Selenium deficiency and scurvy due to an imbalanced diet of snacks and lacto-fermenting drinks: a case report of a 7-year-old boy with autism spectrum disorder.

BACKGROUND: There have been reports of isolated trace elements or vitamin deficiencies due to imbalanced diets, but no cases of selenium deficiency combined with scurvy have been reported. CASE PRESENTATION: A 7 year-old boy diagnosed with autistic spectrum disorder and mild psychomotor retardation, started an imbalanced diet including specific snacks and lacto-fermenting drinks from 5 years of age. Gingival hemorrhage and perioral erosions occurred at 6 years and 8 months of age, and he was referred to our hospital at 7 years of age. Slight tachycardia was found. Serum vitamin C level was 1.1 µg/dL (reference range (rr): 5-17.5 µg/dL), and selenium level was 2.8 µg/dL (rr: 7.7-14.8 µg/dL). He was diagnosed with both selenium deficiency and scurvy. Multivitamins and sodium selenate were administered for 12 days during admission, and symptoms of selenium deficiency and scurvy improved. After discharge, symptoms abated following the administration of multivitamins and regular administration of sodium selenate every 3 months. CONCLUSIONS: We report a complicated case of both selenium deficiency and scurvy due to an imbalanced diet of snacks and lacto-fermenting drinks in a 7-year-old boy with autism spectrum disorder. In patients with imbalanced diet, regular blood tests including trace elements and vitamins are necessary.

A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.

Mitochondrial diseases are a heterogeneous group of genetic disorders caused by pathogenic variants in genes encoding gene products that regulate mitochondrial function. These genes are located either in the mitochondrial or in the nuclear genome. The TOMM7 gene encodes a regulatory subunit of the translocase of outer mitochondrial membrane (TOM) complex that plays an essential role in translocation of nuclear-encoded mitochondrial proteins into mitochondria. We report an individual with a homozygous variant in TOMM7 (c.73T>C, p.Trp25Arg) that presented with a syndromic short stature, skeletal abnormalities, muscle hypotonia, microvesicular liver steatosis, and developmental delay. Analysis of mouse models strongly suggested that the identified variant is hypomorphic because mice homozygous for this variant showed a milder phenotype than those with homozygous Tomm7 deletion. These Tomm7 mutant mice show pathological changes consistent with mitochondrial dysfunction, including growth defects, severe lipoatrophy, and lipid accumulation in the liver. These mice die prematurely following a rapidly progressive weight loss during the last week of their lives. Tomm7 deficiency causes a unique alteration in mitochondrial function; despite the bioenergetic deficiency, mutant cells show increased oxygen consumption with normal responses to electron transport chain (ETC) inhibitors, suggesting that Tomm7 deficiency leads to an uncoupling between oxidation and ATP synthesis without impairing the function of the tricarboxylic cycle metabolism or ETC. This study presents evidence that a hypomorphic variant in one of the genes encoding a subunit of the TOM complex causes mitochondrial disease.

Laryngotracheal separation surgery in a patient with severe Angelman syndrome involving a 19.3 Mb deletion on 15q11.2-q14.

A severe Angelman syndrome (AS) patient with a very large deletion (19.3 Mb) at 15q11.2-q14 required laryngotracheal separation, which is not a common surgery in AS. Comparative genomic hybridization-based microarrays can be useful to confirm deletion size and clinical severity.

An exploratory study to identify neonatal arterial ischemic stroke: A single-center study.

