Gyung Min Lee

A Korean boy with 46,XX testicular disorder of sex development caused by SOX9 duplication

The 46,XX testicular disorder of sex development (DSD), also known as 46,XX male syndrome, is a rare form of DSD and clinical phenotype shows complete sex reversal from female to male. The sex-determining region Y (SRY) gene can be identified in most 46,XX testicular DSD patients; however, approximately 20% of patients with 46,XX testicular DSD are SRY-negative. The SRY-box 9 (SOX9) gene has several important functions during testis development and differentiation in males, and overexpression of SOX9 leads to the male development of 46,XX gonads in the absence of SRY. In addition, SOX9 duplication has been found to be a rare cause of 46,XX testicular DSD in humans. Here, we report a 4.2-year-old SRY-negative 46,XX boy with complete sex reversal caused by SOX9 duplication for the first time in Korea. He showed normal external and internal male genitalia except for small testes. Fluorescence in situ hybridization and polymerase chain reaction (PCR) analyses failed to detect the presence of SRY, and SOX9 intragenic mutation was not identified by direct sequencing analysis. Therefore, we performed real-time PCR analyses with specific primer pairs, and duplication of the SOX9 gene was revealed. Although SRY-negative 46,XX testicular DSD is a rare condition, an effort to make an accurate diagnosis is important for the provision of proper genetic counseling and for guiding patients in their long-term management.

Effect of early postnatal neutropenia in very low birth weight infants born to mothers with pregnancy-induced hypertension

Purpose In this study, we aimed to investigate the perinatal clinical conditions of very low birth weight (VLBW) infants born to mothers with pregnancy-induced hypertension (PIH) focusing on the effects of early postnatal neutropenia. Methods We reviewed the medical records of 191 VLBW infants who were born at Konyang University Hospital, between March 2003 and May 2011. We retrospectively analyzed the clinical characteristics of the infants and their mothers and compared the incidence of perinatal diseases and mortality of the infants according to the presence or absence of maternal PIH and neutropenia on the first postnatal day. Results Infants born to mothers with PIH showed an increased incidence of neutropenia on the first postnatal day (47.4%), cesarean delivery, and intrauterine growth restriction. When the infants born to mothers with PIH showed neutropenia on the first postnatal day, their incidence of respiratory distress syndrome (RDS) was increased (P=0.031); however, the difference was not found to be significant through logistic regression analysis. In all the VLBW infants, neutropenia on the first postnatal day was correlated with the development of RDS. The incidence of the other perinatal diseases involving sepsis and mortality did not significantly differ according to the presence or absence of neutropenia in infants born to mothers with PIH. Conclusion In VLBW infants born to mothers with PIH, the incidence of neutropenia on the first postnatal day was increased and it was not significantly correlated with the development of perinatal diseases involving RDS, sepsis, and mortality.

The Association between Helicobacter pylori Infection and Body Weight among Children

Purpose We performed to reveal the association between the Helicobacter pylori infection and body weight among children. Methods Out retrospective study included patients who underwent the H. pylori immunoglobulin G testing at Konyang University Hospital between March 2011 and June 2014. These patients were classified as seropositive (28 boys, 27 girls; mean age: 9.89±3.28 years) or seronegative (55 boys, 54 girls; mean age: 9.84±3.02 years). Next, we compared various characteristics between the seropositive and negative groups, as well as between obese children (body weight ≥90th percentile) and non-obese children (body weight <90th percentile). Furthermore, we compared the change in body weight after 2 months of treatment with amoxicillin, clarithromycin and omeprazole among the 55 seropositive children (14 treated children and 41 non-treated children). Results There were no differences in the weights and laboratory data for the 55 seropositive children and 109 seronegative children (weight; 40.96±18.11 kg vs. 36.85±13.72 kg, respectively; p=0.14). And, there was no difference in the prevalence of H. pylori infection among the 29 obese and 135 non-obese children (p=0.581). However, after 2 months of eradication, the 14 treated patients exhibited a significant weight gain (+0.91±0.52 kg), compared to the 41 non-treated patients (-0.29±1.16 kg, p=0.025). Conclusion Our findings present that obesity was not associated with the H. pylori infection, although H. pylori eradication led to significant increase in body weight.

No influence of parental origin of intact X chromosome and/or Y chromosome sequences on three-year height response to growth hormone therapy in Turner syndrome

