Muscle mass has a greater impact on serum creatinine levels in older males than in females.

Background and aims: We analyzed the effects of age and sex on the relationship between muscle mass and serum creatinine levels in an apparently healthy population, including older adults. Materials and methods: We retrospectively evaluated 1,502 individuals from the Korea National Health and Nutrition Examination Survey (KNHANES) and 4,586 individuals from the Health Check (HC) groups. We utilized data from the KNHANES and HC groups on serum creatinine levels and skeletal muscle mass index (SMI), determined using dual X-ray absorptiometry or bioelectric impedance analysis. Results: A significant negative correlation between SMI and age was observed in both the KNHANES and HC groups in males but not in females. In males, serum creatinine levels showed a significant negative correlation with age in both the KNHANES (r = -0.522, P < 0.0001) and HC groups (r = -0.451, P < 0.0001). In females, there was no significant correlation between serum creatinine levels and age in the KNHANES (r = -0.016, P = 0.5985) and HC group (r = -0.011, P = 0.5618). Conclusions: Serum creatinine levels decrease more significantly in older males than in older females due to sex-specific muscle mass decline.

HPLC-MS/MS Method Validation for Antifungal Agents in Human Serum in Clinical Application.

BACKGROUND: Therapeutic drug monitoring (TDM) of antifungal drugs is recommended. LC-MS/MS outperforms bioassay and high-performance liquid chromatography (HPLC) for TDM. In this study, we validated TDM for voriconazole, posaconazole, and itraconazole using HPLC-MS/MS with the multiple reaction monitoring (MRM) method. METHODS: For the validation of LC-MS/MS for antifungal TDM, accuracy, precision, linearity, carryover, lower limit of quantitation (LLOQ), ion suppression, and sample stability tests were performed according to the guidelines of the United States Food and Drug Administration (FDA) and the Clinical and Laboratory Standards Institute (CLSI). RESULTS: The LC-MS/MS triazole method showed that all analytes had biases less than 8.9% and coefficients of variation (CV) less than 7.7%. The linearity was validated over the ranges of 0.20 to 5.86 mg/L for voriconazole, 0.12 to 4.96 mg/L for posaconazole, 0.09 to 1.85 mg/L for itraconazole, and 0.12 to 2.38 mg/L for OH-itraconazole. Ion suppression and carryover were negligible. The lower limits of quantitation (LLOQs) for voriconazole, posaconazole, itraconazole, and OH-itraconazole were 0.114 mg/L, 0.206 mg/L, 0.118 mg/L, and 0.065 mg/L, respectively. Voriconazole, posaconazole, itraconazole, and OH-itraconazole can be stored at 4℃ for 4 - 7 days, according to sample stability. Sample preparation took < 15 minutes per batch, and analytical run time was 5 minutes per sample. CONCLUSIONS: We developed and validated a simple, reliable, and quick LC-MS/MS method for triazole antifungal agents TDM suitable for routine hospital practice.

A Case of X-Linked Adrenal Hypoplasia Congenital (AHC) Due to Large Deletion of NR0B1 (DAX1) and Contiguous Gene.

X-linked adrenal hypoplasia congenita (AHC) is caused predominantly by mutations in the NR0B1 (DAX1) gene. Among these, X-linked AHC due to a large deletion of NR0B1 is extremely rare. In Korea, the first case was reported in 2005, and there have been no further documented cases since then. Herein, we report a unique case of X-linked AHC caused by an entire gene deletion that includes the NR0B1 gene and seven other genes. A seven-day-old boy presented to a pediatric endocrine clinic with prolonged postnatal jaundice, skin hyperpigmentation, hyponatremia, and hyperkalemia, suggestive of an adrenal crisis. In genetic analysis, next-generation sequencing panel for congenital adrenal hyperplasia (CAH) showed no variants. However, chromosomal microarray results revealed large deletion of Xp21.2 (29,655,007_30,765,126) including eight protein-coding genes (NR0B1, IL1RAPL1, GK, MAGEB1-4, TASL). In cases of atypical adrenal insufficiency and genetically undiagnosed CAH, NR0B1-related AHC should be suspected, as Xp21 deletion is very rare and not detected in NGS, making microarray the best option for genetic diagnosis.

Establishment of muscle mass-based indications for the cystatin C test in renal function evaluation.

