Publications by authors named "Eungu Kang"

31 Publications

Evaluation of users' level of satisfaction for an artificial intelligence-based diagnostic program in pediatric rare genetic diseases.

Medicine (Baltimore) 2022 Jul 15;101(28):e29424. Epub 2022 Jul 15.

Department of Pediatrics, Korea University College of Medicine, Seoul, South Korea.

The artificial intelligence (AI)-based genetic diagnostic program has been applied to genome sequencing to facilitate the diagnostic process. The objective of the current study was to evaluate the experience and level of satisfaction of participants using an AI-based diagnostic program for rare pediatric genetic diseases. The patients with neurodevelopmental disorders or hearing impairments, their guardians, and their physicians from 16 tertiary general hospitals were enrolled. The study period was from April 2020 to March 2021. A survey was designed to assess their experience and level of satisfaction. A total of 30 physicians and 243 patients and guardians (199 neurodevelopmental disorders and 44 hearing impairments) completed the survey. DNA samples of the subjects were collected through buccal swabs or blood collection: 211 subjects (86.8%) through buccal swab and 29 subjects (11.9%) through blood collection. Average turnaround time for result receipt was 57.54 ± 32.42 days. For the sampling method, 193 patients and guardians (81.1%) and 28 physicians (93.3%) preferred buccal swab. The level of satisfaction of the 2 groups participating in the AI-based diagnostic program was 8.31 ± 1.71 out of 10 in the patient and guardian group and 8.42 ± 1.23 in the physician group. Clinicians, patients, and guardians are satisfied with the AI-based diagnostic program in general. With an increase in AI-based precision medicine solutions, the evaluation of the user's satisfaction with appropriate provision will help improve personal health care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000029424DOI Listing
July 2022

Comparison of Initial Presentation of Pediatric Diabetes Before and During the Coronavirus Disease 2019 Pandemic Era.

J Korean Med Sci 2022 Jun 6;37(22):e176. Epub 2022 Jun 6.

Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea.

Background: Hospital visitation has become challenging during the coronavirus disease 2019 pandemic because of quarantine measures and fear of infection. Consequently, newly diagnosed patients may present with more severe diseases during the pandemic. The present study analyzed the differences in the initial clinical presentations of newly diagnosed patients with type 1 diabetes (T1D) and type 2 diabetes (T2D), comparing pre-pandemic and pandemic periods.

Methods: Newly diagnosed patients with T1D or T2D and aged < 18 years during 2018-2020 were included in the study. Data were collected retrospectively from four academic centers in Gyeonggi-do, South Korea. Initial clinical data were compared between the pre-pandemic (2018-2019) and pandemic (2020) periods.

Results: In the pre-pandemic and pandemic periods, 99 patients (41 T1D and 58 T2D patients) and 84 patients (51 T1D and 33 T2D patients) were identified, respectively. During the pandemic, the proportion of diabetic ketoacidosis (DKA) cases increased compared to the pre-pandemic period (21.2% during 2018-2019 vs. 38.1% in 2020; = 0.012). In the pre-pandemic and pandemic periods, initial pH was 7.32 ± 0.14 and 7.27 ± 0.15, respectively ( = 0.040), and HbA1c values were 11.18 ± 2.46% and 12.42 ± 2.87%, respectively ( = 0.002). During the pandemic, there was an increased risk of DKA in patients with T1D (odds ratio, 2.42; 95% confidence interval, 1.04-5.62; = 0.040).

Conclusion: During the pandemic, the proportion of DKA in newly diagnosed patients with T1D increased and clinical parameters showed a deteriorating pattern. Increased awareness of pediatric diabetes, especially DKA, could facilitate visit to the hospital for an early diagnosis; thus, reducing the number of DKA cases during the pandemic era.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3346/jkms.2022.37.e176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9171352PMC
June 2022

The association between idiopathic scoliosis and growth hormone treatment in short children.

Ann Pediatr Endocrinol Metab 2022 May 16. Epub 2022 May 16.

Department of Pediatrics, Korea University College of Medicine, Seoul, Korea.

Purpose: Idiopathic scoliosis is the most common form of scoliosis, and the risk of both its onset and progression has been found to correlate with growth spurts. Therefore, recombinant human growth hormone (GH) treatment used in short children may affect both the initiation and aggravation of scoliosis. The aim of this study was to investigate the relationship between idiopathic scoliosis and GH treatment in short children.

Methods: The medical records of 113 subjects who were diagnosed with growth hormone deficiency, small for gestational age, and idiopathic short stature between January 2010 and December 2020 were reviewed. Scoliosis was defined as a Cobb angle of over 10° assessed using a spine X-ray. Clinical data and laboratory findings were compared between before and 12 months after GH treatment.

Results: There was a significant increase in height, height-standard deviation scores, insulin-like growth factor 1, and insulin-like growth factor binding protein 3 (P < 0.001) with GH treatment. However, there were no significant differences in the average Cobb angle (6.2±3.3° vs. 6.1±3.5°, P = 0.842) and the prevalence of scoliosis (9.7% vs. 13.3%, P = 0.481) between before and after one year of GH treatment. A comparative analysis of both the initial Cobb angle and the change in Cobb angle during GH treatment showed no relationship with other factors.

Conclusion: Although GH treatment in short children increases height and growth velocity, it is not associated with developing or aggravating idiopathic scoliosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6065/apem.2142186.093DOI Listing
May 2022

Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay.

Mol Med 2022 03 26;28(1):38. Epub 2022 Mar 26.

Department of Pediatrics, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul, 08308, South Korea.

Background: The diagnostic yield of whole-exome sequencing (WES) varies from 30%-50% among patients with mild to severe neurodevelopmental delay (NDD)/intellectual disability (ID). Routine retrospective reanalysis of undiagnosed patients has increased the total diagnostic yield by 10-15%. Here, we performed proband-only WES of 1065 patients with NDD/ID and applied a prospective, daily reanalysis automated pipeline to patients without clinically significant variants to facilitate diagnoses.

