Pulmonary alveolar proteinosis induced by X-linked agammaglobulinemia:A case report

BACKGROUND Pulmonary alveolar proteinosis(PAP)and X-linked agammaglobulinemia(XLA)are rare diseases in children.Many theories infer that immunodeficiency can induce PAP,but these reports are almost all review articles,and there is little clinical evidence.We report the case of a child with both PAP and XLA.CASE SUMMARY A 4-month-old boy sought medical treatment due to coughing and difficulty in breathing for>2 wk.He had been hospitalized multiple times due to respiratory infections and diarrhea.Chest computed tomography and alveolar lavage fluid showed typical PAP-related manifestations.Genetic testing confirmed that the boy also had XLA.Following total lung alveolar lavage and intravenous immunoglobulin replacement therapy,the boy recovered and was discharged.During the follow-up period,the number of respiratory infections was significantly reduced,and PAP did not recur.CONCLUSION XLA can induce PAP and improving immune function contributes to the prognosis of children with this type of PAP.

A novel pathogenic splicing mutation of RPGR in a Chinese family with X-linked retinitis pigmentosa verified by minigene splicing assay

AIM:To report a novel splicing mutation in the RPGR gene(encoding retinitis pigmentosa GTPase regulator)in a three-generation Chinese family with X-linked retinitis pigmentosa(XLRP).METHODS:Comprehensive ophthalmic examinations including best corrected visual acuity,fundus photography,vision field,and pattern-visual evoked potential were performed to identify the disease phenotype of a six-yearold boy from the family(proband).Genomic DNA was extracted from peripheral blood of five available members of the pedigree.Whole-exome sequencing(WES),Sanger sequencing,and pSPL3-based exon trapping were used to investigate the aberrant splicing of RPGR.Human Splice Finder v3.1 and NNSPLICE v0.9 were used for in silico prediction of splice site variants.RESULTS:The proband was diagnosed as having retinitis pigmentosa(RP).He had severe symptoms with early onset.A novel splicing mutation,c.619+1G>C in RPGR was identified in the proband by WES and in four family members by Sanger sequencing.Minigene splicing assays verified that c.619+1G>C in RPGR would result in the formation of a damaging alternative transcript in which the last 91 bp of exon 6 were skipped,leading to the subsequent deletion of 623 correct amino acids(c.529_619del p.Val177Glnfs*16).CONCLUSION:We identify a novel splice donor site mutation causing aberrant splicing of RPGR.Our findings add to the catalog of pathological mutations of RPGR and further emphasize the functional importance of RPGR in RP pathogenesis and its complex clinical phenotypes.

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.

Clinical observations of vitreoretinal surgery for four different phenotypes of X-linked congenital retinoschisis

AIM： To evaluate the outcomes of vitreoretinal surgery for four different phenotypes of X-linked retinoschisis （XLRS）. METHODS： This study included thirty-one eyes of 25 patients who developed XLRS with severe complications. Among the 31 eyes, there were 7 eyes with vitreous hemorrhage, 8 eyes with retinal detachment and vitreous hemorrhage, and 16 eyes with rhegmatogenous retinal detachment. All of the patients underwent standard three-port pars plana vitrectomy. All of the eyes were divided into 4 groups before surgery according to a modified classification scheme, with the first three groups as follows： group A, with foveal cystic schisis; group B with macular lamellar schisis; and group C with foveolamellar changes. Peripheral schisis was not present in these 3 groups; however, group D was a complex group with both macular and peripheral changes. One year after surgery, we analyzed the best corrected visual acuity and postoperative anatomical and functional outcomes of these 4 groups. RESULTS： There were 7 eyes in group A （22.6%）, 1 eye in group B （3.2%）, 15 eyes in group C （48.4%） and 8 eyes in group D （25.8%）. Postoperative anatomical and functional outcomes were satisfactory at the last visit, while the mean visual acuity was increased to 0.27±0.11, with a significant difference （t=-1.049, P=0.000） compared with the results before surgery （0.1±0.08）. Visual acuity was improved in 23 eyes （74.2%）. Complications were found in three eyes： two eyes with proliferative vitreoretinopathy and traction retinal detachment 10 and 12mo after surgery, respectively; and one eye with vitreous hemorrhage 15mo after surgery. These eyes were in groups C and D. The retinas remained attached in these 3 eyes after reoperation. CONCLUSION： We should pay greater attention to XLRS with foveolamellar changes because it is the most changeable phenotype. Once complications occur, vitreoretinal surgery can significantly improve visual acuity and restore the anatomic structure of the retina.

