Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy.

BACKGROUND: Ambroxol (ABX) has been suggested as an augmentative pharmacological agent for neuronopathic Gaucher disease (nGD). This study assessed the long-term safety and efficacy of combined therapy with high-dose ABX and enzyme replacement therapy (ERT) in nGD. METHODS: ABX+ERT therapy was administered for 4.5 years in four patients with nGD. ABX was initiated at a dose of 1.5 mg/kg/day, and the dose was escalated up to 27 mg/kg/day. The target plasma level was 10 µmol/L or less. The changes in glucocerebrosidase activity, biochemical, safety and neurocognitive findings were assessed. RESULTS: Enhanced residual GCcase activity was observed in all patients, as evidenced in both in vitro and in vivo studies. During the first 2 years of study with ABX (up to 21 mg/kg/day), mean seizure frequencies and neurocognitive function worsened. After ABX dosage was increased up to 27 mg/kg/day of ABX, its trough plasma concentration was 3.2-8.8 µmol/L. Drug-to-drug interaction, especially with antiepileptic drug significantly affected the pharmacokinetic parameters of ABX. Importantly, at 27 mg/kg/day of ABX, the seizure frequencies markedly decreased from the baseline, and the neurocognitive function was improved. In addition, Lyso-Gb1, a biomarker for the severity and progression of GD, was normalised in all patients. High-dose ABX was well-tolerated with no severe adverse events. CONCLUSIONS: Long-term treatment with high-dose ABX+ERT was safe and might help to arrest the progression of the neurological manifestations in GD.

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

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.

Biochemical and molecular characterisation of neurological Wilson disease.

BACKGROUND: To identify biochemical and genetic features that characterise neurological Wilson disease as a distinct disease subgroup. METHODS: Detailed biochemical profiles and genotypic characteristics of neurological (86 patients) and hepatic subgroups (233 patients) from 368 unrelated Korean families were analysed. RESULTS: Compared with patients in the hepatic subgroup, patients in the neurological subgroup had a later age at onset, a higher proportion with Kayser-Fleischer rings and higher serum creatinine levels, and a lower proportion with favourable outcome (62% vs 80%, P<0.016). At diagnosis, the neurological subgroup had lower serum ceruloplasmin (3.1±2.1 mg/dL vs 4.2±3.2 mg/dL, P<0.001), total copper (26.4±13.8 µg/dL vs 35.8±42.4 µg/dL, P=0.005), free copper (17.2±12.5 µg/dL vs 23.5±38.2 µg/dL, P=0.038) and urinary copper (280.9±162.9 µg/day vs 611.1±1124.2 µg/day, P<0.001) levels. Serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase and total bilirubin levels, as well as prothrombin time, were also lower in the neurological subgroup. Liver cirrhosis was more common but mostly compensated in the neurological subgroup. Frameshift, nonsense or splice-site ATP7B mutations and mutations in transduction or ATP hinge domains (2.4% vs 23.1%, P=0.006) were less common in the neurological subgroup. CONCLUSION: The neurological subgroup had distinct clinical, biochemical and genetic profiles. Further studies are required to identify the factors, with or without association with copper metabolism, underlying the neurological presentation for which treatment needs to be targeted to improve the clinical outcome of this subgroup.

A case of an infant suspected as IMAGE syndrome who were finally diagnosed with MIRAGE syndrome by targeted Mendelian exome sequencing.

BACKGROUND: Adrenal hypoplasia is a rare congenital disorder, which can be classified into a non-syndromic form, without extra-adrenal features, and a syndromic form, with such features. Despite biochemical and molecular genetic evaluation, etiologic diagnosis cannot be performed in many patients with adrenal hypoplasia. CASE PRESENTATION: The patient in this case was a boy born at 31 weeks of gestation with a weight of 882 g (< 3rd percentile) to non-consanguineous parents. Genital examination showed micropenis and bilateral cryptorchidism. On the third day of life, he manifested hypotension with high urine output, hyponatremia, hyperkalemia, hypernatriuria, high plasma adrenocorticotropic hormone level, and high plasma renin activity, suggesting acute adrenal insufficiency. The serum 17α-hydroxyprogesterone level was normal. Adrenal insufficiency improved following administration of hydrocortisone and 9α-fludrocortisone, but the patient died of recurrent infection at 4 months of age. He was suspected as IMAGE (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies) syndrome. However, no mutation in CDKN1C was identified. Targeted exome sequencing using the TruSight One Sequencing Panel (Illumina) identified a heterozygous mutation of c.2944C > T (p.R982C) in exon 3 in SAMD9. CONCLUSION: This report describes the first Korean case of MIRAGE syndrome. The patient presented with severe primary adrenal insufficiency, intrauterine growth retardation, and recurrent infection. SAMD9 mutation should be considered in patients who present with adrenal hypoplasia and extra-adrenal phenotypes.

