Clinical Pediatric Endocrinology最新文献

Familial neurohypophyseal diabetes insipidus is a rare genetic disease caused by AVP gene variants and is characterized by progressive polyuria and polydipsia in early childhood. Herein, we have reported the clinical symptoms and genetic test results of a Japanese patient with a family history of polyuria and polydipsia for over five generations. The proband was a 6-yr-old boy who was referred for the evaluation of polyuria and polydipsia. A hypertonic saline infusion test showed no increase in AVP levels and a water deprivation test followed by vasopressin administration confirmed the diagnosis of central diabetes insipidus. Genetic analyses of the patient and his affected mother revealed a novel heterozygous missense variant (c.308T>A, p.V103D). This variant was located in the region encoding the neurophysin II moiety. Computational analysis predicted that p.V103D is pathogenic, and a structural change was detected by viewing the three-dimensional structure of the protein model. To our knowledge, this is the first study to identify a novel missense variant, p.V103D, in a Japanese family with central diabetes insipidus. These findings expand the panel of AVP variants and facilitate the genetic diagnosis of familial neurohypophyseal diabetes insipidus.

Autoimmune hypothyroidism is categorized into Hashimoto thyroiditis (HT) and atrophic thyroiditis (AT). Although a consensus exists among Japanese endocrinologists that pediatric AT is associated with severe hypothyroidism, the question remains whether AT and HT are separate conditions. To investigate the clinical characteristics of pediatric AT, we conducted a comprehensive literature review using PubMed and ICHUSHI, a local database. We identified 54 patients (43 females), diagnosed ≤ 18 yr of age, based on 19 English- and 28 Japanese-language publications; 45 patients were Japanese. The onset of the disease typically occurs before puberty. The patients exhibited severe hypothyroidism, with median TSH level of 518.8 μIU/mL (interquartile range [IQR]: 333.0-808.6) and median Free T4 level of 0.16 ng/dL (IQR: 0.08-0.40). Common findings included a low height SD score (median -2.54 SD), low height-velocity SD score (median -3.60 SD), body mass index +1 SD (40%), delayed bone age (64%), pericardial effusion (70%), and an enlarged pituitary gland (78%). Abnormal blood test results were frequently observed, including Hb (82%), CPK (83%), AST (94%), ALT (82%), and total cholesterol (95%). Ultrasound 3D volumetry, conducted for 14 thyroid lobes, revealed 13 lobes below the 25^th percentile. In conclusion, our study underscores the clinical presentation of pediatric AT, marked by severe hypothyroidism and a small thyroid gland. Nevertheless, the paucity of data on non-Japanese patients suggests a need for further research to determine if AT and HT are indeed distinct entities.

Wieacker-Wolff syndrome (WRWF) is an X-linked genetic disorder characterized by neuromusculoskeletal abnormalities caused by loss-of-function variants of the ZC4H2 gene. Here, we report the case of a male infant with WRWF manifesting as multiple joint contractures and congenital anomalies at birth. He underwent gastrostomy to treat the gastroesophageal reflux disease, which caused mixed apnea and transient bradycardia. The patient subsequently developed hyperinsulinemic hypoglycemia (HH) and was diagnosed with dumping syndrome. Although he underwent multiple treatments, including alpha-glucosidase inhibitors (α-GI) administration, he continued to exhibit HH with seizures and loss of consciousness. Whole-exome sequencing revealed a novel missense variant of ZC4H2 [NM_018684.4: c.557T>G, p.(Met186Arg)] at Xq11.2 in both the patient and his mother. Based on these results and clinical symptoms, the patient was diagnosed with WRWF. Although WRWF is not considered a major cause of HH, we regarded it as a related complication based on previous reports. Diazoxide treatment was initiated, and the hypoglycemic attacks resolved almost entirely without any notable side effects after 18 mo. To the best of our knowledge, this is the first report of WRWF-associated HH treated with low-dose diazoxide and α-GI. Therefore, diazoxide is recommended for the treatment of WRWF-associated HH.

Idiopathic infantile hypercalcemia (IIH) is characterized by hypercalcemia, nephrocalcinosis, vomiting, dehydration, and failure to thrive. It is caused by the presence of biallelic loss-of-function variants in the CYP24A1 locus. Although hypercalcemia has been linked to the consumption of vitamin D-fortified milk, no reports have documented its role in triggering IIH in patients with CYP24A1 variants. Herein, we describe a case of IIH triggered by vitamin D-fortified milk consumption in a 9-mo-old male patient carrying a CYP24A1 variant. After BCG vaccination, the patient developed a facial rash, became anorexic, appeared to be in a bad mood, and began consuming vitamin D-fortified milk instead of baby food. Blood tests showed a marked hypercalcemia (18.5 mg/dL), high 1,25-(OH)₂D (98.7 pg/dL) levels, and low parathyroid hormone (PTH) (< 4.0 pg/dL) and PTHrP (< 1.0 pg/dL) levels. The calcium levels were successfully normalized after treatment with saline loading, furosemide, pamidronate, and a low-calcium milk diet. After discharge, blood calcium levels remained normal with no recurrence of symptomatic hypercalcemia, but circulating PTH levels were persistently suppressed. Renal ultrasonography at 8 yr of age revealed high medullary echogenicity and diffuse echogenic foci in both kidneys. Trio-based whole-genome sequencing identified the following biallelic pathogenic variants c.[464G>A];[1324C>T], p.[Trp155Ter];[Gln442Ter], in the CYP24A1 (NM_000782.5) locus. Unexplained hypercalcemia in infants should raise suspicions of abnormal vitamin D metabolism and CYP24A1 locus genotypic analysis can be informative in this regard.