A novel nonsense mutation of GPR143 gene in a Korean kindred with X-linked congenital nystagmus

Dear Editor,I am Dr.Ungsoo Samuel Kim.from Kim＇s Eye Hospital,Konyang University,Seoul,Korea.I write to present a novel mutation of GPR143 in Korean patients with X-linked congenital nystagmus by using exome sequencing.Congenital nystagmus is an inherited ocular disorder that can occur as an X-linked condition.

Expression of second mitochondria-derived activator of caspases, X-linked inhibitor of apoptosis protein, and caspase-3 in pituitary adenomas

Studies concerning correlations between pituitary adenomas and cell apoptosis have mainly focused on upstream apoptosis signaling, but seldom on downstream mediators. In the present study, second mitochondria-derived activator of caspases （Smac）, X-linked inhibitor of apoptosis protein （XIAP）, and caspase-3 protein were qualitatively analyzed using immunohistochemistry, and quantified by western blot. Smac, XIAP, and caspase-3 mRNA expressions were detected by reverse transcription-PCR. Results showed that XIAP protein and mRNA expressions were greater in the invasive pituitary adenoma group compared with the noninvasive pituitary adenoma group. However, Smac and caspase-3 protein and mRNA expressions were lower in the invasive pituitary adenoma group compared with the noninvasive pituitary adenoma group. In the invasive pituitary adenomas, Smac expression was positively correlated with caspase-3 protein and mRNA expression （Protein： r = 0.55, P 0.01; mRNA： r = 0.50, P 0.01）. Smac and caspase-3 expressions were negatively correlated with XIAP protein and mRNA expression （Protein： r = -0.56, -0.64, P 0.01; mRNA： r = -0.69, -0.67, P 0.01）. However, no significant differences in correlation among Smac, XIAP, and caspase-3 were detectable in noninvasive pituitary adenomas. These data indicated that high expression of XIAP and low expression of Smac and caspase-3 suppressed cell apoptosis and led to enhanced invasiveness of pituitary adenomas. Thus, Smac, XIAP, and caspase-3 may be useful markers in determining the invasive behavior of pituitary adenomas.

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.

Expression of X-linked Inhibitor of Apoptosis Protein and Its Effect on Chemotherapeutic Sensitivity of Bladder Carcinoma

The expression of X-linked inhibitor of apoptosis protein (XIAP) gene and its effect on chemotherapeutic sensitivity in bladder carcinoma was explored. By using immunohistochemistry, the expression of XIAP was detected in 47 bladder carcinomas and 5 normal bladder tissues. The XIAP gene was transfected into bladder cancer cell line T24 by liposome and the positive clone was screened by G418. Cellular XIAP mRNA level was detected by RT-PCR. Low-dose mitocycin C was administered to induce the apoptosis of T24 cells. The in vitro growth of bladder carcinoma cells was analyzed by MTT colorimetry, and the apoptosis rate was assayed by TUNEL methods. It was found XIAP was moderately expressed in bladder carcinomas with the the positive rate being 78.73% (37/47), but the positive rate was not correlated with carcinoma stages and grades (P<0.05). XIAP mRNA level in transfected T24 cells was significantly increased by 3.8 times as compared with that in the cells not transfected with XIAP. After treatment with low-dose mitomycin C (0.005 and 0.05 mg/mL), the growth rate in XIAP no-transfected control group was increased by (11.60±0.25)% and (16.51±0.87)% (P<0.05), and the apoptosis rate was decreased by (10.1±0.2)% and (11.9±0.2%) (P<0.05) respectively as compared with XIAP transfected group. It was concluded that XIAP was expressed in most of bladder carcimoma samples. Overexpression of XIAP in T24 could significantly reduce the MMC-induced apoptosis of bladder carcinoma, suggesting its effect on the chemothera- peutic sensitivity of T24 cells.

A novel mutation of RPGR in a Chinese family with X-linked retinitis pigmentosa

·AIM:To identify potential mutations and elucidate the clinical findings of male patients and female carriers of X-Iinked retinitis pigmentosa(XLRP)in a Chinese family.·METHODS:A four generation pedigree was collected that consisted of 20 individuals.Genomic DNA was extracted from peripheral blood,and then the target fragments were amplified by PCR and sequenced directly.In addition,all affected patients and female carriers underwent comprehensively ophthalmic evaluation.·RESULTS:A novel mutation c.2865 G>A p.W955 X in RPGR gene was identified of this family,including four affected individuals and eight carriers.All male patients,aging from 7 to 31 y,tended to have more various,even potentially deleterious clinical features of RP.At the same time,individuals with heterozygous mutations(carriers)manifested a wide spectrum of clinical features.Herein,only two male patients and three female carriers manifested pathological myopia(PM).Among the female carriers,half of subjects who harbor poor visual acuity suffered esotropia or exotropia.Additionally,16.7%and 66.7%of carriers had abnormal electroretinogram(ERG)and fundus,respectively.·CONCLUSION:In this study,a novel mutation of the RPGR gene is identified,which broadens the spectrum of RPGR mutations,and elaborates the relationship between genotype and phenotype.