Characteristic dysmorphic features in congenital disorders of glycosylation type IIb.

Over 100 types of congenital disorders of glycosylation (CDG) have been reported and the number is rapidly increasing. However, each type is very rare and is problematic to diagnose. Mannosyl-oligosaccharide glucosidase (MOGS)-CDG (CDG type IIb) is an extremely rare CDG that has only been reported in three patients from two unrelated families. Using targeted exome sequencing, we identified another patient affected by this condition. This patient had increased serum trisialotransferrin levels. Importantly, a review of the features of all four patients revealed the recognizable clinical hallmarks of MOGS-CDG. The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency.

Low prevalence of argininosuccinate lyase deficiency among inherited urea cycle disorders in Korea.

Argininosuccinic aciduria (ASA), which is considered to be the second most common urea cycle disorder (UCD), is caused by an argininosuccinate lyase deficiency and is biochemically characterized by elevation of argininosuccinic acid and arginine deficiency. In addition to hyperammonemia, other characteristic features of ASA include hepatic fibrosis, hypertension, neurocognitive deficiencies, and trichorrhexis nodosa. Herein, we retrospectively reviewed the clinical findings, biochemical profiles, and genotypic characteristics of five Korean patients with ASA, who showed typical phenotypes and biochemical findings of the disease. Molecular analysis of these patients revealed six novel ASL mutations. Next, we investigated the prevalence of all types of UCDs in Korea. Of note, over a two decade periods, ASA was only detected in 6.3% of patients with a UCD, which made it the fourth most common UCD in Korea. In comparison with Caucasians, in whom ASA is the second most common UCD, ASA is comparatively rare in East Asian populations, including Japanese and Koreans. These findings suggest the possibility of geographic variation in UCDs among ethnic groups.

Long-term endocrine effects and trends in body mass index changes in patients with childhood-onset brain tumors.

As survival rates have improved owing to advances in management strategies for pediatric brain tumors, long-term complications such as endocrine dysfunction, have emerged as a major issue. This study investigated the long-term endocrine effects of childhood-onset brain tumors in a large number of patients. This study included 151 patients with brain tumors diagnosed between January 1995 and December 2016. The following data were retrospectively reviewed: tumor location, tumor histology, endocrine abnormalities, hypothalamic involvement on brain imaging, treatment modalities, and trends in body mass index. The mean age at diagnosis of patients with sellar/suprasellar (SE/SUP-SE) tumors and supra/infratentorial (ST/IT) tumors was 9.9 ± 4.5 and 6.5 ± 4.2 years, respectively. In patient with prepubertal age at diagnosis, height standard deviation score was lower in patients with SE/SUP-SE tumors at diagnosis (P = 0.031), which was lower in patients with ST/IT tumors at the final visit (P < 0.001). The prevalence of combined pituitary hormone deficiencies was higher among patients with SE/SUP-SE tumors than in those with ST/IT tumors (81.7 vs. 36.1%, P < 0.001). Among 98 non-obese patients with SE/SUP-SE tumors, 36.7% developed obesity. The prevalence of combined pituitary hormone deficiencies and obesity was higher in patients with SE/SUP-SE tumors than in those with tumors in other locations; growth impairment was more severe in patients with ST/IT tumors.

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

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, ß-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.

Broad clinical spectrum and diverse outcomes of prolactinoma with pediatric onset: medication-resistant and recurrent cases.

Prolactinoma is a benign tumor of the pituitary gland that rarely occurs in children and adolescents; thus, the clinical spectrum and long-term prognosis in these patients remain unknown. This study was performed to investigate the long-term outcomes of medical treatment and the prognostic factors for remission and relapse in children and adolescents with prolactinoma. Three male subjects and four female subjects between the ages of 7- and 17-years-old were included in this study. The mean initial serum prolactin level was 443 ± 251.8 ng/mL (range, 152-946 ng/mL). During the follow-up period (range, 0.6-20 years), a dopamine agonist was administered, and surgery or radiotherapy was performed in cases of resistance to medical treatment or relapse. Unlike female subjects with macroadenoma who often exhibit a good clinical course, two male subjects with early onset macroadenoma presented with visual disturbances. These subjects showed resistance to medical therapy and relapsed, eventually requiring surgical removal and radiotherapy; one of the subjects manifested a metastatic thrombus in the internal jugular vein. In conclusion, pediatric prolactinoma exhibits a broad clinical spectrum, a relatively high incidence of macroadenoma, resistance to medical therapy, and frequent tumor relapses. In addition, a poor prognosis appears to be correlated with male sex, age at disease onset, and histopathological characteristics.

