Review of Genetic Diagnostic Approaches for Glanzmann Thrombasthenia in Korea

Shim, Ye Jee Interdisciplinary Society of GeneticGenomic Medici 2021 Journal of interdisciplinary genomics Vol.3 No.2

Inherited platelet function disorders (IPFDs) are a disease group of heterogeneous bleeding disorders associated with congenital defects of platelet functions. Normal platelets essential role for primary hemostasis by adhesion, activation, secretion of granules, aggregation, and procoagulant activity of platelets. The accurate diagnosis of IPFDs is challenging due to unavailability of important testing methods, including light transmission aggregometry and flow cytometry, in several medical centers in Korea. Among several IPFDs, Glanzmann thrombasthenia (GT) is a most representative IPFD and is relatively frequently found compare to the other types of rarer IPFDs. GT is an autosomal recessive disorder caused by mutations of ITGA2B or ITGB3. There are quantitative or qualitative defects of the GPIIb/IIIa complex in platelet, which is the binding receptor for fibrinogen, von Willbrand factor, and fibronectin in GT patients. Therefore, patients with GT have normal platelet count and normal platelet morphology, but they have severely decreased platelet aggregation. Thus, GT patients have a very severe hemorrhagic phenotypes that begins at a very early age and persists throughout life. In this article, the general contents about platelet functions and respective IPFDs, the overall contents of GT, and the current status of genetic diagnosis of GT in Korea will be reviewed.

First Korean Case of 16p11.2 Duplication Syndrome Diagnosed by Chromosomal Microarray Analysis

Shim, Ye Jee,Park, So Yun,Jung, Nani,Kang, Seok Jin,Kim, Heung Sik,Ha, Jung-Sook Interdisciplinary Society of GeneticGenomic Medici 2019 Journal of interdisciplinary genomics Vol.1 No.1

A 10-year and 5 month-old girl with developmental delay, intellectual disability, attention deficit hyperactivity disorder, poor weight gain, and microcephaly was transferred to our pediatric clinic for genetic evaluation. Her height was within the 5-10th percentile, and her weight was under the 3rd percentile. On the social maturity scale, her developmental status was scored as 3 years 9 months for social age, and the social quotient was 35.98. A chromosomal microarray analysis was performed and the microduplication at chromosome 16p was observed: arr[GRCh37] 16p11.2 (29580020_30190029)${\times}3$. Currently, the patient is diagnosed with Grade 2 intellectual disability and is attending a computerized cognitive rehabilitation class twice weekly. In addition, nutritional support and growth follow up are also ensured in the Pediatric Gastrointestinal and Endocrinology clinic.

Genetic classification and confirmation of inherited platelet disorders: current status in Korea

Shim, Ye Jee The Korean Pediatric Society 2020 Clinical and Experimental Pediatrics (CEP) Vol.63 No.3

Inherited platelet disorders (IPDs), which manifest as primary hemostasis defects, often underlie abnormal bleeding and a family history of thrombocytopenia, bone marrow failure, hematologic malignancies, undefined mucocutaneous bleeding disorder, or congenital bony defects. Wide heterogeneity in IPD types with regard to the presence or absence of thrombocytopenia, platelet dysfunction, bone marrow failure, and dysmegakaryopoiesis is observed in patients. The individual processes involved in platelet production and hemostasis are genetically controlled; to date, mutations of more than 50 genes involved in various platelet biogenesis steps have been implicated in IPDs. Representative IPDs resulting from defects in specific pathways, such as thrombopoietin/MPL signaling; transcriptional regulation; granule formation, trafficking, and secretion; proplatelet formation; cytoskeleton regulation; and transmembrane glycoprotein signaling are reviewed, and the underlying gene mutations are discussed based on the National Center for Biotechnology Information database and Online Mendelian Inheritance in Man accession number. Further, the status and prevalence of genetically confirmed IPDs in Korea are explored based on searches of the PubMed and KoreaMed databases. IPDs are congenital bleeding disorders that can be dangerous due to unexpected bleeding and require genetic counseling for family members and descendants. Therefore, the pediatrician should be suspicious and aware of IPDs and perform the appropriate tests if the patient has unexpected bleeding. However, all IPDs are extremely rare; thus, the domestic incidences of IPDs are unclear and their diagnosis is difficult. Diagnostic confirmation or differential diagnoses of IPDs are challenging, time-consuming, and expensive, and patients are frequently misdiagnosed. Comprehensive molecular characterization and classification of these disorders should enable accurate and precise diagnosis and facilitate improved patient management.

혈우병 A의 발병에 관여하는 유전적 요인

심예지(Ye Jee Shim),이건수(Kun Soo Lee) 대한의학유전학회 2010 대한의학유전학회지 Vol.7 No.1

Hemophilia A is a sex-linked recessive coagulation disorder associated with diverse mutations of the factor Ⅷ gene and a variety of phenotypes. The type of mutation involved dictates the activity of factor Ⅷ, and in turn the severity of bleeding episodes and development of alloantibodies against factor Ⅷ (inhibitors). Missense mutations are the most common genetic risk factors for hemophilia A, especially mild to moderate cases, but carry the lowest risk for inhibitor development. On the other hand, intron 22 inversion is the most common mutation associated with severe hemophilia A and is associated with high risk of inhibitor formation. Large deletions and nonsense mutations are also associated with high risk of inhibitor development. Additional mutations associated with hemophilia A include frameshift and splice site mutations. It is therefore valuable to assess the mutational backgrounds of hemophilia A patients in order to to interpret their symptoms and manage their health problems.