Background: We aimed to suggest muscle mass-based criteria for using of the cystatin C test for the accurate estimated glomerular filtration rate (eGFR). Materials and methods: We recruited 138 Korean subjects and evaluated eGFRcr (derived from Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) based on creatinine) was compared to eGFRcys based on cystatin C as the reference value. The skeletal muscle mass index (SMI) by bioelectrical impedance analysis (BIA) was used as representative of muscle mass. Calf circumference (CC) was also evaluated. We defined the patients by eGFRcr as those with values of eGFRcr ≥ 60 mL/min/1.73 m2 but eGFRcys < 60 mL/min/1.73 m2 as the detection of hidden renal impairment (DHRI). Cut-off values were determined based on muscle mass for the cases of DHRI suggesting the criteria of cystatin C test in renal function evaluation. Results: We confirmed significant negative correlation between %difference of eGFRcr from eGFRcys and SMI (r, -0.592 for male, -0.484 for female) or CC (r, -0.646 for male, -0.351 for female). SMI of 7.3 kg/m2 for males and 5.7 kg/m2 for females were suggested to be significant cutoffs for indication of cystatin C test. We also suggested CC would be valuable for cystatin C indication. Conclusion: We suggested the muscle mass-based objective criteria relating to SMI and CC that would indicate the use of cystatin C to evaluate renal function test in sarcopenic cases. Our results highlight the importance of muscle mass-based selection of renal function.

18p Deletion Syndrome Originating from Rare Unbalanced Whole-Arm Translocation between Chromosomes 13 and 18: A Case Report and Literature Review.

18p deletion (18p-) syndrome is a rare chromosome abnormality that has a wide range of phenotypes, with short stature, intellectual disability, and facial dysmorphism being the main clinical features. Here, we report the first case in Korea of a 16-year-old male adolescent with 18p- syndrome resulting from de novo unbalanced whole-arm translocation between chromosomes 13 and 18 (45, XY, der(13;18)(q10:q10)). Three rare clinical findings were discovered that had not been reported in the previous literature; morbid obesity without other hormonal disturbances, rib cage deformity leading to the direct compression of the liver, and lumbar spondylolisthesis at the L5-S1 level. This case expands the phenotypic spectrum of 18p- syndrome and highlights the importance of considering chromosomal analysis, since this syndrome can be easily overlooked in a clinical setting, especially without distinctive symptoms of other organs, due to its nonspecific but typical features of short stature and mild intellectual disability with a mildly dysmorphic face. Moreover, since not all cases of 18p- syndrome with unbalanced translocation (13;18) show the same phenotype, multidisciplinary examinations and follow-up seem to be important to monitor evolving and developing clinical manifestations and to predict prognosis in advance associated with the specific genes of 18p breakpoint regions.

Adrenocortical carcinoma and a sporadic MEN1 mutation in a 3-year-old girl: a case report.

Childhood adrenocortical carcinoma (ACC) is a rare disease that is mostly linked to familial cancer syndrome. Although the prevalence of ACC is extremely low in children, it is clinically important to diagnose ACC early because age and tumor stage are closely related to prognosis. From this perspective, understanding the underlying genetics and possible symptoms of ACC is crucial in managing ACC with familial cancer syndromes. In this report, we present the case of a 3-year-old girl who initially presented with symptoms of precocious puberty and was later found to have ACC by imaging analysis. On genetic analysis, the patient was found to have a MEN1 gene mutation. MEN1 mutations are found in patients with multiple endocrine neoplasia type 1 (MEN1), usually precipitating multiple endocrine tumors, including pituitary adenoma, parathyroid hyperplasia, and adrenal tumors. Although MEN1 mutation is usually inherited in an autosomal dominant manner, neither of the patient's parents had the same mutation, making hers a case of sporadic MEN1 mutation with initial presentation of ACC. The clinical course and further investigations of this patient are discussed in detail in this report.

Novel WTX nonsense mutation in a family diagnosed with osteopathia striata with cranial sclerosis: Case report.