BACKGROUND: Neonatal arterial ischemic stroke (NAIS) presents as seizures, including convulsions, subtle seizures, and apnea, and most patients experience neurological sequelae. Diagnosis is often delayed owing to low test sensitivity. The present study aimed to identify the early clinical diagnostic factors for NAIS in neonates with seizures. METHODS: The present study included 54 patients born at ≥36 weeks of gestation during the last 15 years who presented to the neonatal intensive care unit with neonatal seizures and underwent brain magnetic resonance imaging (MRI), 6 of whom were diagnosed with NAIS. Maternal background, clinical characteristics, and transcranial pulsed Doppler sonography results were retrospectively reviewed. RESULTS: Of the 24 patients who presented with convulsions or subtle seizures, 3 (13%) were diagnosed with NAIS and 3 of 30 patients (10%) presented with apnea. Maternal premature ventricular contraction complications were higher in the NAIS group than in the non-NAIS group (p = 0.01). NAIS group showed lower mean middle cerebral artery (MCA) resistance index (RI) was lower the non-NAIS group (p = 0.009), while the left-right RI difference (p = 0.019), mean MCA blood velocity (MnV; p = 0.04), and left-right MnV difference (p < 0.001) in cerebral blood flow velocities (CBFVs) were higher in the NAIS group. CONCLUSIONS: Our results revealed that maternal arrhythmia may be a diagnostic factor for NAIS in neonates with seizures. Early brain MRI is essential in neonates with seizures and findings of low MCA-RI, high MCA-MnV, or high left-right difference in CBFVs to distinguish between NAIS and non-NAIS.

Urinary stone in a 12-year-old adolescent with new-onset type 1 diabetes and diabetic ketoacidosis.

Dehydration and acidosis increase the risk for urinary stone formation. Urinary stones have been reported in three pediatric cases of diabetic ketoacidosis (DKA). A 24-h urine collection was performed for two of the three children. One patient had high urine sodium levels, while the other had low urine citrate excretion. We report the case of a 12-yr-old adolescent boy with urinary stones, new-onset type 1 diabetes mellitus (T1D), and DKA, excluding other metabolic disorders. After DKA was diagnosed, the patient received a 0.9% saline bolus and continuous insulin infusion. Hyperglycemia and ketoacidosis were well-controlled on the third day after admission. However, the patient developed abdominal pain radiating to the back. Urinary stones were suspected, and a urinalysis was performed. The patient's urine revealed significant elevation in red blood cells and calcium oxalate crystals. Computed tomography revealed a high-density left ureteric mass, suggestive of a urinary stone. Although both the previously reported pediatric cases involved metabolic diseases, additional tests in this patient excluded metabolic diseases other than T1D. DKA may be related to the formation of calcium oxalate crystals owing to dehydration and acidosis. Therefore, physicians should consider urinary stone formation in DKA patients.

Clinical guidelines for the diagnosis and treatment of 21-hydroxylase deficiency (2021 revision).

Congenital adrenal hyperplasia is a category of disorders characterized by impaired adrenocortical steroidogenesis. The most frequent disorder of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which is caused by pathogenic variants of CAY21A2 and is prevalent between 1 in 18,000 and 20,000 in Japan. The clinical guidelines for 21-hydroxylase deficiency in Japan have been revised twice since a diagnostic handbook in Japan was published in 1989. On behalf of the Japanese Society for Pediatric Endocrinology, the Japanese Society for Mass Screening, the Japanese Society for Urology, and the Japan Endocrine Society, the working committee updated the guidelines for the diagnosis and treatment of 21-hydroxylase deficiency published in 2014, based on recent evidence and knowledge related to this disorder. The recommendations in the updated guidelines can be applied in clinical practice considering the risks and benefits to each patient.

Estimated Gestational Age From Infant's Foot Length in Japanese.

