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Context: Thyroglobulin (Tg), encoded by TG, is essential for thyroid hormone synthesis. TG defects result in congenital hypothyroidism (CH). Most reported patients were born before the introduction of newborn screening (NBS)., Objective: We aimed to clarify the phenotypic features of patients with TG defects diagnosed and treated since the neonatal period., Methods: We screened 1061 patients with CH for 13 CH-related genes and identified 30 patients with TG defects. One patient was diagnosed due to hypothyroidism-related symptoms and the rest were diagnosed via NBS. Patients were divided into 2 groups according to their genotypes, and clinical characteristics were compared. We evaluated the functionality of the 7 missense variants using HEK293 cells., Results: Twenty-seven rare TG variants were detected, including 15 nonsense, 3 frameshift, 2 splice-site, and 7 missense variants. Patients were divided into 2 groups: 13 patients with biallelic truncating variants and 17 patients with monoallelic/biallelic missense variants. Patients with missense variants were more likely to develop thyroid enlargement with thyrotropin stimulation than patients with biallelic truncating variants. Patients with biallelic truncating variants invariably required full hormone replacement, whereas patients with missense variants required variable doses of levothyroxine. Loss of function of the 7 missense variants was confirmed in vitro., Conclusion: To our knowledge, this is the largest investigation on the clinical presentation of TG defects diagnosed in the neonatal period. Patients with missense variants showed relatively mild hypothyroidism with compensative goiter. Patients with only truncating variants showed minimal or no compensative goiter and required full hormone replacement., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pseudohypoparathyroidism 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by loss-of-function variants of GNAS , which encodes Gsα. We present two unrelated Japanese families with PHP1A and PPHP harboring unreported pathogenic variants of GNAS (c.1141delG, p.Asp381Thrfs*23 and c.1117delC, p.Arg373Alafs*31). These variants introduce abnormal amino acids in the β6 strand/α5 helix of Gsα, which interact with G protein coupling receptor (GPCR). We conclude that these variants alter the association of Gsα with GPCR and cause PHP1A or PPHP., Competing Interests: Authors do not have any conflicts of interest to report., (© 2022 The Authors. Published by Elsevier Inc.)

Congenital generalized lipodystrophy type 4 (CGL4) is a rare disease caused by mutations in the gene polymerase I and transcript release factor ( PTRF ), the main symptoms of which are systemic reductions in adipose tissue and muscular dystrophy. The strategy of treating CGL4 is to improve the insulin resistance and hypertriglyceridemia that result from systemic reductions in adipose tissue. Metreleptin, a synthetic analog of human leptin, is effective against generalized lipodystrophies; however, there are no reports of the use of metreleptin in the treatment of CGL4. Herein, we discuss the treatment of a six-year-old boy diagnosed with CGL4 due to a homozygous mutation in PTRF with metreleptin. His serum triglyceride level and homeostasis model assessment of insulin resistance (HOMA-IR) value decreased after two months of metreleptin treatment. However, the efficacy of metreleptin gradually decreased, and the treatment was suspended because anaphylaxis occurred after the dosage administered was increased. Subsequently, his serum triglyceride level and HOMA-IR value significantly increased. Anti-metreleptin-neutralizing antibodies were detected in his serum, which suggested that these antibodies reduced the efficacy of metreleptin and caused increased hypersensitivity. Thus, metreleptin appeared to be efficacious in the treatment of CGL4 in the short term, although an adverse immune response resulted in treatment suspension. Further studies are needed to evaluate metreleptin treatments for CGL4.

Objective: Serum amino-terminal propeptide of C-type natriuretic peptide (NT-proCNP) levels have been proposed as a biomarker of linear growth in healthy children. The usefulness of NT-proCNP in patients with achondroplasia (ACH)/hypochondroplasia (HCH) remains to be elucidated. The objective was to study whether serum NT-proCNP level is a good biomarker for growth in ACH/HCH and other patients of short stature., Design: This was a longitudinal cohort study., Patients: Sixteen children with ACH (aged 0·4-4·3 years), six children with HCH (2·7-6·3 years), 23 children with idiopathic short stature (ISS) (2·2-9·0 years), eight short children with GH deficiency (GHD) (2·9-6·8 years) and five short children born small for gestational age (SGA) (2·0-6·6 years). Patients with ACH/HCH received GH treatment for 1 year., Measurements: Serum NT-proCNP levels and height were measured., Results: NT-proCNP levels positively correlated with height velocity in these short children (P < 0·05, r = 0·27). NT-proCNP levels inversely correlated with age in children with ISS alone (P < 0·01, r = -0·55). Serum NT-proCNP levels in patients with ACH/HCH were increased 3 months following the initiation of GH treatment (P < 0·05). Height SDS gain during GH treatment for 1 year was positively correlated with the changes in NT-proCNP levels after the initiation of GH (P < 0·01, r = 0·72)., Conclusion: Serum NT-proCNP levels may be a good biomarker to indicate the effect of GH treatment on growth in patients with ACH/HCH at least in the first year and height velocity in short stature patients., (© 2016 John Wiley & Sons Ltd.)

