Genetic backgrounds and genotype-phenotype relationships in anthropometric parameters of 116 Japanese individuals with Noonan syndrome.

Noonan syndrome (NS) is caused by pathogenic variants in genes encoding components of the RAS/MAPK pathway and presents with a number of symptoms, including characteristic facial features, congenital heart diseases, and short stature. Advances in genetic analyses have contributed to the identification of pathogenic genes in NS as well as genotype-phenotype relationships; however, updated evidence for the detection rate of pathogenic genes with the inclusion of newly identified genes is lacking in Japan. Accordingly, we examined the genetic background of 116 individuals clinically diagnosed with NS and the frequency of short stature. We also investigated genotype-phenotype relationships in the context of body mass index (BMI). Genetic testing revealed the responsible variants in 100 individuals (86%), where PTPN11 variants were the most prevalent (43%) and followed by SOS1 (12%) and RIT1 (9%). The frequency of short stature was the lowest in subjects possessing RIT1 variants. No genotype-phenotype relationships in BMI were observed among the genotypes. In conclusion, this study provides evidence for the detection rate of pathogenic genes and genotype-phenotype relationships in Japanese patients with NS, which will be of clinical importance for accelerating our understanding of the genetic backgrounds of Japanese patients with NS.

Multiplex Real-Time PCR-Based Newborn Screening for Severe Primary Immunodeficiency and Spinal Muscular Atrophy in Osaka, Japan: Our Results after 3 Years.

In newborn screening (NBS), it is important to consider the availability of multiplex assays or other tests that can be integrated into existing systems when attempting to implement NBS for new target diseases. Recent developments in innovative testing technology have made it possible to simultaneously screen for severe primary immunodeficiency (PID) and spinal muscular atrophy (SMA) using quantitative real-time polymerase chain reaction (qPCR) assays. We describe our experience of optional NBS for severe PID and SMA in Osaka, Japan. A multiplex TaqMan qPCR assay was used for the optional NBS program. The assay was able to quantify the levels of T-cell receptor excision circles and kappa-deleting recombination excision circles, which is useful for severe combined immunodeficiency and B-cell deficiency screening, and can simultaneously detect the homozygous deletion of SMN1 exon 7, which is useful for NBS for SMA. In total, 105,419 newborns were eligible for the optional NBS program between 1 August 2020 and 31 August 2023. A case each of X-linked agammaglobulinemia and SMA were diagnosed through the optional NBS and treated at early stages (before symptoms appeared). Our results show how multiplex PCR-based NBS can benefit large-scale NBS implementation projects for new target diseases.

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.

Complex intrinsic abnormalities in osteoblast lineage cells of X-linked hypophosphatemia: Analysis of human iPS cell models generated by CRISPR/Cas9-mediated gene ablation.

X-linked hypophosphatemia (XLH) is caused by inactivating variants of the phosphate regulating endopeptidase homolog X-linked (PHEX) gene. Although the overproduction of fibroblast growth factor 23 (FGF23) is responsible for hypophosphatemia and impaired vitamin D metabolism, the pathogenesis of XLH remains unclear. We herein generated PHEX-knockout (KO) human induced pluripotent stem (iPS) cells by applying CRISPR/Cas9-mediated gene ablation to an iPS clone derived from a healthy male, and analyzed PHEX-KO iPS cells with deletions extending from exons 1 to 3 and frameshifts by inducing them to differentiate into the osteoblast lineage. We confirmed the increased production of FGF23 in osteoblast lineage cells differentiated from PHEX-KO iPS cells. In vitro mineralization was enhanced in osteoblast lineage cells from PHEX-KO iPS cells than in those from isogenic control iPS cells, which reminded us of high bone mineral density and enthesopathy in patients with XLH. The extracellular level of pyrophosphate (PPi), an inhibitor of mineralization, was elevated, and this increase appeared to be partly due to the reduced activity of tissue non-specific alkaline phosphatase (TNSALP). Osteoblast lineage cells derived from PHEX-KO iPS cells also showed the increased expression of multiple molecules such as dentine matrix protein 1, osteopontin, RUNX2, FGF receptor 1 and early growth response 1. This gene dysregulation was similar to that in the osteoblasts/osteocytes of Phex-deficient Hyp mice, suggesting that common pathogenic mechanisms are shared between human XLH and Hyp mice. Moreover, we found that the phosphorylation of CREB was markedly enhanced in osteoblast lineage cells derived from PHEX-KO iPS cells, which appeared to be associated with the up-regulation of the parathyroid hormone related protein gene. PHEX deficiency also affected the response of the ALPL gene encoding TNSALP to extracellular Pi. Collectively, these results indicate that complex intrinsic abnormalities in osteoblasts/osteocytes underlie the pathogenesis of human XLH.

Reductions in estimated glomerular filtration rate during puberty in GH-treated children born small for gestational age are associated with prematurity and low birth weight, not the dosage of GH treatment.