Aim In developed countries including Japan, gestational age (GA) is predicted by the last menstrual period (LMP) and/or fetal ultrasound. In some developing countries, GA is predicted by infant's foot length (FL). Pregnant women who did not have pregnancy check-up is not infrequent in Japan, therefore there are sometimes opportunities to estimate the GA from infants after the delivery. The aim of this study is to determine the estimated GA formula from infant's FL in Japanese. Methods This study was a prospective cohort study. Infants between May 2021 and August 2021 at Iizuka Hospital and Tagawa Hospital or transferred from other hospitals within 24 hours of birth were collected. GA was determined using LMP and/or fetal ultrasound. The infant's FL was measured with a digital caliper within 24 hours of birth. The relationship between FL and GA was analyzed by simple regression analysis to determine the coefficient of determination (R2). The infant's FL of males and females, infant's FL of preterm and term, and infant's FL of low birth weight and appropriate weight infants were performed by the t-test as independent samples. A statistically significant difference was p < 0.05. Statistical analysis was performed using JMP Pro 16 (SAS Institute Japan Co., Ltd., Minato-ku, Tokyo). Results Ninety of the 135 infants were enrolled. The average GA was 38.2 ± 1.8 weeks, the average infant's FL was 7.230 ± 0.411 centimeter (cm), and the range of the infant's FL was 5.385 to 8.089 cm. The estimated GA formula, GA = 18.49 + 0.27 x infant's FL (R2 = 0.39), was determined. Conclusions We determined the estimated GA formula from the infant's FL. There are some limitations and care should be taken in the use.

Caffeine Intoxication Due to Antipyretic Analgesic Overdose in an Adolescent.

Recently, high concentrations of caffeine present in energy drinks and over-the-counter (OTC) drugs have become a concern worldwide. Several deaths due to caffeine intoxication have been reported, necessitating caution. Typically, supportive care is used to treat caffeine intoxication. However, in severe cases of caffeine intoxication, hemodialysis may be used. For adults, a lethal blood caffeine concentration is at least 80 µg/mL, whereas lethal blood caffeine concentration is unknown for children. In the present case, a 15-year-old girl took a large dose of an OTC antipyretic analgesic to commit suicide, resulting in caffeine intoxication. In this case, even though blood caffeine concentration was higher than the adult lethal dose, the patient recovered through a simple treatment with intravenous infusion of extracellular fluid.

Temporal changes and control variables of growth differentiation factor 15 levels during the first week of life in hospitalised newborn infants.

Serum growth differentiation factor 15 (GDF15) is a useful biomarker of mitochondrial diseases; its utility in newborns remains unknown. To investigate the temporal change in GDF15 within the first week of life, and to identify its potential control variables, blood samples were obtained from 18 newborns. The GDF15 levels declined to approximately 35% of the cord blood levels within the first week of life and were negatively correlated with postnatal age and Z-score of birth weight but were positively correlated with N-terminal pro-brain natriuretic peptide and lactate levels. GDF15 levels may reflect the progress of postnatal transition to aerobic metabolism.

Increased Serum-Immunoglobulin G4 Levels in a 12-Year-Old Male Patient With Central Diabetes Insipidus.

Immunoglobulin G4 (IgG4)-related disorders are characterized by tissue hypertrophy due to IgG4-positive cell infiltration and increased serum IgG4 levels. IgG4-related hypophysitis (IgG4-RH) is characterized by pituitary hypertrophy, IgG4-positive cell infiltration, central diabetes insipidus, and increased serum IgG4 levels. IgG4-RH is diagnosed through diagnostic criteria. A few cases of IgG4-RH in children have been reported. We report a case of CDI with increased serum IgG4 levels that failed to meet the diagnostic criteria of IgG4-RH. The patient developed polyuria and polydipsia at age 11 and was diagnosed as having idiopathic CDI at age 12. The patient was not treated with steroids and is well controlled with antidiuretic hormones. It has been reported that pediatric IgG4-RH differs from that of adults in several respects. We believe that the pediatric IgG4-RH may not fit the diagnostic criteria of adults. There may be also other cases of increased serum IgG4 levels in pediatric patients with idiopathic CDI. We do not know if they are subtypes of IgG4-RH or if serum IgG4 levels are by chance raised in CDI, however, we report them here because IgG4-RH in children may be different from that in adults.

Severe Hypernatremia in Combined Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State: A Case Report of Two Japanese Children.

