Tohru Yorifuji

Somatrogon is a long-acting recombinant human growth hormone approved in several countries, including Japan, for the treatment of children with growth hormone deficiency (GHD). In this study (Clinicaltrials.gov:NCT03874013) Japanese patients with GHD initially received once-weekly somatrogon or once-daily somatropin (0.175 mg/kg/week) for 12 months in the main study period; those who completed the main study were eligible to enroll in a single-arm, 3-year open-label extension (OLE) and receive once-weekly somatrogon (0.66 mg/kg/week). The primary endpoints of the OLE included annualized height velocity (HV), change in height standard deviation score (SDS), and safety. Of 43 patients who completed the main study, 42 continued into the OLE and 40 completed the OLE. Patients were analyzed by treatment received (somatrogon vs. somatropin) during the main study. Mean (SD) HV at OLE baseline was higher in patients originally randomized to somatrogon vs. somatropin (9.78 [1.59] vs. 7.70 [1.10] cm/year); mean HV was similar between original treatment groups for all other OLE timepoints. Mean height SDS increased from main study baseline through the end of the OLE in both treatment groups. During the OLE, 22 (100%) somatrogon-treated patients and 18 (90%) somatropin-treated patients reported treatment-emergent adverse events (TEAEs). Most TEAEs were mild or moderate in severity and no patients discontinued from the OLE or required dose reductions due to TEAEs. Up to 4 years of treatment with once-weekly somatrogon resulted in improved growth response and was well tolerated in Japanese patients with pediatric GHD, including patients who switched to somatrogon from once-daily somatropin.Clinialtrials.gov:NCT03874013

Context: Monogenic diabetes is often underdiagnosed because of limited genetic testing opportunities and varying screening criteria. Objective: To investigate the genetic and clinical characteristics of monogenic diabetes in Japan and assess the utility of classical screening criteria and the maturity-onset diabetes of the young (MODY) probability calculator. Design and Setting: This study included a total of 232 probands with diabetes onset before age 35, BMI <30 kg/m², and negative islet autoantibodies, recruited from 2019 to 2024. Targeted sequencing of 11 causal genes was performed, followed by multiplex ligation-dependent probe amplification when indicated. Results: Pathogenic or likely pathogenic (P/LP) variants were identified in 67 (28.9%) probands: 25 in GCK, 22 in HNF1A, 7 in HNF1B, 6 in HNF4A, 4 in ABCC8, and 1 each in NEUROD1, PDX1, and INSR. Of these, 64 (95.5%) carried variants in actionable genes potentially affecting treatment strategies (GCK, HNF1A, HNF1B, HNF4A, ABCC8). P/LP carriers were younger at diagnosis, had lower BMI, and better metabolic control than noncarriers. However, clinical heterogeneity was substantial. Notably, 35 cases (52.2%) did not meet classical screening criteria of young-onset (≤25 years) and a three-generation family history. Although MODY probability scores were higher in probands with P/LP carriers (median: 75.5% vs. 58.0%; P <0.001), early insulin initiation substantially lowered the probability scores, warranting caution. Conclusion: We established a nationwide genetic testing platform and identified carriers of actionable variants, offering possibilities for precision medicine. Neither classical criteria nor the MODY calculator identified all monogenic cases, highlighting the need for broader genetic testing.

Aims/Introduction: Phosphatidylinositol 3‐kinase (PI3K) plays a key role in insulin signaling, and mutations in PIK3R1, which encodes a regulatory subunit (p85α) of this enzyme, are responsible for SHORT syndrome, which is associated with insulin‐resistant diabetes. We here describe four Japanese individuals from three families with SHORT syndrome who harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins.Materials and Methods: Gene sequencing was performed to identify PIK3R1 mutations. 3D structural analysis of wild‐type and mutant p85α proteins was performed by homology modeling, and structural optimization and molecular dynamics simulations confirmed stable trajectories. Docking simulations of p85α with a phosphopeptide were also conducted.Results: We identified two families with a common mutation (c.1945C>T, p.R649W) and one family with a previously unidentified mutation (c.1957A>T, p.K653*) of PIK3R1. In silico modeling revealed that both mutations impaired binding of p85α to phosphopeptide, with K653* resulting in the loss of amino acids that contribute to such binding. Docking simulations showed a significant loss of docking energy for the R649W mutant compared with the wild‐type protein (P = 0.00329).Conclusions: The four cases of SHORT syndrome were associated with early‐onset diabetes and intrauterine growth retardation, with the identified mutations likely disrupting the binding of p85α to phosphopeptide and thereby impairing insulin signaling. One case uniquely manifested diabetes without insulin resistance, emphasizing the need for further study of the clinical variability of SHORT syndrome, especially with regard to its associated diabetes.

Background: Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI; however, there have been almost no new therapeutic modalities since the development of diazoxide. Summary: Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in “developed” countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an “essential medicine” by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use. Key Messages: This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited.

