Identification of clinical factors related to antibody-mediated immune response to the subfornical organ.

OBJECTIVE: We recently reported cases of adipsic hypernatremia caused by autoantibodies against the subfornical organ in patients with hypothalamic-pituitary lesions. This study aimed to clarify the clinical features of newly identified patients with adipsic hypernatremia whose sera displayed immunoreactivity to the mouse subfornical organ. DESIGN: Observational cohort study of patients diagnosed with adipsic hypernatremia in Japan, United States, and Europe. METHODS: The study included 22 patients with adipsic hypernatremia but without overt structural changes in the hypothalamic-pituitary region and congenital disease. Antibody response to the mouse subfornical organ was determined using immunohistochemistry. The clinical characteristics were compared between the patients with positive and negative antibody responses. RESULTS: Antibody response to the mouse subfornical organ was detected in the sera of 16 patients (72.7%, female/male ratio, 1:1, 12 pediatric and 4 adult patients). The prolactin levels at the time of diagnosis were significantly higher in patients with positive subfornical organ (SFO) immunoreactivity than in those with negative SFO immunoreactivity (58.9 ± 33.5 vs. 22.9 ± 13.9 ng/ml, p < .05). Hypothalamic disorders were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia. Plasma renin activity levels were significantly higher in patients with serum immunoreactivity to the Nax channel. CONCLUSIONS: The patients with serum immunoreactivity to the SFO had higher prolactin levels and hypothalamic disorders compared to those without the immunoreactivity. The clinical characteristics of patients with serum immunoreactivity to the subfornical organ included higher prolactin levels and hypothalamic disorders, which were frequently associated with central hypothyroidism and the presence of retroperitoneal tumors.

Long-Term Nutritional Counseling for a Patient with Lipoprotein Lipase Deficiency.

A one-year-and-nine-month-old Japanese boy was admitted with hypertriglyceridemia (fasting triglycerides 2548 mg/dL). After close examination, he was diagnosed with lipoprotein lipase (LPL) deficiency (compound heterozygous) and was immediately started on a fat-restricted dietary therapy. He responded well to the regimen (1200 kcal/day, 20 g fat/day) and his triglycerides decreased to 628 mg/dL within 7 days of starting the dietary therapy. It was decided to manage his illness without using any drugs because he was still an infant and responded well to a fat-restricted diet. During his hospital stay, dietitians provided him with nutritional counseling using a food exchange list, which was designed to easily calculate the fat content by including foods that are commonly served. His family quickly learned the skills to prepare a fat-restricted diet. Moreover, since dietary restrictions may have impaired the child's growth and development, the dietitians continued to intervene regularly after the child was discharged from the hospital. The dietitians confirmed that the patient was receiving nutritional intake appropriate for his growth and discussed the dietary concerns in his daily life and how to participate in school events that involved eating and drinking. Nutritional counseling was provided every 3-4 months from disease onset to age 23 years, except for a 14-month break at age 20 years. The patient grew up without developing acute pancreatitis, a serious complication of LPL deficiency. The long-term intervention of dieticians is necessary to achieve a balance between living on a strict diet for disease management and ensuring appropriate nutritional intakes for growth/development.

Association between conditioning intensity and height growth after allogeneic hematopoietic stem cell transplantation in children.