As sodium level in diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) is usually low, normal, or slightly elevated, severe hypernatremia with DKA and/or HHS is rare. Case 1 was a 14-year-old boy, presenting with typical laboratory test values and symptoms consistent with DKA and HHS. His corrected sodium level, 172 mEq/L, might have occurred as a result of consuming 6 L/day of highly carbonated, carbohydrate- and sodium-rich drinks during the week preceding the diagnosis. This patient developed right lung artery thrombosis, which did not require treatment. Case 2 was a 10-year-old girl, presenting with typical laboratory test values and symptoms of DKA and HHS. Her corrected sodium level, 175 mEq/L, might have occurred as a result of large electrolyte-free water loss associated with osmotic diuresis. These two cases of patients presenting with DKA-HHS and severe hypernatremia are the first to be reported in Japan.

Congenital Hypothyroidism Due to Truncating PAX8 Mutations: A Case Series and Molecular Function Studies.

CONTEXT: PAX8 is a transcription factor required for thyroid development, and its mutation causes congenital hypothyroidism (CH). More than 20 experimentally verified loss-of-function PAX8 mutations have been described, and all but one were located in the DNA-binding paired domain. OBJECTIVE: We report the identification and functional characterization of 3 novel truncating PAX8 mutations located outside the paired domain. METHODS: Three CH probands, diagnosed in the frame of newborn screening, had thyroid hypoplasia and were treated with levothyroxine. Next-generation sequencing-based mutation screening was performed. Functionality of the identified mutations were verified with Western blotting, intracellular localization assays, and transactivation assays with use of HeLa cells. Luciferase complementation assays were used to evaluate the effect of mutations on the interaction between PAX8 and its partner, NKX2-1. RESULTS: Each proband had novel truncating PAX8 mutations that were I160Sfs*52, Q213Efs*27, and F342Rfs*85. Western blotting showed destabilization of the I160fs-PAX8 protein. Q213fs-PAX8 and F342fs-PAX8 showed normal protein expression levels and normal nuclear localization, but showed loss of transactivation of the luciferase reporter. By luciferase complementation assays, we showed that PAX8-NKX2-1 interaction was defective in Q213fs-PAX8. We also characterized the recombinant PAX8 proteins, and found that the protein sequence corresponding to exon 10 (363-400 aa residues) was essential for the PAX8-NKX2-1 interaction. CONCLUSIONS: Clinical and molecular findings of 3 novel truncating PAX8 mutations located outside the paired domain were reported. Experiments using cultured cells and recombinant proteins showed that the C-terminal portion (ie, 363-400 aa) of PAX8 is required for the PAX8-NKX2-1 interaction.

Clinical characteristics of cytochrome P450 oxidoreductase deficiency: a nationwide survey in Japan.

Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis that causes various symptoms such as skeletal malformations, disorders of sex development, and adrenal insufficiency. The aim of this study was to elucidate the clinical characteristics, especially age at diagnosis and treatment, of PORD from the perinatal period to adulthood in Japan. The first questionnaire was sent to 183 council members of the Japanese Society for Pediatric Endocrinology on 1 September 2018. The response rate was 65%, and a total of 39 patients with PORD were examined at 20 hospitals. The second questionnaire was sent in November 2018 to the council members examining these 39 patients with PORD. The response rate was 77%, and we received clinical information on 30 of the 39 patients. The two novel clinical findings were the age at diagnosis and the treatment of Japanese patients with PORD. In many cases, PORD can be diagnosed at <3 months of age. Hydrocortisone as the primary treatment during infancy can be used daily or in stressful situations; however, because patients with PORD generally have mild to moderate adrenal insufficiency, some might be able to avoid hydrocortisone treatment. Patients with PORD should be carefully followed up, and treatment should be optimized as for patients with other types of adrenal insufficiency. Other characteristics in the present study were similar to those described in previous reports.

Growth differentiation factor 15 as a useful biomarker of heart failure in young patients with unrepaired congenital heart disease of left to right shunt.

