Effective growth hormone replacement with once-weekly somapacitan in Japanese children with growth hormone deficiency: Results from REAL4, a phase 3 clinical trial.

OBJECTIVE: Somapacitan is a long-acting growth hormone (GH) derivative developed for the treatment of GH deficiency (GHD). This study evaluates the efficacy and tolerability of somapacitan in Japanese children with GHD after 104 weeks of treatment and after switch from daily GH. DESIGN: Subanalysis on Japanese patients from a randomised, open-labelled, controlled parallel-group phase 3 trial (REAL4, NCT03811535). PATIENTS AND MEASUREMENTS: Thirty treatment-naïve patients were randomised 2:1 to somapacitan (0.16 mg/kg/week) or daily GH (0.034 mg/kg/day) up to Week 52, after which all patients received somapacitan. Height velocity (HV; cm/year) at Weeks 52 and 104 were the primary measurements. Additional assessments included HV SD score (SDS), height SDS, bone age, insulin-like growth factor-I (IGF-I) SDS, and observer-reported outcomes. RESULTS: At Week 52, observed mean HV was similar between treatment groups (10.3 vs. 9.8 cm/year for somapacitan and daily GH, respectively). Similar HVs between groups were also observed at Week 104: 7.4 cm/year after continuous somapacitan treatment (soma/soma) and 7.9 cm/year after 1-year somapacitan treatment following switch from daily GH (switch). Other height-related endpoints supported continuous growth. IGF-I SDS increased in both groups with mean IGF-I SDS within -2 and +2 during the study. Somapacitan was well tolerated, one mild injection site reaction was reported, with no reports of injection site pain. Patient preference questionnaires showed that most patients and their caregivers (90.9%) who switched treatment at Week 52 preferred once-weekly somapacitan over daily GH treatment. CONCLUSIONS: Somapacitan showed sustained efficacy in Japanese children with GHD over 104 weeks and for 52 weeks after switching from daily GH. Somapacitan was well tolerated and preferred over daily GH.

Sotos syndrome with marked overgrowth in three Japanese patients with heterozygous likely pathogenic NSD1 variants: case reports with review of literature.

We report three Japanese patients with Sotos syndrome accompanied by marked overgrowth, i.e., a 2 8/12-year-old boy with a height of 105.2 cm (+4.4 SD) (patient 1), the mother of patient 1 with a height of 180.8 cm (+4.1 SD) (patient 2), and a 12 10/12-year-old girl with a height of 189.4 cm (+6.3 SD) (patient 3). In addition to the marked overgrowth (tall stature), patients 1-3 exhibited Sotos syndrome-compatible macrocephaly and characteristic features, whereas intellectual and developmental disabilities remained at a borderline level in patient 1 and were apparently absent from patients 2 and 3. Thus, whole exome sequencing was performed to confirm the diagnosis, revealing a likely pathogenic c.6356A>G:p.(Asp2119Gly) variant in NSD1 of patients 1 and 2, and a likely pathogenic c.6599dupT:p.(Ser2201Valfs*4) variant in NSD1 of patient 3 (NM_022455.5). The results, in conjunction with the previously reported data in nine patients with marked overgrowth (≥4.0 SD), imply that several patients with Sotos syndrome have extreme tall stature even in adulthood. Thus, it is recommended to examine NSD1 in patients with marked overgrowth as the salient feature.

Comparison of lung CT number and airway dimension evaluation capabilities of ultra-high-resolution CT, using different scan modes and reconstruction methods including deep learning reconstruction, with those of multi-detector CT in a QIBA phantom study.

