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.

Proportion of Successful Lumbar Punctures in Infants Younger Than Three Months.

It is important to perform lumbar punctures (LPs) without a single traumatic tap in infants younger than three months owing to the risk of serious complications. The proportion of LPs in which clear cerebrospinal fluid (CSF) was obtained has been previously reported, but some of the procedures involved a traumatic tap. The present study aimed to identify the proportion of LPs in which clear CSF was obtained without a single traumatic tap and the factors associated with successful LPs in infants younger than three months. This retrospective, observational study included children younger than three months who underwent an LP in the pediatric emergency department between April 2018 and March 2021. The primary outcome was the proportion of successful LPs, defined as LPs obtaining clear CSF without a single traumatic tap. Multiple logistic regression analysis was used to identify factors related to successful LPs. Of 126 eligible patients, 121 were included. Among these, 83 (69%) were in the successful group. No factors significantly associated with successful LPs were found. Larger studies based on an accurate definition of successful LPs, such as that provided by this study, are needed to investigate related factors to increase the rate of successful LPs in this age group.

Incidence and Risk Factors for Adrenal Crisis in Pediatric-onset Adrenal Insufficiency: A Prospective Study.

PURPOSE: To determine the incidence and risk factors for adrenal crisis (AC) in patients with pediatric-onset adrenal insufficiency (AI). MATERIALS AND METHODS: This multicenter, prospective cohort study conducted in Japan enrolled patients diagnosed with AI at ≤ 15 years of age. The incidence of AC was calculated as events per person-year (PY), and risk factors for AC were assessed using Poisson regression multivariable analysis. RESULTS: The study population comprised 349 patients (164 male, 185 female) with a total follow-up of 961 PY. The median age at enrollment was 14.3 years (interquartile range [IQR] 8.5-21.2 years), and the median follow-up was 2.8 years (IQR 2.2-3.3 years). Of these patients, 213 (61%) had primary AI and 136 (39%) had secondary AI. Forty-one AC events occurred in 31 patients during the study period. The calculated incidence of AC was 4.27 per 100 PY (95% confidence interval [CI] of 3.15-5.75). Poisson regression analysis identified younger age at enrollment (relative risk [RR] 0.93 [95% CI 0.89-0.97]) and increased number of infections (RR 1.17 [95% CI 1.07-1.27]) as significant risk factors. Female sex (RR 0.99 [95% CI 0.53-1.86]), primary AI (RR 0.65 [95 % CI 0.30-1.41]), or equivalent dosage of hydrocortisone per square meter of body area (RR 1.02 [95% CI 0.96-1.08]) was not a significant risk factor. CONCLUSION: A substantial proportion of patients with pediatric-onset AI experience AC. Younger age and an increased number of infections are independent risk factors for developing AC in these patients.

Utility of basal and peak TSH values in TRH stimulation testing for predicting the long-term therapeutic prognosis of primary congenital hypothyroidism.

In Japan, most neonates undergo screening for congenital hypothyroidism (CH). A TRH stimulation test (TRH-T) may be performed after initial treatment as a useful method for reevaluating the patient's thyroid status. However, no studies have compared basal and peak TSH values in TRH-T in patients with long-term follow-up. This was a retrospective and observational study. The inclusion criteria were as follows: (1) CH diagnosis based on positive newborn screening, (2) follow-up > 15 yr, and (3) TRH-T after LT4 discontinuation. The participants were divided into a no-treatment group (No-T group) and a treatment group (T group). The No-T and T groups included 14 and nine patients, respectively. The age at TRH-T was 5.38 yr for the No-T group and 4.25 yr for the T group, with no significant difference. The basal and peak TSH levels were significantly lower in the No-T group. The areas under the Receiver operating characteristic curve for basal and peak TSH values were 0.984 and 0.905, respectively. When the basal TSH level was under 4.594 IU/mL, the No-T group had a sensitivity of 1.00 and a specificity of 0.93. Basal TSH levels alone may be sufficient for predicting the long-term therapeutic prognosis of patients with CH.

Acute Adrenal Insufficiency Caused by Mental Stress in a Patient With Adrenocorticotropic Hormone Deficiency.