Purpose Whether parental origin of the intact X chromosome and/or the presence of Y chromosome sequences (Yseq) play a role in three-year height response to growth hormone (GH) were investigated. Methods Paternal (Xp) or maternal (Xm) origin of X chromosome was assessed by microsatellite marker analysis and the presence of hidden Yseq was analyzed. The first-, second-, and third-year GH response was measured as a change in height z-score (Z_Ht) in Turner syndrome (TS) patients with 45,Xp (n=10), 45,Xm (n=15), and 45,X/46,X,+mar(Y) (Xm_Yseq) (n=8). Results The mean baseline Z_Ht did not differ according to Xp or Xm origin, however the mean baseline Z_Ht was higher in the Xm_Yseq group than in Xm group, after adjusting for bone age delay and midparental Z_Ht (P=0.04). There was no difference in the height response to GH between the 3 groups. The height response to GH decreased progressively each year (P<0.001), such that the third-year increase in Z_Ht was not significant. This third-year decrease in treatment response was unaffected by Xp, Xm, and Xm_Yseq groups. Increasing GH dosage from the second to third-year of treatment positively correlated with the increase in Z_Ht (P=0.017). Conclusion There was no evidence of X-linked imprinted genes and/or Yseq affecting height response to 3 years of GH therapy. Increasing GH dosages may help attenuate the decrease in third-year GH response in TS patients with 45,X and/or 46,X/+mar(Y).

CD4+FOXP3+ Regulatory T Cells Exhibit Impaired Ability to Suppress Effector T Cell Proliferation in Patients with Turner Syndrome

Objective We investigated whether the frequency, phenotype, and suppressive function of CD4+FOXP3+ regulatory T cells (Tregs) are altered in young TS patients with the 45,X karyotype compared to age-matched controls. Design and Methods Peripheral blood mononuclear cells from young TS patients (n = 24, 17.4–35.9 years) and healthy controls (n = 16) were stained with various Treg markers to characterize their phenotypes. Based on the presence of thyroid autoimmunity, patients were categorized into TS (–) (n = 7) and TS (+) (n = 17). Tregs sorted for CD4+CD25bright were co-cultured with autologous CD4+CD25− target cells in the presence of anti-CD3 and -CD28 antibodies to assess their suppressive function. Results Despite a lower frequency of CD4+ T cells in the TS (-) and TS (+) patients (mean 30.8% and 31.7%, vs. 41.2%; P = 0.003 and P < 0.001, respectively), both groups exhibited a higher frequency of FOXP3+ Tregs among CD4+ T cells compared with controls (means 1.99% and 2.05%, vs. 1.33%; P = 0.029 and P = 0.004, respectively). There were no differences in the expression of CTLA-4 and the frequency of Tregs expressing CXCR3+, and CCR4+CCR6+ among the three groups. However, the ability of Tregs to suppress the in vitro proliferation of autologous CD4+CD25− T cells was significantly impaired in the TS (–) and TS (+) patients compared to controls (P = 0.003 and P = 0.041). Meanwhile, both the TS (–) and TS (+) groups had lower frequencies of naïve cells (P = 0.001 for both) but higher frequencies of effector memory cells (P = 0.004 and P = 0.002) than did the healthy control group. Conclusions The Tregs of the TS patients could not efficiently suppress the proliferation of autologous effector T cells, despite their increased frequency in peripheral CD4+ T cells.

A lack of association between vitamin D-binding protein and 25-hydroxyvitamin D concentrations in pediatric type 1 diabetes without microalbuminuria

Purpose Vitamin D deficiency is reported to be more common in type 1 diabetes patients and might be associated with the increased urinary loss of vitamin D binding protein (VDBP) consequent to impaired 25-hydroxyvitamin D (25(OH)D) circulation. We aimed to evaluate the possible increased urinary loss of VDBP, a correlation between VDBP and circulating 25(OH)D level, and risk factors influencing low vitamin D level in pediatric type 1 diabetes patients without microalbuminuria. Methods This is a cross-sectional study of subjects who visited Seoul National University Children’s Hospital between January and March 2013. Forty-two type 1 diabetes patients and 29 healthy controls were included. Biochemical parameters including serum and urine VDBP concentrations were analyzed. Results There was no significant difference in the frequency of vitamin D deficiency or serum 25(OH)D level between the 2 groups. The serum and urine VDBP concentrations did not show any difference between the 2 groups. Serum 25(OH) D level did not correlate with serum or urine VDBP. Multivariate regression analysis revealed that daylight outdoor hours (β=2.948, P=0.003) and vitamin D intake (β=2.865, P=0.003) affected the 25(OH)D level; the presence of type 1 diabetes or urinary VDBP excretion was not significant. Conclusions In pediatric type 1 diabetes patients, urinary VDBP excretion did not contribute to low serum 25(OH)D level in the setting of normoalbuminuria. The factors associated with 25(OH)D level during winter periods were daylight outdoor hours and vitamin D intake. Further studies including both micro- and macroalbuminuria patients with type 1 diabetes are warranted.