Aims/Introduction: To investigate the genetic background of Japanese patients with suspected maturity‐onset diabetes of the young (MODY).Materials and Methods: On 340 proband patients referred from across Japan, genomic variants were analyzed using a targeted multigene panel analysis combined with the multiplex ligation probe amplification (MLPA) analysis, mitochondrial m.3243A > G analysis and methylation‐specific polymerase chain reaction of the imprinted 6q24 locus. Pathogenic/likely pathogenic variants were listed according to the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Additionally, variants with a population frequency 20 (CS >20) were listed as rare variants of uncertain significance‐CS >20.Results: A total of 157 pathogenic/likely pathogenic variants and 44 rare variants of uncertain significance‐CS >20 were identified. In the pathogenic/likely pathogenic variants, alterations in the GCK gene were the most common (82, 52.2%) followed by HNF1A (29, 18.5%), HNF4A (13, 8.3%) and HNF1B (13, 8.3%). One patient was a 29.5% mosaic with a truncating INSR variant. In the rare variants of uncertain significance‐CS >20, 20 (45.5%) were in the genes coding for the adenosine triphosphate‐sensitive potassium channel, KCNJ11 or ABCC8, and four were in the genes of the insulin‐signaling pathway, INSR and PIK3R1. Four variants in ABCC8 were previously reported in patients with congenital hyperinsulinism, suggesting the inactivating nature of these variants, and at least two of our patients had a history of congenital hyperinsulinism evolving into diabetes. In two patients with INSR or PIK3R1 variants, insulin resistance was evident at diagnosis.Conclusions: Causative genomic variants could be identified in at least 46.2% of clinically suspected MODY patients. ABCC8‐MODY with inactivating variants could represent a distinct category of MODY. Genes of insulin resistance should be included in the sequencing panel for MODY.

Objective: We recently reported cases of adipsic hypernatremia caused by autoantibodies against the subfornical organ in patients with hypothalamic‐pituitary lesions. This study aimed to clarify the clinical features of newly identified patients with adipsic hypernatremia whose sera displayed immunoreactivity to the mouse subfornical organ.Design: Observational cohort study of patients diagnosed with adipsic hypernatremia in Japan, United States, and Europe.Methods: The study included 22 patients with adipsic hypernatremia but without overt structural changes in the hypothalamic‐pituitary region and congenital disease. Antibody response to the mouse subfornical organ was determined using immunohistochemistry. The clinical characteristics were compared between the patients with positive and negative antibody responses.Results: Antibody response to the mouse subfornical organ was detected in the sera of 16 patients (72.7%, female/male ratio, 1:1, 12 pediatric and 4 adult patients). The prolactin levels at the time of diagnosis were significantly higher in patients with positive subfornical organ (SFO) immunoreactivity than in those with negative SFO immunoreactivity (58.9 ± 33.5 vs. 22.9 ± 13.9 ng/ml, p < .05). Hypothalamic disorders were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid‐onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia. Plasma renin activity levels were significantly higher in patients with serum immunoreactivity to the Na_x channel.Conclusions: The patients with serum immunoreactivity to the SFO had higher prolactin levels and hypothalamic disorders compared to those without the immunoreactivity. The clinical characteristics of patients with serum immunoreactivity to the subfornical organ included higher prolactin levels and hypothalamic disorders, which were frequently associated with central hypothyroidism and the presence of retroperitoneal tumors.

Introduction: Somatrogon is a long-acting recombinant human growth hormone being developed as a once-weekly treatment for children with growth hormone deficiency (GHD). The objective of this phase 3 study (NCT03874013) was to compare the efficacy and safety of once-weekly somatrogon with once-daily Genotropin in Japanese children with GHD. Methods: In this open-label, randomized, active-controlled study, 44 prepubertal Japanese children with GHD (boys: 3 to <11 years; girls: 3 to <10 years) were randomized 1:1 to receive once-weekly somatrogon or once-daily Genotropin (0.025 mg/kg/day) for 12 months. Dose escalation for somatrogon-treated subjects occurred in the first 6 weeks (0.25, 0.48, and 0.66 mg/kg/week; 2 weeks each) with the remaining 46 weeks at a dose of 0.66 mg/kg/week. The study’s primary endpoint was annualized height velocity (HV) at 12 months. Results: Baseline characteristics were similar between treatment groups. Compared with Genotropin-treated subjects, somatrogon-treated subjects had higher least-squares mean HV at 12 months (9.65 cm/year vs. 7.87 cm/year). Once-weekly somatrogon was concluded as being comparable to once-daily Genotropin as the mean treatment difference (somatrogon-Genotropin) in HV was +1.79 cm/year (95% confidence interval, 0.97–2.61), which was greater than the preestablished margin (−1.8 cm/year). For both treatment groups, most adverse events were mild to moderate in severity and a similar proportion of subjects reported injection-site pain, although the somatrogon group reported more painful injections. Conclusion: In prepubertal Japanese children with GHD, once-weekly somatrogon was comparable to once-daily Genotropin in terms of annualized (12-month) HV. Both treatments had similar safety and tolerability profiles.