터너증후군의 핵형과 표현형간의 연관성

심예지(Ye Jee Shim),황영주(Young Ju Hwang),이건수(Kun Soo Lee) 대한의학유전학회 2009 대한의학유전학회지 Vol.6 No.1

목적 : 터너증후군 환자들에게는 다양한 핵형과 표현형이 나타나지만 우리나라에서는 그 연관성에 대한 연구가 미미한 실정이다. 그리하여 본 연구에서는 터너증후군으로 진단받은 환자들의 염색체 이상, 임상 양상, 동반 질환에 대해 조사하였다. 대상 및 방법 : 경북대학교병원에서 터너증후군으로 진단 받은 환자 92명을 대상으로 염색체 핵형을 분류하였으며, 그 중 62명을 대상으로 임상 양상 및 동반 질환을 조사하였다. 결과 : 핵형이 45,X인 환자는 54.3%였고. 섞임증 및 구조 이상이 나머지를 차지하였다. 섞임증의 경우 45,X에 비하여 Turner stigmata의 빈도가 낮았다. 46,X,del(Xp) 및 45,X/46,X,del(Xq)에서는 모두 골격 이상이 나타난 반면, 46,X, del(Xq)에서는 나타나지 않았다. 46,X,del(Xp)에서는 성적유치증이 나타나지 않았지만, 46,X,del(Xq) 및 45,X/46,X,del(Xq)의 경우에는 이차 성징 지연이 지연 및 무월경이 나타났다. 46,X,i(Xq) 및 45,X/46,X,i(Xq)의 경우 이차 성징이 발현되지 않았고 모두 일차 무월경을 보였다. 그 외에 장완의 isochromosome이 있는 경우 청력 장애 및 갑상선 질환이 더 빈번하게 나타났다. 결론 : 터너증후군 환자들의 핵형과 표현형 사이의 연관성을 조사하는 작업은 성염색체에 위치하는 유전자자리를 예측하는 정보를 얻을 수 있다는 점에서 중요하다고 생각한다. Purpose : In spite of the karyotype and phenotype diversity in Turner syndrome patients, there are few reports about such differences in Korea. We reviewed the data of chromosome abnormalities, clinical manifestations, and comorbidities of Turner syndrome patients in Kyungpook National University Hospital to compare them to the recent hypotheses about sex chromosome gene loci related to Turner symptoms. Materials and Methods : We identified the cytologic findings of 92 patients with Turner syndrome and the clinical findings of 62 patients among them. Results : 54.3 percent of patients had 45,X while 45.7 percent showed other karyotype combinations (45,X/46,XX, 45,X/46,XX/47,XXX, 46,X,del(Xp), 46,X,del(Xq), 45,X/46,X,del(Xq), 46,X,i(Xq), 45,X/46,X,i (Xq)). The Turner symptoms found included short neck, high arched palate, broad chest, Madelung deformity, short metacarpals, scoliosis, cubitus valgus, low hair line, webbed neck, edematous extremities, pigmented nevus, and sexual infantilism. The specific diseases associated Turner syndrome included renal abnormalities, congenital heart disease, hearing defects, diabetes mellitus, hyperlipidemia, and decreased bone density. The phenotype of the mosaicism group was milder than that of the monosomy group. In the case of 46,X,del(Xp) and 45,X/46,X,del(Xq) groups, all had skeletal abnormalities, but the 46,X,del(Xq) group had none. In the case of 46,X,del(Xp) group, all showed short statures and skeletal abnormalities, but no sexual infantilism was observed. In the case of 46,X,i(Xq) and 45,X/46,X,i(Xq) groups, they all showed delayed puberty and had primary amenorrhea. Conclusion : It is important to study karyotype-phenotype correlations in patients with Turner syndrome to obtain interesting information about the genotype-phenotype correlations related to the X chromosome.

A rare case of pediatric immune thrombocytopenia with secondary antiphospholipid syndrome in Korea

Eun Ji Mun,Ye Jee Shim,Heung Sik Kim 대한혈액학회 2022 Blood Research Vol.57 No.3

Korean clinical practice guidelines for the diagnosis of hereditary hemolytic anemia

최희원,Sang Mee Hwang,Ye Jee Shim,Jae Min Lee,Hee Sue Park,Joon Hee Lee,Youngwon Nam,김남희,Hye Lim Jung,Hyoung Soo Choi,on behalf of Korean RBC Disorder Working Party 대한혈액학회 2022 Blood Research Vol.57 No.2

