Phosphate as a Signaling Molecule and Its Sensing Mechanism.

In mammals, phosphate balance is maintained by influx and efflux via the intestines, kidneys, bone, and soft tissue, which involves multiple sodium/phosphate (Na+/Pi) cotransporters, as well as regulation by several hormones. Alterations in the levels of extracellular phosphate exert effects on both skeletal and extra-skeletal tissues, and accumulating evidence has suggested that phosphate itself evokes signal transduction to regulate gene expression and cell behavior. Several in vitro studies have demonstrated that an elevation in extracellular Pi activates fibroblast growth factor receptor, Raf/MEK (mitogen-activated protein kinase/ERK kinase)/ERK (extracellular signal-regulated kinase) pathway and Akt pathway, which might involve the type III Na+/Pi cotransporter PiT-1. Excessive phosphate loading can lead to various harmful effects by accelerating ectopic calcification, enhancing oxidative stress, and dysregulating signal transduction. The responsiveness of mammalian cells to altered extracellular phosphate levels suggests that they may sense and adapt to phosphate availability, although the precise mechanism for phosphate sensing in mammals remains unclear. Unicellular organisms, such as bacteria and yeast, use some types of Pi transporters and other molecules, such as kinases, to sense the environmental Pi availability. Multicellular animals may need to integrate signals from various organs to sense the phosphate levels as a whole organism, similarly to higher plants. Clarification of the phosphate-sensing mechanism in humans may lead to the development of new therapeutic strategies to prevent and treat diseases caused by phosphate imbalance.

Factors associated with low bone mineral density in Turner syndrome: a multicenter prospective observational study.

Turner syndrome (TS) is associated with a high risk of fracture due to low bone mineral density (BMD). While hypogonadism is known to play a role in decreasing BMD, other factors have not been studied well. Focusing on diet, exercise, and bone metabolism markers, the present, multicentric, prospective, observational study aimed to identify factors contributing to decreased BMD in TS. In total, 48 patients with TS aged between 5 and 49 years comprising a pre-pubertal group (n = 9), a cyclical menstruation group (n = 6), and a hormone replacement therapy (HRT) group (n = 33) were enrolled. The cyclical menstruation group and the HRT group were referred to collectively as the post-pubertal group. The bone mineral apparent density (BMAD) Z-score was higher in the pre-pubertal group than in the post-pubertal group (-0.3 SD vs. -1.8 SD; p = 0.014). Within the post-pubertal group, the median BMAD Z-score was -0.2 SD in the cyclical menstruation group and -2.3 SD in the HRT group (p = 0.016). Spearman's rank correlation revealed no correlation between the BMAD Z-score and bone metabolism markers. No significant relationship was observed between the BMAD Z-score and either the vitamin D sufficiency rate or the step sufficiency rate. A negative correlation was found between BMAD Z-score and serum sclerostin in the pre-pubertal group and serum FSH in the post-pubertal group. In conclusion, the present study found no relationship between the vertebral BMAD Z-score and diet or exercise habits in TS, indicating that estrogen deficiency is the chief reason for low BMD in TS.

A Report of a Case With Pediatric Ovarian Steroid Cell Tumor, Not Otherwise Specified, Found With Precocious Puberty.

A 4-year-old girl was admitted to our hospital because of precocious puberty. Radiologic findings revealed a fist-sized solid tumor in the left ovary without ascites, peritoneal dissemination, and distant metastasis. The patient underwent left salpingo-oophorectomy without spillage. The size of the excised tumor was 10.0×9.0×4.8 cm. On pathologic examination, the tumor was diagnosed as an ovarian steroid cell tumor, not otherwise specified. In the present case, although the diameter of the tumor (>7 cm) and three mitoses per 10 high-power fields represented some potential for malignancy, we opted for careful observation without chemotherapy as the tumor was of clinical stage Ia.

Very young children with Prader-Willi syndrome are refractory to growth hormone-associated decreases in free thyroxine levels.

