Classification of pseudohypoaldosteronism type II as type IV renal tubular acidosis: results of a literature review.

Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have been considered to be genetic and pediatric counterparts to type IV renal tubular acidosis (RTA). Type IV RTA is frequently found in adults with chronic kidney disease and is characterized by hyperchloremic hyperkalemic acidosis with normal anion gap (AG). However, we recently observed that PHA1 was not always identical to type IV RTA. In this study, we focused on the acid-base balance in PHA2. Through a literature search published between 2008-2020, 46 molecularly diagnosed cases with PHA2 were identified (median age of 14 years). They comprised 11 sets of familial and 16 sporadic cases and the pathology was associated with mutations in WNK 4 (n = 1), KLHL3 (n = 17), and CUL3 (n = 9). The mean potassium (K+) level was 6.2 ± 0.9 mEq/L (n = 46, range 4.0-8.6 mEq/L), whereas that of chloride (Cl-) was 110 ± 3.5 mEq/L (n = 41, 100-119 mEq/L), with 28 of 41 cases identified as hyperchloremic. More than half of the cases (18/35) presented with metabolic acidosis. Although AG data was obtained only in 16 cases, all but one cases were within normal AG range. Both Cl- and HCO3- levels showed significant correlations with K+ levels, which suggested that the degree of hyperchloremia and acidosis reflect the clinical severity, and is closely related to the fundamental pathophysiology of PHA2. In conclusion, our study confirmed that PHA2 is compatible with type IV RTA based on laboratory findings.

Diagnosis of congenital hyperinsulinism: Biochemical profiles during hypoglycemia.

OBJECTIVES: To define the ranges of biochemical markers during hypoglycemia for the diagnosis of congenital hyperinsulinism (CHI), using high sensitivity insulin assays. SUBJECTS: A total of 298 patients with CHI and 58 control patients with non-hyperinsulinemic hypoglycemia, who were diagnosed after 2007. METHODS: The levels of biochemical markers (glucose, insulin, ß-hydroxybutyrate [BHB], free fatty acids [FFA], lactate, ammonia) at the time of hypoglycemia were analyzed along with the maximal glucose infusion rate (GIR) to maintain euglycemia and clinical outcomes. RESULTS: Median levels of blood glucose in patients with CHI and in controls were 30 and 46 mg/dL, while insulin levels were 9.90 and undetectable (<.5) µU/mL, respectively. Similarly, median levels of BHB were 17.5 and 3745 µmol/L, and those of FFA were 270.5 and 2660 µmol/L, respectively. For patients after 5 months, cutoffs of insulin >1.25 µU/mL, BHB < 2000 µmol/L, and FFA < 1248 µmol/L predicted CHI with sensitivities of 97.5, 96.2, and 95.2% and specificities of 84.2, 89.3, and 92.3%, respectively. Maximal GIR in the CHI groups tended to decrease with age. In addition, decreased gestational age, low birth weight, and elevated lactate at hypoglycemia were significantly more common in patients who were off treatment within 100 days without pancreatectomy. CONCLUSIONS: After introduction of high-sensitive assays, the diagnostic value of insulin was improved, allowing for more efficient cutoffs to be set for diagnosis of CHI. Premature birth, low birth weight and elevated lactate might be helpful in predicting early remission of hypoglycemia.

A novel de novo germline mutation Glu40Lys in AKT3 causes megalencephaly with growth hormone deficiency.

Germline or somatic gain-of-function mutations in the v-akt murine thymoma viral oncogene homolog 3 (AKT3) have been reported to cause syndromic megalencephaly. We describe a novel germline mutation, p.Glu40Lys, in AKT3. Phenotypically, the patient presented with megalencephaly with hypotonia, apparent connective tissue laxity, and growth hormone (GH) deficiency. To our knowledge, this is the first instance of a patient with megalencephaly with GH deficiency, harboring a germline de novo mutation in AKT3. © 2017 Wiley Periodicals, Inc.

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

CONTEXT: Adrenal crisis (AC) is a life-threatening complication that occurs during follow-up of patients with adrenal insufficiency (AI). No prospective study has thoroughly investigated AC in children with primary and secondary AI. OBJECTIVE: This work aimed to determine the incidence and risk factors for AC in patients with pediatric-onset AI. METHODS: This multicenter, prospective cohort study conducted in Japan enrolled patients diagnosed with AI at age ≤15 years. 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% CI, 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.