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

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.

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

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 STAR 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 STAR 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 STAR 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.

Effects of Multidisciplinary Health Promotion Program Among Children in Community Childcare Center.

In this study, the effects of a 12-month multidisciplinary education program on the health status, dietary quality, and eating habits of children and adolescents attending community childcare centers were investigated. A total of 88 participants aged 7 to 17 years from 7 community childcare centers in Gyeonggi-do were enrolled. The intervention consisted of 12 multidisciplinary education sessions covering topics such as nutrition, exercise, and psychological education. All participants received the same education, and the effectiveness of the program was evaluated by categorizing them into a high participation group (HPG) and a low participation group (LPG) based on their participation rates. After intervention, in physical activities, moderate-intensity exercise was significantly reduced in the LPG, and there was no significant difference in psychological parameters. However, notable differences were observed in nutritional data. After intervention, intakes of calorie, carbohydrate, protein, and fat were significantly increased in both groups, and in particular, the change was found to be greater in HPG. Additionally, dietary fiber intake compared to the 2015 Korean Dietary Reference Intakes was increased in both groups. Daily food intake also increased dietary fiber intake in HPG, and meat and fruit intake was increased in LPG. In the nutrition quotient, there was a significant difference in HPG's pre- and post-scores in the diversity category, and in nutrient adequacy ratio (NAR), the NAR of phosphorus was increased in both groups. The findings of this study suggest that multidisciplinary education implemented at community childcare centers primarily enhanced nutrition-related factors rather than physical activity or psychological aspects. Trial Registration: Clinical Research Information Service Identifier: KCT0002718.

Which obesity index is the most useful marker for predicting hepatic steatosis in children and adolescents with obesity? A cross-sectional study using quantitative magnetic resonance imaging.

INTRODUCTION: We aimed to evaluate the relationships between hepatic steatosis and various indices of obesity, and to identify the most useful index for the prediction of hepatic steatosis in children and adolescents with obesity. METHODS: A total of 226 children and adolescents with a mean body mass index (BMI) z-score of 2.65 and a mean age of 11.4 years were subjected to anthropometric and body composition measurements, laboratory testing, abdominal fat mass assessment, and hepatic fat accumulation by magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF). The participants were divided into quartiles according to the severity of their hepatic steatosis, and the presence of hepatic steatosis was defined using an MRI-PDFF ≥ 5%. RESULTS: The multivariate ordinal regression analysis showed that the severity of hepatic steatosis was positively associated with BMI, waist circumference, waist-to-hip ratio, waist-to-height ratio, fat mass, fat-free mass, visceral adiposity, and abdominal subcutaneous adiposity. Higher activities of liver enzymes and higher concentrations of triglyceride, C-reactive protein, fasting insulin, and leptin were associated with more severe hepatic steatosis, whereas high-density lipoprotein-cholesterol and adiponectin were negatively associated with hepatic steatosis. The indices of obesity with areas under the receiver operating characteristic curves (AUCs) > 0.8 for the prediction of hepatic steatosis were liver enzymes, visceral adipose tissue area, waist-to-hip ratio, and waist-to-height ratio. CONCLUSION: The severity of hepatic steatosis significantly correlated with various indices of obesity and cardiometabolic markers in children and adolescents with obesity. The indices of abdominal obesity would be the most useful for the prediction of hepatic steatosis.

Additive Effects of Exercise or Nutrition Intervention in a 24-Month Multidisciplinary Treatment with a Booster Intervention for Children and Adolescents with Overweight or Obesity: The ICAAN Study.

This study compared the effects of a real-world multidisciplinary intervention with additional exercise or nutritional elements and investigated the effectiveness of a booster intervention after weight regain. A total of 242 children and adolescents (age- and sex-specific body mass index [BMI] ≥ 85th percentile, mean age: 10.82 years, 60% male) were allocated to three groups: usual care, exercise, or nutrition. Six-month active treatment with 1:1 session and a maintenance stage with group activities were repeated twice to comprise a 24-month intervention. The primary outcome was change % of the BMI z-score (zBMI). A total of 110 (45.4%) participants completed the 24-month intervention. A mixed-effects model analysis indicated no significant interaction effect of the intervention group and treatment phase on the zBMI change % (p = 0.976). However, there was a significant main effect of the treatment phase on zBMI change % at 6 months (ß = -2.98, [95% CI, -5.69-0.27]), 18 months (ß = -3.99, [95% CI, -6.76-1.22]), and 24 months (ß = -3.23, [95% CI, -5.94-0.52]; p = 0.042). The improvements in zBMI, body fat %, and cardiometabolic markers were observed only among males. Whereas the additive effect of intensive exercise or nutritional feedback was not detected in the long term, a booster intervention with 1:1 counseling was effective even after weight regain during the maintenance period. It may be useful to combine individualized counseling with a less intensive form of group care for long-term maintenance in a real-world setting.