Type 1 diabetes mellitus (T1DM) is a lifelong disorder that affects all aspects of the lives of children and their families. A Health Needs Assessment (HNA) survey was conducted at two diabetes camps in Batu, East Java, and Parung, West Java, to evaluate the challenges and burdens faced by families of children living with T1DM in Indonesia. A total of forty-one respondents, comprising parents/caregivers, participated in the HNA. Most respondents had to pay for diabetes-related expenses, such as insulin (31.7%), self-monitoring blood glucose (31.7%), needles and syringes (63.4%), travel expenses (97.6%), and additional laboratory examinations (24.4%). The majority of the children in this study attended school (97.6%) and most liked going to school (95%). Diabetes camps were reported to be very helpful (95.1%) for gaining more knowledge and social support within the community. A family-centered approach focusing on community support and individualized solutions is required to strengthen support, share resources, increase knowledge, and ultimately improve the quality of life of children and families living with T1DM.

In Japan, newborn screening (NBS) for congenital adrenal hyperplasia (CAH) began in 1989. NBS is useful for early diagnosis and preventing gender misidentification, however, it has a higher false positive rate for CAH compared to other diseases detected by neonatal screening. Recently, it has become clear that using liquid chromatography with tandem mass spectrometry (LC-MS/MS) for second-tier testing reduces false positive rates and repeat blood sampling. LC-MS/MS commonly measures cortisol (F), androstenedione (A4), 11-deoxycortsiol (11DOF), 21-deoxycortisol (21DOF), and 17-hydroxyprogesterone (17OHP) levels. The ratios for (21DOF+17OHP)/F and (17OHP+A4)/F have been used to establish cut-off values for the second-tier test. In Japan, the recall rate is reduced using the 11DOF/17OHP ratio as well as the ratios for (21DOF+17OHP)/F and (17OHP+A4)/F for the second-tier test. Currently, second-tier testing using LC-MS/MS for CAH neonatal screening is unfeasible in all regions of Japan due to equipment costs, however, it will hopefully be available nationwide in the future.

Measuring cortisol is crucial for assessing adrenal function in patients under stress; however, its value can fluctuate owing to various clinical factors. This study aimed to identify predictors of cortisol levels in pediatric patients with acute physiological stress. Children who were urgently admitted to the general ward or pediatric intensive care unit for acute illness or postoperative care were enrolled, while those with suspected adrenal function abnormalities or on current steroid therapy were excluded. Cortisol was measured in serum samples collected within 72 h of registration and its association with clinical factors was explored. A total of 397 samples from 217 patients were analyzed between August and November 2021 showing a median cortisol level of 375 nmol/L (interquartile range: 190-646 nmol/L). Multiple regression analysis with a mixed-effects model identified the following predictors of higher cortisol levels: heart rate z-score (+43.8 nmol/L/point), body temperature (+42.3 nmol/L/°C), Pediatric Early Warning System score (+44.3 nmol/L/point), age 3-6 yr (+68.8 nmol/L vs. < 1 yr), elapsed time < 4 h (+130.9 nmol/L vs. 4-12 h), and sampling time 6-10 AM (+96.4 nmol/L vs. 10 AM-2 PM). These variables independently predicted cortisol levels in pediatric patients during acute physiological stress.

Solitary median maxillary central incisor (SMMCI) syndrome, the mildest form of the holoprosencephaly spectrum, is a rare anomaly characterized by the presence of a single midline central incisor in both the deciduous and permanent dentitions. Affected individuals can present with additional midline defects beyond dental findings. The 22q11.2 deletion syndrome (22q11.2 DS) arises from heterozygous microdeletions on chromosome 22q11.2, with breakpoints frequently located in eight clusters of low-copy repeats (LCR22A-H). Herein, we report an atypical case of 22q11.2 microdeletion in a male patient with SMMCI and additional features including hypothyroidism, ventricular septal defect, and several facial anomalies. The telomeric breakpoint was located in a segmental duplication 0.5 Mb distal to LCR22D, whereas the centromeric breakpoint was within LCR22C. Both segmental duplications shared a high level of sequence identity (97.2%), indicating the possibility of non-allelic homologous recombination (NAHR). This report supports the critical role of NAHR in the formation of rearrangements between regions other than LCR blocks and establishes a clinical association between 22q11.2 microdeletion and SMMCI.

The mechanisms underlying the maintenance of hypertension in renovascular hypertension (RVH) are not well understood. To test the current concept of RVH pathophysiology, circulating aldosterone levels in clinical cases were investigated through a literature survey of pediatric cases. Fifty-four patients with documented aldosterone levels were identified. Of these, 42 patients (78%) were assigned to the high renin (HR) group and the rest to the low-normal renin (LR) group. Patients in the HR group were more likely to have unilateral lesions (35/42) than those in the LR group (6/12). In the LR group (corresponding to volume-dependent RVH), 50% (6/12) of patients had elevated aldosterone levels, indicating that the equilibrium between renin and aldosterone shifted towards aldosterone dominance. In the HR group (corresponding to renin-dependent RVH), aldosterone levels were much higher, with 76% (32/42) of patients exceeding the reference range and 14 patients developing hypokalemia. These results are consistent with the notion that pressure natriuresis allows continuous aldosterone action in renin-dependent RVH. In conclusion, the aldosterone status observed in the clinical cases is in agreement with the current understanding of the pathophysiology of RVH, in which a complex equilibrium state involving renin, angiotensin-II, pressure natriuresis, and aldosterone exists.