Feeding choice has a gender-associated effect on infant growth.

BACKGROUND: Appropriate nutrition during childhood is important for preventing future development of lifestyle-related diseases. The effect of feeding choice on infant growth in Japan is not known. METHODS: Data from 204 healthy schoolchildren (age, 6-9 years) were obtained retrospectively from their parents by questionnaires. Breast-fed (BF) and formula-fed (FF) groups were defined as those fed only breast milk or formula milk at 4 months of age, respectively. There were 71 children (M/F, 31/40) in BF and 30 (M/F, 19/11) in FF. Anthropometric data at birth, and at 1, 4, 7, 10, 18, and 36 months of age in male and female infants were compared between the groups. RESULTS: In male infants, height was significantly lower at 4 months, bodyweight was lower from 4 to 18 months, and body mass index (BMI) was lower from 10 to 36 months in BF than in FF. The standard deviation scores (SDS) for height, weight and BMI had a similar pattern. No significant differences were observed for these variables for female infants in BF compared with FF. Multiple regression analysis showed that birthweight, mother's pre-pregnancy weight, and infant feeding choice were significant factors associated with weight-SDS at 18 and 36 months. Feeding choice was the only factor associated with BMI-SDS at 18 months. CONCLUSIONS: Infant feeding choice had a gender-associated effect on growth during infancy. When evaluating infant growth, not only birthweight and mother's pre-pregnancy weight, but also infant feeding choice and gender should be considered.

Cord serum adiponectin is positively related to postnatal body mass index gain.

BACKGROUND: The roles of adiponectin and leptin in the early stages of life are poorly understood. We previously studied longitudinal changes in these adipocytokines from birth to 12 months of age. The aim of this investigation was to evaluate the correlation between cord serum adipocytokine levels and postnatal growth by 3 years of age. METHODS: A questionnaire was sent to obtain the general physical measurements of 3-year-olds from 56 healthy newborn infants born at a gestational age of 35 weeks or more; 45 valid responses were obtained. The correlations between variables, including cord serum adipocytokine levels at birth and general physical measurements at 3 years, were investigated. RESULTS: Body mass index (BMI) Z-score gain from birth to 3 years was negatively correlated with birthweight SD scores (ß=-0.395, P= 0.019) and gestational age (ß=-0.557, P= 0.016), and positively correlated with cord serum adiponectin levels (ß= 0.253, P= 0.043). BMI Z-score gain from birth to 6 months was negatively correlated with only birthweight SD score (ß=-0.442, P= 0.017). Cord serum leptin levels were not a significant predictor of BMI Z-scores gain in our subjects. BMI Z-scores at 6 months, 12 months, and 3 years of age were not related to cord serum adiponectin or leptin levels. CONCLUSIONS: Birthweight SD score, gestational age, and cord serum adiponectin levels are significant predictors of BMI Z-score gain from birth to 3 years of age in Japanese infants.

Acid-Base Imbalance in Pseudohypoaldosteronism Type 1 in Comparison With Type IV Renal Tubular Acidosis.

Context: Pseudohypoaldosteronism type 1 (PHA1) has been treated as a genetic variant of type IV renal tubular acidosis (RTA), leading to the conception that PHA1 develops hyperchloremic acidosis with a normal anion gap (AG). Objective: To delineate the acid-base imbalance in PHA1A (dominant type) and PHA1B (recessive type). Methods: We conducted the following: (1) a retrospective chart review of our patient with PHA1B, and (2) a literature search of PHA1 cases focusing on acid-base balance. The main outcome measures were the incidence and nature of acidosis, including chloride levels and AG. Results: In our patient with PHA1B, 7 salt-wasting episodes were analyzed. Acidosis was ascertained each time, and it was accompanied by hypochloremia except in 1 episode. AG was elevated in 5 episodes, while hyperlacticaemia was present in 3. In the literature, 41 cases of PHA1A and 65 cases of PHA1B have been identified. During salt-wasting crises, acidosis developed in 85% of PHA1A cases and 87% of PHA1B cases. Hypochloremia was present in 69% of PHA1A cases with available data (n = 13) and 54% of eligible PHA1B cases (n = 13), with mean chloride levels of 96 mEq/L and 95 mEq/L, respectively. Increased AG was less frequently reported (14% in PHA1A and 44% in PHA1B). Conclusions: Patients with PHA1 frequently presented with metabolic acidosis. However, hyperchloremia may not be a universal finding, whereas hypochloremia and increased AG may occur in a substantial proportion of the patients.