ABSTRACT: Rationale: Osteopathia striata with cranial sclerosis is characterized by linear striations in the metaphysis of the long bones and pelvis with cranial sclerosis. It is an X-linked dominant sclerosing bone dysplasia and affected males show fetal or neonatal lethality. Mutations in the gene encoding Wilms tumor on the X chromosome (WTX) was identified as the cause of X-linked osteopathia striata with cranial sclerosis. About 30 pathogenic mutations in WTX have been reported recently. We have identified a novel nonsense mutation in the family diagnosed as osteopathia striata with cranial sclerosis. PATIENT CONCERNS: The proband came to our attention at age 9 for the evaluation of toe-out gait and planovalgus deformity. Clinically, the proband showed coarse facial features including frontal bossing, ocular hypertelorism, wide depressed nasal bridge, dental malocclusion, mild macrocephaly and low set ears. Radiologically, sclerotic linear striations were seen in the X-rays of the pelvis and the metaphyseal region of femur and tibia and the cranial sclerosis was observed. The proband's mother presented similar facial features and the X-rays of the pelvis, femur, and tibia revealed same sclerotic linear striations as the proband's. DIAGNOSES: Osteopathia striata with cranial sclerosis. INTERVENTIONS: A genetic analysis was conducted on genomic DNA isolated from peripheral blood leukocytes of the proband and the mother for confirming the clinical suspicion of osteopathia striata with cranial sclerosis. WTX on Xq11.2 gene was analyzed in direct sequencing for coding exons including intron-exon boundaries. OUTCOMES: One novel nonsense mutation (c.1003C>T, p.Gln335∗) and known single nucleotide variant were observed in a heterozygous form. LESSONS: We found a novel nonsense mutation in a family diagnosed as osteopathia striata with cranial sclerosis. The relationship between various clinical features and genetic mutations can be clarified by accumulation of genetic database.

Transient Neonatal Diabetes Mellitus in SHORT Syndrome: A Case Report.

SHORT syndrome is a rare autosomal dominant disorder characterized by multiple congenital defects and is historically defined by its acronym: short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay. Herein, we report a male infant with SHORT syndrome who presented with transient neonatal diabetes mellitus (TNDM) with insulin resistance. The proband was born at 38 weeks of gestation but displayed facial dysmorphic features. Intrauterine growth restriction (IUGR) was detected on a prenatal ultrasonography test. His birth weight was 1.8 kg (<3rd percentile), length 44 cm (<3rd percentile), and head circumference 31 cm (<3rd percentile). The patient's blood glucose level started to increase at 5 days of age (218-263 mg/dl) and remained high at 20 days of age (205-260 mg/dl). He was treated with subcutaneous insulin and the blood glucose level gradually stabilized. Blood glucose level was stabilized over time without insulin treatment at 6 weeks of age. Clinical exome sequencing showed a heterozygous pathogenic variant, NM_181523.3:c.1945C>T (p.Arg649Trp) in exon 15 of the phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) known as the causative gene for SHORT syndrome. Examination of the patient at 10 months of age revealed no hyperglycemic episode and glycated hemoglobin level was 5.2%. To the best of our knowledge, this is the first case of TNDM in SHORT syndrome due to a pathogenic variant of PIK3R1. We believe that our case can aid in expanding the phenotypes of SHORT syndrome.

Multilevel Airway Stenosis Being Bypassed by a Customized Tracheostomy Tube in an Infant with Myhre Syndrome.

Background: Myhre syndrome is a rare connective tissue disorder caused by heterozygous pathogenic variants in the SMAD4 gene. Although recognizing Myhre syndrome in early childhood is challenging, it is important to manage airway stenosis in patients with Myhre syndrome. Case Presentation: We report the case of a 2-month-old boy who initially presented with severe multilevel airway stenosis, dysmorphic face, and multiple abnormalities. Lung fibrosis and mild aortic valve stenosis were additionally observed on follow-up examinations. A heterozygous missense variant, c.1499T>C (p.Ile500Thr), in SMAD4 was identified through exome sequencing. Tracheostomy was performed, and the patient has maintained stable respiration through a customized tracheostomy tube with a home ventilator. Conclusions: Patients who have dysmorphic face, airway stenosis, and cardiovascular anomalies that do not fit the diagnosis of common syndromes should be evaluated for rare diseases, including Myhre syndrome. Since respiratory complications can be life threatening, early diagnosis and suitable intervention are necessary.

Optimizing the Diagnostic Strategy to Identify Genetic Abnormalities in Miscarriage.