The earlier initiation of growth hormone (GH) treatment for patients with Prader-Willi syndrome (PWS) who are younger than 2 years has become more prevalent. Because free thyroxine (FT4) levels are low during this period, GH may induce further reductions; however, limited information is currently available on this issue. Therefore, we herein performed age-dependent and time-course analyses of thyroid hormone levels in GH-treated PWS children. This retrospective analysis included genetically diagnosed PWS patients (N = 37, median age of 26 months). An age-dependent analysis was performed by subdividing subjects based on age [a younger group aged between 1 and 24 months (N = 16) and an older group between 25 and 84 months (N = 21)] and was followed by a multiple regression analysis with adjustments for sex and the cumulative GH dose per bodyweight. A time-course analysis of subjects who had not received levothyroxine during the first 18 months of GH treatment (N = 28) was conducted. A one-month treatment with GH decreased FT4 levels in the older group, but not in the younger group, and this was associated with increases in thyroid-stimulating hormone levels. A positive correlation was noted between age and decreases in FT4 levels independent of the cumulative GH dose per bodyweight. The time-course analysis revealed no changes in FT4 levels in the younger group, while transient decreases were observed in the older group. In conclusion, GH treatment causes age-dependent changes in FT4 levels. This result will help clinicians establish a therapeutic strategy to decide the necessity of levothyroxine supplementation in GH-treated children with PWS.

Dosage of hydrocortisone during late infancy is positively associated with changes in body mass index during early childhood in patients with 21-hydroxylase deficiency.

Obesity is a major complication in children with 21-hydroxylase deficiency (21-OHD). There is evidence to show that higher body mass index (BMI) during infancy and early childhood is associated with an increased risk for the subsequent development of obesity in the general population; however, limited information is currently available on this issue in 21-OHD patients. Additionally, despite the frequent use of supraphysiological dosages of hydrocortisone in 21-OHD, the association between BMI and hydrocortisone dosage during these periods remains largely unclear; therefore, we retrospectively investigated BMI at approximately 1 and 3 years old and its association with hydrocortisone dosage in 56 children with 21-OHD. The median BMI-standard deviation score (SDS) was 0.28 (Interquartile range [IQR]: -0.53 to 1.09) and 0.39 (IQR: -0.44 to 1.14) at approximately 1 and 3 years old, respectively, and no association was observed between hydrocortisone dosage and BMI-SDS at either time-point; however, multivariate analysis revealed that hydrocortisone dosage at approximately 1 year old was positively associated with changes in BMI (ß = 0.57, p = 0.013) and BMI-SDS (ß = 0.59, p = 0.011) between approximately 1 and 3 years old after adjustment for age, sex, and changes in hydrocortisone dosage during the same period. The average dosage of hydrocortisone between approximately 6 months and 1 year old also showed similar results. These results indicate that a higher dosage of hydrocortisone during late infancy is associated with a higher BMI at approximately 3 years old, which may lead to the development of obesity later in life in children with 21-OHD.

A questionnaire-based survey of medical conditions in adults with Prader-Willi syndrome in Japan: implications for transitional care.

Prader-Willi syndrome (PWS) is a multisystem disorder with increased mortality predominantly due to obesity-associated complications; therefore, the management of obesity has been centric to therapeutic strategies for PWS. Although a multidisciplinary team approach has been successful for this purpose during childhood, it is generally difficult to implement during adulthood because of the lack of a structured transitional care program. A more detailed understanding of the current medical conditions of adults with PWS is needed to establish this program; however, limited information is currently available on this issue in Japan. Accordingly, we performed a questionnaire-based survey on 425 patients with PWS. There were 162 adult patients aged 18 years or older with median body mass indexes (kg/m2) of 29.4 and 30.4 in males and females, respectively. The frequencies of type 2 diabetes mellitus (T2DM) and hypertension in adults with PWS were 40.4 and 19.4%, respectively. Growth hormone (GH) therapy during childhood correlated with lower rates of T2DM and hypertension during adulthood. Among adult patients, 54% were treated by pediatricians, whereas 44% were seen by internists with an endocrinologist/diabetologist being the most prevalent. Adult patients treated with GH during childhood showed a higher rate of being seen by pediatricians than those without, demonstrating that the multidisciplinary team approach, typically applied with GH therapy, may be continuously provided even after they reach adulthood. These results emphasize the importance of the seamless provision of the multidisciplinary team approach, which is of clinical importance for establishing an optimal transitional care program for PWS.

Circulating insulin-like growth factor 1 levels are reduced in very young children with Prader-Willi syndrome independent of anthropometric parameters and nutritional status.