Genetic Analysis of Japanese Children Clinically Diagnosed with Familial Hypercholesterolemia.

AIM: This study aimed to elucidate the gene and lipid profiles of children clinically diagnosed with familial hypercholesterolemia (FH). METHODS: A total of 21 dyslipidemia-related Mendelian genes, including FH causative genes (LDLR, APOB, and PCSK9) and LDL-altering genes (APOE, LDLRAP1, and ABCG5/8), were sequenced in 33 Japanese children (mean age, 9.7±4.2 years) with FH from 29 families. RESULTS: Fifteen children (45.5%) with pathogenic variants in LDLR (eight different heterozygous variants) and one child (3.0%) with the PCSK9 variant were found. Among 17 patients without FH causative gene variants, 3 children had variants in LDL-altering genes, an APOE variant and two ABCG8 variants. The mean serum total cholesterol (280 vs 246 mg/dL), LDL-cholesterol (LDL-C, 217 vs 177 mg/dL), and non-HDL cholesterol (228 vs 188 mg/dL) levels were significantly higher in the pathogenic variant-positive group than in the variant-negative group. In the variant-positive group, 81.3% of patients had LDL-C levels ≥ 180 mg/dL but 35.3% in the variant-negative group. The mean LDL-C level was significantly lower in children with missense variants, especially with the p.Leu568Val variant, than in children with other variants in LDLR, whereas the LDL-altering variants had similar effects on the increase in serum LDL-C to LDLR p.Leu568Val. CONCLUSION: Approximately half of the children clinically diagnosed with FH had pathogenic variants in FH causative genes. The serum LDL-C levels tend to be high in FH children with pathogenic variations, and the levels are by the types of variants. Genetic analysis is useful; however, further study on FH without any variants is required.

Galectin-9 expands immunosuppressive macrophages to ameliorate T-cell-mediated lung inflammation.

Galectin-9 (Gal-9) plays pivotal roles in the modulation of innate and adaptive immunity to suppress T-cell-mediated autoimmune models. However, it remains unclear if Gal-9 plays a suppressive role for T-cell function in non-autoimmune disease models. We assessed the effects of Gal-9 on experimental hypersensitivity pneumonitis induced by Trichosporon asahii. When Gal-9 was given subcutaneously to C57BL/6 mice at the time of challenge with T. asahii, it significantly suppressed T. asahii-induced lung inflammation, as the levels of IL-1, IL-6, IFN-gamma, and IL-17 were significantly reduced in the BALF of Gal-9-treated mice. Moreover, co-culture of anti-CD3-stimulated CD4 T cells with BALF cells harvested from Gal-9-treated mice on day 1 resulted in diminished CD4 T-cell proliferation and decreased levels of IFN-gamma and IL-17. CD11b(+)Ly-6C(high)F4/80(+) BALF Mphi expanded by Gal-9 were responsible for the suppression. We further found in vitro that Gal-9, only in the presence of T. asahii, expands CD11b(+)Ly-6C(high)F4/80(+) cells from BM cells, and the cells suppress T-cell proliferation and IFN-gamma and IL-17 production. The present results indicate that Gal-9 expands immunosuppressive CD11b(+)Ly-6C(high) Mphi to ameliorate Th1/Th17 cell-mediated hypersensitivity pneumonitis.

Galectin-9 increases Tim-3+ dendritic cells and CD8+ T cells and enhances antitumor immunity via galectin-9-Tim-3 interactions.

