Central precocious puberty (CPP) is a condition in which the hypothalamus–pituitary–gonadal system is activated earlier than the normal developmental stage. The etiology includes organic lesions in the brain; however, in the case of idiopathic diseases, environmental and/or genetic factors are involved in the development of CPP. A genetic abnormality in KISS1R, that encodes the kisspeptin receptor, was first reported in 2008 as a cause of idiopathic CPP. Furthermore, genetic alterations in KISS1, MKRN3, DLK1, and PROKR2 have been reported in idiopathic and/or familial CPP. Of these, MKRN3 has the highest frequency of pathological variants associated with CPP worldwide; but, abnormalities in MKRN3 are rare in patients in East Asia, including Japan. MKRN3 and DLK1 are maternal imprinting genes; thus, CPP develops when a pathological variant is inherited from the father. The mechanism of CPP due to defects in MKRN3 and DLK1 has not been completely clarified, but it is suggested that both may negatively control the progression of puberty. CPP due to such a single gene abnormality is extremely rare, but it is important to understand the mechanisms of puberty and reproduction. A further development in the genetics of CPP is expected in the future.

11-Oxyandrogens, such as 11-ketotestosterone (11-KT), 11-ketodihydrotestosterone (11-KDHT), 11β-hydroxytestosterone (11-OHT), 11β-hydroxyandrostenedione (11-OHA4), and 11-KA4, are newly specified human androgens. These 11-oxyandrogens are present in the cord blood and placenta, as well as in the blood of men and women of various ages, and are produced primarily in the adrenal gland. Accumulating evidence suggests that these steroids contribute to androgen excess in patients with 21-hydroxylase deficiency or polycystic ovary syndrome. More importantly, unlike classic androgens, 11-oxyandrogens produced in maternal tumors can pass through the placenta without being converted into estrogens, and cause severe virilization of female fetuses. Thus, overproduction of 11-oxyandrogens represents a new mechanism of 46,XX disorders of sex development. On the other hand, the physiological roles of 11-oxyandrogens remain to be clarified. This mini-review introduces the current understanding of 11-oxyandrogens, from the perspective of pediatric endocrinology.

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.

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.

Thyroid function in patients with chronic thyroiditis (CT) varies depending on the clinical course. Serum antithyroglobulin antibody (TgAb) and antithyroid peroxidase antibody (TPOAb) levels may be used to predict hypothyroidism in CT. In this retrospective cohort study, patients with CT, defined as having a high TgAb or TPOAb value, were divided into a hypothyroid group (HG) and euthyroid group (EG), after a mean follow-up of 2.5 years. The definitions of the two groups was based on the maximum TSH value from the initial measurement to the most recent follow-up: HG was defined as TSH 10.0 μIU/mL or higher, and EG was defined as TSH < 10.0 μIU/mL. There were 20 and 113 patients in the HG and EG, respectively. There were no significant differences in age, sex, underlying diseases, or TgAb and TPOAb levels between the groups. Receiver operating characteristic curve analyses of TgAb and TPOAb values for predicting thyroid function showed areas under the curve of 0.714 and 0.757, respectively. The value with the highest diagnostic accuracy was 106 IU/mL for TgAb and 16 IU/mL for TPOAb. Thus, TgAb > 106 IU/mL and TPOAb > 16 IU/mL may predict hypothyroidism in children and young adults with CT.

A 3-mo-old male infant was referred to our hospital with micropenis. Since his serum LH, FSH, and testosterone levels were low (< 0.3 mIU/mL, 0.08 mIU/mL, and < 0.03 ng/mL, respectively), Kallmann syndrome/normosmic hypogonadotropic hypogonadism was suspected. In the process of searching for complications of Kallmann syndrome/normosmic hypogonadotropic hypogonadism, a right adrenal gland tumor was incidentally discovered. The patient was diagnosed with stage 1 neuroblastoma. A homozygous p.P147L (c.C440T) mutation in the KISS1R gene was detected as a cause of the congenital hypogonadotropic hypogonadism. KISS1-KISS1R signaling, which is essential for GnRH secretion, exhibits anti-metastatic and/or anti-tumoral roles in numerous cancers. High KISS1 expression levels reportedly predict better survival outcomes than low KISS1 expression levels in neuroblastoma. Therefore, decreased KISS1-KISS1R signaling may have played a role in the neuroblastoma in this patient.

