In females, endogenous estrogen secretion increases gradually before pubertal development. The benefits of low-dose estrogen therapy in patients with Turner syndrome were originally discussed by Ross et al. and Quigley et al. These seminal studies used ethinyl estradiol (EE2), starting at a dose of 25 ng/kg/d. We hypothesized that the initial dosage of estrogen could be titrated to more closely mimic physiological increments of endogenous estrogen. Therefore, our recent study initiated EE2 treatment at a dosage of 1–2 ng/kg/d, an ultra-low-dose estrogen therapy in pediatric patients with Turner syndrome. The ultra-low-dose estrogen therapy in this syndrome produced a good final height outcome but achieved suboptimal bone mineral density (BMD). In the present review, we have explained our findings to clarify the merits and demerits of this new therapy and to promote further discussion and research. This type of ultra-low-dose estrogen therapy, initiated at an early age, could be ideal for estrogen replacement in female patients with hypogonadism, such as Turner syndrome.

Existing guidelines recommend long-term follow-up of childhood cancer survivors (CCS). However, in Japan, transitional care for CCS has not been established. To ascertain the current status in Japan, and to cultivate a better understanding, a questionnaire survey was conducted on transitional care in CCS, and adolescent and young adult (AYA) cancer survivors. Questionnaires were distributed to 183 councilors (137 institutions) of the Japanese Society for Pediatric Endocrinology. A total of 131 responses, representative of 174 councilors, were obtained. The response rate was 95%. Among the respondents, 91% had experience in medical care for cancer patients, while 63% had experience in transitional care; however, the number of patients referred to adult clinics was small. Further, 89% acknowledged the availability of adult endocrinologists who were willing to accept these patients; although their numbers were insufficient. Pediatric endocrinologists highlighted difficulties in medical examinations concerning infertility, obesity, pregnancy/delivery, and gonadal dysfunction, in that order. Staff and time shortages were listed as some of the challenges faced by medical staff, while multisystem morbidity was listed for patients. This nationwide questionnaire survey revealed that Japanese pediatric endocrinologists require cooperation between related departments and collaborative infrastructure to develop transitional care for cancer survivors.

We investigated the effect of zinc supplementation on growth and serum IGF-1 levels in 10 prepubertal Japanese children with idiopathic short statures, who had serum zinc levels of less than 80 µg/dL. Subjects were started on oral zinc supplementation at a dose of 25 mg once daily. In three children, the doses were increased by 50 mg once daily during the study period of 12 mo. The serum zinc levels rose in all subjects and reached a normal range (beyond 80 µg/dL). However, it was found that zinc supplementation did not promote growth. Although the mean IGF-1 standard deviations significantly increased, the majority did not reach the normal range. There were no significant adverse events other than mild gastrointestinal symptoms in 4 out of 10 subjects during the supplementation period. The most likely reason why growth was not promoted is that the zinc supplementation dosage was not enough to stimulate IGF-1 generation and subsequent growth velocity.

Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMT-MCT) causes tumor-induced osteomalacia (TIO). Most cases follow a benign clinical course, with rare occurrences of malignant transformation. We report a case of malignant PMT-MCT and review previous malignant cases to identify predictive factors for transformation. A 13-yr-old female, who presented with hypophosphatemic rickets, elevated serum intact fibroblast growth factor 23 (FGF23) levels, and a nodule in the back, received a diagnosis of TIO because of the benign PMT histopathology. After resection of the primary tumor, regular imaging analyses did not indicate any relapse. At 17 years of age, a tumor developed in the left leg and increased in size. The resected tumor showed a histopathology of pleomorphic sarcoma positive for the TP53 mutation. Despite amputation of the affected leg, the patient died due to multiple metastases at 18 years of age. A literature review revealed that 14 out of 15 reported malignant PMT-MCT tumors occurred in adults, and found no predictive factors for malignant transformation and treatment outcome. Changes in size or number of the tumors along with intact FGF23 levels have been considered as the only sign of malignant transformation. This pediatric case report and literature review indicate the need for prolonged regular monitoring for PMT-MCT.

Neonatal diabetes mellitus (NDM) is a very rare disorder and its diagnosis can be challenging especially in mild and transient cases. Herein, we describe a 2.4-kg female infant born at 38 wk of gestation who showed hyperglycemia (388 mg/dL) on Day 1. Intermittent blood sampling showed glucose concentrations of 100–150 mg/dL on Day 2–5. However, continuous glucose monitoring (CGM) from Day 7 revealed hyperglycemia (> 200 mg/dL) after every feeding. The patient required low-dose (0.1–0.2 U/kg/d) insulin therapy for a short period (7 d). During the treatment, hypoglycemic (< 50 mg/dL) events were not detected by real- time CGM. Follow-up CGM from Day 32 showed normoglycemia for 3 full days; therefore, we ascertained that the diabetes had been transient. Later genetic analysis revealed an abnormal methylation pattern on chromosome 6q24, which is the most frequent cause of transient NDM. Most cases of 6q24-related NDM relapse after puberty, implying that long term follow up is required. We speculate that the NDM in this case might not have been diagnosed without CGM. This report highlights the usefulness of CGM for the initial diagnosis, monitoring during insulin therapy, and confirmation of improvement in patients with transient NDM.

Prader-Willi syndrome (PWS) is often related to severe obesity and diabetes mellitus (DM). Clinical findings suggesting the benefits of glucagon-like peptide-1 (GLP-1) receptor agonists for glycemic control of DM in PWS have been recently increasing. However, there are only a few reports describing the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors for PWS. We present a diabetic female with PWS, whose glycemic control was deteriorated at the age of 19 but improved to a certain extent by introducing the GLP-1 analog liraglutide. At the age of 20, the SGLT2 inhibitor empagliflozin was administered. Subsequently, her HbA1c level and body weight markedly decreased. Improvement in both insulin resistance and secretion was observed during the subsequent six months. In addition to GLP-1 receptor agonists, SGLT2 inhibitors may be a potential approach for the management of DM in PWS, especially in young patients whose pancreatic insulin secretion capabilities are still preserved.