OBJECTIVE: Insulin growth factor-1 (IGF-1) is used to evaluate growth hormone (GH) sufficiency and is decreased in children with Prader-Willi syndrome (PWS). Although IGF-1 is negatively affected by body size and nutritional status, both of which are impaired in PWS children, these variables are typically not considered when assessing IGF-1 levels in these subjects. Here, we compared IGF-1 levels in PWS children to controls matched for age, sex, anthropometric parameters, and nutritional status. DESIGN/PATIENTS/MEASUREMENTS: The retrospective analysis included genetically diagnosed PWS subjects (n = 65, median age; 14.0 months) and controls (n = 111, 14.3 months) matched for age, sex, anthropometric parameters (height-standard deviation score [SDS], weight-SDS, body mass index-SDS), and serum albumin levels, a marker for nutritional status. IGF-1 SDS was compared between PWS subjects and controls after adjustment for confounding variables. The GH provocation test was performed in 29 PWS subjects, and IGF-1 SDS was compared between GH-sufficient (n = 20) and GH-deficient (n = 9) subjects. Spearman's rank correlation coefficient was performed to investigate the association between age and IGF-1 SDS. None had received GH or levothyroxine treatment. RESULTS: After adjustment for confounding variables, IGF-1 SDS was significantly lower in PWS subjects than controls (-1.56 vs. -1.01, p = .003), while it was not different between GH-sufficient and GH-deficient PWS subjects. Correlation analysis failed to show an association between age and IGF-1 SDS both in control and PWS groups. CONCLUSIONS: IGF-1 SDS is lower in very young children with PWS independent of anthropometric parameters and nutritional status, suggesting the presence of hypothalamic dysfunction of GH secretion.

Beta-human chorionic gonadotropin-producing neuroblastoma: an unrecognized cause of gonadotropin-independent precocious puberty.

The pathogenesis of gonadotropin-independent precocious puberty (PP) includes both congenital and acquired forms, the latter of which may be associated with neoplasms, such as sex-steroid hormone-producing tumors. Beta-human chorionic gonadotropin (ß-hCG)-producing tumors also cause gonadotropin-independent PP by stimulating the production of testosterone in Leydig cells. Germ cell tumors and hepatoblastoma both produce ß-hCG; however, there is limited evidence to show that gonadotropin-independent PP is caused by other ß-hCG-producing tumors. We herein report the first case of ß-hCG-producing neuroblastoma associated with the development of gonadotropin-independent PP. A 2-year-old boy presented with an increased penile length, enlargement of the testes, pigmentation of the external genitalia, and growth acceleration. Imaging, blood, and urinary examinations revealed the presence of neuroblastoma in the right adrenal region. Decreased levels of luteinizing hormone and follicle-stimulating hormone with an increased testosterone level were indicative of gonadotropin-independent PP. Since serum ß-hCG was elevated, ß-hCG-producing neuroblastoma was suspected. Histological findings of the resected tumor were compatible with neuroblastoma. An immunohistochemical analysis using serial sections revealed staining for ß-hCG in synaptophysin-positive cells. Furthermore, immunofluorescence showed the co-staining of ß-hCG with neuron-specific enolase. These results suggested that ß-hCG was produced by tumor cells. Surgical removal of the tumor promptly normalized serum ß-hCG and testosterone levels. In conclusion, we propose the addition of neuroblastoma to the list of differential diagnoses of gonadotropin-independent PP with ß-hCG positivity in serum that includes germ cell tumors and hepatoblastoma.

Disruption of the circadian rhythms and its relationship with pediatric obesity.

The circadian clock system is an evolutionarily conserved system by which organisms adapt their metabolic activities to environmental inputs, including nutrient availability. The disruption of this system has been pathogenically linked to the disintegration of metabolic homeostasis, leading to the development of metabolic complications, including obesity. Lifestyle factors that disrupt this system have been found to be associated with the development of metabolic disorder, which is most evidenced by the finding that shift workers are at an increased risk of developing various disorders, such as obesity and obesity-related complications. Lifestyle factors that contribute to a misalignment between the internal clock system and environmental rhythms have also been identified in children. A short sleep duration and skipping breakfast are prevalent in children and there is mounting evidence that these factors are associated with an increased risk of pediatric obesity; however, the underlying mechanisms have not yet been elucidated in detail. Our current understanding of the impact of lifestyle factors that cause a misalignment between the internal clock system and environmental rhythms on the development of pediatric obesity is summarized herein, with a discussion of potential mechanistic factors.