Multisystem inflammatory syndrome in children (MIS-C) is a disease related to coronavirus disease 2019 (COVID-19). Although the effects of COVID-19 on many systems are known, there is limited data regarding its effects on the endocrine system. This study aimed to discuss the effect of COVID-19 on cortisol dynamics in a patient who developed adrenal insufficiency after COVID-19 infection. An 11-yr-old boy with polymerase chain reaction-proven COVID-19 one month previously was referred with a five-day history of fever, vomiting, and rash. On admission, he had hypotension, tachycardia, and severe hyponatremia. After the evaluation, he was diagnosed with MIS-C and glucocorticoid therapy was initiated. During follow-up, the patient experienced adrenal insufficiency, and hydrocortisone treatment was initiated at a crisis dose. Four months later, the adrenal axis function had not recovered. The adrenocortical response in COVID-19 patients may be significantly impaired, resulting in increased mortality or morbidity.

Neonatal diabetes mellitus is a rare monogenic condition affecting 1 in 100,000–300,000 live births. Mutations in the subunits of ATP-sensitive potassium (K_ATP) channels, which are the central gatekeepers of electrical activity, are the common cause of this condition, thereby reducing insulin secretion in the pancreatic beta cells. Most cases are diagnosed before 6 mo of age. The development of this condition in the latter half of the first year of life is rare; hence, testing in older infants is not routinely performed. Here, we describe the case of a patient who presented with neonatal diabetes mellitus and diabetic ketoacidosis at 10 mo of age. All the pancreatic autoantibodies were undetectable, prompting us to pursue genetic testing. At 13 yr of age, a heterozygous missense variant, C42R, was identified in the KCNJ11 gene by exome sequencing. Subsequently, sulfonylurea was initiated, and insulin therapy was discontinued that resulted in improved blood glucose control and increased C-peptide levels. Given the potential benefit of switching to oral medication, genetic testing should be extended to all infants diagnosed with antibody-negative diabetes before 1 yr of age.

Recent studies have indicated that heterozygous loss-of-function variants in fibroblast growth factor receptor 1 (FGFR1) are involved in the development of congenital hypogonadotropic hypogonadism and combined pituitary hormone deficiency (CPHD). We encountered a Japanese boy with short stature and pubertal failure. Endocrine studies showed GH, TSH, and LH/FSH deficiencies, and brain magnetic resonance imaging delineated hypoplastic anterior pituitary and ectopic posterior pituitary. The patient was treated with GH, l-thyroxine, and hCG/rFSH. Next-generation sequencing panel for pituitary dysfunction identified a probably weak disease-associated heterozygous missense variant in FGFR1 (NM_023110.3:c.176A>T:p.(Asp59Val)), together with a probably non-deleterious heterozygous missense variant in KISS1R (NM_032551.5:c.769G>C:p.(Val257Leu)). We also review six previously reported CHPD patients with probably deleterious FGFR1 variants. The data, in conjunction with the previously reported cases, argue for the relevance of FGFR1 variants to the development of CPHD.

Neonatal diabetes mellitus (NDM) is a rare metabolic disorder that is mainly present in the first 6 months of life and necessitates insulin treatment. Sensor-augmented pump (SAP) therapy has been widely used in children with type 1 diabetes mellitus, but its use in patients with NDM is limited. We report three patients with NDM who received SAP therapy using the MiniMed™ 640G system starting in the neonatal period. Two patients were treated for 3 months, and one patient continued treatment up to an age of 22 mo. The MiniMed 640G system can automatically suspend insulin delivery (SmartGuard™ Technology) to avoid hypoglycemia when the sensor glucose level is predicted to approach the predefined threshold. We suggest that SmartGuard Technology is particularly useful for infants in whom hypoglycemia cannot be identified. The MiniMed 640G system automatically records the trends of sensor glucose levels and the total daily dose of insulin, which can make the management more accurate and reduce the family’s effort. SAP therapy for patients with NDM automatically prevents severe hypoglycemia and is useful for long-term management; however, attention should be paid to its application.

