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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Context: Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. Classic (CLCAH) and nonclassic (NCLCAH) forms were reported as total and partial deficiencies, respectively, of adrenal and gonadal steroid hormones. The rarity of LCAH has precluded large-scale epidemiological and clinical investigations.Objective: To determine the epidemiological and clinical characteristics of 2 forms of LCAH.Design: A multicenter cross-sectional cohort study in Japan on December 1, 2017.Participants: Fifty-seven patients with LCAH (median age, 23.7 years; range, 0.0-47.5 years).Main Outcome Measures: Patient demographics, STAR genotype, Quigley grade, endocrinological and imaging data, treatment, and prognosis.Results: Fifty-three and 4 patients fulfilled definite and probable diagnostic criteria for LCAH, respectively. When NCLCAH was defined as either Quigley grade 1 in XY karyotype, no episode of salt losing or requirement of fludrocortisone, or onset of primary adrenal insufficiency (PAI) at 1 year or older, patients were divided into groups of 43 patients with CLCAH (75.4%), 11 with NCLCAH (19.3%), and 3 with unclassified LCAH (5.3%). All of the patients with CLCAH and 7/11 NCLCAH (63.6%) were treated with fludrocortisone. CLCAH was diagnosed at a significantly younger age than NCLCAH (median, 0.0 vs 4.0 years). STAR-Arg272Cys or -Met225Thr was identified only in NCLCAH (8/11, 72.7%).Conclusions: We demonstrated the relative proportions and clinical and molecular characteristics of NCLCAH and CLCAH in Japan. These criteria for NCLCAH correspond to all previously published cases and our cases whose masculinization of the external genitalia, ability of mineralocorticoid production, and onset of PAI were described. [ABSTRACT FROM AUTHOR]

Selenium (Se) is an essential trace element that is involved in numerous biological processes in the form of a selenoprotein such as iodothyronine deiodinase (DIO). Se deficiency may prevent the conversion of T4 to T3 through reducing DIO expression and thereby affecting thyroid hormone status. However, this has not been well documented in humans. In this study, to clarify the association between Se and thyroid hormone status, we investigated the thyroid hormone levels in patients with severe Se deficiency (< 2 μg/dl). Severe Se deficiency was associated with increases in free T4 levels, but not with decreases and increases in free T3 and thyroid stimulating hormone (TSH) levels, respectively. Increases in free T4 levels during Se deficiency were reduced with Se supplementation; however, neither free T3 nor TSH levels were affected. Taken together, these findings indicate that free T4 may be a useful biomarker for Se status when serum Se levels are severely low. [ABSTRACT FROM AUTHOR]

Congenital hyperinsulinism is a rare condition and following recent advances in diagnosis and treatment, it was considered necessary to formulate evidence-based clinical practice guidelines reflecting the most recent progress, to guide the practice of neonatologists, pediatric endocrinologists, general pediatricians and pediatric surgeons. These guidelines cover a range of aspects, including general features of congenital hyperinsulinism, diagnostic criteria and tools for diagnosis, first-and second-line medical treatment, criteria for and details of surgical treatment, and future perspectives. These guidelines were generated as a collaborative effort between The Japanese Society for Pediatric Endocrinology and The Japanese Society of Pediatric Surgeons and followed the official procedures of guideline generation to identify important clinical questions, perform a systematic literature review (April 2016), assess the evidence level of each paper, formulate the guidelines and obtain public comments. [ABSTRACT FROM AUTHOR]