CREB activation in hypertrophic chondrocytes is involved in the skeletal overgrowth in epiphyseal chondrodysplasia Miura type caused by activating mutations of natriuretic peptide receptor B.

Natriuretic peptide receptor B (NPRB) produces cyclic guanosine monophosphate (cGMP) when bound by C-type natriuretic peptide (CNP). Activating mutations in NPRB cause a skeletal overgrowth disorder, which has been named epiphyseal chondrodysplasia, Miura type (ECDM; OMIM #615923). Here we explored the cellular and molecular mechanisms for the skeletal overgrowth in ECDM using a mouse model in which an activating mutant NPRB is specifically expressed in chondrocytes. The mutant mice (NPRB[p.V883M]-Tg) exhibited postnatal skeletal overgrowth and increased cGMP in cartilage. Both endogenous and transgene-derived NPRB proteins were localized at the plasma membrane of hypertrophic chondrocytes. The hypertrophic zone of growth plate was thickened in NPRB[p.V883M]-Tg. An in vivo BrdU-labeling assay suggested that some of the hypertrophic chondrocytes in NPRB[p.V883M]-Tg mice continued to proliferate, although wild-type (WT) chondrocytes stopped proliferating after they became hypertrophic. In vitro cell studies revealed that NPRB activation increased the phosphorylation of cyclic AMP-responsive element binding protein (CREB) and expression of cyclin D1 in matured chondrocytes. Treatment with cell-permeable cGMP also enhanced the CREB phosphorylation. Inhibition of cyclic adenosine monophosphate (cAMP)/protein kinase A pathway had no effects on the CREB phosphorylation induced by NPRB activation. In immunostaining of the growth plates for the proliferation marker Ki67, phosphorylated CREB and cyclin D1, most signals were similarly observed in the proliferating zone in both genotypes, but some cells in the hypertrophic zone of NPRB[p.V883M]-Tg were also positively stained. These results suggest that NPRB activation evokes its signal in hypertrophic chondrocytes to induce CREB phosphorylation and make them continue to proliferate, leading to the skeletal overgrowth in ECDM.

Starting age of oestrogen-progestin therapy is negatively associated with bone mineral density in young adults with Turner syndrome independent of age and body mass index.

OBJECTIVE: Osteoporosis is an important health issue in patients with Turner syndrome (TS), and oestrogen sufficiency has been implicated in increased bone mineral density (BMD); however, the impact of the starting age of hormone replacement therapy (HRT) on bone mineral density remains unclear, particularly during young adulthood. DESIGN: A retrospective study from three tertiary care hospitals in Japan. PATIENTS: One hundred and three patients with TS aged between 18 and 30 years of age who underwent dual-energy X-ray absorptiometry. MEASUREMENTS: Anthropometric parameters, lumbar bone mineral density (L-BMD), including areal BMD (aBMD) and volumetric BMD (vBMD), karyotypes, the presence of spontaneous menarche, the starting ages of oestrogen replacement therapy (ERT) and oestrogen-progestin therapy (EPT), and the duration between starting ages of oestrogen replacement therapy and oestrogen-progestin therapy were investigated. vBMD was calculated based on the Kröger method. RESULTS: aBMD was lower in young adults with TS than in an age-matched reference population. L-BMD positively correlated with weight and body mass index (BMI). L-BMD was higher in subjects with spontaneous menarche (N = 22) than in those without. A dose escalation regimen of oestrogen replacement therapy was used in 84% of subjects without spontaneous menarche (N = 81). The starting age of oestrogen replacement therapy and the duration between the starting ages of oestrogen replacement therapy and oestrogen-progestin therapy negatively and independently correlated with aBMD, but not with vBMD, after adjustment with age and BMI. The starting age of oestrogen-progestin therapy negatively correlated with L-BMD independent of age and BMI. CONCLUSIONS: Early introduction of hormone replacement therapy, particularly oestrogen-progestin therapy, is important to accrue better L-BMD in young adults with TS.

Central hypothyroidism improves with age in very young children with Prader-Willi syndrome.