OBJECTIVE: Ultra-high-resolution CT (UHR-CT), which can be applied normal resolution (NR), high-resolution (HR), and super-high-resolution (SHR) modes, has become available as in conjunction with multi-detector CT (MDCT). Moreover, deep learning reconstruction (DLR) method, as well as filtered back projection (FBP), hybrid-type iterative reconstruction (IR), and model-based IR methods, has been clinically used. The purpose of this study was to directly compare lung CT number and airway dimension evaluation capabilities of UHR-CT using different scan modes with those of MDCT with different reconstruction methods as investigated in a lung density and airway phantom design recommended by QIBA. MATERIALS AND METHODS: Lung CT number, inner diameter (ID), inner area (IA), and wall thickness (WT) were measured, and mean differences between measured CT number, ID, IA, WT, and standard reference were compared by means of Tukey's HSD test between all UHR-CT data and MDCT reconstructed with FBP as 1.0-mm section thickness. RESULTS: For each reconstruction method, mean differences in lung CT numbers and all airway parameters on 0.5-mm and 1-mm section thickness CTs obtained with SHR and HR modes showed significant differences with those obtained with the NR mode on UHR-CT and MDCT (p < 0.05). Moreover, the mean differences on all UHR-CTs obtained with SHR, HR, or NR modes were significantly different from those of 1.0-mm section thickness MDCTs reconstructed with FBP (p < 0.05). CONCLUSION: Scan modes and reconstruction methods used for UHR-CT were found to significantly affect lung CT number and airway dimension evaluations as did reconstruction methods used for MDCT. KEY POINTS: • Scan and reconstruction methods used for UHR-CT showed significantly higher CT numbers and smaller airway dimension evaluations as did those for MDCT in a QIBA phantom study (p < 0.05). • Mean differences in lung CT number for 0.25-mm, 0.5-mm, and 1.0-mm section thickness CT images obtained with SHR and HR modes were significantly larger than those for CT images at 1.0-mm section thickness obtained with MDCT and reconstructed with FBP (p < 0.05). • Mean differences in inner diameter (ID), inner area (IA), and wall thickness (WT) measured with SHR and HR modes on 0.5- and 1.0-mm section thickness CT images were significantly smaller than those obtained with NR mode on UHR-CT and MDCT (p < 0.05).

Safety and accuracy of neonatal continuous glucose monitoring.

BACKGROUND: Hypoglycemia is a significant problem for all neonates and requires minimally invasive and reliable monitoring. The primary objective of this study was to verify the safety and accuracy of the continuous glucose monitoring (CGM) of full-term neonates using Freestyle Libre, a flash glucose monitoring (FGM) device. METHODS: The study was conducted on 20 neonates. Shortly after birth, we placed the FGM sensor on the outside of the neonates' thighs. We scanned the CGM values at 60, 120, 180, and 360 min after birth and simultaneously obtained blood glucose values with plantar capillaries by heel puncture. The neonates wore the sensors for up to 6 h and then they were removed. RESULTS: Of the 75 data points to be measured, 65 points (86.7%) were obtained by scan. There was no change in the sensor attachment site in 12 of 18 completed cases in this study but we observed slight induration in four cases (22.2%) and slight redness in one case (5.5%) at the sensor puncture site. A moderate correlation was observed between the CGM and blood glucose values. The CGM values tended to be low at 120, 180, and 360 min after birth, and tended to be high only at 60 min after birth. CONCLUSIONS: The CGM device was safe to wear on the neonate and the CGM data correlated well with blood glucose levels. There was dissociation between CGM data and blood glucose levels in the acute period soon after birth when the blood glucose levels changed rapidly.

ACAN biallelic variants in a girl with severe idiopathic short stature.

Although ACAN heterozygous loss-of-function variants often cause idiopathic short stature (ISS) phenotype, there is no report describing ISS phenotype caused by ACAN biallelic loss-of-function variants. We encountered a 4 1/12-year-old Japanese girl with a height of 80.4 cm (-5.2 SD), a weight of 11.4 kg (-1.9 SD), a head circumference of 48.7 cm (-0.6 SD), and an arm span/height ratio of 1.0 (+1.1 SD). Endocrine studies and bone survey showed no abnormal findings. Whole exome sequencing revealed biallelic rare variants in ACAN, i.e., NM_013227.4:c.4214delC:p.(Pro1405Leufs*3) derived from her father and paternal grandfather with short stature (-2.9 and -2.0 SD, respectively) and NM_013227.4:c.7124 A>G:p.(Gln2375Arg) inherited from her mother and maternal grandmother with short stature (-2.1 and -3.0 SD, respectively). The frameshift variant underwent nonsense mediated mRNA decay, and the missense variant was assessed to have high pathogenicity. The results imply for the first time that ACAN biallelic loss-of-function variants can cause severe ISS phenotype.

