSM scanning at 3.0T magnetic resonance imaging(MRI)were included in this study.Histopathology and immunohistochemistry staining were used to determine glioma grades,and isocitrate dehydrogenase(IDH)1 and alpha thalassemia/mental retardation syndrome X-linked gene(ATRX)subtypes.Tumor segmentation was performed manually using Insight Toolkit-SNAP program(www.itksnap.org).An inception convolutional neural network(CNN)with a subsequent linear layer was employed as the training encoder to capture multi-scale features from MRI slices.Fivefold cross-validation was utilized as the training strategy(seven samples for each fold),and the ratio of sample size of the training,validation,and test dataset was 4:1:1.The performance was evalu-ated by the accuracy and area under the curve(AUC).With the inception CNN,single modal of QSM showed better perfor-mance in differentiating glioblastomas(GBM)and other grade gliomas(OGG,grade II–III),and predicting IDH1 mutation and ATRX loss(accuracy:0.80,0.77,0.60)than either T2 FLAIR(0.69,0.57,0.54)or T1WI+C(0.74,0.57,0.46).When combining three modalities,compared with any single modality,the best AUC/accuracy/F1-scores were reached in grading gliomas(OGG and GBM:0.91/0.89/0.87,low-grade and high-grade gliomas:0.83/0.86/0.81),predicting IDH1 mutation(0.88/0.89/0.85),and predicting ATRX loss(0.78/0.71/0.67).As a supplement to conventional MRI,DL-assisted QSM is a promising molecular imaging method to evaluate glioma grades,IDH1 mutation,and ATRX loss.