Methods: The study included 1065 consecutive patients from 1056 nonconsanguineous unrelated families from 10 multimedical centers in South Korea between April 2018 and August 2021. WES data were analyzed daily using automatically updated databases with variant classification and symptom similarity scoring systems.

Results: At the initial analysis, 402 patients from 1056 unrelated families (38.0%, 402/1,056 families) had a positive genetic diagnosis. Daily prospective, automated reanalysis resulted in the identification of 34 additional diagnostic variants in 31 patients (3%), which increased our molecular diagnostic yield to 41% (433/1056 families). Among these 31 patients, 26 were diagnosed with 23 different diseases that were newly discovered after 2019. The time interval between the first analysis and the molecular diagnosis by reanalysis was 1.2 ± 0.9 years, which was shorter in the patients enrolled during the latter part of the study period.

Conclusion: Daily updated databases and reanalysis systems enhance the diagnostic performance in patients with NDD/ID, contributing to the rapid diagnosis of undiagnosed patients by applying the latest molecular genetic information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s10020-022-00464-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8962085PMC
March 2022

Whole-body MRI evaluation in neurofibromatosis type 1 patients younger than 3 years old and the genetic contribution to disease progression.

Orphanet J Rare Dis 2022 01 29;17(1):24. Epub 2022 Jan 29.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88, Olympic-ro 43-Gil, Songpa-Gu, Seoul, 05505, Korea.

Background: Neurofibromatosis type 1 (NF1) is a common human genetic disease with age-dependent phenotype progression. The overview of clinical and radiological findings evaluated by whole-body magnetic resonance imaging (WBMRI) in NF1 patients < 3 years old assessed with a genetic contribution to disease progression is presented herein.

Methods: This study included 70 clinically or genetically diagnosed NF1 patients who received WBMRI before 3 years old. Clinical, genetic, and radiologic features were collected by retrospective chart review. In NF1, widely spread diffuse cutaneous neurofibromas, developmental delay, autism, seizure, cardiac abnormalities, hearing defect, optic pathway glioma, severe plexiform neurofibromas (> 3 cm in diameter, disfigurement, accompanying pain, bony destruction, or located para-aortic area), brain tumors, nerve root tumors, malignant peripheral nerve sheath tumors, moyamoya disease, and bony dysplasia were included.

Results: The age at WBMRI was 1.6 ± 0.7 years old, and NF1 mutations were found in 66 patients (94.3%). Focal areas of signal intensity (FASI) were the most common WBMRI finding (66.1%), followed by optic pathway glioma (15.7%), spine dural ectasia (12.9%), and plexiform neurofibromas (10.0%). Plexiform neurofibromas and NF1 were more prevalent in familial case (28.7% vs 5.7%, p = 0.030; 71.4% vs 30.2%, p = 0.011). Follow-up WBMRI was conducted in 42 patients (23 girls and 19 boys) after 1.21 ± 0.50 years. FASI and radiologic progression were more frequent in patients with mutations involving GTPase activating protein-related domain (77.8% vs 52.4%, p = 0.047; 46.2% vs 7.7%, p = 0.029).

Conclusions: WBMRI provides important information for the clinical care for young pediatric NF1 patients. As NF1 progresses in even these young patients, and is related to family history and the affected NF1 domains, serial evaluation with WBMRI should be assessed based on the clinical and genetic features for the patients' best care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-022-02174-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8800361PMC
January 2022

Weight changes of children in 1 year during COVID-19 pandemic.

J Pediatr Endocrinol Metab 2022 Mar 8;35(3):297-302. Epub 2021 Dec 8.

Department of Pediatrics, College of Medicine Korea University, Seoul, South Korea.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has changed everyday life. The Korean government urged schools to close as a measure of social distancing, and children and adolescents seemed to gain weight due to home confinement. We aimed to investigate the trends in weight changes in children during the pandemic period.

Materials And Methods: This retrospective study included 139 children aged between 6 and 12 years who visited the pediatric endocrine clinic for regular growth follow-up for 1 year during the COVID-19 pandemic. We analyzed changes in the body mass index (BMI), BMI z-score, and proportion of children who were overweight or obese over a period of 1 year.

Results: The BMI and BMI z-scores of the 139 children increased significantly over the year. The increase was maximum during the first three months of the COVID-19 pandemic, with little change between the third and sixth month of the pandemic. The proportion of children who were overweight or obese increased over time, from 24.5% at the COVID-19 pandemic baseline to 38.1% 1 year later (p < 0.001).

Conclusions: The COVID-19-related lockdown resulted in significant weight gain in Korean children. Changes in BMI showed different trends depending on the degree of school closure. An overall shift from normal weight to overweight or obesity was observed during the pandemic period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/jpem-2021-0554DOI Listing
March 2022

Efficacy of Triptorelin 3-Month Depot Compared to 1-Month Depot for the Treatment of Korean Girls with Central Precocious Puberty in Single Tertiary Center.

J Korean Med Sci 2021 Aug 30;36(34):e219. Epub 2021 Aug 30.

Department of Pediatrics, Korea University College of Medicine, Seoul, Korea.

Background: Triptorelin depot is largely used to treat central precocious puberty (CPP) in children, and a 3-month depot has been introduced. However, data about the 3-month gonadotropin-releasing hormone use for treatment of CPP in Korean girls are not available. This study was conducted to compare the efficacy of a triptorelin 11.25 mg 3-month depot with that of a 3.75 mg 1-month depot in suppressing pubertal development for the treatment of CPP.

Methods: A retrospective study, including 106 girls with CPP treated with triptorelin, was conducted. Fifty patients were treated with a triptorelin 3-month depot, and 56 were treated with a triptorelin 1-month depot. Serum luteinizing hormone (LH), follicle-stimulating hormone, and estradiol levels were analysed every 6 months after the visit. The height and bone age of each patient was evaluated at the beginning of treatment, after 6 months, and one year after therapy.

