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Blau syndrome is a rare genetic disorder characterized by the a mix of granulomatous arthritis, uveitis, and dermatitis. Patients typically manifest multisystem involvement, including ocular, skin, and skeletal abnormalities. Blau syndrome is extremely rare, with a global incidence of less than one in a million among children. In this multidisciplinary consultation, we present a case of a 21-year-old young female patient having multisystemic involvement since early childhood. She was presented with multiple joint swelling, skin lesions, increased eye discharge, and accompanied by hypertension and arterial abnormalities, and received a diagnosis of uveitis. The patient had been receiving steroid treatment since the age of 6 and has tried various medications, with some improvement in joint swelling and ocular symptoms. Through this rare disease multidisciplinary consultation, we aim to provide guidance in the molecular diagnosis of the patient, multisystem assessment, and the selection and formulation of treatment plans. Additionally, we hope that by reporting this case, clinical physicians can gain a better understanding of the diagnosis and comprehensive treatment strategies for Blau syndrome, thereby improving the management and treatment of rare diseases.
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A 15-year-old female was referred to the hospital with intermittent fever, where multiple systemic abnormalities were found, such as splenomegaly, secondary hypersplenism, retinitis pigmentosa, and ectodermal dysplasia. Medical history revealed that she had suffered recurrent respiratory infections, blurred vision at night, and dysplasia of teeth and nail beds since childhood. Then she was suspected to be experiencing ROSAH syndrome, a rare disease newly recognized in recent years, which was finally confirmed by gene sequencing results. During a course of treatment with tumor necrosis factor inhibitors, recurrent fever with elevated inflammatory markers reappeared, and the child developed headaches. To guide the comprehensive treatment and improve the patient's quality of life, the multidisciplinary team in Peking Union Medical College Hospital discussed together and directed the following treatment.
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Objective:To identify the clinical characteristics and pathogenic gene of a Chinese Han family with achromatopsia (ACHM).Methods:The method of pedigree investigation was adopted.A Chinese Han ACHM family was recruited in Peking Union Medical College Hospital form July 2010 to July 2019, including 5 members of 2 generations.There were 2 patients and 3 phenotypically normal individuals.The medical history was collected and comprehensive ophthalmic examinations were performed, including visual acuity, colour vision, color fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), visual field and electroretinogram (ERG).Genomic DNA was extracted from peripheral blood sample from the patients and family members.Pathogenic variant was screened by whole exome sequencing (WES) and verified by Sanger sequencing and co-segregation analysis.The variant was annotated with the 1000 Genomes, Human Gene Mutation Database (HGMD), ExAC, ClinVar and OMIM databases to detect the single nucleotide polymorphism and whether it had been reported previously.The pathogenicity of the variant was evaluated according to the standards and guidelines of the American College of Medical Genetics and Genomics (ACMG).This study adhered to the Declaration of Helsinki.The study protocol was approved by the Institutional Review Board of Peking Union Medical College Hospital (No.JS-2059).Written informed consent was obtained from the guardians of juvenile patients.Results:There was consanguinity between the proband's parents and this family was consistent with autosomal recessive inheritance.Both male patients presented the reduction of visual acuity accompanied with photophobia and color blindness since childhood.Barely visible foveal light reflex in fundus images, hypofluorescence of foveal areas in FAF images, foveal defect with disruption of ellipsoid zone and interdigitation zone in OCT images were found in both patients.Central scotoma with or without peripheral visual field defects was detected.Generally normal scotopic 0.01, 3.0 and 10.0 responses, decreased oscillatory potentials amplitudes, no photopic 3.0 and 30 Hz flicker responses were observed.No sign of progression was found during the 9-year follow-up.It was confirmed that both patients carried a novel homozygous disease-causing variant c. 947insA (p.Asn316Lysfs*46) in ATF6 gene.Their mother had the heterozygous variant.The unaffected brother did not carry the variant.This family was consistent with co-segregation.This variant was labeled as pathogenic according to the ACMG standards and guidelines. Conclusions:A novel variant c.947insA (p.Asn316Lysfs*46) in ATF6 gene is the pathogenic variant of this achromatopsia family.This is the first time that this variant has been reported.