INTRODUCTION: The single most common cause of miscarriage is genetic abnormality. OBJECTIVE: We conducted a prospective cohort study to compare the performance of conventional karyotyping and chromosomal microarray analysis (CMA) using array comparative genomic hybridization (array-CGH) and single nucleotide polymorphism array (SNP-array) to identify genetic abnormalities in miscarriage specimens. METHODS: A total of 63 miscarriage specimens were included. Conventional karyotyping, array-CGH, and SNP-array were performed and the results compared. RESULTS: Genetic abnormalities were detected in 31 cases (49.2%) by at least one testing modality. Single autosomal trisomy was the most common defect (71.0%), followed by polyploidy (16.1%), multiple aneuploidy (9.7%), and monosomy X (3.2%). Mosaicisms were identified in four cases and confirmed by fluorescence in situ hybridization (FISH) using appropriate probes. SNP-array had a higher detection rate of genetic abnormalities than array-CGH (93.5 vs. 77.4%), and conventional karyotyping had the lowest detection rate (76.0%). SNP-array enabled the detection of all types of genetic abnormalities, including polyploidy. CONCLUSIONS: Although conventional karyotyping and FISH are still needed, SNP-array represents the first choice for miscarriage because the technique showed excellent performance in the detection of genetic abnormalities and minimized the probability of testing failure as well as time, costs, and labor.

Case Report: Co-occurrence of Duchenne Muscular Dystrophy and Frontometaphyseal Dysplasia 1.

Herein, we present a rare case of co-occurring Duchenne muscular dystrophy (DMD) and frontometaphyseal dysplasia 1 (FMD1), two different X-linked diseases, in a 7-year-old boy. He presented with proximal muscle weakness and elevated creatine phosphokinase levels. A multiplex ligation-dependent probe amplification study of DMD revealed the de novo duplications of exons 2-37, thereby confirming the diagnosis of DMD. Initial evaluation revealed atypical features, such as facial dysmorphism, multiple joint contractures, and severe scoliosis, at an early age. However, these were overlooked and were assumed to be atypical manifestations of DMD. Then, the patient's maternal cousin was diagnosed with FMD1 with pathogenic missense variant in FLNA (NM_001110556.2: c.3557C>T/p.Ser1186Leu). A family genetic test revealed that the patient and his mother had the same pathogenic variant in FLNA. The patient's atypical manifestations were considered symptoms of FMD1. Therefore, if one disease does not fully explain the patient's clinical features, an expanded genetic study is needed to detect coincidental disease.

Andersen-Tawil Syndrome With Novel Mutation in KCNJ2: Case Report.

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant disorder characterized by a classic symptom triad: periodic paralysis, ventricular arrhythmias associated with prolonged QT interval, and dysmorphic skeletal and facial features. Pathogenic variants of the inwardly rectifying potassium channel subfamily J member 2 (KCNJ2) gene have been linked to the ATS. Herein, we report a novel KCNJ2 causative variant in a proband and her father showing different ATS-associated symptoms. A 15-year-old girl was referred because of episodic weakness and periodic paralysis in both legs for 2-3 months. The symptoms occurred either when she was tired or after strenuous exercise. These attacks made walking or climbing stairs difficult and lasted from one to several days. She had a short stature (142 cm, <3rd percentile) and weighed 40 kg. The proband also showed orbital hypertelorism, dental crowding, mandibular hypoplasia, fifth-digit clinodactyly, and small hands. Scoliosis in the thoracolumbar region was detected by chest X-ray. Since she was 7 years old, she had been treated for arrhythmia-associated long QT interval and underwent periodic echocardiography. Brain MRI revealed cerebrovascular abnormalities indicating absence or hypoplasia of bilateral internal carotid arteries, and compensation of other collateral vessels was observed. There were no specific findings related to intellectual development. The proband's father also had a history of periodic paralysis similar to the proband. He did not show any cardiac symptoms. Interestingly, he was diagnosed with hyperthyroidism during an evaluation for paralytic symptoms. Clinical exome sequencing revealed a novel heterozygous missense variant: Chr17(GRCh37):g.68171593A>T, NM_000891.2:c.413A>T, p.(Glu138Val) in KCNJ2 in the proband and the proband's father.

Total and Exchangeable Copper Assay Using Inductively Coupled Plasma Mass Spectrometry and Establishment of a Pediatric Reference Interval.

