Characteristic phenotypes of ADH5/ALDH2 deficiency during childhood.

ADH5/ALDH2 deficiency is a rare inherited syndrome characterized by short stature, microcephaly, delayed mental development, and hematopoietic dysfunction and has recently been proposed as a disease paradigm. Acute and severe presentations include aplastic anemia, myelodysplastic syndrome, or leukemia, requiring bone marrow transplantation during childhood. Conversely, non-hematological manifestations may exhibit a prolonged and nonspecific clinical trajectory, with growth failure and developmental delay, most of which are often overlooked, particularly in patients with milder symptoms. Here, we describe the clinical course of a girl with a wide spectrum of clinical presentations, including nonspecific hematopoietic disorders, growth retardation, mild developmental delay, amblyopia, hemophagocytic lymphohistiocytosis, and verruca vulgaris, culminating in a genetic diagnosis of AMeD syndrome at 12 years of age. We also summarized the clinical manifestations of previously reported cases of AMeD syndrome. Cumulatively, 13 females and 5 males have been documented, with a cardinal triad of symptoms, aplastic anemia, short stature, and intellectual disability. Additional characteristic observations included pigmentary deposition in approximately half of the cases and skeletal difficulties in one-quarter. We propose that early diagnosis of patients who exhibit relatively mild phenotypes of skin or skeletal lesions is important for managing and improving the quality of life of patients with AMeD syndrome.

Asymptomatic 3-methylglutaconic aciduria type 1 detected by high C5-OH on newborn screening.

3-Methylglutaconic aciduria type 1 (MGCA1) is an inborn error of leucine catabolism caused by pathogenic variants of the AUH gene. MGCA1 can be identified by newborn screening (NBS) with elevated C5-OH levels. We herein report a girl with MGCA1 detected by NBS. On day 5 after birth, NBS detected high C5-OH levels of 1.17 µmol/L (1.56 µmol/L [retest]). A urinary organic acid analysis revealed the abnormal excretion of 3-methylglutaconic, 3-methylglutaric, and 3-hydroxyisovaleric acids. Two novel heterozygous loss-of-function variants in the AUH gene were identified by genetic testing. We observed the patient without any treatment, such as a leucine-restricted diet. She had episodes of febrile illness several times in infancy but did not develop febrile convulsions or encephalopathy. She is now two years and six months old, and her physical growth and psychomotor development have progressed normally. In a review of the literature and our case, four children with MGCA1 identified during the neonatal period were asymptomatic or exhibited speech delay, regardless of whether or not they had been managed with specific treatments. Treatments such as dietary leucine restriction and carnitine supplementation may have little effect on MGCA1 in childhood; however, further investigation is warranted to evaluate the benefits of specific treatments to prevent potential long-term neurological complications.

Incidence and Risk Factors for Adrenal Crisis in Pediatric-onset Adrenal Insufficiency: A Prospective Study.

PURPOSE: To determine the incidence and risk factors for adrenal crisis (AC) in patients with pediatric-onset adrenal insufficiency (AI). MATERIALS AND METHODS: This multicenter, prospective cohort study conducted in Japan enrolled patients diagnosed with AI at ≤ 15 years of age. The incidence of AC was calculated as events per person-year (PY), and risk factors for AC were assessed using Poisson regression multivariable analysis. RESULTS: The study population comprised 349 patients (164 male, 185 female) with a total follow-up of 961 PY. The median age at enrollment was 14.3 years (interquartile range [IQR] 8.5-21.2 years), and the median follow-up was 2.8 years (IQR 2.2-3.3 years). Of these patients, 213 (61%) had primary AI and 136 (39%) had secondary AI. Forty-one AC events occurred in 31 patients during the study period. The calculated incidence of AC was 4.27 per 100 PY (95% confidence interval [CI] of 3.15-5.75). Poisson regression analysis identified younger age at enrollment (relative risk [RR] 0.93 [95% CI 0.89-0.97]) and increased number of infections (RR 1.17 [95% CI 1.07-1.27]) as significant risk factors. Female sex (RR 0.99 [95% CI 0.53-1.86]), primary AI (RR 0.65 [95 % CI 0.30-1.41]), or equivalent dosage of hydrocortisone per square meter of body area (RR 1.02 [95% CI 0.96-1.08]) was not a significant risk factor. CONCLUSION: A substantial proportion of patients with pediatric-onset AI experience AC. Younger age and an increased number of infections are independent risk factors for developing AC in these patients.