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Gene therapy is expected to restore the function of genetic material fundamentally and it has become a new trend in inherited retinal dystrophy treatment.Antisense oligonucleotide (AON) is a kind of small molecule nucleic acid drug, which can specifically bind to messenger RNA through the base pairing principle, thus interfering or modifying gene expression at the transcription and translation level.Possessing the advantages of high specificity and efficiency, wide targeting range, low immunogenicity and limited adverse effect, AON has become a novel remedy for inherited retinal dystrophy.Currently, three different AON drugs have already been used in clinical trials for inherited retinal dystrophy.In this review, the chemical structure modification, properties and mechanism of AON, and the therapeutic strategies of AON in different inherited retinal dystrophy diseases in recent years were summarized.
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Inherited retinal degeneration (IRD), a group of diseases often causing irreversible blindness, with multiple pathogenesis, still lacks effective treatments currently.Development of effective therapeutics is a primary research goal.Despite rapid advances in gene therapy during the past decades, the most challenging aspect of gene therapy in clinical applications for IRD is to deliver the curative molecules to achieve optimal expression levels in target cells safely.Apart from high gene transfection efficiency, there are still many limitations, such as immunogenicity, biosafety issue, etc.in the application of viral vectors, which drive the development of gene therapy based on non-viral vectors.As one of the hot research topics in non-viral vectors, encouraging progress has been made in DNA nanoparticles for IRD treatment.The polymer/DNA complex nanoparticle is compacted and encapsulated DNA via peptides, lipids, or polysaccharides.Besides, the non-viral delivery system shows cost, preparation, packaging capacity, and safety advantages, providing a promising non-viral platform for safe and effective treatment of IRD, such as retinitis pigmentosa, Stargardt disease, X-linked juvenile retinoschisis, Leber congenital amaurosis, and so on.In this article, advances in transfection efficiency, targeting ability and safety of non-viral gene therapy and its application in IRD were reviewed.
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Inherited eye disease is a heterogeneous group of eye disorders caused by genetic defects, which has many genetic characteristics, such as multiple inheritance modes and numerous gene variation types. Over the past few decades, genetic testing has improved significantly, with more and more known diseasecausing gene variants identified. With the rapid development of high-throughput sequencing technology, clinical diagnosis and treatment of eye genetic diseases have been accelerated, and molecular diagnosis of eye genetic diseases has become an important step in accurate diagnosis and treatment. How to correctly select and evaluate each kind of genetic testing technology, reasonably standardize the use of genetic testing technology, and provide patients with more accurate genetic counseling are problem that clinicians need to seriously consider.
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Objective:To access the genetic defects and clinical characteristics of patients with KCNV2-associated cone dystrophy. Methods:Three pedigrees with KCNV2-associated cone dystrophy were recruited in Peking Union Medical College Hospital from August 2017 to December 2019.Peripheral blood from each patient and their parents was collected, and genomic DNA was extracted.Targeted exome capture plus next-generation sequencing (NGS) was used to detect the candidate variants.Suspected causative variants were validated by Sanger sequencing and segregation analysis.Comprehensive ocular examinations were performed, including vision acuity, colour vision, fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), visual field and electroretinogram (ERG). This study was approved by the Institutional Review Board of Peking Union Medical College Hospital and adhered to the tenets of the Declaration of Helsinki.Written informed consent was obtained from each patient prior to any medical examination. Results:Three probands from three unrelated Chinese families were confirmed carrying biallelic KCNV2 disease-causing variants.Two patients harbored compound heterozygous variants and one patient with history of consanguinity was identified carrying homozygous variant.Five novel variants in the KCNV2 gene were identified, including p. T121M, p.R244C, p.C199Y, p.M250R and p. L171Pfs*201.All patients enrolled in this study were male with age of 25, 16 and 2 years old, respectively.Three affected individuals complained of vision loss and photophobia and two patients demonstrated reduced color perception and nystagmus.Macular discoloration (bull's eye maculopathy or gold foil macular reflex) was observed in fundus photographs.Macular hypofluorescence was illustrated in FAF imaging, which accompanying a broad hyperfluorescent ring surrounding the central atrophy or not.Macular thinning with loss of the inner segment ellipsoid zone was noted in OCT images, and the disruption was more profound in older patients.Central scotoma with or without peripheral visual field defects was observed in perimetry.Severe cone function loss and variable scotopic rod impairment were demonstrated in ERG, whereas a broad a-wave trough response to scotopic bright flash stimulation was noted. Conclusions:Patients with KCNV2-associated cone dystrophy show a characteristic ERG manifestation.ERG results and KCNV2 variants in Chinese patients differ from those in foreigners.