BACKGROUND: Growth differentiation factor 15 (GDF 15) is a member of the transforming growth factor-beta superfamily and is considered to be a useful biomarker for severity of heart failure (HF) in repaired congenital heart disease (CHD). The aim of this study was to determine the clinical implication of GDF 15 in children with unrepaired CHD. METHODS: Subjects included 69 patients (≤14 years old) who had unrepaired CHD with left to right shunt and underwent cardiac catheterization. Demographic and hemodynamic data, including oxygen demand-supply relationship, were collected from medical records. Severity of HF was evaluated using modified Ross score. Serum GDF 15 levels were determined using enzyme-linked immunosorbent assay and correlated with patients' demographics, hemodynamic data, and blood chemistry data. RESULTS: Subjects had median age of 71 (range 1-173) months and simple acyanotic CHDs with mean pulmonary to systemic flow ratio of 2.0 (1.0-5.6), median N-terminal pro type Brain natriuretic peptide (NT-pro-BNP) of 162.8 (17.1-8789) pg/mL, and median GDF 15 of 242.1 (13.6-1116.7) pg/mL. GDF 15 significantly positively correlated with the modified Ross score, mean pulmonary artery pressure, oxygen extraction rate (OER), and Ln NT-pro-BNP, but negatively correlated with age, oxygen delivery and its components, and estimated glomerular filtration rate (eGFR). Multiple linear regression analysis revealed significant correlation of GDF 15 levels with the modified Ross score, OER, and eGFR. CONCLUSIONS: GDF 15 mainly reflects oxygen demand-supply relationship and can be used as a diagnostic marker of HF in unrepaired CHD with left to right shunt for a wide range of age and diagnoses.

GDF-15, a mitochondrial disease biomarker, is associated with the severity of multiple sclerosis.

GDF-15, a member of the transforming growth factor beta superfamily, regulates inflammatory and apoptotic pathways in various diseases, such as heart failure, kidney dysfunction, and cancer. We aimed to clarify potentially confounding variables affecting GDF-15 and demonstrate its utility as a mitochondrial biomarker using serum samples from 15 patients with mitochondrial diseases (MD), 15 patients with limbic encephalitis (LE), 10 patients with multiple sclerosis/neuromyelitis optica spectrum disorders (MS/NMOSD), and 19 patients with amyotrophic lateral sclerosis (ALS). GDF-15 and FGF-21 were significantly elevated in MD. GDF-15 and FGF-21 showed a good correlation in MD but not in LE, MS, and ALS. GDF-15 was potentially influenced by age in LE, MS/NMOSD, and ALS but not in MD. FGF-21 was not correlated with age in MS/NMOSD, ALS, LE, and MD. GDF-15 was not correlated with clinical features in LE or BMI or body weight in ALS. GDF-15 positively correlated with the Expanded Disability Status Scale (EDSS) in MS/NMOSD, while EDSS showed no correlation with age. In conclusion, the results revealed that GDF-15 may be influenced by EDSS in MS/NMOPSD and by age in LE, MS/NMOSD, and ALS but not in MD. Mitochondrial damage in MS/NMOSD is a potentially confounding variable affecting GDF-15.

A case of combined 21-hydroxylase deficiency and CHARGE syndrome featuring micropenis and cryptorchidism.