Esophagogastric landmarks are recognizable in the same way both in children and in adults, and palisade-shaped vessels can be observed at the distal position of esophageal mucosa, even in infants. Few studies have been done in respect to Barrett's esophagus (BE) in children. Incidence of endoscopically suspected BE among all children undergoing esophagogastroduodenoscopy (EGD) is approximately 0.25-1.4%, but can be up to 9.7% in patients with gastroesophageal reflux disease (GERD). Some data suggest that BE is an acquired disorder and point to the possibility of a congenital component in combination with severe mucosal injury. Recent reports noted that multilayered epithelium (ME), which shows morphological and immunocytochemical characteristics of both squamous and columnar epithelium, is associated with goblet cell metaplasia in adult patients with columnar-lined esophagus. The role of ME in the development of intestinal metaplasia in children is uncertain. Furthermore, detailed mechanisms about how short-segment BE (SSBE) changes to long-segment BE (LSBE) are not yet well understood. Further studies are required to understand the pathological esophagogastric junction (EGJ) and BE in children based on reliable epidemiological data and analysis especially in children who have reflux symptoms. Better understanding of the pediatric EGJ and BE may allow improved diagnosis, monitoring, therapy and, therefore, prognosis of GERD-related disorders in adulthood. [ABSTRACT FROM AUTHOR]

A clinical diagnosis of septo-optic dysplasia (SOD) is made when two or more of the classical triad of optic nerve hypoplasia, pituitary hormone abnormalities or midline brain defects. To date, a clinical study of SOD, regarding its endocrinological features in particular, has not been undertaken in Japan. We retrospectively evaluated 14 SOD patients at our institution. Hormonal dysfunction was present in 78% of cases: ten cases presented combined hypopituitarism and one case presented precocious puberty. GHD and hypothyroidism were the most common endocrinopathies. A thin pituitary stalk and a gradual decrease in hormone secretion were the main characteristics. SOD patients usually visited ophthalmologists during early infancy because of eye problems; however, the medical examination did not always lead to endocrine assessments being made. Consequently, children who have eye problems with optic nerve hypoplasia should undergo head MRI imaging. If diagnosed with SOD, it is very important to evaluate pituitary functions. Their endocrinological status should be followed for a long time, even if they do not exhibit any endocrinological problems at evaluation. [ABSTRACT FROM AUTHOR]

The presence of Y chromosome material in patients with disorders of sex development (DSD) has been associated with a high risk of gonadoblastoma. Therefore, gonadectomy is recommended in females with bilateral streak gonads and Y chromosome material. The aim of this study was to present our experience with prophylactic gonadectomy in those patients and evaluate their risk of gonadal tumors. We reviewed the charts of 11 female patients who had bilateral gonadectomy (by laparoscopically in 9 patients, by laparotomy in 2 patients) between 1991 and 2012 at our hospital. Seven patients with Turner syndrome (TS) who carry a Y mosaic karyotype in peripheral blood, 3 patients with Swyer syndrome and one patient with Frasier syndrome were included. All patients had an unambiguous female phenotype. Age at surgery and follow-up ranged from 2 to 23 (mean 11) and 0.5 to 20 (mean 8) yr, respectively. Pathologic examination revealed gonadal tumors in 6 of 11 patients (56%), including 4 with TS, the youngest of which was 2 yr old, one with Swyer syndrome and one with Frasier syndrome. A gonadoblastoma was detected in 8 gonads, and an association of dysgerminoma with gonadoblastoma was detected in 2 gonads. Imaging studies showed no metastasis, and the postoperative course was uneventful in all patients. In our series of DSD patients with bilateral streak gonads and Y chromosome material, the risk of gonadal tumor was high. Considering the early occurrence of gonadoblastoma and its high potential for malignant transformation, early prophylactic gonadectomy is strongly recommended. [ABSTRACT FROM AUTHOR]

CHARGE syndrome is a congenital disorder caused by mutation of the chromodomain helicase DNA binding protein 7 (CHD7) gene and is characterized by multiple anomalies including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genital and/ or urological abnormalities, ear anomalies, and hearing loss. In the present study, 76% of subjects had some type of endocrine disorder: short stature (72%), hypogonadotropic hypogonadism (60%), hypothyroidism (16%), and combined hypopituitarism (8%). A mutation in CHD7 was found in 80% of subjects. Here, we report the phenotypic spectrum of 25 Japanese patients with CHARGE syndrome, including their endocrinological features. [ABSTRACT FROM AUTHOR]