Machine learning for lung texture analysis on thin-section CT: Capability for assessments of disease severity and therapeutic effect for connective tissue disease patients in comparison with expert panel evaluations.

BACKGROUND: The need for quantitative assessment of interstitial lung involvement on thin-section computed tomography (CT) has arisen in interstitial lung diseases including connective tissue disease (CTD). PURPOSE: To evaluate the capability of machine learning (ML)-based CT texture analysis for disease severity and treatment response assessments in comparison with qualitatively assessed thin-section CT for patients with CTD. MATERIAL AND METHODS: A total of 149 patients with CTD-related ILD (CTD-ILD) underwent initial and follow-up CT scans (total 364 paired serial CT examinations), pulmonary function tests, and serum KL-6 level tests. Based on all follow-up examination results, all paired serial CT examinations were assessed as "Stable" (n = 188), "Worse" (n = 98) and "Improved" (n = 78). Next, quantitative index changes were determined by software, and qualitative disease severity scores were assessed by consensus of two radiologists. To evaluate differences in each quantitative index as well as in disease severity score between paired serial CT examinations, Tukey's honestly significant difference (HSD) test was performed among the three statuses. Stepwise regression analyses were performed to determine changes in each pulmonary functional parameter and all quantitative indexes between paired serial CT scans. RESULTS: Δ% normal lung, Δ% consolidation, Δ% ground glass opacity, Δ% reticulation, and Δdisease severity score showed significant differences among the three statuses (P < 0.05). All differences in pulmonary functional parameters were significantly affected by Δ% normal lung, Δ% reticulation, and Δ% honeycomb (0.16 ≤r2 ≤0.42; P < 0.05). CONCLUSION: ML-based CT texture analysis has better potential than qualitatively assessed thin-section CT for disease severity assessment and treatment response evaluation for CTD-ILD.

Insulin resistant diabetes mellitus in SHORT syndrome: case report and literature review.

SHORT syndrome is a rare developmental disorder frequently associated with growth failure and insulin resistant diabetes mellitus (IRDM). Since GH has a diabetogenic effect, GH therapy has been regarded as a contraindication. We observed a Brazilian girl with SHORT syndrome who received GH therapy from 4 6/12 years of age for SGA short stature. GH dosage was increased from 0.23 to 0.36 mg/kg/week, but statural response to GH therapy remained poor. Her blood HbA1c level, though it remained 5.5-6.0% in childhood, began to elevate with puberty and increased to 9.2% at 10 6/12 years of age, despite the discontinuation of GH therapy at 9 11/12 years of age. Laboratory studies indicated antibody-negative IRDM. She was treated with metformin and canagliflozin (a sodium glucose co-transporter 2 (SGLT2) inhibitor), which ameliorated overt diurnal hyperglycemia and mild nocturnal hypoglycemia and reduced her blood HbA1c around 7%. Whole exome sequencing revealed a de novo heterozygous pathogenic variant (c.1945C>T:p.(Arg649Trp)) in PIK3R1 known as the sole causative gene for SHORT syndrome. Subsequent literature review for patients with molecularly confirmed SHORT syndrome revealed the development of IRDM in 10 of 15 GH-untreated patients aged ≥12 years but in none of three GH-treated and six GH-untreated patients aged ≤10 years. These findings imply a critical role of pubertal development and/or advanced age rather than GH therapy in the development of IRDM, and a usefulness of SGLT2 inhibitor in the treatment of IRDM.

Effect of Manual Upper Eyelid Elevation on Intraocular Pressure Measurement by Four Different Tonometers.