CONTEXT.­: Recently, an exchangeable copper (CuEXC) assay has been suggested as a robust and feasible diagnostic tool for Wilson disease (WD). Although WD is a disorder that requires lifelong treatment and monitoring, few data are currently available regarding the status of copper levels in children. OBJECTIVE.­: To evaluate the performance of copper assays and establish a reference interval for total copper and CuEXC in the pediatric population. DESIGN.­: Serum samples from children aged 1-5 (n = 122), 6-12 (n = 125), and 13-18 years (n = 120) were analyzed. Total copper and CuEXC concentrations were directly measured using inductively coupled plasma mass spectrometry, and relative CuEXC levels were calculated. Total copper reference intervals, CuEXC levels, and relative CuEXC levels were determined based on the 2.5th and 97.5th percentiles of the data with 90% confidence intervals. RESULTS.­: There were significant differences in the median concentrations of total copper and relative CuEXC among the age groups. Reference intervals determined for total copper were 82 to 167, 75 to 139, and 64 to 133 µg/dL for children aged 1 to 5, 6 to 12, and 13 to 18 years, respectively. The reference intervals for CuEXC were 4.29 to 9.79, 4.02 to 9.09, and 3.55 to 8.25 µg/dL for children aged 1 to 5, 6 to 12, and 13 to 18 years, respectively. Among 11 patients with suspected WD, relative CuEXC values were elevated in all 3 diagnosed with WD. CONCLUSIONS.­: The pediatric reference intervals derived in this study are expected to be useful for the diagnosis, differential diagnosis, treatment, and monitoring of pediatric patients with WD.

Relationship Between Circulating Netrin-1 Concentration, Impaired Fasting Glucose, and Newly Diagnosed Type 2 Diabetes.

Background: The protein netrin-1 has demonstrated anti-inflammatory, tissue regeneration, and immune modulation properties. Although inflammation is a major contributing factor in the development of insulin resistance and type 2 diabetes, little is known about a possible relationship between serum netrin-1 and type 2 diabetes. Therefore, we investigated the association between circulating levels of netrin-1 and glycometabolic parameters predictive of type 2 diabetes. Methods: Serum samples were collected from 41 normal controls, 85 subjects with impaired fasting glucose (IFG), and 92 subjects with newly diagnosed type 2 diabetes. Clinical and laboratory parameters were assessed and netrin-1 levels were measured by commercial enzyme-linked immunosorbent assay. Spearman correlation analyses and multivariable-adjusted regression analyses were conducted to examine the relationship between serum netrin-1 levels and glycometabolic parameters. Results: Serum netrin-1 levels in subjects with type 2 diabetes or IFG were significantly higher compared to normal controls (441.0, 436.6, and 275.9 pg/mL, respectively; P for trend < 0.001). Serum netrin-1 levels were significantly positively correlated with fasting glucose, HbA1c, and insulin resistance index (all Ps < 0.01). Serum netrin-1 levels were independently associated with IFG or type 2 diabetes (standardized ß = 0.405, P < 0.001) after adjusting for covariates and potential confounders. In addition, the receiver operating characteristic (ROC) analysis showed that serum netrin-1 levels could identify the presence of IFG and type 2 diabetes with the area under the ROC curve (AUC) of 0.784 (P < 0.001). Conclusions: Our results suggest that elevated serum netrin-1 levels are significantly associated with the presence of IFG and type 2 diabetes.

Effects of two types of medical contrast media on routine chemistry results by three automated chemistry analyzers.

OBJECTIVES: The use of iodinated contrast media has grown in popularity in the past two decades, but relatively little attention has been paid to the possible interferential effects of contrast media on laboratory test results. Herein, we investigate medical contrast media interference with routine chemistry results obtained by three automated chemistry analyzers. METHODS: Ten levels of pooled serum were used in the study. Two types of medical contrast media [Iopamiro (iopamidol) and Omnipaque (iohexol)] were evaluated. To evaluate the dose-dependent effects of the contrast media, iopamidol and iohexol were spiked separately into aliquots of serum for final concentrations of 1.8%, 3.6%, 5.5%, 7.3%, and 9.1%. The 28 analytes included in the routine chemistry panel were measured by using Hitachi 7600, AU5800, and Cobas c702 analyzers. We calculated the delta percentage difference (DPD) between the samples and the control, and examined dose-dependent trends. RESULTS: When the mean DPD values were compared with the reference cut-off criteria, the only uniformly interferential effect observed for all analyzers was in total protein with iopamidol. Two additional analytes that showed trends toward interferential effects only in few analyzers and exceeded the limits of the allowable error were the serum iron and the total CO2. The other combinations of analyzer and contrast showed no consistent dose-dependent propensity for change in any analyte level. CONCLUSIONS: Our study suggests that many of the analytes included in routine chemistry results, except total protein and serum iron, are not significantly affected by iopamidol and iohexol. These results suggest that it would be beneficial to apply a flexible medical evaluation process for patients requiring both laboratory tests and imaging studies, minimizing the need for strict regulations for sequential tests.