Array-Based Comparative Genomic Hybridization in 190 Korean Patients with Developmental Delay and/or Intellectual Disability: A Single Tertiary Care University Center Study

이차곤,박상진,윤전노,고정민,김현주,임신영,손영배 연세대학교의과대학 2013 Yonsei medical journal Vol.54 No.6

Purpose: This study analyzed and evaluated the demographic, clinical, and cytogenetic data [G-banded karyotyping and array-based comparative genomic hybridization (array CGH)] of patients with unexplained developmental delay or intellectual disability at a single Korean institution. Materials and Methods: We collected clinical and cytogenetic data based on retrospective charts at Ajou University Medical Center, Suwon, Korea from April 2008 to March 2012. Results: A total of 190 patients were identified. Mean age was 5.1±1.87 years. Array CGH yielded abnormal results in 26 of 190 patients (13.7%). Copy number losses were about two-fold more frequent than gains. A total of 61.5% of all patients had copy number losses. The most common deletion disorders included 22q11.2 deletion syndrome, 15q11.2q12 deletion and 18q deletion syndrome. Copy number gains were identified in 34.6% of patients, and common diseases among these included Potocki-Lupski syndrome, 15q11-13 duplication syndrome and duplication 22q. Abnormal karyotype with normal array CGH results was exhibited in 2.6% of patients; theses included balanced translocation (n=2), inversion (n=2) and low-level mosaicism (n=1). Facial abnormalities (p<0.001) and failure to thrive were (p<0.001) also more frequent in the group of patients with abnormal CGH findings. Conclusion: Array CGH is a useful diagnostic tool in clinical settings in patients with developmental delay or intellectual disability combined with facial abnormalities or failure to thrive.

Brain abscess in Korean children: A 15-year single center study

이차곤,강성훈,신형진,최현신,이지훈,이문향,김예진 대한소아청소년과학회 2010 Clinical and Experimental Pediatrics (CEP) Vol.53 No.5

Purpose: A brain abscess is a serious disease of the central nerve system. We conducted this study to summarize the clinical manifestations and outcomes of brain abscesses. Methods: A retrospective chart review of pediatric patients diagnosed with brain abscesses from November 1994 to June 2009was performed at Samsung Medical Center, Seoul, Korea. Results: Twenty-five patients were included in this study. On average, 1.67 cases per year were identified and the median age was 4.3 years. The common presenting clinical manifestations were fever (18/25, 72%), seizure (12/25, 48%), altered mental status (11/25, 44%), and signs of increased intracranial pressure (9/25,36%). A total of 14 (56%) patients had underlying illnesses, with congenital heart disease (8/25, 32%) as the most common cause. Predisposing factors were identified in 15 patients (60%). The common predisposing factors were otogenic infection (3/25, 12%)and penetrating head trauma (3/25, 12%). Causative organisms were identified in 64% of patients (16/25). The causative agents were S. intermedius (n=3), S. aureus (n=3), S. pneumoniae (n=1), Group B streptococcus (n=2), E. coli (n=1), P. aeruginosa (n=1), and suspected fungal infection (n=5). Seven patients received medical treatment only while the other 18 patients also required surgical intervention. The overall fatality rate was 16% and 20% of patients had neurologic sequelae. There was no statistical association between outcomes and the factors studied. Conclusion: Although uncommon, a brain abscess is a serious disease. A high level of suspicion is very important for early diagnosis and to prevent serious consequences.

Reciprocal Deletion and Duplication of 17p11.2-11.2: Korean Patients with Smith-Magenis Syndrome and Potocki-Lupski Syndrome

이차곤,Sang-Jin Park,Jun-No Yun,임신영,손영배 대한의학회 2012 Journal of Korean medical science Vol.27 No.12