Vascular Alterations Preceding Arterial Wall Thickening in Overweight and Obese Children.

BACKGROUND: Childhood obesity is linked to adverse cardiovascular outcomes in adulthood. This study aimed to assess the impact of childhood obesity on the vasculature and to investigate whether vascular alteration precedes arterial wall thickening in childhood. METHODS: A total of 295 overweight (body mass index [BMI] 85th to 95th percentile, n = 30) and obese (BMI ≥ 95th percentile, n = 234) children aged 7-17 years and 31 normal-weight controls with similar age and gender were prospectively recruited. We assessed anthropometric data and laboratory findings, and measured the carotid intima-media thickness (IMT), carotid artery (CA) diameter, M-mode-derived arterial stiffness indices, and velocity vector imaging parameters, including the CA area, fractional area change, circumferential strain, and circumferential strain rate (SR). RESULTS: The mean ± standard deviation age of the participants was 10.8 ± 2.1 years; 172 (58%) children were male. Regarding structural properties, there was no difference in the IMT between the three groups. The CA diameter was significantly increased in obese children, whereas the CA area showed a significant increase beginning in the overweight stage. Regarding functional properties, contrary to ß stiffness and Young's elastic modulus, which were not different between the three groups, the circumferential SR showed a significant decrease beginning in the overweight stage and was independently associated with BMI z-scores after adjusting for covariates. CONCLUSION: We have demonstrated that arterial stiffening and arterial enlargement precede arterial wall thickening, and that these vascular alterations begin at the overweight stage in middle childhood or early adolescence.

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

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.

Clinical and genetic features of four patients with Pearson syndrome: An observational study.

ABSTRACT: Pearson syndrome (PS) is a multisystem mitochondrial cytopathy arising from deletions in mitochondrial DNA. Pearson syndrome is a sporadic disease that affects the hematopoietic system, pancreas, eyes, liver, and heart and the prognosis is poor. Causes of morbidity include metabolic crisis, bone marrow dysfunction, sepsis, and liver failure in early infancy or childhood. Early diagnosis may minimize complications, but suspicion of the disease is difficult and only mitochondrial DNA gene testing can identify mutations. There is no specific treatment for PS, which remains supportive care according to symptoms; however, hematopoietic stem cell transplantation may be considered in cases of bone marrow failure.We herein describe the clinical and genetic characteristics of four patients with PS. One patient presented with hypoglycemia, two developed pancytopenia, and the final patient had hypoglycemia and acute hepatitis as the primary manifestation. All patients had lactic acidosis. Additionally, all patients showed a variety of clinical features including coagulation disorder, pancreatic, adrenal, and renal tubular insufficiencies. Two patients with pancytopenia died in their early childhood. Our experience expands the phenotypic spectrum associated with PS and its clinical understanding.

Clinical and genetic analyses of patients with lateralized overgrowth.

BACKGROUND: The genetic features and treatment strategies of lateralized overgrowth have been elusive. We performed this study to analyze the genetic characteristics and treatment results of propranolol- or alpelisib-treated patients with lateralized overgrowth. METHODS: Fifteen patients with lateralized overgrowth were involved. Clinical characteristics and whole-body magnetic resonance imaging (WB-MRI) findings were evaluated. Targeted exome sequencing with a gene panel of affected tissue and peripheral white blood cells was performed. Propranolol was administered and treatment results were evaluated. The PIK3CA inhibitor alpelisib was prescribed via a managed access program. RESULTS: The identified mutations were PIK3CA (n = 7), KRAS (n = 2), PTEN (n = 1), MAP2K3 (n = 1), GNAQ (n = 1), TBC1D4 (n = 1), and TEK (n = 1). Propranolol was prescribed in 12 patients, and 7 experienced mild improvement of symptoms. Alpelisib was prescribed in two patients with a PIK3CA mutation, and the reduction of proliferated masses after 1 year of treatment was proved by WB-MRI. CONCLUSIONS: Targeted exome sequencing identified various genetic features of lateralized overgrowth. Propranolol could be applied as an adjuvant therapy for reducing vascular symptoms, but a PIK3CA inhibitor would be the primary therapeutic strategy for PIK3CA-related overgrowth syndrome.

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

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.