BACKGROUND: The present study aimed to examine the association between the conditioning intensity and height growth in pediatric patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: We reviewed the clinical records of 89 children with malignant diseases who underwent initial allo-HSCT between 2003 and 2021. Height measurements were standardized using standard height charts prepared by the Japanese Society for Pediatric Endocrinology to calculate standard deviation score (SDS). We defined short stature as a height SDS less than -2.0 in that reference. Myeloablative conditioning (MAC) comprised total-body irradiation at more than 8 Gy and busulfan administration at more than 8 mg/kg (more than 280 mg/m2 ). Other conditioning regimens were defined as reduced intensity conditioning (RIC). RESULTS: A total of 58 patients underwent allo-HSCT with MAC, and 31 patients received allo-HSCT with RIC. There were significant differences in the height SDS at 2 and 3 years after allo-HSCT between MAC and RIC group (-1.33 ± 1.20 vs. -0.76 ± 1.12, p = 0.047, -1.55 ± 1.28 vs. -0.75 ± 1.11, p = 0.022, respectively). Multivariate logistic regression analysis with the adjustments for potential confounding factors of patients less than 10 years of age at allo-HSCT and chronic graft-versus host disease demonstrated that MAC regimen was associated with a markedly increased risk of a short stature at 3 years after allo-HSCT (adjusted odds ratio, 5.61; 95% confidence interval, 1.07-29.4; p = 0.041). CONCLUSION: The intensity of conditioning regimen may be associated with short statures after allo-HSCT.

Safe administration of sotrovimab to a COVID-19 patient with acute phase type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) and poor glycemic control are risk factors for severe coronavirus disease 2019 (COVID-19). Sotrovimab can treat mild-to-moderate COVID-19 in patients at a high risk of progression to severe COVID-19. However, its safety and efficacy in T1DM patients remain to be elucidated. We report the case of a 12-yr-old patient who was treated with sotrovimab for COVID-19 immediately after treatment for diabetic ketoacidosis (DKA) due to new-onset T1DM. He presented with nausea and sore throat and was diagnosed with severe DKA and COVID-19. A productive cough and sputum developed after admission. On the 3rd day of admission, the DKA resolved, and sotrovimab was administered to prevent exacerbation of COVID-19. Although the blood glucose levels increased after the administration of sotrobimab, there was no recurrence of DKA. Hyperglycemia may be a sotrovimab-related adverse event in T1DM patients. Nevertheless, the benefits of sotrovimab treatment may far outweigh the potential risks. Thus, sotrovimab was considered safe for patients with T1DM immediately after treatment of severe DKA.

Mild progressive osseous heteroplasia overlap syndrome with PTH and TSH resistance appearing during adolescence and not early childhood.

PURPOSE: Progressive osseous heteroplasia (POH), a genetic disorder, is associated with Albright's hereditary osteodystrophy (AHO), pseudohypoparathyroidism, and primary osteoma cutis and has common features of superficial ossification and GNAS-inactivating mutations. Disorders due to GNAS-inactivating mutations are classified as "inactivating parathyroid hormone (PTH)/PTHrP signaling disorder type 2." This study reports a case of mild POH overlap syndrome to improve understanding of genotype-phenotype correlations. METHODS: A 13-year and 6-month-old Japanese boy was referred to our hospital with a chief complaint of the lower limb length difference. He underwent clinical, biochemical, radiological, and genetic studies. RESULTS: He showed sporadic GNAS mutation, deep ectopic ossification, small for gestational age (SGA), congenital tooth defect, and lack of AHO features; he met the diagnostic criteria for POH, and mild PTH and TSH resistance was detected. He had constant hyperphosphatasemia and hypocalciuria. At the age of 10 years, he occasionally experienced high iPTH levels. The pituitary stimulation test showed a normal response of all hormones at 3 years of age, but TSH response was decreased (previously 0.770, peak value 4.144 µIU/mL) in the TRH loading test at age 13 years and 6 months. DNA analysis showed a heterozygous p.D189MfsTer14 mutation of GNAS. The parents did not carry this mutation. CONCLUSION: We report a rare case of POH overlap syndrome with PTH/TSH resistance that appeared in adolescence rather than early childhood. Cases diagnosed with POH in early childhood also require reassessment during adolescence. Further studies of the GNAS heterozygous mutation p.D189MfsTer14 may reveal factors involved in POH overlap syndrome.

Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait.