Deletion and duplication of the -3.7-Mb region in 17p11.2 result in two reciprocal syndrome, Smith-Magenis syndrome and Potocki-Lupski syndrome. Smith-Magenis syndrome is a well-known developmental disorder. Potocki-Lupski syndrome has recently been recognized as a microduplication syndrome that is a reciprocal disease of Smith-Magenis syndrome. In this paper, we report on the clinical and cytogenetic features of two Korean patients with Smith-Magenis syndrome and Potocki-Lupski syndrome. Patient 1(Smith-Magenis syndrome) was a 2.9-yr-old boy who showed mild dysmorphic features,aggressive behavioral problems, and developmental delay. Patient 2 (Potocki-Lupski syndrome), a 17-yr-old boy, had only intellectual disabilities and language developmental delay. We used array comparative genomic hybridization (array CGH) and found a 2.6 Mbsized deletion and a reciprocal 2.1 Mb-sized duplication involving the 17p11.2. These regions overlapped in a 2.1 Mb size containing 11 common genes, including RAI1 and SREBF.

Clinical outcome of acute necrotizing encephalopathy in related to involving the brain stem of single institution in Korea

이차곤,김지혜,이문향,이지훈 대한소아청소년과학회 2014 Clinical and Experimental Pediatrics (CEP) Vol.57 No.6

Purpose: Acute necrotizing encephalopathy (ANE) is a fulminant disease of the brain characterized bybilateral thalamic lesions, and is prevalent among children in East Asia. The prognosis of ANE is usuallypoor with a high mortality rate and neurological sequelae. This study aimed to delineate the clinicalcharacteristics and prognostic factors of ANE. Methods: We retrospectively analyzed clinical data of 399 pediatric patients with encephalitis who wereadmitted to Samsung Medical Center from December 1998 to March 2011. We enrolled ten patients (11cases) with ANE and analyzed their demographic, clinical, and neuroimaging data. The location and extent ofthe brain regions were checked based on fluid-attenuated inversion recovery, T1-, and T2-weighted imagingfindings; the presence of contrast enhancement, restricted diffusion, and hemorrhage. Results: Ten patients were identified, including one patient with two episodes. The median age ofonset was 1.5 years (0.4–8.4 years). The mortality rate was 40%, and only 30% of patients survivedwithout neurological sequelae. The definite involvement of the brainstem on brain magnetic resonanceimaging was significantly correlated with mortality (P =0.04). Conclusion: Broad and extensive brainstem involvement suggested the fulminant course of ANE. Earlydiagnosis of ANE before brainstem involvement, through careful identification of symptoms of braindysfunction, may be the best way to achieve better neurological outcomes.

Low-frequency Mosaicism of Trisomy 14, Missed by Array CGH

이차곤,윤준노,박상진,손영배 대한의학유전학회 2013 대한의학유전학회지 Vol.10 No.1

Mosaic trisomy 14 syndrome is a well-known but unusual chromosomal abnormality with a distinct and recognizable phenotype. Array comparative genomic hybridization (CGH) analysis has recently become a widely used method for detecting DNA copy number changes, in place of traditional karyotype analysis. However, the array CGH shows a limitation for detecting the low-level mosaicism. Here, we report the detailed clinical and cytogenetic findings of patient with low-frequency mosaic trisomy 14, initially considered normal based on usual cut-off levels of array CGH, but confirmed by G-banding karyotyping. Our patient had global developmental delay, short stature, congenital heart disease, craniofacial dysmorphic features, and dark skin patches over her whole body. Estimated mosaicism proportion was 23.3% by G-banding karyotyping and 18.0% by array CGH.

심한 폐동맥 고혈압을 동반한 좌우 단락 질환 환자의 수술 후 경과

이차곤,정수인,허준,이흥재,양지혁,전태국,강이석 대한소아청소년과학회 2010 Clinical and Experimental Pediatrics (CEP) Vol.53 No.2