The Relationships between Respiratory Virus Infection and Aminotransferase in Children

Purpose We sought to examine the relationship between the clinical manifestations of nonspecific reactive hepatitis and respiratory virus infection in pediatric patients. Methods Patients admitted to the pediatric unit of Konyang University Hospital for lower respiratory tract disease between January 1, 2014 and December 31, 2014 and who underwent reverse transcriptase polymerase chain reaction tests were examined. The patients were divided into those with increased levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and those with normal ALT or AST levels. Further, patients with increased ALT and AST levels were individually compared with patients in the normal group, and the blood test results were compared according to the type of respiratory virus. Results Patients with increased ALT or AST levels had one more day of hospital stay, on average, compared with patients in the normal group (5.3±3.1 days vs. 4.4±3.0 days, p=0.019). Patients in the increased ALT level group were younger and had a longer mean hospital stay, compared with patients in the normal group (p=0.022 and 0.003, respectively). The incidences of increased ALT or AST were the highest in adenovirus infections (6/24, 25.0%), followed by enterovirus (2/11, 18.2%) and respiratory syncytial virus A (21/131, 16.0%) infections. Conclusion Nonspecific reactive hepatitis is more common among patients with adenovirus, enterovirus and respiratory syncytial virus infection, as well as among those infected at a younger age. Compared with AST levels, ALT levels are better indicators of the severity of nonspecific reactive hepatitis.

Interstitial deletion of 5q33.3q35.1 in a boy with severe mental retardation.

Constitutional interstitial deletions of the long arm of chromosome 5 (5q) are quite rare, and the corresponding phenotype is not yet clearly delineated. Severe mental retardation has been described in most patients who present 5q deletions. Specifically, the interstitial deletion of chromosome 5q33.3q35.1, an extremely rare chromosomal aberration, is characterized by mental retardation, developmental delay, and facial dysmorphism. Although the severity of mental retardation varies across cases, it is the most common feature described in patients who present the 5q33.3q35.1 deletion. Here, we report a case of a de novo deletion of 5q33.3q35.1, 46,XY,del(5)(q33.3q35.1) in an 11-year-old boy with mental retardation; to the best of our knowledge this is the first case in Korea to be reported. He was diagnosed with severe mental retardation, developmental delay, facial dysmorphisms, dental anomalies, and epilepsy. Chromosomal microarray analysis using the comparative genomic hybridization array method revealed a 16-Mb-long deletion of 5q33. 3q35.1(156,409,412-172,584,708)x1. Understanding this deletion may help draw a rough phenotypic map of 5q and correlate the phenotypes with specific chromosomal regions. The 5q33.3q35.1 deletion is a rare condition; however, accurate diagnosis of the associated mental retardation is important to ensure proper genetic counseling and to guide patients as part of long-term management.

Phenotypic Analysis of Korean Patients with Abnormal Chromosomal Microarray in Patients with Unexplained Developmental Delay/Intellectual Disability

Purpose The present study aimed to investigate chromosomal microarray (CMA) and clinical data in patients with unexplained developmental delay/intellectual disability (DD/ID) accompanying dysmorphism, congenital anomalies, or epilepsy. We also aimed to evaluate phenotypic clues in patients with pathogenic copy number variants (CNVs). Materials and Methods We collected clinical and CMA data from patients at Konyang University Hospital between September 2013 and October 2014. We included patients who had taken the CMA test to evaluate the etiology of unexplained DD/ID. Results All of the 50 patients identified had DD/ID. Thirty-nine patients had dysmorphism, 19 patients suffered from epilepsy, and 12 patients had congenital anomalies. Twenty-nine of the 50 patients (58%) showed abnormal results. Eighteen (36%) were considered to have pathogenic CNVs. Dysmorphism (p=0.028) was significantly higher in patients with pathogenic CNVs than in those with normal CMA. Two or more clinical features were presented by 61.9% (13/21) of the patients with normal CMA and by 83.3% (15/18) of the patients with pathogenic CMA. Conclusion Dysmorphism can be a phenotypic clue to pathogenic CNVs. Furthermore, pathogenic CNV might be more frequently found if patients have two or more clinical features in addition to DD/ID.

Age-adjusted plasma N-terminal pro-brain natriuretic peptide level in Kawasaki disease

Purpose Recent reports showed that plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) could be a useful biomarker of intravenous immunoglobulin (IVIG) unresponsiveness and coronary artery lesion (CAL) development in Kawasaki disease (KD). The levels of these peptides are critically influenced by age; hence, the normal range and upper limits for infants and children are different. We performed an age-adjusted analysis of plasma NT-proBNP level to validate its clinical use in the diagnosis of KD. Methods The data of 131 patients with KD were retrospectively analyzed. The patients were divided into 2 groups—group I (high NT-proBNP group) and group II (normal NT-proBNP group)—comprising patients with NT-proBNP concentrations higher and lower than the 95th percentile of the reference value, respectively. We compared the laboratory data, responsiveness to IVIG, and the risk of CAL in both groups. Results Group I showed significantly higher white blood cell count, absolute neutrophil count, C-reactive protein level, aspartate aminotransferase level, and troponin-I level than group II (P<0.05). The risk of CAL was also significantly higher in group I (odds ratio, 5.78; P=0.012). IVIG unresponsiveness in group I was three times that in group II (odds ratio, 3.35; P= 0.005). Conclusion Age-adjusted analysis of plasma NT-proBNP level could be helpful in predicting IVIG unresponsiveness and risk of CAL development in patients with KD.