SIGNIFICANCE: This study is the first to show that the manual upper eyelid elevation (manual UEE) that is commonly used to prevent disruption of the IOP measurement due to blinking or upper eyelid contact with the tip of the tonometer does not affect the IOP values. PURPOSE: We investigated whether manual UEE affects the IOP readings using three rebound tonometers (Icare TA01i, Icare PRO, and Icare ic100) and Goldmann applanation tonometry (GAT). METHODS: One eye was measured for 101 patients (56 eyes of primary open-angle glaucoma patients and 45 healthy subjects). The IOPs were measured without and with manual UEE. Each IOP was measured twice; the measurement order using the tonometers was randomly selected. In addition, palpebral fissure height (distance between the upper and lower eyelids) was measured. RESULTS: The IOPs without manual UEE were 12.1 ± 2.9, 13.3 ± 2.7, 11.7 ± 2.9, and 16.0 ± 3.2 mmHg (Icare TA01i, Icare PRO, Icare ic100, and GAT), and those with manual UEE were 12.3 ± 3.0, 13.3 ± 2.8, 11.7 ± 2.9, and 16.0 ± 3.3, respectively. No significant difference was found between the IOP without and with manual UEE (IOP difference; all, P > .50; paired t test). Multiple linear regression analyses revealed that palpebral fissure height did not affect IOP difference for any of the tonometers. CONCLUSIONS: Simple manual UEE when measuring the IOP has little effect on the IOP obtained using all current rebound tonometers and GAT.

Comparison of Xenon-Enhanced Area-Detector CT and Krypton Ventilation SPECT/CT for Assessment of Pulmonary Functional Loss and Disease Severity in Smokers.

OBJECTIVE: The objective of this study was to compare the capability of xenon-enhanced area-detector CT (ADCT) performed with a subtraction technique and coregistered 81mKr-ventilation SPECT/CT for the assessment of pulmonary functional loss and disease severity in smokers. SUBJECTS AND METHODS: Forty-six consecutive smokers (32 men and 14 women; mean age, 67.0 years) underwent prospective unenhanced and xenon-enhanced ADCT, 81mKr-ventilation SPECT/CT, and pulmonary function tests. Disease severity was evaluated according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. CT-based functional lung volume (FLV), the percentage of wall area to total airway area (WA%), and ventilated FLV on xenon-enhanced ADCT and SPECT/CT were calculated for each smoker. All indexes were correlated with percentage of forced expiratory volume in 1 second (%FEV1) using step-wise regression analyses, and univariate and multivariate logistic regression analyses were performed. In addition, the diagnostic accuracy of the proposed model was compared with that of each radiologic index by means of McNemar analysis. RESULTS: Multivariate logistic regression showed that %FEV1 was significantly affected (r = 0.77, r2 = 0.59) by two factors: the first factor, ventilated FLV on xenon-enhanced ADCT (p < 0.0001); and the second factor, WA% (p = 0.004). Univariate logistic regression analyses indicated that all indexes significantly affected GOLD classification (p < 0.05). Multivariate logistic regression analyses revealed that ventilated FLV on xenon-enhanced ADCT and CT-based FLV significantly influenced GOLD classification (p < 0.0001). The diagnostic accuracy of the proposed model was significantly higher than that of ventilated FLV on SPECT/CT (p = 0.03) and WA% (p = 0.008). CONCLUSION: Xenon-enhanced ADCT is more effective than 81mKr-ventilation SPECT/CT for the assessment of pulmonary functional loss and disease severity.

De novo IGF2 mutation on the paternal allele in a patient with Silver-Russell syndrome and ectrodactyly.

Although paternally expressed IGF2 is known to play a critical role in placental and body growth, only a single mutation has been found in IGF2. We identified, through whole-exome sequencing, a de novo IGF2 indel mutation leading to frameshift (NM_000612.5:c.110_117delinsAGGTAA, p.(Leu37Glnfs*31)) in a patient with Silver-Russell syndrome, ectrodactyly, undermasculinized genitalia, developmental delay, and placental hypoplasia. Furthermore, we demonstrated that the mutation resided on the paternal allele by sequencing the long PCR product harboring the mutation- and methylation-sensitive SmaI and SalI sites before and after SmaI/SalI digestion. The results, together with the previous findings in four cases from a single family with a paternally inherited IGF2 nonsense mutation and those in patients with variable H19 differentially methylated region epimutations leading to compromised IGF2 expression, suggest that the whole phenotype of this patient is explainable by the IGF2 mutation, and that phenotypic severity is primarily determined by the IGF2 expression level in target tissues.