Thyroglobulin gene abnormalities cause thyroid dyshormonogenesis. A 6-yr-old boy of consanguineous parents presented with a large goiter and mild hypothyroidism (thyroid-stimulating hormone [TSH] 7.2 μIU/mL, free T3 [FT3] 3.4 pg/mL, free T4 [FT4] 0.6 ng/dL). Despite levothyroxine (LT4) administration and normal TSH levels, the goiter progressed slowly and increased rapidly in size at the onset of puberty. Thyroid scintigraphy revealed a remarkably high ¹²³I uptake of 75.2%, with a serum thyroglobulin level of 13 ng/ml, which was disproportionately low for the goiter size. DNA sequencing revealed a novel homozygous missense variant, c.434G>A [p.Gly145Glu], in the thyroglobulin gene. Goiter growth was suppressed by increasing the LT4 dose. Thyroidectomy was performed at 17-yr-of-age. Thyroglobulin analysis of the thyroid tissue detected mutant thyroglobulin present in the endoplasmic reticulum, demonstrating that thyroglobulin transport from the endoplasmic reticulum to the Golgi apparatus was impaired by the Gly145Glu variant. During the clinical course, an elevated FT3/FT4 ratio was observed along with thyroid enlargement. A high FT3/FT4 ratio and goiter seemed to be compensatory responses to impaired hormone synthesis. Thyroglobulin defects with goiter should be treated with LT4, even if TSH levels are normal.

Severe diabetic ketoacidosis (DKA), rarely, may be associated with elevated troponin and proBNP levels in adults with a history of diabetes. However, few cases have reported this association in children with severe and complicated DKA. We describe a case of severe DKA (pH: 6.89, HCO3: 6.5) in a 14-yr-old female adolescent in which the symptoms of DKA were presented days before the diagnosis. The patient was under the effect of acidosis (Kussmaul respiration) for 12 h before admission to our hospital, where she was admitted in a critical clinical condition. After successful treatment with DKA with intensive intravenous fluid and regular insulin, the patient presented with abnormal cardiac rhythm, disturbance of interventricular septum motility, a mild decrease in left ventricular systolic function, negative T waves in leads III and aVF, and a marked increase in troponin and brain natriuretic peptide (NT-proBNP) levels. All abnormal findings completely resolved within 8 days after the initiation of DKA treatment. The phenomenon in our case was transient, and the patient had a good long-term outcome. However, it represents a challenge for clinicians; therefore, emphasis should be given to cardiac monitoring during the course of severe and prolonged DKA in children and adolescents.

Dehydration and acidosis increase the risk for urinary stone formation. Urinary stones have been reported in three pediatric cases of diabetic ketoacidosis (DKA). A 24-h urine collection was performed for two of the three children. One patient had high urine sodium levels, while the other had low urine citrate excretion. We report the case of a 12-yr-old adolescent boy with urinary stones, new-onset type 1 diabetes mellitus (T1D), and DKA, excluding other metabolic disorders. After DKA was diagnosed, the patient received a 0.9% saline bolus and continuous insulin infusion. Hyperglycemia and ketoacidosis were well-controlled on the third day after admission. However, the patient developed abdominal pain radiating to the back. Urinary stones were suspected, and a urinalysis was performed. The patient’s urine revealed significant elevation in red blood cells and calcium oxalate crystals. Computed tomography revealed a high-density left ureteric mass, suggestive of a urinary stone. Although both the previously reported pediatric cases involved metabolic diseases, additional tests in this patient excluded metabolic diseases other than T1D. DKA may be related to the formation of calcium oxalate crystals owing to dehydration and acidosis. Therefore, physicians should consider urinary stone formation in DKA patients.