Background: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder characterized by recurrent epistaxis, skin/mucocutaneous telangiectasia, and organ/visceral arteriovenous malformations (AVM). HHT is mostly caused by mutations either in the ENG or ACVRL1 genes, and there are regional differences in the breakdown of causative genes. The clinical presentation is also variable between populations suggesting the influence of environmental or genetic backgrounds. In this study, we report the largest series of mutational and clinical analyses for East Asians. Methods: Using DNAs derived from peripheral blood leukocytes of 281 Japanese HHT patients from 150 families, all exons and exon–intron boundaries of the ENG, ACVRL1, and SMAD4 genes were sequenced either by Sanger sequencing or by the next-generation sequencing. Deletions/amplifications were analyzed by the multiplex ligation-dependent probe amplification analyses. Clinical information was obtained by chart review. Results: In total, 80 and 59 pathogenic/likely pathogenic variants were identified in the ENG and ACVRL1 genes, respectively. No pathogenic variants were identified in the SMAD4 gene. In the ENG gene, the majority (60/80) of the pathogenic variants were private mutations unique to a single family, and the variants were widely distributed without any distinct hot spots. In the ACVRL1 gene, the variants were more commonly found in exons 5–10 which encompasses the serine/threonine kinase domain. Of these, 25/59 variants were unique to a single family while those in exons 8–10 tended to be shared by multiple (2–7) families. Pulmonary and cerebral AVMs were more commonly found in ENG-HHT (69.1 vs. 14.4%, 34.0 vs. 5.2%) while hepatic AVM was more common in ACVRL1-HHT (31.5 vs. 73.2%). Notable differences include an increased incidence of cerebral (34.0% in ENG-HHT and 5.2% in ACVRL1-HHT), spinal (2.5% in ENG-HHT and 1.0% in ACVL1-HHT), and gastric AVM (13.0% in ENG-HHT, 26.8% in ACVRL1-HHT) in our cohort. Intrafamilial phenotypic heterogeneity not related to the age of examination was observed in 71.4% and 24.1% of ENG- and ACVRL1-HHT, respectively. Conclusions: In a large Japanese cohort, ENG-HHT was 1.35 times more common than ACVRL1-HHT. The phenotypic presentations were similar to the previous reports although the cerebral, spinal, and gastric AVMs were more common.

Objectives: Constitutional delay of growth (CDG) is usually associated with a delay in pubertal onset (CDGP) and a catch-up growth after puberty. Some individuals, however, have earlier-than-expected pubertal onset resulting in a shorter adult height. We investigated the current incidence of such individuals and that of 30 years ago. Methods: The study subjects are 1,312 consecutive Japanese children referred to Osaka City General Hospital (OCGH) for short stature during 2010–2018, and a cohort of 11,256 individuals in the Ogi Growth Research (OGR, 1979–1992). Individuals with the height standard deviation score <−1.0, the bone age (BA)/chronological age (CA) ratio <0.8 at first visits, and without other identifiable causes of short stature were extracted from the record of OCGH. Similarly, individuals meeting the height and bone age criteria were extracted from the OGR record. The pubertal growth onset was auxologically determined as the upward shift from the prepubertal growth curve fitted to a quadratic function. Earlier-than-expected onset was defined as the onset earlier than the population average +1 year. Results: From the OCGH cohort, 55 children (38 boys, 17 girls) met the criteria, and earlier-than-expected onset was observed in 34.2% of boys and 29.4% of girls. In the 73 short individuals with delayed bone age in the OGR cohort, earlier-than-expected onset was less common (13.0% for boys and 14.8% for girls). There was no significant association between the timing of pubertal growth onset and the BA/CA ratio, IGF-1, and midparental height. Conclusions: Earlier-than-expected pubertal growth onset is common in CDG and possibly increasing.

Introduction: Transient neonatal diabetes mellitus (TNDM) is a rare condition that is characterized by the presence of diabetes mellitus during the first 6 months of life and remission by 18 months of age. It usually relapses at a median age of 14 years. Hyperinsulinaemic hypoglycaemia is a relatively common complication during remission. Although β-cell function is reported to be impaired at relapse, the clinical course of glycaemic profiles during remission in patients with TNDM remains largely unknown. Case Presentation: Longitudinal glycaemic profiles were investigated annually from remission (185 days) to relapse (14.5 years) in a patient with TNDM due to paternal 6q24 duplication using the oral glucose tolerance test (glucose intake: 1.75 g/kg to a maximum of 75 g). The patient’s β-cell function and insulin sensitivity were assessed by calculating the insulinogenic index, homeostasis model assessment of β-cell function (HOMA-β), homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index, and Matsuda index. Early insulin response to glucose intake was impaired throughout remission, whereas fasting insulin and β-cell function by HOMA-β gradually increased in the first few years since remission, followed by a gradual decline in function. In contrast, HOMA-IR fluctuated and peaked at 6.5 years of age. Conclusion: This is the first report of annual longitudinal glycaemic profiles in a patient with 6q24-related TNDM during remission. We identified fluctuations in β-cell function and insulin resistance during remission.