FGFR1 Analyses in Four Patients with Hypogonadotropic Hypogonadism with Split-Hand/Foot Malformation: Implications for the Promoter Region.

Heterozygous loss-of-function mutations of FGFR1 (fibroblast growth factor receptor 1) cause various disorders including hypogonadotropic hypogonadism with split-hand/foot malformation (HH-SHFM). We examined FGFR1 in four Japanese patients with HH-SHFM (cases 1-4) and the mother of case 4 with HH only. Cases 1 and 2 had heterozygous loss-of-function mutations with no dominant negative effect (c.289G>A, p.[G97S]; and c.2231G>C, p.[R744T]), and case 3 had a splice donor site mutation (c.1663+1G>T). Notably, case 4 had a maternally inherited 8,312 bp microdeletion that involved noncoding exon 1U and impaired FGFR1 expression. Furthermore, consistent with the presence of transcription-related histone marks (e.g., H3K4Me3, H3K4Me1, and H3K27Ac) and multiple transcription factor-binding sites around exon 1U, functional studies demonstrated a marked transactivation function of a 414-bp segment harboring the transcription start site. These results support the relevance of FGFR1 mutations to HH-SHFM, and argue for the presence of the FGFR1 core-promoter elements around exon 1U.

Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty.

The human genome encodes ~750 G-protein-coupled receptors (GPCRs), including prokineticin receptor 2 (PROKR2) involved in the regulation of sexual maturation. Previously reported pathogenic gain-of-function mutations of GPCR genes invariably encoded aberrant receptors with excessive signal transduction activity. Although in vitro assays demonstrated that an artificially created inactive mutant of PROKR2 exerted paradoxical gain-of-function effects when co-transfected with wild-type proteins, such a phenomenon has not been observed in vivo. Here, we report a heterozygous frameshift mutation of PROKR2 identified in a 3.5-year-old girl with central precocious puberty. The mutant mRNA escaped nonsense-mediated decay and generated a GPCR lacking two transmembrane domains and the carboxyl-terminal tail. The mutant protein had no in vitro signal transduction activity; however, cells co-expressing the mutant and wild-type PROKR2 exhibited markedly exaggerated ligand-induced Ca2+ responses. The results indicate that certain inactive PROKR2 mutants can cause early puberty by enhancing the functional property of coexisting wild-type proteins. Considering the structural similarity among GPCRs, this paradoxical gain-of-function mechanism may underlie various human disorders.

Dynamic Contrast-Enhanced Perfusion Area-Detector CT: Preliminary Comparison of Diagnostic Performance for N Stage Assessment With FDG PET/CT in Non-Small Cell Lung Cancer.

OBJECTIVE: The objective of our study was to directly compare the capability of dynamic first-pass contrast-enhanced (CE) perfusion area-detector CT (ADCT) and FDG PET/CT for differentiation of metastatic from nonmetastatic lymph nodes and assessment of N stage in patients with non-small cell lung carcinoma (NSCLC). SUBJECTS AND METHODS: Seventy-seven consecutive patients, 45 men (mean age ± SD, 70.4 ± 5.9 years) and 32 women (71.2 ± 7.7 years), underwent dynamic first-pass CE-perfusion ADCT at two or three different positions for covering the entire thorax, FDG PET/CT, surgical treatment, and pathologic examination. From all ADCT data for each of the subjects, a whole-chest perfusion map was computationally generated using the dual- and single-input maximum slope and Patlak plot methods. For quantitative N stage assessment, perfusion parameters and the maximum standardized uptake value (SUVmax) for each lymph node were determined by measuring the relevant ROI. ROC curve analyses were performed for comparing the diagnostic capability of each of the methods on a per-node basis. N stages evaluated by each of the indexes were then statistically compared with the final pathologic diagnosis by means of chi-square and kappa statistics. RESULTS: The area under the ROC curve (Az) values of systemic arterial perfusion (Az = 0.89), permeability surface (Az = 0.78), and SUVmax (Az = 0.85) were significantly larger than the Az values of total perfusion (Az = 0.70, p < 0.05) and distribution volume (Az = 0.55, p < 0.05). For each of the threshold values, agreement for systemic arterial perfusion calculated using the dual-input maximum slope model was substantial (κ = 0.70, p < 0.0001), and agreement for SUVmax was moderate (κ = 0.60, p < 0.0001). CONCLUSION: Dynamic first-pass CE-perfusion ADCT is as useful as FDG PET/CT for the differentiation of metastatic from nonmetastatic lymph nodes and assessment of N stage in patients with NSCLC.