목적:본 연구에서는 좌우 단락에 의한 심한 폐동맥 고혈압으로 수술 가능 여부가 불확실했던 환자들의 수술 후 중기 임상 경과를 보고하고자 한다방법:1995년 이후 삼성서울병원에서 좌우 단락에 의한 폐동맥 고혈압으로 심도자술 후 수술 받은 환자들 중, 만 1세 이후, 폐혈관 저항 8 Wood unit 이상이었던 21명의 환자를 대상으로 이들의 수술 전후 및 추적 기간 중 임상 증상, 폐동맥 압력 변화를 후향적으로 검토하였다. 대상 환자의 수술 당시 평균 연령은 26 (1-58)세였다. 진단은 심방 중격 결손(n=11), 심실 중격 결손(n=4), 심실 중격 결손과 동맥관 개존(n=4), 그리고 동맥관 개존(n=2)이었다. 수술 여부는 폐혈관 가역성에 기초하여 결정하였으며, 5명에서는 좌우 단락을 완전히 막았고, 16명의 환자는 작은 좌우 단락을 남겨 놓는 형태의 수술을 시행 받았다. 결과:수술 직후 폐동맥에 삽입한 도관이나 심초음파로 추정한 폐동맥 압력은 모든 환자에서 수술 전보다 감소되었다. 또한 이러한 수술 직후의 폐동맥 압력은 수술 전 결손의 일시적 폐쇄 당시의 폐동맥 압력과 유사한 값을 보였다. 두 명의 환자를 제외한 대부분 환자에서 추적 기간 동안 폐동맥 압력이 감소추세를 유지하였다. 임상증상은 NYHA functional class 기준으로 한 명의 환자를 제외하고는 모두 호전을 보였다. 수술 직후뿐만 아니라 추적 관찰 기간 동안에도 사망이나, 수술과 관련된 특별한 합병증은 없었다. 결론:본 연구에서는 좌우 단락에 의한 심한 폐동맥 고혈압 환자들을 폐동맥 고혈압 가역성에 근거하여 수술하였고, 큰 위험 없이 심장 수술이 가능하였다. 폐동맥 확장제 흡입에 반응을 보이지 않았던 환자들에서 결손의 일시적 폐쇄 상태에서는 반응을 보인 경우가 많았고, 이는 수술 직후 폐동맥 압력과 유사하여 유용한 정보를 얻을 수 있었다. 대부분의 환자에서 폐동맥 압력이 감소하고 임상 양상의 호전을 보였으나, 다시 증가하거나 정상까지 감소하지 않을 수 있으므로 세심한 관찰과 장기적인 추적이 필요하다. Purpose:Despite recent advances in pulmonary hypertension management and surgery, appropriate guidelines remain to be developed for operability in congenital heart disease with pulmonary artery hypertension (PAH). Our aim was to evaluate clinical outcomes of patients with severe PAH who underwent surgical closure of left-to-right shunt lesions (LRSL) on the basis of pulmonary reactivity. Methods:We retrospectively reviewed 21 patients who underwent surgical closure of LRSL with severe PAH (≥8 Wood unit) from January 1995 to April 2009. The median age at operation was 26 years. Atrial septal defect, ventricular septal defect (VSD), VSD and patent ductus arteriosus (PDA), and PDA was present in 11, 4, 4, and 2 patients, respectively. Results:Operability was based on vasoreactivity of PAH. Of the 21 patients, 5 showed response to pulmonary vasodilator therapy and 8 showed vasoreactivity after balloon occlusion of defects. The remaining 8 patients were considered operable because of significant left-to-right shunt (Qp/Qs ≥1.5). Five patients underwent total closure of defects and 16 were left with small residual shunts. The median follow-up duration was 32 months. There was no significant postoperative mortality or morbidity. Systolic pulmonary artery pressure (PAP) decreased in all but 2 patients. All patients except 1 showed improvement of New York Heart Association functional class. Conclusion:Closure of LRSL in patients with severe PAH on the basis of pulmonary vasoreactivity seems reasonable. PAP and clinical symptoms improved in most patients. Further research is needed for the evaluation of long-term results.