In patients with chronic adrenal insufficiency, physical stress increases the requirement for glucocorticoid therapy. Although mental stress may cause acute adrenal insufficiency, it is debatable how patients should be treated when experiencing mental stress. Here, we report the case of a female patient with septo-optic dysplasia who had been treated for adrenocorticotropic hormone deficiency since infancy. After her grandfather died when she was 17 years old, she complained of nausea and stomach pain. Her symptoms failed to improve despite treatment with stress doses of oral hydrocortisone and self-administered glucagon injection. Her general condition improved after she began receiving continuous hydrocortisone and glucose infusions. Glucocorticoid stress doses should be given early if a patient is likely to experience mental stress.

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.

Viral loads of parainfluenza virus type 3 and severity of respiratory diseases in children.

BACKGROUND: Parainfluenza virus type 3 (PIV-3) is one of the common pathogens for respiratory infections in children. Whether viral load of PIV-3 is associated with severity of respiratory diseases in children is not yet known. Our aim was to determine significance of PIV-3 viral load among infected children. METHODS: We conducted a single-center, retrospective study at Tokyo Metropolitan. Children's Medical Center, Japan, from June to August 2021. Hospitalized children were screened with a posterior nasal swab for multiplex PCR, and viral load was subsequently measured from remained samples by real-time PCR. Demographic data were collected from digital charts. PIV-3 positive patients were categorized into mild group with no oxygen demand, moderate group with low-flow oxygen demand and severe group with high-flow nasal cannula oxygen or non-invasive positive pressure ventilation or mechanical ventilation. Viral loads were compared among mild, moderate and severe groups. RESULTS: 151 patients were positive for PIV-3. We found no statistically significant association among PIV-3 viral load and severity of respiratory diseases (p = 0.35), and no statistically significant association between severity of illness and co-detection of other viruses. In each severity group, relatively high viral load per posterior nasal swab was observed at the time of testing. CONCLUSION: Among PIV-3 patients, we could not find statistically significant between viral load and their severity, therefore we could not conclude that viral load is a good surrogate marker for clinical severity of PIV-3.

Adrenal gland involvement in 11-ketotestosterone production analyzed using LC-MS/MS.

Introduction: 11-ketotestosterone (11KT), which is derived by the bioconversion of testosterone via 11ß-hydroxytestosterone (11OHT), is a potent agonist of the human androgen receptor. The adrenal gland is considered an important organ in 11KT production because CYP11B1, which catalyzes testosterone to 11OHT, is expressed in the adrenal glands. The present study aimed to demonstrate adrenal gland involvement in 11KT production in prepubertal children, a topic which has not yet been addressed by any previous studies. Methods: Three, retrospective, observational studies were performed. Study 1 enrolled patients aged 8 months to 7 years with severe Kawasaki disease (KD) who were treated with mPSL pulse. Studies 2 and 3 included patients who had received a corticotropin-releasing hormone (CRH) stimulation test and adrenocorticotropic hormone (ACTH) stimulation test, respectively. Samples were collected before and after treatment or drug administration, and serum 11KT, 11OHT, and other 11-oxygenated androgens were measured by LC-MS/MS. Steroid hormone values before and after medication were analyzed using the Wilcoxon signed rank test. Results: Studies 1, 2, and 3 included twenty patients with severe KD, eight patients with a CRH stimulation test, and eight patients with an ACTH stimulation test, respectively. Study 1 demonstrated that the median (IQR) 11KT level was significantly higher before, than after, mPSL pulse (0.39 (0.28-0.47) nmol/L versus 0.064 (0.012-0.075) nmol/L; P < 0.001). Studies 2 and 3 indicated no significant difference in the median 11KT value before and after the CRH or ACTH stimulation test while the 11OHT value was significantly higher after the test. Conclusion: In conclusion, the mediation of 11KT production by ACTH demonstrated the importance of the adrenal glands in the synthesis of this androgen in prepubertal children.

Natto intake is a risk factor of Bacillus subtilis bacteremia among children undergoing chemotherapy for childhood cancer: A case-control study.