CONTEXT: Familial hypophosphatemic rickets is usually transmitted as an X-linked dominant disorder (XLH), although autosomal dominant forms have also been observed. Genetic studies of these disorders have identified mutations in PHEX and FGF23 as the causes of X-linked dominant disorder and autosomal dominant forms, respectively. OBJECTIVE: The objective of the study was to describe the molecular genetic findings in a family affected by hypophosphatemic rickets with presumed autosomal dominant inheritance. PATIENTS: We studied a family in which the father and the elder of his two daughters, but not the second daughter, were affected by hypophosphatemic rickets. The pedigree interpretation of the family suggested that genetic transmission of the disorder occurred as an autosomal dominant trait. METHODS AND RESULTS: Direct nucleotide sequencing of FGF23 and PHEX revealed that the elder daughter was heterozygous for an R567X mutation in PHEX, rather than FGF23, suggesting that the genetic transmission occurred as an X-linked dominant trait. Unexpectedly, the father was heterozygous for this mutation. Single-nucleotide primer extension and denaturing HPLC analysis of the father using DNA from single hair roots revealed that he was a somatic mosaic for the mutation. Haplotype analysis confirmed that the father transmitted the genotypes for 18 markers on the X chromosome equally to his two daughters. The fact that the father transmitted the mutation to only one of his two daughters indicated that he was a germline mosaic for the mutation. CONCLUSIONS: Somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance.

Decreased insulin secretion and dyslipidemia coexist in subjects with impaired fasting glucose.

We examined the fasting plasma glucose (FPG) levels at which the compensatory mechanism of pancreatic beta cells could act and dyslipidemia would occur in Japanese subjects. A 75 g oral glucose tolerance test (OGTT) was performed on 8923 subjects. The relationship between FPG and immunoreactive insulin (IRI) was analyzed. The mean Sigma IRI (sum of IRI during OGTT) level formed an inverted U-shaped curve with a peak level at FPG of 110-130 mg/dl. The mean IRI level 30 min after glucose administration (as a marker of initial insulin secretion) began to decrease at an FPG level of approximately 100 mg/dl. The mean triglyceride level increased linearly with the elevation of the FPG level at FPG levels of 80-120 mg/dl. The mean high-density lipoprotein-cholesterol level decreased linearly with increasing FPG at FPG levels of 80-110 mg/dl. In Japanese, total insulin secretion during OGTT was affected at FPG levels >110-130 mg/dl. Moreover, subjects with FPG levels >110 mg/dl showed decreased initial insulin secretion and dyslipidemia. These results may indicate the necessity of intervention in individuals with impaired fasting glucose.

Gonadotropin-independent precocious puberty associated with a somatic activating mutation of the LH receptor gene: detection of a mutation present in only a small fraction of cells from testicular tissue using wild-type blocking polymerase chain reaction and laser-capture microdissection.

OBJECTIVE: Leydig cells are the principal source of testosterone, and boys with Leydig cell tumors typically have signs of gonadotropin-independent precocious puberty as a result of testosterone secretion by the tumor. A single somatic activating mutation of the LH receptor gene, Asp578His, limited to the tumoral Leydig cells, has been described in a few boys with gonadotropin-independent precocious puberty. We report a molecular study of a boy with gonadotropin-independent precocious puberty caused by a Leydig cell tumor. DESIGN AND SETTING: This is a clinical case report from the Kobe Children's Hospital. PATIENT AND METHODS: One patient with gonadotropin-independent precocious puberty caused by a Leydig cell tumor underwent a left orchidectomy. We performed a genetic study of the tumoral Leydig cells. RESULT: Using wild-type blocking PCR (WTB-PCR) and laser-capture microdissection (LCM), we found that the Asp578His mutation of the LH receptor gene was exclusively localized to the tumoral Leydig cells and was absent in the adjacent normal tissue and leukocytes. CONCLUSIONS: WTB-PCR and LCM are powerful techniques that can detect a somatic mutation present in only a small fraction of cells from heterozygous tissue samples.