A Tim-3 ligand, galectin-9 (Gal-9), modulates various functions of innate and adaptive immune responses. In this study, we demonstrate that Gal-9 prolongs the survival of Meth-A tumor-bearing mice in a dose- and time-dependent manner. Although Gal-9 did not prolong the survival of tumor-bearing nude mice, transfer of naive spleen cells restored a prolonged Gal-9-induced survival in nude mice, indicating possible involvement of T cell-mediated immune responses in Gal-9-mediated antitumor activity. Gal-9 administration increased the number of IFN-gamma-producing Tim-3(+) CD8(+) T cells with enhanced granzyme B and perforin expression, although it induced CD4(+) T cell apoptosis. It simultaneously increased the number of Tim-3(+)CD86(+) mature dendritic cells (DCs) in vivo and in vitro. Coculture of CD8(+) T cells with DCs from Gal-9-treated mice increased the number of IFN-gamma producing cells and IFN-gamma production. Depletion of Tim-3(+) DCs from DCs of Gal-9-treated tumor-bearing mice decreased the number of IFN-gamma-producing CD8(+) T cells. Such DC activity was significantly abrogated by Tim-3-Ig, suggesting that Gal-9 potentiates CD8(+) T cell-mediated antitumor immunity via Gal-9-Tim-3 interactions between DCs and CD8(+) T cells.

A pediatric patient with hyponatremic hypertensive syndrome without persistent hypertension in acute phase: A case report and review of literature.

Hyponatremic hypertensive syndrome is characterized by hypertension, hyponatremia, and hypokalemia due to unilateral renal artery stenosis. We herein report a 1-year-old hyponatremic hypertensive syndrome infant without persistent hypertension in the acute phase. On the ninth hospital day, his systolic and diastolic blood pressure increased up to 154-160 and 70-84 mmHg, respectively. Acute gastroenteritis and dehydration might transiently mask his hypertension. By percutaneous transluminal balloon angioplasty for right renal artery, his blood pressure finally normalized without antihypertensive drugs. We reviewed 23 previously reported pediatric patients with hyponatremic hypertensive syndrome under the age of 15 years. Including our patient, there are only three reports on hyponatremic hypertensive syndrome without persistent hypertension in the acute phase. Hyponatremic hypertensive syndrome is curable with proper diagnosis and timely intervention. Therefore, pediatricians should pay attention to the signs and symptoms associated with hyponatremic hypertensive syndrome, even if persistent hypertension was absent in the acute phase.

Galectin-9 expands unique macrophages exhibiting plasmacytoid dendritic cell-like phenotypes that activate NK cells in tumor-bearing mice.

Galectin-9 (Gal-9) inhibits the metastasis of tumor cells by blocking their adhesion to endothelium and the extracellular matrix. In this study, we addressed the involvement of Gal-9 in anti-tumor activity. Gal-9 significantly prolonged the survival of B16F10 melanoma-bearing mice. Gal-9 increased the numbers of NK cells, CD8 T cells and macrophages in tumor-bearing mice. Gal-9-mediated anti-tumor activity was not induced in NK cell-, macrophage- and CD8 T cell-depleted mice. NK cells from Gal-9-treated mice, compared to PBS-treated mice, exhibited significantly higher cytolytic activity. Co-culture of naïve NK cells with macrophages from Gal-9-treated mice resulted in enhanced NK activity, although Gal-9 itself did not enhance the NK activity. We also found that Ly-6C(+)CD11b(+)F4/80(+) macrophages with plasmacytoid cell (pDC)-like phenotypes (PDCA-1 and B220) were responsible for the enhanced NK activity. These results provide evidence that Gal-9 promotes NK cell-mediated anti-tumor activity by expanding unique macrophages with a pDC-like phenotype.

Galectin-9 suppresses tumor metastasis by blocking adhesion to endothelium and extracellular matrices.

We previously described an inverse correlation between galectin-9 (Gal-9) expression and metastasis in patients with malignant melanoma and breast cancer. This study verified the ability of Gal-9 to inhibit lung metastasis in experimental mouse models using highly metastatic B16F10 melanoma and Colon26 colon cancer cells. B16F10 cells transfected with a secreted form of Gal-9 lost their metastatic potential. Intravenous Gal-9 administration reduced the number of metastases of both B16F10 and Colon26 cells in the lung, indicating that secreted Gal-9 suppresses metastasis. Analysis of adhesive molecule expression revealed that B16F10 cells highly express CD44, integrin alpha1, alpha 4, alpha V, and beta1, and that Colon26 cells express CD44, integrin alpha2, alpha 5, alpha V, and beta1, suggesting that Gal-9 may inhibit the adhesion of tumor cells to vascular endothelium and the extracellular matrix (ECM) by binding to such adhesive molecules. Indeed, Gal-9 suppressed the binding of hyaluronic acid to CD44 on both B16F10 and Colon26 cells, and also suppressed the binding of vascular cell adhesion molecule-1 to very late antigen-4 on B16F10 cells. Furthermore, Gal-9 inhibited the binding of tumor cells to ECM components, resulting in the suppression of tumor cell migration. The present results suggest that Gal-9 suppresses both attachment and invasion of tumor cells by inhibiting the binding of adhesive molecules on tumor cells to ligands on vascular endothelium and ECM.