BACKGROUND: Natto, a popular, daily food in Japan, is made from soybeans fermented by Bacillus subtilis. The aim of this retrospective case-control study (matched 1: 4) is to determine whether natto intake is a risk factor of B. subtilis bacteremia in this population. METHODS: The retrospective, matched case-control study was conducted at Tokyo Metropolitan Children's Medical Center between April 2012 and June 2020 and included pediatric patients younger than 15 years who received chemotherapy for cancer. Patients who received hematopoietic stem cell transplantation were excluded. Patients with B. subtilis bacteremia were compared with controls matched for age and underlying diseases. Dietary information within seven days from the date of blood culture collection was extracted from medical records. Multivariate logistic regression was performed to define the risk factors of B. subtilis bacteremia. RESULTS: In total, 23 patients with B. subtilis bacteremia were identified and matched to 92 controls. The percentage of patients and controls who ingested natto within seven days from the date of blood culture collection was 78% and 50%, respectively. On univariate analysis, the odds ratio of natto intake for B. subtilis bacteremia was 3.6 (95% confidence interval [CI]: 1.2-10.5). Multivariable logistic regression tests after controlling for neutropenia revealed that B. subtilis bacteremia was associated significantly with natto intake at odds ratio 3.3 (95% CI: 1.1-9.6). CONCLUSION: Natto intake was associated with B. subtilis bacteremia during chemotherapy for childhood cancer.

Fracture risk, underlying pathophysiology, and bone quality assessment in patients with Turner syndrome.

Turner syndrome (TS), the most common type of X chromosomal disorder, has various, clinical manifestations. Among these, primary hypogonadism, which may lead to osteoporosis, is a life-long health issue. A high prevalence of fractures associated with osteoporosis is a major problem in patients with TS, where it may be 1.4-2.2 times higher than in healthy individuals and increases with age. Among the risk factors associated with fractures in TS, hypogonadism is arguably the most important. Estrogen deficiency due to hypogonadism leads to low bone mineral density (BMD), resulting in a high prevalence of bone fractures. Estrogen replacement therapy (ERT) in patients with TS reportedly improved their BMD. However, other causes of low BMD may exist, given that this condition begins in the prepubertal period in patients with TS. Most previous studies have reported low BMD in patients with TS using dual-energy X-ray absorptiometry (DXA), but this method has some limitations. Areal BMD values assessed by DXA were influenced by bone size and short stature, resulting in an underestimation of BMD. Currently, volumetric BMD values may be accurately obtained using peripheral quantitative computed tomography (pQCT). pQCT, high-resolution pQCT, and the trabecular bone score can also be used to evaluate bone quality, including bone geometry and microarchitecture, in TS. The present review discusses the high fracture risk, role of estrogen deficiency in low BMD, advantages and disadvantages of various bone assessment methods, and characteristics of bone quality in TS.

Oral disintegrating desmopressin tablet is effective for partial congenital nephrogenic diabetes insipidus with AVPR2 mutation: a case report.

Congenital nephrogenic diabetes insipidus (NDI) is a rare disease that causes polydipsia and polyuria, and there are currently no effective treatments for most cases, particularly severe ones. The present report describes the case of a 1-yr-5-mo-old male patient with partial congenital NDI who was successfully treated with oral disintegrating 1-deamino-8-D-arginine vasopressin (DDAVP). The patient presented with poor weight gain and polydipsia (fluid, 1.5 L/d) and received a diagnosis of NDI after genetic analysis revealed an AVPR2 mutation (c.383A>C, p.Y128S). His water-restricted urine osmolality increased from 360 mOsm/kg/H2O to 667 mOsm/kg/H2O after subcutaneous AVP injection, indicating that he had some urine concentrating ability. Oral disintegrating DDAVP therapy was started at 360 µg/d with hydrochlorothiazide and increased to 720 µg/d without any adverse effects. A 30% decrease in urine output and water intake was followed by an increase in body weight. The present study is the first to report the effectiveness and safety of oral disintegrating DDAVP in a patient with partial congenital NDI due to an AVPR2 gene mutation. The severity of NDI at which DDAVP therapy is the most effective remains to be determined.

Genetic Analysis of Japanese Children Clinically Diagnosed with Familial Hypercholesterolemia.