Long-term clinical course in three patients with MAMLD1 mutations.

Although MAMLD1 on chromosome Xq28 is known as a causative gene for 46,XY disorders of sex development, clinical information is virtually limited in patients of infancy to early childhood. Here, we report long-term genital and hormonal findings in three previously described Japanese patients with MAMLD1 mutations, i.e., patients 1 and 2 with p.E197X and patient 3 with p.R726X. As previously reported, patients 1-3 exhibited penoscrotal hypospadias with chordee, microphallus, bifid/hypoplastic scrotum, and/or bilateral cryptorchidism/retractile testes, in the presence of sufficiently high serum basal or hCG-stimulated testosterone values in the mini-pubertal period to early childhood. Subsequently, patient 1 had low serum hCG-stimulated testosterone value (126 ng/dL) at 13 11/12 years of age, and manifested microphallus (4.5 cm), relatively small testes (left 8 mL and right 10 mL), Tanner stage 3 genitalia and pubic hair development at 18 3/12 years of age. Similarly, patients 2 and 3 showed mild hypergonadotropic hypogonadism at 7 0/12 and 9 9/12 years of age, respectively, with serum GnRH-stimulated LH values of 5.5 and 7.2 mIU/mL and FSH values of 10.3 and 19.8 mIU/mL and hCG-stimulated testosterone values of 70 and 80 ng/dL, respectively. Testis ultrasound studies delineated microlithiasis in patients 1 and 3. These results imply for the first time deterioration of testicular function with age in patients with pathologic MAMLD1 mutations.

Solitary pulmonary nodules: Comparison of dynamic first-pass contrast-enhanced perfusion area-detector CT, dynamic first-pass contrast-enhanced MR imaging, and FDG PET/CT.

PURPOSE: To prospectively compare the capabilities of dynamic perfusion area-detector computed tomography (CT), dynamic magnetic resonance (MR) imaging, and positron emission tomography (PET) combined with CT (PET/CT) with use of fluorine 18 fluorodeoxyglucose (FDG) for the diagnosis of solitary pulmonary nodules. MATERIALS AND METHODS: The institutional review board approved this study, and written informed consent was obtained from each subject. A total of 198 consecutive patients with 218 nodules prospectively underwent dynamic perfusion area-detector CT, dynamic MR imaging, FDG PET/CT, and microbacterial and/or pathologic examinations. Nodules were classified into three groups: malignant nodules (n = 133) and benign nodules with low (n = 53) or high (n = 32) biologic activity. Total perfusion was determined with dual-input maximum slope models at area-detector CT, maximum and slope of enhancement ratio at MR imaging, and maximum standardized uptake value (SUVmax) at PET/CT. Next, all indexes for malignant and benign nodules were compared with the Tukey honest significant difference test. Then, receiver operating characteristic analysis was performed for each index. Finally, sensitivity, specificity, and accuracy were compared with the McNemar test. RESULTS: All indexes showed significant differences between malignant nodules and benign nodules with low biologic activity (P < .0001). The area under the receiver operating characteristic curve for total perfusion was significantly larger than that for other indexes (.0006 ≤ P ≤ .04). The specificity and accuracy of total perfusion were significantly higher than those of maximum relative enhancement ratio (specificity, P < .0001; accuracy, P < .0001), slope of enhancement ratio (specificity, P < .0001; accuracy, P < .0001), and SUVmax (specificity, P < .0001; accuracy, P < .0001). CONCLUSION: Dynamic perfusion area-detector CT is more specific and accurate than dynamic MR imaging and FDG PET/CT in the diagnosis of solitary pulmonary nodules in routine clinical practice.