OBJECTIVE: Abnormalities in the hypothalamic-pituitary-thyroid (HPT) axis have been implicated in Prader-Willi syndrome (PWS); however, limited information is currently available on age-dependent alterations in the HPT axis. We herein investigated age-dependent differences in thyroid hormone levels in PWS children. DESIGN/PATIENTS/MEASUREMENTS: Free T4 (FT4), free T3 (FT3) and thyroid-stimulating hormone (TSH) concentrations were retrospectively compared between genetically confirmed PWS children (N = 43, median age: 11.2 months) and controls (N = 85, median age: 14.5 months) matched for age, sex, body weight-SD score (SDS), height-SDS, body mass index-SDS and serum albumin level, a marker of the nutritional status. Subjects were subdivided into two groups based on their age: an infant group aged between 1 and 11 months (PWS: N = 22, controls: N = 30) and a toddler group aged between 12 and 47 months (PWS: N = 21, controls: N = 55). None of the subjects had ever been treated with growth hormone or levothyroxine. RESULTS: After adjustments for confounding variables, in the infant group, FT4 levels (pmol/L) were significantly lower in PWS (11.24 in PWS vs 14.32 in controls, P = .0002), whereas no significant differences were observed in FT3 or TSH levels. In the toddler group, no significant differences were noted in FT4 (12.23 in PWS vs 15.31 in controls, P = .10), FT3 or TSH levels. The FT3/FT4 ratio was significantly increased in PWS in both groups. FT4 levels were positively correlated with age in PWS. CONCLUSIONS: Infants with PWS had lower FT4 levels, but FT3 levels were normal, indicating that the levothyroxine replacement therapy may not need to be routinely performed.

Constitutional mismatch repair deficiency in childhood colorectal cancer harboring a de novo variant in the MSH6 gene: a case report.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is caused by biallelic pathogenic variants in one of the mismatch repair genes, and results in early onset colorectal cancer, leukemia, brain tumors and other childhood malignancies. Here we report a case of CMMRD with compound heterozygous variants in the MSH6 gene, including a de novo variant in multiple colorectal cancers. CASE PRESENTATION: An 11-year-old girl, who presented with multiple spots resembling café-au-lait macules since birth, developed abdominal pain, diarrhea and bloody stool over two months. Colonoscopy revealed multiple colonic polyps, including a large epithelial tumor, and pathological examination revealed tubular adenocarcinoma. Brain magnetic resonance imaging (MRI) showed an unidentified bright object (UBO), commonly seen in neurofibromatosis type 1 (NF1). Genetic testing revealed compound heterozygous variants, c. [2969T > A (p.Leu990*)] and [3064G > T (p.Glu1022*)] in the MSH6 gene; c.2969T > A (p.Leu990*) was identified as a de novo variant. CONCLUSIONS: We present the first report of a CMMRD patient with a de novo variant in MSH6, who developed colorectal cancer in childhood. CMMRD symptoms often resemble NF1, as observed here. Physicians should become familiar with CMMRD clinical phenotypes for the screening and early detection of cancer.

Renal function in short-statured children born small for gestational age and treated with growth hormone.

BACKGROUND: Children born small for gestational age (SGA), particularly when associated with an extremely low birthweight (ELBW), have a higher risk of renal dysfunction. Growth hormone (GH) treatment is used to treat short-statured children born SGA; however, its effects on renal function remain elusive, especially in those born SGA with ELBW. METHODS: Short-statured children born SGA (N = 42) were included. Subjects were subdivided into two groups based on their birthweight: the ELBW group (N = 15) with a birthweight of <1,000 g, and the non-ELBW group (N = 27) with birthweights ranging between 1,000 and 2,500 g. The creatinine-based estimated glomerular filtration rates (eGFR) before (pre-eGFR) and 5 years after GH treatment (post-eGFR) were compared. Correlations between eGFR, anthropometric, or birth parameters, and cumulative GH dose were evaluated using Spearman's rank correlation coefficient. RESULTS: The ELBW group had a lower pre- and post-eGFR than the non-ELBW group. Five-year GH treatment did not significantly reduce eGFR in either group. Post-eGFR was positively associated with gestational week and birthweight. However, the cumulative GH dose was not correlated with pre-eGFR, post-eGFR, or percentage change in eGFR (%ΔeGFR). The change in bodyweight standard deviation score during GH treatment was positively correlated with %ΔeGFR in the ELBW group. CONCLUSIONS: The current results indicated that GH treatment was unlikely a risk for the reduction in eGFR in short-statured children born SGA. However, eGFR should be carefully monitored, especially in those born SGA with ELBW because these subjects had lower eGFR than non-ELBW subjects.