Results: The baseline characteristics of the girls treated with a 3-month depot were similar to those of the girls treated with a 1-month depot. A suppressed levels of LH to the triptorelin injection (serum LH < 2.5 IU/L) at 6 months was seen in 90.0% and 98.2% of the girls treated with the 3-month and 1-month depots, respectively ( = 0.160). After 1 year of treatment, a suppressed levels of LH was seen in 93.5% and 100% of the girls treated with the 3-month and 1-month depots, respectively ( = 0.226). Height velocity showed no significant difference between the two groups. Degree of bone age advancement decreased from 1.22 ± 0.07 and 1.22 ± 0.08 years at baseline ( = 0.914) to 1.16 ± 0.07 and 1.17 ± 0.08 in the girls treated with the 3-month and 1-month depots after 1 year, respectively ( = 0.481).

Conclusion: This study showed that the efficacy of long-acting triptorelin 3-month was comparable to 1-month depot regarding hormonal suppression and inhibition of bone maturation. The triptorelin 11.25 mg 3-month depot is an effective treatment for girls with CPP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3346/jkms.2021.36.e219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405405PMC
August 2021

Serum Levels of Thyroid Stimulating Hormone and Luteinizing Hormone Are Decreased in Girls with Central Precocious Puberty after 12-Month GnRH Agonist Treatment.

Tohoku J Exp Med 2020 11;252(3):193-197

Department of Pediatrics, Korea University College of Medicine.

Puberty is the transitional period from childhood to adult that leads to growth spurt, sexual maturation and attainment of reproductive capacity. Precocious puberty is defined when secondary sexual characteristics develop before the age of eight for girls and nine for boys. Central precocious puberty (CPP) is diagnosed when the process is driven by premature activation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion. Many factors promote CPP, and the thyroid function is thought to be one of them. In our previous study, thyroid stimulating hormone (TSH) was higher in the CPP group than that of the participants without CPP. This elevation of TSH in CPP is said to be associated with pubertal luteinizing hormone (LH) elevation. The aim of this study was to evaluate the causal relationship between TSH and LH in CPP patients. A total of 221 girls diagnosed with CPP and treated with GnRH agonists were included. All participants except one showed LH suppression (peak LH < 3 IU/L), and serum levels of follicle stimulating hormone (FSH) were also lower after the treatment. These results indicate that puberty has slowed down and that the patients were successfully treated for CPP. As for thyroid hormones, TSH was significantly lower and free thyroxine (fT4) levels were higher after 12 months of GnRH agonist treatment compared with baseline. With GnRH agonist treatment, the serum levels of LH and TSH were decreased, suggesting that the increase in serum TSH levels is associated with premature LH elevation in girls with CPP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1620/tjem.252.193DOI Listing
November 2020

Association between ARID2 and RAS-MAPK pathway in intellectual disability and short stature.

J Med Genet 2021 11 13;58(11):767-777. Epub 2020 Oct 13.

Medical Genetics Center, Asan Medical Center, Seoul, Republic of Korea

Background: ARID2 belongs to the Switch/sucrose non-fermenting complex, in which the genetic defects have been found in patients with dysmorphism, short stature and intellectual disability (ID). As the phenotypes of patients with mutations partially overlap with those of RASopathy, this study evaluated the biochemical association between ARID2 and RAS-MAPK pathway.

Methods: The phenotypes of 22 patients with either an heterozygous mutation or haploinsufficiency were reviewed. Comprehensive molecular analyses were performed using somatic and induced pluripotent stem cells (iPSCs) of a patient with haploinsufficiency as well as using the mouse model of haploinsufficiency by CRISPR/Cas9 gene editing.

Results: The phenotypic characteristics of deficiency include RASopathy, Coffin-Lowy syndrome or Coffin-Siris syndrome or undefined syndromic ID. Transient knockout HeLa cells using an shRNA increased ERK1 and ERK2 phosphorylation. Impaired neuronal differentiation with enhanced RAS-MAPK activity was observed in patient-iPSCs. In addition, haploinsufficient mice exhibited reduced body size and learning/memory deficit. haploinsufficiency was associated with reduced IFITM1 expression, which interacts with caveolin-1 (CAV-1) and inhibits ERK activation.

Discussion: haploinsufficiency is associated with enhanced RAS-MAPK activity, leading to reduced IFITM1 and CAV-1 expression, thereby increasing ERK activity. This altered interaction might lead to abnormal neuronal development and a short stature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2020-107111DOI Listing
November 2021

Neurofibromatosis type I: points to be considered by general pediatricians.

Clin Exp Pediatr 2021 Apr 15;64(4):149-156. Epub 2020 Jul 15.

Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Neurofibromatosis type 1 (NF1), a prevalent genetic disease that is transmitted in an autosomal dominant manner, is characterized by multiple cutaneous café-au-lait spots and neurofibromas as well as various degrees of neurological, skeletal, and neoplastic manifestations. The clinical features of NF1 increase in frequency with age, while the clinical diagnosis can remain undetermined in some pediatric patients. Importantly, affected patients are at risk for developing tumors of the central and peripheral nervous system. Therefore, adequate counseling for genetic testing, age-appropriate surveillance, and management are important. This review suggests several issues that should be considered to help general pediatricians provide adequate clinical care and genetic counseling to patients with NF1 and their families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3345/cep.2020.00871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024119PMC
April 2021

Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types.

J Hum Genet 2020 Jan 28;65(2):79-89. Epub 2019 Nov 28.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88, Olympic-ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.