Development of waist circumference percentiles for Japanese children and an examination of their screening utility for childhood metabolic syndrome: a population-based cross-sectional study.

BACKGROUND: In Japan, waist circumference (WC) percentiles to screen for childhood metabolic syndrome (MetS) are unavailable. The objectives of this study were to develop WC and WC-to-height ratio (WC/Ht) percentile curves by age and sex for Japanese children, and to test their utility in screening for MetS in children with obesity who are otherwise healthy. METHODS: The WC and WC/Ht percentiles were developed using the LMS method of summarizing growth standards, which monitors changing skewness (L), medians (M), and coefficients of variation (S) in childhood distributions. A representative dataset was used, which consisted of 3,634 boys and 3,536 girls aged 4.5-12.75 years in Shizuoka prefecture, Japan, between 2010 and 2012. Children who were obese (355 boys and 230 girls) aged 6-12 years from Osaka prefecture, Japan, were screened for childhood MetS using the new percentiles and the International Diabetes Federation's (IDF's) definition of MetS. RESULTS: The number of participants with certain metabolic abnormalities (high systolic and diastolic blood pressure, and a high level of triglycerides) was significantly higher in boys aged 10-12 years, with a WC ≥ 90th percentile, than among those with a WC < 90th percentile. None of the participants with a WC < 90th percentile exhibited two or more metabolic abnormalities, regardless of their age or sex. Among the participants aged 10-12 years, 11.4 % of boys and 4.4 % of girls with a WC ≥ 90th percentile were diagnosed with MetS. CONCLUSIONS: The new percentiles may have a certain level of potential to screen Japanese children for childhood MetS in accordance with the IDF definition.

A novel GNAS-Gsα splice donor site variant in a girl with pseudohypoparathyroidism type 1A and her mother with pseudopseudohypoparathyroidism.

We encountered a Chinese girl with pseudohypoparathyroidism type 1A (PHP1A) and her mother with pseudopseudohypoparathyroidism (PPHP). Sequencing analysis of GNAS-Gsα revealed a heterozygous c.212+2T>C variant (NM_000516.4) affecting the canonical splice donor site of intron 2 in the girl and her mother. RT-PCR performed on mRNA samples obtained from cycloheximide-treated and cycloheximide-untreated lymphoblastoid cell lines of this girl revealed the utilization of an alternative splice donor site at 33-34 bp from the boundary between exon 2 and intron 2 and the production of an aberrant mRNA with a retention of a 32 bp intronic sequence between exon 2 and exon 3 (p.(Gly72Lysfs*39)), which satisfied the condition for the occurrence of nonsense-mediated mRNA decay, as predicted by SpliceAI. This study revealed the molecular consequences of disruption of the canonical splice donor site and confirmed the clinical utility of SpliceAI.

A Case of 17α-hydroxylase/17,20-lyase Deficiency Diagnosed at 45 Years of Age with Hyperaldosteronism.

17α-hydroxylase deficiency is a type of congenital adrenocortical hyperplasia that is typically diagnosed in childhood or adolescence. It manifests as hypertension with gonadal dysfunction as the primary symptom. We herein report 17α-hydroxylase/17,20-lyase deficiency (17OHD) diagnosed at the age of 45 years. The patient presented with hypertension, irregular menstruation, and hyperaldosteronism. The clinical manifestations of 17OHD vary based on the specific variant pattern of CYP17A1. In this case, the variant was c.157_159 TCC del p. Phe53del, which has been frequently reported in Japan. The enzymatic deficiency due to this variant is partial, leading to a delay in making a correct diagnosis.