Although the prevalence of hereditary hemolytic anemia (HHA) is relatively low in Korea, it has been gradually increasing in recent decades due to increment in the proportions of hemoglobinopathies from immigrants of South East Asia, raising awareness of the disease among clinicians, and advances in diagnostic technology. As such, the red blood cell (RBC) Disorder Working Party (WP), previously called HHA WP, of the Korean Society of Hematology (KSH) developed the Korean Standard Operating Procedures (SOPs) for the diagnosis of HHA in 2007. These SOPs have been continuously revised and updated following advances in diagnostic technology [e.g., flow cytometric osmotic fragility test (FOFT) and eosin-5-maleimide (EMA) binding test], current methods for membrane protein or enzyme analysis [e.g., liquid chromatography-tandem mass spectrometry (LC-MS/MS), ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), high-performance liquid chromatography (HPLC)], and molecular genetic tests using next-generation sequencing (NGS). However, the diagnosis and treatment of HHA remain challenging as they require considerable experience and understanding of the disease. Therefore, in this new Korean Clinical Practice Guidelines for the Diagnosis of HHA, on behalf of the RBC Disorder WP of KSH, updated guidelines to approach patients suspected of HHA are summarized. NGS is proposed to perform prior to membrane protein or enzyme analysis by LC-MS/MS, UPLC-MS/MS or HPLC techniques due to the availability of gene testing in more laboratories in Korea. We hope that this guideline will be helpful for clinicians in making diagnostic decisions for patients with HHA in Korea.

A retrospective analysis of etiology and outcomes of hemophagocytic lymphohistiocytosis in children and adults

( Abraham Kwak ),( Nani Jung ),( Ye Jee Shim ),( Heung Sik Kim ),( Hyun Ji Lim ),( Jae Min Lee ),( Mi Hwa Heo ),( Young Rok Do ) 영남대학교 의과대학 2021 Yeungnam University Journal of Medicine Vol.38 No.3

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe, life-threatening inflammatory condition if untreated. We aimed to investigate the etiologies, outcomes, and risk factors for death in children and adults with HLH. Methods: The medical records of patients who met the HLH criteria of two regional university hospitals in Korea between January 2001 and December 2019 were retrospectively investigated. Results: Sixty patients with HLH (35 children and 25 adults) were included. The median age at diagnosis was 7.0 years (range, 0.1-83 years), and the median follow-up duration was 8.5 months (range, 0-204 months). Four patients had primary HLH, 48 patients had secondary HLH (20 infection-associated, 18 neoplasm-associated, and 10 autoimmune-associated HLH), and eight patients had HLH of unknown cause. Infection was the most common cause in children (14/35, 40.0%), whereas neoplasia was the most common cause in adults (13/25, 52.0%). Twenty-eight patients were treated with HLH-2004/94 immunochemotherapy. The 5-year overall survival (OS) rate for all HLH patients was 59.9%. The 5-year OS rates for patients with primary, infection-associated, neoplasm-associated, autoimmune-associated, and unknown cause HLH were 25.0%, 85.0%, 26.7%, 87.5%, and 62.5%, respectively. Using multivariate analysis, neoplasm-induced HLH (p=0.001) and a platelet count <50×10⁹/L (p=0.008) were identified as independent risk factors for poor prognosis in patients with HLH. Conclusion: Infection was the most common cause of HLH in children, while it was neoplasia in adults. The 5-year OS rate for all HLH patients was 59.9%. HLH caused by an underlying neoplasm or a low platelet count at the time of diagnosis were risk factors for poor prognosis.

An infant with severe hemophilia A with intracranial hemorrhage mistaken for child abuse: a case report

Ji Won Youn,Ye Jee Shim,Jun Chul Byun,Sae Min Kwon 대한혈액학회 2022 Blood Research Vol.57 No.2

Current Status of Molecular Diagnosis of Hereditary Hemolytic Anemia in Korea

Chueh Hee Won,Shim Ye Jee,Jung Hye Lim,Kim Namhee,Hwang Sang Mee,Kim Myungshin,Choi Hyoung Soo 대한의학회 2024 Journal of Korean medical science Vol.39 No.18

Hereditary hemolytic anemia (HHA) is considered a group of rare hematological diseases in Korea, primarily because of its unique ethnic characteristics and diagnostic challenges. Recently, the prevalence of HHA has increased in Korea, reflecting the increasing number of international marriages and increased awareness of the disease. In particular, the diagnosis of red blood cell (RBC) enzymopathy experienced a resurgence, given the advances in diagnostic techniques. In 2007, the RBC Disorder Working Party of the Korean Society of Hematology developed the Korean Standard Operating Procedure for the Diagnosis of Hereditary Hemolytic Anemia, which has been continuously updated since then. The latest Korean clinical practice guidelines for diagnosing HHA recommends performing nextgeneration sequencing as a preliminary step before analyzing RBC membrane proteins and enzymes. Recent breakthroughs in molecular genetic testing methods, particularly nextgeneration sequencing, are proving critical in identifying and providing insight into cases of HHA with previously unknown diagnoses. These innovative molecular genetic testing methods have now become important tools for the management and care planning of patients with HHA. This review aims to provide a comprehensive overview of recent advances in molecular genetic testing for the diagnosis of HHA, with particular emphasis on the Korean context.