Neurofibromatosis type 1 (NF1) is caused by heterozygous mutation in the NF1 gene. NF1 is one of the most common human genetic diseases. However, the overall genotype-phenotype correlation has not been known, due to a wide spectrum of genotypic and phenotypic heterogeneity. Here we describe the detailed clinical and genetic features of 427 Korean NF1 patients from 389 unrelated families. Long range PCR and sequencing of genomic DNA with multiplex ligation-dependent probe amplification analysis identified 250 different NF1 mutations in 363 families (93%), including 94 novel mutations. With an emphasis on phenotypes requiring medical attention (classified and termed: NF1), we investigated the correlation of NF1 and mutation types. NF1 was more prevalent in patients with truncating/splicing mutations and large deletions than in those with missense mutations (59.6%, 64.3% vs. 36.6%, p = 0.001). This difference was especially significant in the patients younger than age 19 years. The number of items in NF1 was a higher in the former groups (0.95 ± 0.06, 1.18 ± 0.20 vs. 0.56 ± 0.10, p = 0.002). These results suggest that mutation types are associated not only with higher prevalence of severe phenotypes in NF1 but also with their earlier onset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-019-0695-0DOI Listing
January 2020

Lysinuric protein intolerance with homozygous SLC7A7 mutation caused by maternal uniparental isodisomy of chromosome 14.

J Hum Genet 2019 Nov 19;64(11):1137-1140. Epub 2019 Aug 19.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea.

Lysinuric protein intolerance (LPI) is caused by mutations in the SLC7A7 gene at 14q11.2. Its clinical presentation includes failure to thrive, protein intolerance due to a secondary urea cycle defect, interstitial lung disease, renal tubulopathy, and immune disorders. Maternal uniparental disomy 14 (UPD14mat) is the most common cause of Temple syndrome (TS14), which is characterized by severe intrauterine and postnatal growth failure. Here, we describe a severe form of LPI accompanied by TS14 in an 11-month-old girl, which presented as profound failure to thrive and delayed development. LPI was diagnosed by the detection of a homozygous mutation of c.713 C>T (p.Ser238Phe) in SLC7A7, which was eventually found to co-occur with UPD14mat. Despite receiving a protein-restricted diet with citrulline and lysine supplementation, the severe failure to thrive has persisted at follow-up of the patient at 4 years of age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-019-0657-6DOI Listing
November 2019

The phenotypic heterogeneity of patients with Marfan-related disorders and their variant spectrums.

Medicine (Baltimore) 2018 May;97(20):e10767

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul Department of Pediatrics, Jeju National University School of Medicine, Jeju Department of Pediatrics, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri Medical Genetics Center, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are the connective tissue disorders characterized by aortic root aneurysm and/or dissection and various additional features. We evaluated the correlation of these mutations with the phenotypes and determined the clinical applicability of the revised Ghent criteria.The mutation spectrum and phenotypic heterogeneities of the 83 and 5 Korean patients with suspected MFS and LDS were investigated as a retrospective manner. In patients with suspected MFS patients, genetic testing was conducted in half of 44 patients who met the revised Ghent criteria clinically and half of 39 patients who did not meet these criteria.Fibrillin1 gene (FBN1) variants were detected in all the 22 patients (100%) who met the revised Ghent criteria and in 14 patients (77.8%) who did not meet the revised Ghent criteria (P = .0205). Patients with mutations in exons 24-32 were diagnosed at a younger age than those with mutations in other exons. Ectopia lentis was more common in patients with missense mutations than in patients with other mutations. Aortic diameter was greater in patients with missense mutations in cysteine residues than in patients with missense mutations in noncysteine residues. Five LDS patients had either TGFBR1 or TGFBR2 variants, of which 1 patient identified TGFBR1 variant uncertain significance.The revised Ghent criteria had very high clinical applicability for detecting FBN1 variants in patients with MFS and might help in selecting patients with suspected MFS for genetic testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000010767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976283PMC
May 2018

Biochemical and molecular analyses of infantile sialic acid storage disease in a patient with nonimmune hydrops fetalis.

Clin Chim Acta 2018 Jul 11;482:199-202. Epub 2018 Apr 11.

Department of Pediatrics, Asan Medical Center, Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea; Medical Genetics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea. Electronic address:

Nonimmune hydrops fetalis is the most severe clinical manifestation of lysosomal storage diseases (LSDs). Around 14 different LSDs have been accounted for as 1-15% of the cause of nonimmune hydrops fetalis. We report a Korean infant affected by an extremely rare but severe form of sialic acid storage disease. The patient presented with nonimmune hydrops fetalis, dysmorphic facial features, hepatosplenomegaly, and dysostosis multiplex and died at 39 days of age due to persistent pulmonary hypertension. LSD was suspected based on the presence of diffuse vacuolation of syncytiotrophoblast, villous stromal cells, and intermediate trophoblast in placental biopsy. Increased excretion of urinary free sialic acid was detected by liquid chromatography-tandem mass spectrometry. The patient was compound heterozygous of the c.908G>A (p.Trp303Ter) and the splicing mutation c.1259+5G>T (IVS9+5 G>T) in the SLC17A5 gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cca.2018.04.016DOI Listing
July 2018

Clinical characteristics and treatment outcomes in Camurati-Engelmann disease: A case series.

Medicine (Baltimore) 2018 Apr;97(14):e0309

Department of Pediatrics Medical Genetics Center, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background: Camurati-Engelmann disease is an extremely rare disease characterized by hyperostosis of multiple long bones. This condition is caused by heterozygous mutations in the TGFB1 gene.

Methods: We describe the clinical and genetic characteristics of 4 Korean patients with this rare disease diagnosed at Asan Medical Center in Korea between June 2012 and May 2016, to increase awareness about this condition among general physicians and orthopedists. The presenting features, biochemical findings, radiographic and nuclear imaging findings, molecular analysis, and treatment outcomes of 4 patients were reviewed retrospectively.

Results: Two patients had sporadic disease, whereas the other 2 were familial cases. The average age at symptom onset was 8.8 ± 5.5 (4-14) years. Symptoms included waddling gait or leg pain. Bone pain and easy fatigability were documented in all patients. Skeletal deformities such as osteoporosis, genu valgum, and severe scoliosis were observed. Visual and otologic manifestations presenting as exophthalmos, retinal detachment, and vestibulopathy were found in 3 patients. Skeletal survey showed diaphyseal expansion with diffuse cortical thickening of long bones in all patients. Bone scintigraphy images showed increased uptake of radioactive material in the calvarium and diaphysis of long bones. The mean erythrocyte sedimentation rate was 46.5 ± 22.2 (20-72) mm/h. Sequence analysis of TGFB1 revealed the previously reported mutations p.Arg218His, p.Arg218Cys, and p.Glu169Lys. Corticosteroid was effective in relieving pain, and losartan was used as maintenance therapy.