STS Gene in a Pedigree with X-linked Ichthyosis

To investigate the gene mutation in a pedigree with X-linked iehthyosis （XLI） and to explore the relationship between the mutation and its clinical manifestations, genomic DNA of affected members, the normal member of the pedigree and 50 unrelated normal members was extracted with a whole blood genomie DNA extraction kit and the DNA was used as a template for the polymerase chain reaction （PCR） mediated amplification of exon 1 and exon 10 of the STS gene. hHb6 （human hair basic keratin） gene was used as the internal control. Our results showed that the STS gene was deleted in affected members in the pedigree with X-linked ichthyosis. The normal member of the pedigree and 50 unrelated normal members had no such deletion. The proband and his mother had products in the internal control after PCR amplification. The blank control had no product. It is concluded that deletion of the STS gene existed in this pedigree with X-linked iehthyosis, and it is responsible for the unique skin lesions of X-linked ichthyosis.

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.

Multimodal imaging of the carriers of choroideremia and X-linked retinitis pigmentosa

Dear Editor,We are Dr. Zhi-Qing Li and Dr. Jin Yang, from the Neuro-ophthalmology and Medical Retinal Department of Tianjin Medical University Eye Hospital, Tianjin, China. We here present two cases of X-linked inheritable retinal diseases with genetic confirmation of the multimodal imaging findings of the patients, especially the female carriers. This study was approved by the institutional review board of Tianjin Medical University Eye Hospital, and the protocols adhered to the tenets of the Declaration of Helsinki. This letter mainly describes a novel imaging modality, multispectral imaging （MSI）, which appeared to be sensitive in detecting the pattern of chorioretinal degeneration and the tapetal-like reflex.

Four Cases of X-Linked Hypophosphatemic Rickets, Clinical Description and Genetic Testing

One of the major causes of congenital hypophosphatemic rickets is the X-linked hypophosphatemic rickets (XHR), due to a defect on PHEX gene. The XHR increases the renal elimination of phosphate, that condition leads a defective mineralization of bones and also affects the growth in children. Clinical diagnosis should be suspected in children with signs of rickets and hypophosphatemia with normal calcium levels. We describe clinical characteristics and genetic results of four patients diagnosed and treated in our Nephrology Section. All patients have a “de novo” XHR as none familiars are affected. Early diagnosis should be suspected before the bone deformities have been submitted and the growth would have been impaired.

X-linked deafness: A review of clinical and radiological findings and current management strategies

X-linked deafness is a rare genetic disorder causing a severe mixed hearing loss. This is due to an abnormal connection between the internal auditory meatus(IAM) and the basal turn of the cochlear leading to a "3rd window effect" and cochlear conductive hearing loss. Patients are traditionally treated with conventionalhearing aids however these are often unsatisfactory. Cochlear implantation is a high-risk procedure in such cases due to the risk of inadvertent electrode placement in the IAM. We present three paediatric cases where the hearing loss was managed with a combination of a bone anchored hearing aid in combination with a conventional behind the ear hearing aid. We also present a review of the current literature regarding the management of X-linked deafness.

X-Linked Dominant Congenital Ptosis Cosegregating with an Interstitial Insertion of a Chromosome 1p21.3 Fragment into a Quasipalindromic Sequence in Xq27.1

Blepharoptosis (ptosis) is defined as the abnormal drooping of the upper eyelid and is a feature of many conditions. It can be in isolated or syndromic form, bilateral or unilateral and congenital or acquired. Previously we have carried out linkage analysis on a family with dominantly inherited congenital bilateral isolated ptosis and found the condition to be linked to a region of approximately 20 megabases of chromosome Xq24-Xq27.1 with a cumulative LOD score of 5.89. We now describe further analysis using array comparative genomic hybridisation (array CGH), fluorescence in situ hybridisation (FISH), long range PCR and sequencing. This has enabled us to identify and characterise at the level of DNA sequence an insertional duplication and rearrangement involving chromosomes 1p21.3 and a small quasipalindromic sequence in Xq27.1, disruption of which has been associated with other phenotypes but which is cosegregating with X-linked congenital bilateral isolated ptosis in this family. This work highlights the significance of the small quasipalindromic sequence in genomic rearrangements involving Xq27.1 and the importance of comprehensive molecular and molecular cytogenetic investigations to fully characterise genomic structural complexity.