Growth hormone treatment for extremely low birthweight children born small for gestational age.

BACKGROUND: The effectiveness of growth hormone (GH) treatment for height gain in short-stature children born small for gestational age (SGA) with extremely low birthweight (ELBW; birthweight <1,000 g) remains largely unknown. METHODS: In study 1, 35 prepubertal Japanese children born SGA with ELBW were categorized into three groups based on the presence or absence of catch-up growth by age 3 (CU(+) and CU(-), respectively) and GH treatment (GH(+) and GH(-), respectively). Height standard deviation (SD) scores (HT-SDS) in the CU-/GH+ group (n = 19) were compared with those in the age-matched CU+/GH- (n = 9) and CU-/GH- groups (n = 7). In study 2, 66 prepubertal Japanese SGA children treated with GH were divided into three groups by birthweight: <1,000 g (n = 19), 1,000-2,000 g (n = 20), and >2,000 g (n = 27). Changes in HT-SDS during the initial 3 years of GH treatment were compared among the three groups. RESULTS: In study 1, the mean HT-SDS in the CU-/GH+ group (-1.15 SD) was similar to that in the CU+/GH- group (-1.39 SD) but higher than that in the CU-/GH- group (-2.24 SD). In study 2, GH achieved a height gain of +1.62 SD in the ELBW group, which was similar to that in the other groups (1,000-2,000 g: +1.46 SD, >2,000 g: +1.53 SD). CONCLUSIONS: Growth hormone treatment in short-stature children born SGA with ELBW increased HT-SDS, which was similar to that in SGA children born with a birthweight ≥1,000 g. These results indicate that GH treatment may be an effective approach to promote adequate growth recovery for short-stature children born SGA with ELBW.

Hypophosphatasia in Japan: ALPL Mutation Analysis in 98 Unrelated Patients.

Hypophosphatasia (HPP) is highly variable in clinical expression and is generally classified into six subtypes. Although it would be beneficial to be able to predict the clinical course from the ALPL genotype, studies on this issue are limited. Here, we aimed to clarify the features of Japanese HPP and the relationships between genotype and clinical manifestations. We analyzed 98 unrelated Japanese patients to investigate the percentage of each clinical form, frequently detected mutations, and the relationship between the genotype and phenotype. Some of the identified mutants were characterized by transfection experiments. Perinatal severe form was the most frequent (45.9%), followed by perinatal benign form (22.4%). Among the 196 alleles, p.Leu520ArgfsX86 (c.1559delT) was detected in 89 alleles, and p.Phe327Leu (c.979T>C) was identified in 23 alleles. All of the homozygotes for p.Leu520ArgfsX86 were classified into perinatal severe form, and patients carrying p.Phe327Leu in one of the alleles were classified into perinatal benign or odonto HPP. Twenty of the 22 patients with perinatal benign HPP were compound heterozygous for p.Phe327Leu and another mutation. Most patients with odonto HPP were found to be monoallelic heterozygotes for dominant-negative mutations or compound heterozygotes with mutants having residual activity. The high prevalence of p.Leu520ArgfsX86 and p.Phe327Leu mutations might underlie the high rate of perinatal severe and perinatal benign forms, respectively, in Japanese HPP. Although ALPL genotyping would be beneficial for predicting the clinical course to an extent, the observed phenotypical variability among patients sharing the same genotypes suggests the presence of modifiers.

Visceral adipose tissue resides within the reference range in children with Prader-Willi syndrome receiving nutritional intervention on a regular basis.