Evaluation of Hip/HeightP Ratio as an Index for Adiposity and Metabolic Complications in Obese Children: Comparison with Waist-related Indices.

AIM: To investigate whether body adiposity index (BAI; hip/height1.5-18), pediatric BAI (BAIp; hip/height0.8 - 38), and other hip/heightP ratios are useful in obese children. METHOD: Ninety obese Japanese children, 55 boys and 35 girls, who visited our University Clinic, were enrolled. The age was 9.92±2.6 (mean±SD) years, and the percentage overweight (POW) was 51.6±18.8%. We set the power value of the hip/heightP 0, 0.5, 0.8, 1, 1.5, and 2 and studied the association with overweight indices, biochemical data, and fat area measured by computed tomography. Waist, waist/height ratio, and waist/hip ratio were also evaluated. RESULTS: Hip/height and hip/height0.8 (BAIp) were more closely correlated with POW, body mass index percentile, and percentage body fat than hip/height1.5 (BAI). The correlation coefficient of hip/height with POW (r =0.855) was the highest among the studied hip/heightP indices. The approximate line to predict POW was 411×hip/height-207. The waist/height was also highly correlated with POW (r=0.879). Hip and hip/height0.5 were more closely correlated with visceral fat area than hip/height, BAIp, and hip/height1.5. Hip and hip/height0.5 were significantly correlated with insulin. Only hip was also significantly associated with dyslipidemia. All hip/heightP indices were not significantly correlated with alanine aminotransferase (ALT). Waist was significantly correlated with serum lipids, ALT, and insulin. CONCLUSION: Hip/height and BAIp are better markers for overweight (adiposity) in obese children than BAI. However, hip/height, BAIp, and BAI are not useful to predict metabolic complications. Waist appears to be the best index for obese children overall at this time.

AICAR Attenuates TNFα-Induced Inappropriate Secretion of Monocyte Chemoattractant Protein-1 and Adiponectin in 3T3-L1 Adipocytes.

AIM: The increase in monocyte chemoattractant protein-1 (MCP-1) and the decrease in adiponectin production from hypertrophic adipocytes are associated with adipose tissue inflammation and its metabolic complications. The aim of this study was to determine whether 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR), an adenosine monophosphate-activated protein kinase (AMPK) activator, modulates these adipocytokine productions in tumor necrosis factor-α (TNFα)-treated adipocytes. METHODS: AICAR and/or other reagents were added to the culture medium, and then, TNFα was added to fully differentiated 3T3-L1 adipocytes. The MCP-1 and adiponectin production in the culture supernatant was measured by ELISA. AMPK, phosphatidylinositol 3-kinase (PI3K), and nuclear factor-κB (NF-κB) activities were also assayed. RESULTS: Treatment with TNFα increased MCP-1 and decreased adiponectin secretion dose-dependently in the 3T3-L1 adipocytes, and AICAR significantly inhibited these TNFα-mediated changes. Interestingly, metformin, another AMPK activator, did not have such effects on these adipocytokines. Both the AMPK and PI3K systems in the cells were significantly activated by the AICAR treatment, but the effects of AICAR on adipocytokines were not weakened by the addition of dorsomorphin, an AMPK inhibitor, or LY294002, a PI3K inhibitor. Pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, showed protective effects similar to those as AICAR. AICAR, but not metformin, significantly inhibited the TNFα-stimulated activation of NF-κB, and dorsomorphin did not change AICAR's effect. CONCLUSION: AICAR attenuates the TNFα-induced secretion of MCP-1 and adiponectin in 3T3-L1 adipocytes. The observed effects of AICAR seem to be mainly due to the inhibition of NF-κB activation rather than the activation of the AMPK pathway, at least in TNFα-treated adipocytes.