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Objective To analyze the clinical features of cancer-associated retinopathy (CAR).Methods The clinical data of 10 patients who diagnosed as CAR during 5 years were retrospectively analyzed.All patients underwent detailed ocular examinations,including electroretinogram (ERG),optical coherence tomography (OCT),visual field (VF) and autofluorescence(AF).Results The primary malignancy was lung carcinoma in 3 patients,thymoma in 3 patients,thyroid carcinoma in 1 patients,maxillary sinus tumor in 1 patients,nasopharyngeal carcinoma in 1 patients and rectal cancer in 1 patients.All patients complained progressive visual reducing.Three patients manifested night blindness.The best corrected visual acuity (BCVA)＜0.1 was in three eyes,≤0.1-＜0.5 in seven eyes,and ≥0.5 in ten eyes.Patients showed normal fundi or mild abnormality.OCT images showed disorganization and/or loss of the ellipsoid zone in the macular area in 4 patients,and other six patients had only central foveal ellipsoid zone preserved.Eight patients had moderately or severely reduced ffERG,and 2 patients demonstrated electro-negative ERG.Five patients revealed peripheral visual defect.AF images were from normal to low or high AF patches in the posterior pole and mid-peripheral retina.Conclusions The clinical manifestations of CAR are varied as common characteristics of progressive visual decrease with or without night blindness,visual field defect and abnormal ffERG recording.
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Objective To provide detailed clinical and molecular genetic findings and describe the characteristics of natural history in Chinese choroideremia (CHM) patients.Methods The patients with CHM who met the inclusion criteria of at least two visits over a minimum period of 5 years were recruited on a voluntary basis at the Ophthalmic Genetics Clinic in Peking Union Medical College Hospital from April 2009 to August 2017.Molecular genetic analysis results,best-corrected visual acuity (BCVA),color fundus photograph,optical coherence tomography (OCT),visual field (VF),full-field electroretinography (fERG) were obtained.This study protocol was approved by the Institutional Review Board of Peking Union Medical College Hospital (S-K125).Written informed consent was obtained from each participant.Results Ten Chinese Han patients from seven CHM families were included.The mutations were confirmed by molecular genetic analysis,and two novel mutations were found.The median age of 10 patients at first visit was 44 years (range 8-52 years).The mean first-last visit period was 6.08 years (range 5.03-7.24 years).The mean BCVA at first visit in logMAR equivalents was 0.56 (range 0.0-2.0) or approximately 0.28 decimal acuity.The correlation between BCVA at first visit and age showed that relative good vision remained until 35 years old and BCVA subsequently reduced rapidly.OCT showed a thickening of the central retinal thickness at early stage,followed by a thinning over decades.Outer retinal tabulation (ORT) was shown in some patients.There was a strong negative correlation (r=-0.861,P＜0.001) between residual VF and age.Five patients did not need to record fERG because of serious fundus lesions.Two patients exhibited decreased amplitudes for both rod and cone-driven responses,and three patients exhibited no fERG amplitudes.Conclusions The progression of CHM may be severer and faster in Chinese patients than that in Western patients.ORT is an important manifestation of OCT in CHM patients.VF and fERG are applicable to evaluate the condition of very-early phase of CHM.
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It is clear that genetic background contributes to the development and progression of diabetic retinopathy (DR).However,the identification of susceptibility loci through candidate gene approaches,linkage disequilibrium analysis of case-control data and genome wide association study is still in its infancy and faces many challenges due to the complexity of the disease itself.China has rich resources of clinical samples.In order to facilitate elucidating the susceptibility genes of DR in China,we look forward multi-disciplinary,multi-regional collaboration studies integrating novel technologies,such as proteomics,metabolomics and next-generation sequencing to analyze gene-gene and gene-environment interaction factors comprehensively.
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ObjectiveTo establish and evaluate the methods which can quantify the ocular hemodynamics by combined scanning laser ophthalmoscopy video fluorescein angiography with computerized digital image processing system．MethodsAfter acquiring serial digital images by video capture from some angiography videotapes and measuring the gray values of some fixed areas over time in these serial images，the gray value curves and some parameters were obtained．The inter- and intra-observer reproducibility surveys were carried out．ResultsThe hemodynamic parameters were obtained，which included sectional choroidal filling time and rate，sectional papillary filling time and rate，retinal arterial and venous filling time and rate，arterovenous passing time and diameter of artery and vein．The intra- and inter-observer reproducibility were fairly good．Conclusioncomputerized digital image processing system is useful for understanding retinal and choroidal circulation．