A Novel Bruton’s Tyrosine Kinase Mutation in Russian Patient with X-Linked Agammaglobulinemia

X-Linked Agammaglobulinemia (XLA) is the major primary immunodeficiency in which the body is unable to produce the antibodies responsible for the defense against bacteria and viruses. The patient (a 6-month-old boy) was born at term to non-consanguineous parents. Both parents and older sister are clinically healthy. At 3, 5 months of age he presented acute viral infection with glue ear. At 4 month—serous meningitis, at 5 month—laryngotracheitis and serous meningitis. The levels of immunoglobulins were decreased for Ig A and IgG isotypes. The virtual lack of CD19+ B-lymphocytes was defined. Additionally there was found a complete absence of KREC (kappa-deleting recombination excision circle) in dried blood spot. The molecular diagnostics of coding region of the BTK gene was performed. DNA sequencing analysis of patient showed a 13-bp deletion in exon 2 (c.64_76delCCTCTAAACTTCA), leading to occurrence of frameshift and premature termination codon (p.Pro22fsTer28). This mutation was not described earlier. The mother and the sister of proband showed heterozygosity at the same position. Prenatal diagnostic testing has become available to this family for next pregnancy.

A Multiplex PCR-Based Next-Generation Sequencing Approach Has Detected a Common Large Deletion in STS Gene in a Patient with X-Linked Ichthyosis

Several nuclear genes have been found to be linked to ichthyosis, and Next Generation Sequencing approach on panels of targeted genes has turned out to be particularly useful in analyzing diseases characterized by significant genetic and phenotypic heterogeneity. We developed a panel of 26 genes to be screened with the Ion Personal Genome Machine (PGM) for causative mutations relating to ichthyosis. Sequencing runs were obtained from a patient with ichthyosis using the Ion Torrent PGM and then processed with Ion Torrent Suite, Variant Caller, Coverage Analysis and wANNOVER tools. No causative mutations were found using Variant Caller and wANNOVER softwares, whereas the “Coverage Analysis” tool revealed a common large deletion in STS gene in a patient with X-linked ichthyosis. Identification of indels in Next Generation Sequencing (NGS) data is a veritable challenge. This study demonstrates the efficacy and effectiveness of using NGS approach to detect large deletions without resorting to specific algorithms for “indel” detection. Our results indicate that the NGS panel is a useful, rapid and cost-effective screening test for patients whose features are suggestive of a genetic etiology involving one of the genes embedded in the panel. It is an excellent alternative to Sanger sequencing as for costs, ease of analysis, and turnaround time.

SPECTRAL CHARACTERISTICS OF ELECTRORETINOGRAM IN X-LINKED DICHROMATS-A PRELIMINARY STUDY

Spectral characteristics of X-linked Dichromats(13 protanopes, 20 deuteranopes) were studied with spectral ERG. The results are as follows: The maximal spectral response of the b-wave in protanopes tended to shift toward the short wavelength side and the sensitivity to long wavelengths decreased obviously. The ratio value of the amplitude in 500nm and in 620nm(500/620) was greater in the protanope than that in the normal subject. Like the normals, the maximal response of the b-wave in deuteranopes appea...

Mutation Analysis of Gap Junction Protein Beta 1 and Genotype-Phenotype Correlation in X-linked Charcot-Marie- Tooth Disease in Chinese Patients

Background： Among patients with Charcot-Marie-Tooth disease （CMT）, the X-linked variant （CMTX） caused by gap junction protein beta 1 （GJB1） gene mutation is the second most frequent type, accounting for approximately 90% of all CMTX. More than 400 mutations have been identified in the GJB1 gene that encodes connexin 32 （CX32）. CX32 is thought to form gap junctions that promote the diffusion pathway between cells. GJB1 mutations interfere with the formation of the functional channel and impair the maintenance of peripheral myelin, and novel mutations are continually discovered. Methods： We included 79 unrelated patients clinically diagnosed with CMT at the Department of Neurology of the Chinese People＇s Liberation Army General Hospital from December 20, 2012, to December 31, 2015. Clinical examination, nerve conduction studies, and molecular and bioinformatics analyses were performed to identify patients with CMTX 1. Results： Nine GJBI mutations （c.283G〉A, c.77C〉T, c.643C〉T, c.515C〉T, c.191G〉A, c.610C〉T, c.490C〉T, c.491G〉A, and c.44G〉A） were discovered in nine patients. Median motor nerve conduction velocities of all nine patients were 〈 38 m/s, resembling CMT Type 1. Three novel mutations, c.643C〉T, c.191G〉A, and c.610C〉T, were revealed and bioinformatics analyses indicated high pathogenicity. Conclusions： The three novel missense mutations within the GJB1 gene broaden the mutational diversity ofCMT1X. Molecular analysis of family members and bioinformatics analyses of the afflicted patients confirmed the pathogenicity of these mutations.