BACKGROUND: 21-hydroxylase deficiency (21-OHD) is caused due to CYP21A2 gene variant. In males, the excess androgens produce varying degrees of penile enlargement and small testes. CHARGE syndrome (CS) has a broad spectrum of symptoms. In males, genital features such as micropenis and cryptorchidism are found in 48% of CS. There are no reports of patients with combined 21-OHD and CS; therefore, it is unknown whether the external genitalia shows penile enlargement or micropenis with/without cryptorchidism. CASE: A boy, born at 37 weeks and 5 days of gestational age with no consanguineous marriage, was admitted to our hospital due to congenital cleft lip, cleft palate, micropenis, cryptorchidism, and a ventricular septal defect. He had severe hyponatremia and hyperkalemia on day 10. He was diagnosed to have 21-OHD and CS. His external genitalia demonstrated both cryptorchidism and micropenis, but not penile enlargement. METHODS: DNA was extracted from peripheral leukocytes using standard procedures. Sanger sequence was performed in CYP21A2. Exome sequence was performed, and then, Sanger sequence was performed around variant in CHD7. RESULTS: Genetic screening for CYP21A2 gene was performed and compound heterozygous variants of c.293-13A/C>G (IVS2-13A/C>G) and c.518T>A (p.I172N) were detected in chromosome 6p21.3. His mother had been heterozygous variant of c.293-13A/C>G, and his father had been heterozygous variant of c.518T>A. Simultaneously, a de novo splicing acceptor alteration in c.7165-4 A>G, in chromodomain helicase DNA binding protein-7 (CHD7), located in chromosome 8q12 was detected, and the patient was diagnosed with 21-OHD and CS. CONCLUSION: Although these two disorders exhibit different modes of inheritance and their co-morbidity is extremely rare, we encountered one male patient who suffered from both 21-OHD and CS.

(Epi)genetic defects of MKRN3 are rare in Asian patients with central precocious puberty.

We sequenced MKRN3, the major causative gene of central precocious puberty in Western countries, in 24 Japanese or Chinese patients and examined the DNA methylation and copy-number statuses of this gene in 19 patients. We identified no (epi)genetic defects except for one previously reported mutation. These results, together with reports from Korea, indicate that MKRN3 defects are rare in Asian populations. The ethnic differences likely reflect Western country-specific founder mutations and the rarity of de novo mutations.

Temple syndrome diagnosed in an adult patient with clinical autism spectrum disorder.

Temple syndrome (TS14) leads to growth failure, precocious puberty, and diabetes mellitus. However, the long-term prognosis, including the development of social behavior in TS14 patients, remains unclarified. We report the clinical course of a male patient with autism spectrum disorder that received a diagnosis of TS14 at 33 years of age.

Nonalcoholic fatty liver disease with prolactin-secreting pituitary adenoma in an adolescent: A case report.

RATIONALE: Nonalcoholic fatty liver disease (NAFLD), among the commonest chronic liver disorders in children and adolescents, is considered a reflection of the current obesity epidemic in children and adults. This liver disease has been linked with various metabolic disorders, but not with prolactinoma (PRLoma). PATIENT CONCERNS: A 13-year-old Japanese girl manifested obesity, serum transaminase and γ-glutamyltransferase elevations, and amenorrhea. Abdominal ultrasonography showed fatty liver. Her serum prolactin concentration was elevated, and cranial magnetic resonance imaging showed a pituitary mass consistent with macroadenoma. DIAGNOSES: NAFLD and PRLoma. INTERVENTIONS AND OUTCOMES: After the patient's NAFLD failed to respond to diet and exercise, cabergoline treatment of the PRLoma decreased body weight, serum transaminase and γ-glutamyltransferase elevations, and ultrasonographic fatty liver grade as the tumor became smaller. LESSONS: Physicians should consider the possibility of PRLoma when diet and exercise fail to improve fatty liver disease in a patient with endocrine symptoms such as amenorrhea.

An unclassified variant of CHD7 activates a cryptic splice site in a patient with CHARGE syndrome.

CHARGE syndrome is a rare autosomal dominant disease that is typically caused by heterozygous CHD7 mutations. A de novo variant in a CHD7 splicing acceptor site (NM_017780.3:c.7165-4A>G) was identified in a Japanese boy with CHARGE syndrome. This variant has been considered to be an "unclassified variant" due to its position outside the consensus splicing sites. In this study, abnormal splicing derived from this known variant was confirmed by cDNA sequencing.