GH treatment has been widely utilized for short-statured children born small for gestational age (SGA). Although SGA children are at a higher risk of renal dysfunction, the effect of GH treatment on renal function is still unclear. We have previously shown that GH treatment is not associated with renal dysfunction during the prepubertal period; however, its effect during the pubertal period has not been investigated. Accordingly, we herein retrospectively investigated creatinine-based estimated glomerular filtration rates (eGFR) in 26 short-statured children born SGA during puberty, defined as the period between the onset of puberty and cessation of GH treatment, and their association with parameters at birth and GH treatment. We found that eGFR did not decrease during the pubertal period; however, gestational week and birth weight were negatively and significantly correlated with percentage decrease in eGFR during the pubertal period. The percentage decrease in eGFR did not correlate with changes in the insulin-like growth factor-1 standard deviation score or average weekly GH dose. In conclusion, GH treatment was not associated with a reduction in eGFR in short-statured SGA children during puberty. Since low birth weight and prematurity were associated with reductions in eGFR during puberty, monitoring for renal function was mandatory regardless of GH treatment in short-statured children born SGA.

Pubertal induction in Turner syndrome without gonadal function: A possibility of earlier, lower-dose estrogen therapy.

Delayed and absent puberty and infertility in Turner syndrome (TS) are caused by primary hypogonadism. A majority of patients with TS who are followed at hospitals during childhood will not experience regular menstruation. In fact, almost all patients with TS need estrogen replacement therapy (ERT) before they are young adults. ERT in TS is administered empirically. However, some practical issues concerning puberty induction in TS require clarification, such as how early to start ERT. The present monograph aims to review current pubertal induction therapies for TS without endogenous estrogen production and suggests a new therapeutic approach using a transdermal estradiol patch that mimics incremental increases in circulating, physiological estradiol. Although evidence supporting this approach is still scarce, pubertal induction with earlier, lower-dose estrogen therapy more closely approximates endogenous estradiol secretion.

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.

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.

Somapacitan in children born small for gestational age: a multi-centre, open-label, controlled phase 2 study.

OBJECTIVE: Investigate efficacy, safety, and tolerability of 3 once-weekly somapacitan doses compared with daily growth hormone (GH) administration in short children born small for gestational age (SGA). DESIGN: Randomised, multi-centre, open-label, controlled phase 2 study comprising a 26-week main phase and a 4-year extension (NCT03878446). The study was conducted at 38 sites across 12 countries. 26-week main phase results are presented here.Sixty-two GH treatment-naïve, prepubertal short children born SGA were randomised and exposed; 61 completed the main phase. Three somapacitan doses (0.16 [n = 12], 0.20 [n = 13], 0.24 [n = 12] mg/kg/week) and 2 daily GH doses (0.035 [n = 12], 0.067 [n = 13] mg/kg/day) were administered subcutaneously. RESULTS: After 26 weeks of treatment, the estimated mean annualised height velocity (HV) was 8.9, 11.0, and 11.3 cm/year for somapacitan 0.16, 0.20, and 0.24 mg/kg/week, respectively, compared to 10.3 and 11.9 cm/year for daily GH 0.035 and 0.067 mg/kg/day. Changes from baseline in HV standard deviation score (SDS), height SDS, and insulin-like growth factor I (IGF-I) SDS showed similar dose-dependent responses. Exposure-response modelling indicated the greatest efficacy correlated with the highest somapacitan exposure. Similar safety and tolerability were demonstrated for all weekly somapacitan and daily GH doses. CONCLUSIONS: Based on the totality of data on improvements in height-based parameters combined with exposure-response analyses, somapacitan 0.24 mg/kg/week appears most efficacious, providing similar efficacy, safety, and tolerability as daily GH 0.067 mg/kg/day in short children born SGA after 26 weeks of treatment.

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.

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.

Histological analysis of testes in patients with 5 alpha-reductase deficiency type 2: Comparison with cryptorchid testes in patients without endocrinological abnormalities and a review of the literature.

As evidenced by the intact histology of the testes during infancy, testicular differentiation during the prenatal period occurs normally in individuals with 5 alpha-reductase type 2 deficiency (5αRD); however, a majority of these individuals suffer from azoospermia or oligospermia during adulthood, indicating that impaired spermatogenesis occurs postnatally. Although the accompanying cryptorchidism may be partly responsible for this process, the underlying mechanisms remain largely unknown. To address this issue, we retrospectively compared the histological findings of descended testes in a 3-mo-old patient and undescended testes in an 18-yr-old patient with 5αRD. In the latter, testicular histology was compared to that of cryptorchid testes obtained from five adolescent patients without endocrinological abnormalities. Histological findings of a 3-mo-old patient revealed normal number of germ cells with intact seminiferous tubules. In contrast, an 18-yr-old patient showed marked reduction in germ cell number and atrophic seminiferous tubules. The findings were very similar to those observed in cryptorchid testes without endocrinological abnormalities. These findings suggest that the decrease in germ cells in 5αRD patients may be at least partly caused by accompanying cryptorchidism. As the number of germ cells did not decrease during the infantile period, early orchiopexy is recommended to prevent a decrease in germ cell number and preserve fertility.