First identified Korean family with Tatton-Brown-Rahman Syndrome caused by the novel DNMT3A variant c.118G>C p.(Glu40Gln)

이차곤,Ja-Hyun Jang,서지영 대한소아내분비학회 2019 Annals of Pediatirc Endocrinology & Metabolism Vol.24 No.4

Tatton-Brown-Rahman Syndrome (TBRS), an overgrowth syndrome caused by heterozygous mutation of DNMT3A, first was described in 2014. Approximately 60 DNMT3A variants, including 32 missense variants, have been reported, with most missense mutations located on the DNMT3A functional domains. Autosomal dominant inheritance by germ-line mutation of DNMT3A has been reported, but vertical transmission within a family is extremely rare. Herein, we report the first Korean family with maternally inherited TBRS due to the novel heterozygous DNMT3A variant c.118G>C p.(Glu40Gln), located outside the main functional domain and identified by multigene panel sequencing. The patient and her mother had typical clinical features, including tall stature during childhood, macrocephaly, intellectual disability, and characteristic facial appearance. TBRS shows milder dysmorphic features than other overgrowth syndromes, potentially leading to underdiagnosis and underestimated prevalence; thus, targeted multigene panel sequencing including DNMT3A will be a useful tool in cases of overgrowth and unexplained mild intellectual disability for early diagnosis and genetic counseling.

Xeroderma pigmentosum group A with mutational hot spot (c.390-1G>C in XPA) in South Korea

최정윤,윤형호,이차곤 대한의학유전학회 2016 대한의학유전학회지 Vol.13 No.1

Purpose: Xeroderma pigmentosum (XP) is rare autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet light is deficient. We reported the first molecularly confirmed Korean patient of XP by targeted exome sequencing. The prevalence of XP included all subtype and carrier frequency of XP-A the using public data were estimated for the first time in South Korea. Materials and Methods: We described a 4-year-old Korean girl with clinical diagnosis of XP. We performed targeted exome sequencing in the patient for genetic confirmation considering disease genetic heterogeneity and for differential diagnosis. We verified a carrier frequency of c.390-1G>C in XPA gene known as mutational hot spot using Korean Reference Genome Data Base. We estimated the period prevalence of all subtypes of XP based on claims data of the Health Insurance Review and Assessment Service in South Korea. Results: We identified homozygous splicing mutation of XPA (c.390-1G>C) in the patient. The carrier frequency of risk for XPA (c.390-1G>C) was relatively high 1.608 e-03 (allele count 2/1244). The prevalence of XP in South Korea was 0.3 per million people. Conclusion: We expect that c.390-1G>C is hot spot for the mutation of XPA and possible founder variant in South Korea. However, the prevalence in South Korea was extremely low compared with Western countries and Japan.

A case of pulmonary vascular air embolism in a very-low-birth-weight infant with massive hydrops

김묘징,유희준,이차곤,박수경,장윤실,박원순 대한소아청소년과학회 2009 Clinical and Experimental Pediatrics (CEP) Vol.52 No.12

Pulmonary vascular air embolism is a rare and, universally, almost a fatal complication of positive pressure ventilation in newborn infants. Here, we report a case of this unusual complication in a very-low-birth-weight infant who showed the clinical and radiological features of this complication along with pulmonary hypoplasia and massive hydrops. The possible pathogenesis has been discussed and a brief review of related literature has been presented.

Successful Desensitization of Oxcarbazepine: First Case in Pediatric Patient

이옥정,유희준,이차곤,남숙현,이보련,이지훈,이문향 대한소아신경학회 2011 대한소아신경학회지 Vol.19 No.3

Aromatic antiepileptic drugs (AEDs), such as diphenylhydantoin, phenobarbital, or carbamazepine (CBZ), are frequently associated with hypersensitivity reactions. This may restrict treatment options considerably due to cross reactivity with other aromatic AEDs. Desensitization can be very helpful for patients who show cross sensitivity with other AEDs. We report a case an 8-year-old patient who had cross sensitivity to oxcarbazepine (OXC) and CBZ and successfully managed by desensitization to OXC. The patient presented with intractable frontal lobe epilepsy. He had become seizure free with OXC; however OXC had to be discontinued due to whole body rash. CBZ also caused a hypersensitivity reaction. Therefore, OXC desensitization was attempted; he then had very subtle seizures during sleep with a frequency of 5 to 6 episodes per month on the 18th month of desensitization. Desensitization can be considered in a patient with limited treatment options due to hypersensitivity to aromatic AEDs.