Diabetic lipemia as a predisposing state to acute pancreatitis: a case report and literature review.

Hypertriglyceridemia has been recognized as a common complication of diabetes ketoacidosis (DKA), whereas severe hypertriglyceridemia, also known as diabetic lipemia, rarely occurs and is associated with an increasing risk of acute pancreatitis. We report the case of a 4-year-old girl with new-onset DKA associated with remarkable hypertriglyceridemia. Her serum triglyceride (TG) level was as high as 2490 mg/dL on admission and 11,072 mg/dL on day two during treatment with hydration and intravenous insulin infusion, whereas the critical situation was successfully stabilized by standard treatment for DKA without the occurrence of pancreatitis. We reviewed 27 cases of diabetic lipemia with or without pancreatitis that were described in the relevant literature to identify risk factors for the occurrence of pancreatitis in children with DKA. As a result, the severity of hypertriglyceridemia or ketoacidosis, age at onset, type of diabetes, and presence of systemic hypotension, were not associated with the development of pancreatitis; however, the occurrence of pancreatitis in girls over 10 years old tended to be higher than that in boys. The serum TG levels and DKA successfully normalized in most of the cases with insulin infusion therapy with hydration, without other specific treatments (e.g., heparin therapy and plasmapheresis). We conclude that the occurrence of acute pancreatitis in diabetic lipemia could be avoided with appropriate hydration and insulin therapy, without specific treatment for hypertriglyceridemia.

Long-term trends of pediatric type 1 diabetes incidence in Japan before and after the COVID-19 pandemic.

Type 1 diabetes incidence has increased worldwide, although the long-term trends on pediatric type 1 diabetes in Japan remain elusive. To investigate the incidence and secular trend of pediatric type 1 diabetes from 1999 to 2021, including the coronavirus disease 2019 (COVID-19) pandemic years, in Oita Prefecture, Japan. We investigated the number of newly diagnosed patients with type 1 diabetes aged < 15 years from 1999 to 2021. We surveyed hospital databases in Oita Prefecture in Japan. The type 1 diabetes incidence in children aged < 15 years increased annually by 5.3% among all children, especially in boys aged 10-14 years by 8.1%, over the past 23 years. The average incidence rate of 3.9/100,000/year was nearly consistent with the previous reports on Asian countries. No significant change was found in the increasing incidence trend of type 1 diabetes before and during the COVID-19 pandemic. The incidence of pediatric type 1 diabetes has significantly increased over the past 23 years in Oita Prefecture, Japan, which is consistent with the worldwide trend.

Secular Trends in Obesity and Serum Lipid Values among Children in Oita City, Japan, during a 27-Year Period.

AIMS: We assessed 27-year trends in obesity and blood lipid levels of 10-year-old children to estimate the risk of metabolic syndrome in adulthood. METHODS: Based on a screening program for lifestyle-related diseases in school children in Oita City, Japan, we evaluated secular trends in height, weight, percentage of overweight (POW), total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL-C), and non-HDL cholesterol (non-HDL-C) of fifth graders (median age: 10.8 years) in Oita City from 1991 to 2017. We focused on the secular trend in the percentage of children with inappropriate serum levels of each lipid. We also evaluated the long-term trends in the 95th, 50th, and 5th percentiles for each parameter, as dependent variables, with the calendar year as an independent variable. Percentages of children with mild obesity (POW-20), moderate obesity (POW-30), and severe obesity (POW-50) were set as dependent variables. RESULTS: A total of 58,699 boys and 56,864 girls were evaluated during the study period. The percentage of children with severe obesity (POW-50) consistently increased during these years, and the 95th percentile of degree of obesity significantly increased in both boys and girls. The plot of percentages of children with inappropriate levels of TC, TG, and non-HDL-C showed a mild inverted U shape during the study period. The HDL-C level typically decreased in the study period, and the TC, TG, and non-HDL-C levels were markedly higher while the HDL level was lower in obese children than in non-obese children. CONCLUSION: The number of children with severe obesity increased, and obese children had higher percentages of inappropriate lipid levels than non-obese children. The rate of dyslipidemia with low HDL levels gradually increased in all children in Oita City, Japan, over the past 27 years.

Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish.

Leucyl-tRNA synthetase (LARS) is an enzyme that catalyses the ligation of leucine with leucine tRNA. LARS is also essential to sensitize the intracellular leucine concentration to the mammalian target of rapamycin complex 1 (mTORC1) activation. Biallelic mutation in the LARS gene causes infantile liver failure syndrome type 1 (ILFS1), which is characterized by acute liver failure, anaemia, and neurological disorders, including microcephaly and seizures. However, the molecular mechanism underlying ILFS1 under LARS deficiency has been elusive. Here, we generated Lars deficient (larsb-/-) zebrafish that showed progressive liver failure and anaemia, resulting in early lethality within 12 days post fertilization. The atg5-morpholino knockdown and bafilomycin treatment partially improved the size of the liver and survival rate in larsb-/- zebrafish. These findings indicate the involvement of autophagy in the pathogenesis of larsb-/- zebrafish. Indeed, excessive autophagy activation was observed in larsb-/- zebrafish. Therefore, our data clarify a mechanistic link between LARS and autophagy in vivo. Furthermore, autophagy regulation by LARS could lead to development of new therapeutics for IFLS1.

Sphenoethmoidal meningoencephalocele with variable hypopituitarism: A case report and review of literature.

Sphenoethmoidal meningoencephalocele is a rare congenital meningocele with unclear clinical course. Its clinical symptoms are diverse, and this disease is widely observed across all ages. The prognosis of this disease depends on the severity of the central nervous system complications. We reported a case of sphenoethmoidal meningoencephalocele incidentally discovered in a 2-yr-old patient, with the subsequent appearance of diabetes insipidus at school age. An endocrinological evaluation performed when the patient was nine years old using the TRH/CRH/LH-RH load test showed a low response of gonadotropins and slightly hyper-response and normal response of ACTH and TSH, respectively. GH provocative tests indicated severe GH deficiency. Desmopressin and GH treatment efficiently improved his growth rate and quality of life. His pituitary function had presumably been normal from the neonatal period to infancy, but the dysfunction gradually progressed over the next few years along with his physical growth. The symptoms were suspected to be the product of the natural course of his hypothalamus or pituitary gland degeneration, or were otherwise due to gradual damage by chronic mechanical compression or extension. These findings underscore the importance of conducting careful systemic management in the long term, specifically with respect to the endocrinological evaluation of sphenoethmoidal meningoencephalocele.

The long-term management of congenital generalized lipodystrophy (Berardinelli-Seip syndrome): the clinical manifestations of Japanese siblings for approximately 20 years.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disease that is characterized by loss of subcutaneous and visceral adipose tissues, and associated with dysregulation of glycolipid metabolism. In the present study, we reported the clinical manifestations and treatments of Japanese siblings with CGL caused by BSCL2 gene mutations with a clinical course of approximately 20 yr. Comprehensive management with metreleptin therapy, dietary control with additional medication, and psychosocial counseling in line with the patients' stages of growth and development were important in achieving long-term metabolic control of this condition.

Central hypoadrenocorticism associated with Rathke's cleft cyst.

Rathke's cleft cysts (RCCs) are non-neoplastic, sellar or suprasellar epithelium-lined cysts originating from Rathke's pouch in the pituitary gland. Patients with RCCs are usually asymptomatic, but some have only been identified when symptoms manifested in middle age. The characteristics of these patients during childhood or adolescence remains unknown. We describe an 18-year-old girl who had occasionally suffered from malicious fatigue in the morning since her early teens. Brain magnetic resonance imaging (MRI) revealed T1 hyperintense/T2 hypointense signals between the anterior and posterior pituitary glands, indicating the presence of RCC. Based on an authentic endocrinological evaluation, her adrenal function seemed normal; nevertheless, her serum cortisol level strangely dropped around noon. Furthermore, daily supplementation of oral hydrocortisone bizarrely suppressed ACTH secretion to below the detection range in the morning. These data appeared compatible with the presence of central adrenal dysfunction. We also review the literature for previously reported cases. In conclusion, the symptoms and endocrinological data for dysfunction of the hypothalamic pituitary system might be non-specific and vary among patients, especially in teenagers. Brain MRI and daily cortisol profiling in blood are key to obtaining a diagnosis of an impaired hypothalamic adrenal function due to RCC.