AIM: This study aimed to elucidate the gene and lipid profiles of children clinically diagnosed with familial hypercholesterolemia (FH). METHODS: A total of 21 dyslipidemia-related Mendelian genes, including FH causative genes (LDLR, APOB, and PCSK9) and LDL-altering genes (APOE, LDLRAP1, and ABCG5/8), were sequenced in 33 Japanese children (mean age, 9.7±4.2 years) with FH from 29 families. RESULTS: Fifteen children (45.5%) with pathogenic variants in LDLR (eight different heterozygous variants) and one child (3.0%) with the PCSK9 variant were found. Among 17 patients without FH causative gene variants, 3 children had variants in LDL-altering genes, an APOE variant and two ABCG8 variants. The mean serum total cholesterol (280 vs 246 mg/dL), LDL-cholesterol (LDL-C, 217 vs 177 mg/dL), and non-HDL cholesterol (228 vs 188 mg/dL) levels were significantly higher in the pathogenic variant-positive group than in the variant-negative group. In the variant-positive group, 81.3% of patients had LDL-C levels ≥ 180 mg/dL but 35.3% in the variant-negative group. The mean LDL-C level was significantly lower in children with missense variants, especially with the p.Leu568Val variant, than in children with other variants in LDLR, whereas the LDL-altering variants had similar effects on the increase in serum LDL-C to LDLR p.Leu568Val. CONCLUSION: Approximately half of the children clinically diagnosed with FH had pathogenic variants in FH causative genes. The serum LDL-C levels tend to be high in FH children with pathogenic variations, and the levels are by the types of variants. Genetic analysis is useful; however, further study on FH without any variants is required.

Optical Genome Mapping for a Patient with a Congenital Disorder and Chromosomal Translocation.

We performed optical genome mapping (OGM), a newly developed cytogenetic technique, for a patient with a disorder of sex development (DSD) and a 46,XX,t(9;11)(p22;p13) karyotype. The results of OGM were validated using other methods. OGM detected a 9;11 reciprocal translocation and successfully mapped its breakpoints to small regions of 0.9-12.3 kb. OGM identified 46 additional small structural variants, only three of which were detected by array-based comparative genomic hybridization. OGM suggested the presence of complex rearrangements on chromosome 10; however, these variants appeared to be artifacts. The 9;11 translocation was unlikely to be associated with DSD, while the pathogenicity of the other structural variants remained unknown. These results indicate that OGM is a powerful tool for detecting and characterizing chromosomal structural variations, although the current methods of OGM data analyses need to be improved.

Epidemiology of anaphylaxis and biphasic reaction in Japanese children.

AIM: Anaphylaxis is common, but can sometimes be fatal. However, data on the epidemiology and characteristics of anaphylaxis are limited. Although 0.9%-14.7% of anaphylactic reactions in children are biphasic, it is unclear what the characteristics of biphasic reaction are and how long patients with this reaction should be observed. The present study aimed to investigate the epidemiology of anaphylaxis and biphasic reactions and identify the characteristics of the latter. METHODS: We conducted an observational study of patients who visited the pediatric emergency department (PED) and were hospitalized for anaphylaxis between March 2010 and March 2017. RESULTS: Of the 264,689 children who visited our PED, 353 (1.3 per 1,000 patient) were hospitalized for anaphylaxis, and six (1.7%) had a biphasic reaction. Of the patients with a biphasic reaction, the median time from initial anaphylaxis to the biphasic reaction was 5.9 (interquartile range [IQR] = 3.3-7.6) hours. Symptoms of the initial episode and the biphasic reaction varied. One (0.3%) of the 353 patients developed a clinically important biphasic reaction that required epinephrine administration. CONCLUSIONS: The rate of biphasic reactions was 1.7%, and that of clinically important biphasic reactions was 0.3%. Patients with anaphylaxis need to be carefully monitored because of the regular occurrence of biphasic reactions.

Errata to "Ultra-low-dose estrogen therapy for female hypogonadism".

[This corrects the article DOI: 10.1297/cpe.29.49.].

Ultra-low-dose estrogen therapy for female hypogonadism.

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.