Conclusions: Our experience suggests that this rare condition can be suspected in patients with characteristic symptoms and skeletal findings. Considering the presence of effective medical treatment, efforts are needed to identify more cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000010309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902284PMC
April 2018

Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening.

BMC Pediatr 2018 03 8;18(1):103. Epub 2018 Mar 8.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88, Olympic-ro 43-Gil, Songpa-Gu, Seoul, 05505, Korea.

Background: Fatty acid oxidation disorders (FAODs) include more than 15 distinct disorders with variable clinical manifestations. After the introduction of newborn screening using tandem mass spectrometry, early identification of FAODs became feasible. This study describes the clinical, biochemical and molecular characteristics of FAODs patients detected by newborn screening (NBS) compared with those of 9 patients with symptomatic presentations.

Methods: Clinical and genetic features of FAODs patients diagnosed by NBS and by symptomatic presentations were reviewed.

Results: Fourteen patients were diagnosed with FAODs by NBS at the age of 54.8 ± 4.8 days: 5 with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, 5 with medium chain acyl-CoA dehydrogenase (MCAD) deficiency, 1 with primary carnitine deficiency, 1 with carnitine palmitoyltransferase 1A (CPT1A) deficiency, 1 with long-chain 3-hydroxyacyl-CoA dehydrogenase or mitochondrial trifunctional protein (LCAHD/MTP) deficiency, and 1 with short chain acyl-CoA dehydrogenase (SCAD) deficiency. Three patients with VLCAD or LCHAD/MTP deficiency developed recurrent rhabdomyolysis or cardiomyopathy, and one patient died of cardiomyopathy. The other 10 patients remained neurodevelopmentally normal and asymptomatic during the follow-up. In 8 patients with symptomatic presentation, FAODs manifested as LCHAD/MTP deficiencies by recurrent rhabdomyolysis or cadiomyopathy (6 patients), and VLCAD deficiency by cardiomyopathy (1 patient), and CPT1A deficiency by hepatic failure (1 patient). Two patients with LCHAD/MTP deficiencies died due to severe cardiomyopathy in the neonatal period, and developmental disability was noted in CPT1A deficiency (1 patient).

Conclusions: NBS helped to identify the broad spectrum of FAODs and introduce early intervention to improve the clinical outcome of each patient. However, severe clinical manifestations developed in some patients, indicating that careful, life-long observation is warranted in all FAODs patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12887-018-1069-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842515PMC
March 2018

Fabry disease: characterisation of the plasma proteome pre- and post-enzyme replacement therapy.

J Med Genet 2017 11 23;54(11):771-780. Epub 2017 Aug 23.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Background: Fabry disease is characterised by the progressive accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in vascular endothelial cells. Enzyme replacement therapy (ERT) clears this accumulation. We analysed plasma proteome profiles before and after ERT to characterise its molecular pathology.

Methods: Two-dimensional electrophoresis and matrix-assisted laser desorption/ionisation-time of flight tandem mass spectrometry (MALDI-TOF MS) and tandem mass spectrometry (MS/MS) were done using plasma samples before and after ERT in eight patients with classical Fabry disease RESULTS: After short-term ERT (4-12 months), the levels of 15 plasma proteins involved in inflammation, oxidative and ischaemic injury, or complement activation were reduced significantly. Among them, β-actin (ACTB), inactivated complement C3b (iC3b), and C4B were elevated significantly in pre-ERT Fabry disease plasma compared with control plasma. After longer-term ERT (46-96 months), iC3b levels gradually decreased, whereas the levels of other proteins varied. The gradual reduction of iC3b was comparable to that of Gb3 levels. In addition, iC3b increased significantly in pre-ERT Fabry disease mouse plasma, and C3 deposits were notable in renal tissues of pre-enzyme replacement therapy patients.

Conclusion: These results indicated that C3-mediated complement activation might be altered in Fabry disease and ERT might promote its stabilisation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2017-104704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740533PMC
November 2017

DEND Syndrome with Heterozygous KCNJ11 Mutation Successfully Treated with Sulfonylurea.

J Korean Med Sci 2017 Jun;32(6):1042-1045

Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Korea.

Permanent neonatal diabetes mellitus (PNDM) is caused by mutations in the ATP-sensitive potassium channel (KATP channel) subunits. Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome is the most severe form of PNDM and is characterized by various neurologic features. We report on a patient with DEND syndrome following initial misdiagnosis with type 1 DM, who was successfully switched from insulin to sulfonylurea therapy. A 50-day-old male presented with fever and seizure, complicated by persistent hyperglycemia. Insulin therapy was initiated. At 10 months of age, the patient was unable to hold his head up and make eye contact with others. At 17.9 years of age, direct sequencing of KCNJ11 identified a heterozygous mutation of c.602G>A (p.R201H). Since then, treatment with gliclazide was initiated and the insulin dose was gradually reduced. Following 3 months, insulin was discontinued with a gliclazide dose of 2.4 mg/kg. The patient continued to have excellent glycemic control with a glycated hemoglobin (HbA1c) level of 5.8% after 5 months. However, the patient's psychomotor retardation did not improve. This study reports the first case of DEND syndrome in Korea caused by a KCNJ11 mutation and emphasizes the necessity to screen mutations in KATP channel genes in patients with neonatal diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3346/jkms.2017.32.6.1042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426229PMC
June 2017

Mutation Spectrum of STAR and a Founder Effect of the p.Q258* in Korean Patients with Congenital Lipoid Adrenal Hyperplasia.