The Lack of Bmal1, a Core Clock Gene, in the Intestine Decreases Glucose Absorption in Mice.

The circadian clock network is an evolutionarily conserved system that regulates systemic metabolism, such as glucose homeostasis. Intestinal tissue is a pivotal organ for the regulation of glucose metabolism, mainly via glucose absorption into the circulation; however, the significance of the intestinal circadian clock network for glucose metabolism remains largely unclear. We herein utilized a mouse model in which Bmal1, a core clock gene, was deleted in an intestine-specific manner (Bmal1Int-/- mice) and demonstrated a rhythmic expression of Sglt1 with its peak at zeitgeber time (ZT) 10.7 ±â€…2.8 in control mice, whereas this was lost in Bmal1Int-/- mice. Mechanistically, chromatin immunoprecipitation analysis revealed rhythmic binding of CLOCK to the E-box elements in the Sglt1 gene in control mice; however, this was absent in Bmal1Int-/- mice. Accordingly, SGLT1 protein levels were decreased during the dark phase in Bmal1Int-/- mice and this was associated with impaired glucose absorption, leading to a decline in hepatic glycogen levels at ZT4, which was restored by ingestion of high-sucrose water. Additionally, when mice were starved from ZT0, greater expression of the lipolysis-related gene Pnpla2 was observed in adipose tissue of Bmal1Int-/- mice, and this was not noted when glycogen storage was restored by high-sucrose water prior to fasting, suggesting that higher Pnpla2 expression in Bmal1Int-/- mice was likely caused by lower glycogen storage. These results indicate that disruption of the intestinal circadian clock system impairs glucose absorption in the intestine and affects systemic glucose homeostasis.

Growth-related skeletal changes and alterations in phosphate metabolism.

Serum inorganic phosphate (Pi) levels are higher in children than in adults; however, the underlying mechanisms remain unclear. Therefore, we herein attempted to elucidate the mechanisms altering Pi metabolism from youth to adulthood using 4-week-old (young) and 12-week-old (adult) mice. Despite higher serum Pi levels, serum fibroblast growth factor 23 (FGF23) levels were lower in young mice, and the amount of FGF23 in bone tended to increase from youth to adulthood. Increases in serum FGF23 levels during growth were associated with the up- and down-regulation of the renal expression of Cyp24a1 encoding vitamin D-24-hydroxylase and Slc34a3 encoding the type IIc sodium/phosphate (Na+/Pi) co-transporter, respectively, suggesting an enhancement in the FGF23-mediated bone-kidney axis from youth to adulthood. We then isolated osteoblasts and osteocytes from young and adult mice and compared the expression of genes involved in Pi metabolism and/or mineralization. In contrast to the growth-related increase in Fgf23 expression, the expression of some genes, including the dentin matrix protein 1 (Dmp1) and phosphate-regulating gene with homologies to endopeptidases on the X chromosome (Phex) markedly decreased from youth to adulthood. The down-regulation of Dmp1 and Phex may contribute to growth-related increases in FGF23. The responses of isolated osteoblasts and osteocytes to high Pi levels also markedly differed between young and adult mice. Treatment of isolated osteocytes with high Pi increased the production of FGF23 in adult mice but not in young mice. These results indicate a close relationship between skeletal changes from youth to adulthood and an alteration in Pi metabolism, and provide insights into the mechanisms by which osteoblasts and osteocytes maintain Pi homeostasis.

Subcutaneous adipose tissue is a positive predictor for bone mineral density in prepubertal children with Prader-Willi syndrome independent of lean mass.

OBJECTIVES: Emerging evidence suggests a fat depot-specific relationship with bone mineral density (BMD) in children, particularly in those who are overweight/obese. However, this has not yet been investigated in detail in children with Prader-Willi syndrome (PWS), a genetic syndrome characterized by a decreased lean mass (LM) and increased fat mass (FM). The objective of this study is to investigate the relationships of LM and FM, particularly fat distribution, with bone mineral parameters. METHODS: This is a retrospective and cross-sectional study. Forty-seven prepubertal Japanese children with PWS (22 males, mean age: 6.86 years) were included. No subjects had type 2 diabetes mellitus or osteoporotic medications. LM, FM, and BMD and bone mineral content in the total body less head and the lumbar spine were measured using dual-energy x-ray absorptiometry, in addition to subcutaneous/visceral adipose tissue (SAT/VAT), and the ratio of VAT to SAT (V/S) by computed tomography at the umbilical level. Bone mineral apparent density was calculated to correct for bone size. RESULTS: LM positively correlated with bone mineral parameters after controlling for age, sex, growth hormone (GH) treatment, and FM. Although FM did not correlate with bone mineral parameters, compartment-specific analysis revealed that SAT positively and V/S negatively correlated with bone mineral parameters after controlling for age, sex, GH treatment and LM. CONCLUSIONS: A compartment-specific effect of FM on bone mineral parameters was noted such that SAT was a positive predictor for BMD independent of LM in prepubertal children with 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.