Nutritional intervention for maintaining an appropriate body composition is central to the management of Prader-Willi syndrome (PWS). Despite evidence that visceral adipose tissue (VAT) is associated with increased metabolic risks, the effects of nutritional intervention on fat distribution have not been evaluated for PWS children. We herein investigated fat distribution in 20 genetically diagnosed PWS children (9 males and 11 females); 17 of which received nutritional intervention with or without growth hormone (GH) treatment [GH-treated group (n = 8), GH-untreated group (n = 9)]. GH treatment continued for median of 4.9 years. GH treatment significantly increased height standard deviation score (SDS) whereas body weight SDS and body mass index SDS were not affected in GH-treated group. In GH-untreated group, height SDS significantly decreased during approximately 5 years of follow-up. Fat distribution was evaluated at the median age of 6.93 years in GH-treated group and 7.01 years in GH-untreated group. VAT was maintained within the reference range in both groups. Subcutaneous adipose tissue (SAT) was elevated in GH-untreated groups compared to reference values whereas it was not in GH-treated group. The remaining three subjects, who had never received nutritional intervention or GH treatment, showed increased VAT and SAT. In conclusion, nutritional intervention is beneficial in maintaining VAT within the reference range during childhood, although excessive nutritional intervention may cause unfavorable effect on linear growth.

A retrospective multicenter study of bone mineral density in adolescents and adults with Turner syndrome in Japan.

Osteoporosis is one of the clinical features of women with Turner syndrome (TS). The reasons for low bone mineral density (BMD) and increased bone fragility are multifactorial, including estrogen deficiency, X-chromosome abnormalities, and environmental factors. Few, large-scale studies on bone mineral density in either adolescents or adults with TS have been done in Japan. The goal of the present study was to investigate spinal BMD in women with TS, assess its relationship with clinical parameters, especially estrogen replacement therapy, and investigate its longitudinal changes. The spinal BMD and clinical data of 149 Japanese women with TS aged 15 to 49 years who were followed at the four participating hospitals were retrospectively analyzed. The BMD Z-scores of the women with TS ranged from -5.30 to +1.89. Women with TS aged 15-39 years had lower BMD than healthy Japanese women (p < 0.01) while women with spontaneous menstruation had a significantly higher BMD Z-score than those without spontaneous menstruation (-0.73 ± 1.11 vs. -1.67 ± 1.18, p < 0.01). In women without spontaneous menstruation, BMD Z-scores correlated with the duration of their estrogen therapy (r = 0.167, p < 0.01). Women aged 15-39 years with TS had low BMD, which was associated with primary amenorrhea and short estrogen replacement therapy duration.

Fat distribution in short-stature children born small for gestational age.

BACKGROUND: Children born small for gestational age (SGA) with catch-up growth are at high risk for developing obesity; however, the characteristics of body composition, especially fat distribution, before and after growth hormone (GH) treatment in SGA children without catch-up growth remains largely unknown. METHODS: Anthropometric characteristics, body composition by dual-energy X-ray absorption, and fat distribution by computed tomography at the umbilical level were examined in 27 prepubertal short-stature children born SGA before and 1 year after GH treatment. RESULTS: Before GH treatment, short-stature SGA children had lean phenotypes, and both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were significantly lower than the age- and sex-matched Japanese reference values. Growth hormone treatment significantly increased height standard deviation scores (SDS), without affecting body mass index SDS. Percentage fat mass decreased with GH treatment; however, fat mass was not altered. Both VAT and SAT were significantly lower than the reference values after GH treatment. The ratio of VAT over SAT significantly increased by GH treatment. CONCLUSIONS: Both VAT and SAT were within or below the age- and sex-matched Japanese reference values in short-stature children born SGA before and after GH treatment, indicating that GH treatment may not have unfavorable effects on adiposity in short-stature children born SGA, although it may alter fat distribution.

Policy statement of enteral nutrition for preterm and very low birthweight infants.

For preterm and very low birthweight infants, the mother's own milk is the best nutrition. Based on the latest information for mothers who give birth to preterm and very low birthweight infants, medical staff should encourage and assist mothers to pump or express and provide their own milk whenever possible. If the supply of maternal milk is insufficient even though they receive adequate support, or the mother's own milk cannot be given to her infant for any reason, donor human milk should be used. Donors who donate their breast milk need to meet the Guideline of the Japan Human Milk Bank Association. Donor human milk should be provided according to the medical needs of preterm and very low birthweight infants, regardless of their family's financial status. In the future, it will be necessary to create a system to supply an exclusive human milk-based diet (EHMD), consisting of human milk with the addition of a human milk-derived human milk fortifier, to preterm and very low birthweight infants.