Mol Med 2017 07 2;23:149-154. Epub 2017 May 2.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Congenital lipoid adrenal hyperplasia (CLAH) is the most severe form of congenital adrenal hyperplasia, caused by defects in the steroidogenic acute regulatory protein (STAR). The p.Q258* mutation is the most common mutation in China, Japan, and Korea, suggesting a founder effect. This study aimed to investigate the phenotypic and mutation spectrum of defects and identify a founder effect of the p.Q258* mutation in Korean patients with CLAH. For 45 patients from 42 independent pedigrees, haplotype analysis was performed in 10 unrelated trio families, including patients with the p.Q258* mutation whose DNA samples were available, using 1,972 single nucleotide polymorphism (SNP) and six short tandem repeat (STR) markers. An Illumina Infinium® Human Omni2.5-8 v1.3 performed the SNP genotyping. Among 84 alleles from 42 unrelated families, mutation p.Q258* was found in 74 alleles (88.1%) from 41 families. A shared haplotype was identified in 17 of 20 alleles from 10 patients (size, 198 kb). The age of the founder mutation was estimated as 4,875 years (95% credible set: 3,575-7,925 years) assuming an intergenerational time interval of 25 years. The p.Q258* mutation is the most common in Korean patients with CLAH, suggesting a founder effect. The age of the mutation corresponded with the date when the Korean people settled in the Korean peninsula. The high prevalence of p.Q258* in Japan and China also suggests a founder effect in Asian countries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2119/molmed.2017.00023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522967PMC
July 2017

Diabetes mellitus caused by secondary hemochromatosis after multiple blood transfusions in 2 patients with severe aplastic anemia.

Ann Pediatr Endocrinol Metab 2017 Mar 31;22(1):60-64. Epub 2017 Mar 31.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Hemochromatosis is an inherited or secondary disorder caused by excessive iron storage leading to multiple organ damage. We describe 2 patients with diabetes mellitus caused by hemochromatosis secondary to multiple blood transfusions due to severe aplastic anemia. Subject 1, who was diagnosed with severe aplastic anemia at 15 years of age, received multiple red blood cell transfusions before he underwent autologous peripheral blood stem cell transplantation (PBSCT) at 22 years of age. At 21 years of age, hyperglycemia was detected with increased hemoglobin A1c and serum ferritin levels, 9.7% and 12,910 ng/mL (normal range, 20-320 ng/mL), respectively. The 24-hour urine C-peptide level was normal with negative antiglutamic acid decarboxylase antibody. Subsequently, metformin and an iron-chelating agent were administered. However, an intensive insulin regimen was necessary 2 years after the onset of diabetes. Subject 2, who was diagnosed with severe aplastic anemia at 2 years of age, received multiple blood transfusions until she underwent haploidentical PBSCT at 13 years of age. At 11 years of age, she developed diabetes mellitus with a high serum ferritin level (12,559.8 ng/mL). She is currently 18 years old and has been treated with an intensive insulin regimen and estrogen/progesterone replacement therapy because of hypogonadotropic hypogonadism. It is presumed that the loss of insulin secretory capacity and insulin resistance played a role in the pathogenesis of diabetes mellitus due to hemochromatosis in these cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6065/apem.2017.22.1.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401825PMC
March 2017

Rare Frequency of Mutations in Pituitary Transcription Factor Genes in Combined Pituitary Hormone or Isolated Growth Hormone Deficiencies in Korea.

Yonsei Med J 2017 May;58(3):527-532

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: Congenital hypopituitarism is caused by mutations in pituitary transcription factors involved in the development of the hypothalamic-pituitary axis. Mutation frequencies of genes involved in congenital hypopituitarism are extremely low and vary substantially between ethnicities. This study was undertaken to compare the clinical, endocrinological, and radiological features of patients with an isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD).

Materials And Methods: This study included 27 patients with sporadic IGHD and CPHD. A mutation analysis of the POU1F1, PROP1, LHX3, LHX4, and HESX1 genes was performed using genomic DNA from peripheral blood leukocytes.

Results: IGHD and CPHD were observed in 4 and 23 patients, respectively. Mean age at diagnosis was 8.28±7.25 years for IGHD and 13.48±10.46 years for CPHD (p=0.37). Serum insulin-like growth factor-1 and peak growth hormone (GH) levels following GH stimulation tests were significantly lower in patients with CPHD than in those with IGHD (p<0.05). Sellar MRI findings revealed structural abnormalities in 3 patients with IGHD (75%) and 21 patients with CPHD (91.3%) (p=0.62). A mutation analysis identified homozygous p.R109Q mutations in HESX1 in a patient with CPHD. Patients with CPHD had more severe GHD than those with IGHD.

Conclusion: The frequency of defects in the genes encoding pituitary transcription factors was extremely low in Korean patients with congenital hypopituitarism. Environmental factors and the impact of other causative genes may contribute to this clinical phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3349/ymj.2017.58.3.527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368137PMC
May 2017

Life-threatening bleeding from gastric mucosal angiokeratomas during anticoagulation: A case report of Fabry disease.

Medicine (Baltimore) 2017 Feb;96(6):e6063

Department of Pediatrics, Asan Medical Center Children's Hospital Division of Cardiology, Cardiac Imaging Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Rationale: Angiokeratomas are the earliest manifestation of Fabry disease (FD), and the extent of their appearance is related to disease severity. Angiokeratomas are mostly found on cutaneous regions.

Patient Concerns, Diagnoses, Interventions, And Outcomes: Here we report an FD patient with widespread gastrointestinal angiokeratomas who developed life-threatening bleeding following anticoagulation for atrial fibrillation.

Lessons: Careful observation for gastrointestinal bleeding is warranted for patients on anticoagulation with extensive cutaneous angiokeratomas. Furthermore, our experience suggests that surveillance is needed to assess the prevalence and extent of gastrointestinal angiokeratomas in patients with FD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000006063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313015PMC
February 2017

Diagnostic yield of targeted gene panel sequencing to identify the genetic etiology of disorders of sex development.

Mol Cell Endocrinol 2017 03 24;444:19-25. Epub 2017 Jan 24.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

Disorders of sex development (DSD) vary phenotypically and are caused by a number of genetic etiologies. This study investigated the genetic etiology of DSD patients using targeted exome sequencing of 67 known DSD-associated genes in humans. This study included 37 patients with 46, XY DSD and seven patients with 46, XX DSD. We identified known pathogenic mutations or deletion in nine (20.5%) patients in the AR, CYP17A1, SRD5A1, and DMRT1/2 genes. Novel variants were identified in nine patients (20.5%) in the AR, ATRX, CYP17A1, CHD7, MAP3K1, NR5A1, and WWOX genes. Among them, four patients harbored pathogenic or likely pathogenic variants, while the remaining five patients (11.4%) had variants of uncertain significance. We were able to make a genetic diagnosis in 29.5% of patients with pathogenic or likely pathogenic mutations. Targeted exome sequencing is an efficient tool to improve the diagnostic yield of DSD, despite its phenotypic and genetic heterogeneity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mce.2017.01.037DOI Listing
March 2017

Long-term Consequences of Congenital Adrenal Hyperplasia due to Classic 21-hydroxylase Deficiency in Adolescents and Adults.

Exp Clin Endocrinol Diabetes 2017 Mar 10;125(3):196-201. Epub 2017 Jan 10.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

The management of congenital adrenal hyperplasia (CAH) from pediatric to adulthood is challenging to achieve optimal growth and puberty. This study characterizes the clinical outcomes of 21-hydroxylase deficiency. 53 CAH patients were included (33 females, 15 and 18 patients with the salt-wasting [SW] and simple-virilizing [SV] forms; and 20 males, 16 and 4 patients with the SW and SV forms). We reviewed growth parameters, pubertal status, and long-term morbidities. In females, the age at pubertal onset and pubarche was 9.6±0.9 and 10.5±1.9 years respectively, which was significantly earlier in the SV form (0.005). In males, the ages at pubertal onset and pubarche were 10.1±2.0 and 10.7±2.5 years, respectively, which were not significantly different between the groups. Forty patients reached adult height: -2.1±1.6 SDS in males and -1.5±1.1 SDS in females. Obesity and overweight was significantly common in adult patients. Testicular adrenal rest tumors were found in 4 SW males. 5 patients had adrenal tumor including adenoma, adenocarcinoma, or myelolipoma. Reduced adult height and obesity/overweight are prevalent in adulthood. Adolescents and adults with 21-hydroxylase deficiency should be monitored for long-term consequences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0042-123037DOI Listing
March 2017

Long-term clinical outcome and the identification of homozygous gene mutations in a patient with vitamin D hydroxylation-deficient rickets type 1A.

Ann Pediatr Endocrinol Metab 2016 Sep 30;21(3):169-173. Epub 2016 Sep 30.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Vitamin D hydroxylation-deficient rickets type 1A (VDDR1A) is an autosomal recessively-inherited disorder caused by mutations in encoding the 1α-hydroxylase enzyme. We report on a female patient with VDDR1A who presented with hypocalcemic seizure at the age of 13 months. The typical clinical and biochemical features of VDDR1A were found, such as hypocalcemia, increased alkaline phosphatase, secondary hyperparathyroidism and normal 25-hydroxyvitamin D3 (25(OH)D). Radiographic images of the wrist showed metaphyseal widening with cupping and fraying of the ulna and distal radius, suggesting rickets. A mutation analysis of the gene identified a homozygous mutation of c.589+1G>A in the splice donor site in intron 3, which was known to be pathogenic. Since that time, the patient has been under calcitriol and calcium treatment, with normal growth and development. During the follow-up period, she did not develop genu valgum, scoliosis, or nephrocalcinosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6065/apem.2016.21.3.169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073165PMC
September 2016

Etiology and therapeutic outcomes of children with gonadotropin-independent precocious puberty.

Ann Pediatr Endocrinol Metab 2016 Sep 30;21(3):136-142. Epub 2016 Sep 30.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: This study was performed to investigate the etiology, clinical features, and outcomes of patients with gonadotropin-independent precocious puberty (GIPP).

Methods: The study included 16 patients (14 female and 2 male patients) who manifested secondary sexual characteristics, elevated sex hormones, or adrenal androgens with prepubertal luteinizing hormone levels after gonadotropin releasing hormone stimulation diagnosed between May 1994 and December 2015. Patients with congenital adrenal hyperplasia were excluded. Clinical features, laboratory findings, treatment modalities, and outcomes were retrospectively reviewed.

Results: The median age at diagnosis was 2.6 years (range, 0.7-7.9 years) and median follow-up duration was 4.6 years (range, 1 month-9.8 years). Patients with McCune-Albright syndrome (n=5) and functional ovarian cysts (n=4) presented with vaginal bleeding and elevated estradiol levels (23.3±17.5 pg/mL); adrenocortical tumors (n=4) with premature pubarche and elevated dehydroepiandrosterone sulfate levels (87.2-6,530 µg/dL); and human chorionic gonadotropin (hCG)-producing tumor (n=1) with premature pubarche and elevated β-human chorionic gonadotropin levels (47.4 mIU/mL). Two patients were idiopathic. Six patients transited to gonadotropin-dependent precocious puberty median 3.3 years (range, 0.3-5.1 years) after the onset of GIPP. Initial and follow-up height standard deviation scores (0.99±0.84 vs. 1.10±1.10, =0.44) and bone age advancement (1.49±1.77 years vs. 2.02±1.95 years, =0.06) were not significantly different.

Conclusion: The etiologies of GIPP are heterogeneous, and treatment and prognosis is quite different according to the etiology. Efficacy of treatment with aromatase inhibitors needs to be evaluated after long-term follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6065/apem.2016.21.3.136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073159PMC
September 2016

MPV17 mutations in patients with hepatocerebral mitochondrial DNA depletion syndrome.

Mol Genet Metab Rep 2016 Sep 4;8:74-6. Epub 2016 Aug 4.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea; Medical Genetics Center, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.

MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (MDS) is a very rare condition, and only a few cases have been reported in East Asian countries. Here, we describe four Korean children affected by hepatocerebral MDS. The DGUOK, POLG1, and MPV17 genes were analyzed, and all patients had MPV17 mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgmr.2016.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976613PMC
September 2016

Long-term enzyme replacement therapy for Fabry disease: efficacy and unmet needs in cardiac and renal outcomes.

J Hum Genet 2016 Nov 23;61(11):923-929. Epub 2016 Jun 23.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Fabry disease is a progressive lysosomal storage disease caused by alpha-galactosidase A deficiency. This condition is characterized by progressive accumulation of glycosphingolipids with functional impairment in various organs, including the kidney, heart and cerebrovascular system. Enzyme replacement therapy (ERT) is essential because it attenuates the disease progression. The present study investigated the long-term efficacy of ERT in 19 Korean Fabry patients (11 adult males, 4 symptomatic female carriers and 4 pediatric males) who had received ERT for 8.1±2.2 years (range, 5.3-10.5 years). In the 11 adult males, the mean reduction in the estimated glomerular filtration rate (eGFR) was -3.8±4.5 ml min 1.73 m. The rate of eGFR decline was significantly lower in patients with lower proteinuria (<1 g per day) before ERT. The left ventricular mass index decreased or was stable throughout the ERT in male patients with or without left ventricular hypertrophy before ERT initiation. In female carriers and pediatric male patients, renal and cardiac functions remained stable with ERT. Arrhythmias were observed in 10 adult males and 1 female patient before ERT and persisted during ERT. One pediatric patient newly developed arrhythmia despite ERT. In conclusion, long-term ERT has beneficial effects on the renal and cardiac outcomes of Fabry patients but has limited effect in patients with irreversible organ damage. Identification of patients in the early disease stage and rapid ERT initiation might be the best strategy to improve the natural course of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/jhg.2016.78DOI Listing
November 2016

Long-term efficacy of recombinant human growth hormone therapy in short-statured patients with Noonan syndrome.

Ann Pediatr Endocrinol Metab 2016 Mar 31;21(1):26-30. Epub 2016 Mar 31.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: Noonan syndrome (NS) is characterized by short stature, heart anomalies, developmental delays, dysmorphic features, cryptorchidism, and coagulation defects. Several studies reported the short-term effects of recombinant human growth hormone (rhGH) treatment on the improvement of height. This study was performed to evaluate the long-term efficacy of rhGH in children with NS in Korea.

Methods: This study included 15 prepubertal NS children who received rhGH subcutaneously at a dose of 50-75 µg/kg/day for 6 days a week for at least >3 years. Preand posttreatment data, such as height, weight, bone age, insulin-like growth factor 1 (IGF-1), and IGF binding protein 3 (IGFBP-3) levels, were collected every 6 months.

Results: Chronologic age and bone age at the start of treatment were 7.97±1.81 and 5.09±2.12 years, respectively. Height standard deviation score (SDS) was increased from -2.64±0.64 to -1.54±1.24 years after 3 years (P<0.001). Serum IGF-1 SDS levels were elevated from -1.28±1.03 to -0.10±0.94 (P<0.001). Height SDS was more increased in subjects without PTPN11 mutations compared to those with mutations after 3 years (P=0.012). However, the other parameters, including bone age, IGF-1 SDS, and IGFBP-3 SDS, were not significantly different between patients with and without PTPN11 mutations.

Conclusion: Although this study included a relatively small number of patients, long-term rhGH therapy in NS patients was safe and effective at improving height, growth velocity, and serum IGF-1 levels, in accordance with previous studies. However, the meticulous monitoring of potential adverse events is still needed because of high dose of rhGH and preexisting hyperactivity of RAS-MAPK pathway. Patients with PTPN11 mutations demonstrated a decreased response to rhGH therapy compared to those without mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6065/apem.2016.21.1.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835558PMC
March 2016

Endocrine dysfunctions in children with Williams-Beuren syndrome.

Ann Pediatr Endocrinol Metab 2016 Mar 31;21(1):15-20. Epub 2016 Mar 31.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: Williams-Beuren syndrome (WBS) is caused by a hemizygous microdeletion of chromosome 7q11.23 and is characterized by global cognitive impairment, dysmorphic facial features, and supravalvular aortic stenosis. Endocrine dysfunctions have been reported in patients with WBS. This study was performed to investigate the frequency, clinical features, and outcomes of endocrine dysfunctions in children with WBS.

Methods: One hundred two patients were included. The diagnosis was confirmed by chromosome analysis and fluorescent in situ hybridization. Medical charts were reviewed retrospectively to analyze endocrine dysfunctions such as short stature, precocious puberty, thyroid dysfunctions, and hypocalcemia.

Results: The age at diagnosis was 3.7±4.4 years (one month to 19 years). Height- and weight-standard deviation score (SDS) were -1.1±1.1 and -1.4±1.4 at presentation, respectively. Short stature was found in 26 patients (28.3%) among those older than 2 years. Body mass index-SDS increased as the patients grew older (P<0.001). Two males and one female (2.9%) were diagnosed with central precocious puberty. Nine patients (8.8%) were diagnosed with primary hypothyroidism at age 4.0±4.3 years (one month to 12.1 years); their serum thyroid stimulating hormone and free T4 levels were 15.2±5.4 µU/mL and 1.2±0.2 ng/dL, respectively. Hypercalcemia was observed in 12 out of 55 patients under age 3 (22%) at the age of 14.3±6.6 months (7 to 28 months) with a mean serum calcium level of 13.1±2.1 mg/dL.

Conclusion: Endocrine dysfunctions are not uncommon causes of morbidity in patients with WBS. The severity and outcomes of their endocrine manifestations were heterogeneous. Long-term follow-up is needed to predict the prognosis of endocrine features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6065/apem.2016.21.1.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835556PMC
March 2016
-->