The initial treatment of childhood-onset Graves' disease is based on the result of clinical trials of adult-onset disease. The major adverse events associated with methimazole, the only medication approved for childhood-onset disease in Japan, are considered to depend on the dose, and the risk of adverse events is increased in patients requiring higher doses for initial treatment. The serum levels of thyroid hormones are partially dependent on the enterohepatic circulation, especially under thyrotoxicosis. Cholesterol absorption inhibitors suppressing the enterohepatic circulation have the possibility of controlling thyrotoxicosis. In this clinical trial, 13 patients with childhood-onset Graves' disease (5.5 to 15.3 yr old) were divided into three treatment groups: low-dose (0.25 mg/kg/d) methimazole monotherapy, high-dose (1.0 mg/kg/d) methimazole monotherapy, and combination (low-dose methimazole + a cholesterol absorption inhibitor) therapy. The therapeutic efficacy was determined based on the rates of decrease of thyroid hormones for four weeks. The high-dose methimazole regimen was superior in efficacy to the low-dose methimazole regimen, while the combination therapy demonstrated effects equal to those of the high-dose monotherapy. Therefore, combination therapy with a cholesterol absorption inhibitor can improve thyrotoxicosis, and the dose of methimazole can be reduced in the initial treatment of child-onset Graves' disease.

Premature thelarche in later childhood (such as at 5-7 yr of age) is not always easy to distinguish from GnRH-dependent precocious puberty. In this study, a GnRH stimulation test was performed on 21 girls from 5 to 7.5 yr of age with early breast development. In 8 of 11 girls within 1 yr after thelarche, i.e., breast development, the GnRH stimulation test showed a prepubertal response, and in all 10 girls at more than 1 yr after breast development, the GnRH stimulation test showed a pubertal response. In observations of 4 girls with a prepubertal response, the GnRH stimulation test showed to a pubertal response by 1 yr or more after breast development in 3 of 4 the girls. These results indicate the possibility that almost all cases of breast development in later childhood consist of premature thelarche and that premature thelarche in later childhood may easily lead to early puberty at 1 yr or more after breast development. Careful observations are therefore recommended for at least 1 yr, even if early breast development is considered to be associated with premature thelarche in later childhood.

A novel missense mutation of the growth hormone receptor (GHR) gene was identified in a Japanese short boy with GH insensitivity. The analysis of the GHR gene revealed a novel heterozygous T51I mutation in exon 4. To clarify the effect of this mutation on GH signaling, the mutant GHR was expressed in CHO cells and its functional properties were investigated. The signal transducer and activator of transcription 5 (STAT5)-mediated transcriptional activation in mutant GHR (GHR-T51I)-expressing cells was significantly reduced as compared with wild-type GHR (GHR-wt)-expressing cells. The CHO cells co-expressing the GHR-T51I and GHR-wt, however, revealed no functional differences as compared with cells expressing GHR-wt alone, indicating that the T51I mutation does not exert the dominant negative effect. In addition, the mother and the elder brother of the proband, whose heights were normal, possessed the same heterozygous mutation. These results suggest that the heterozygous T51I mutation of GHR does not inhibit the signal transduction of GH and is not responsible for GH insensitivity.

Pharmacokinetics, clinical efficacy and safety of teicoplanin (TEIC) were evaluated in pediatric and neonate patients with MRSA sepsis in the dosages approved in overseas. The administrated dose for pediatrics patients was 10 mg/kg once at hour 0, 12 and 24, followed by every 24 hours intervals. In neonates patients, first dose was 16 mg/kg, then 8 mg/kg every 24 hours intervals. 1. Pharmacokinetic results. All 17 patients (9 neonates and 8 pediatrics) who received TEIC were evaluated for pharmacokinetics. Trough concentrations were analyzed in 16 patients (9 neonates and 7 pediatrics) excluding one patient for lack of measurement of drug concentration at day 7. No patient with a concentration exceeding 60 micrograms/mL in peak or trough concentrations were reported. Mean concentrations in trough at day 3, 4 and 7 in neonates were 15.2, 14.7 and 17.8 micrograms/mL, and in pediatrics were 12.5, 12.2 and 13.1 micrograms/mL, respectively. These results were similar to those reported in foreign pediatrics and neonates patients. 2. Efficacy and safety results. Since no patient was excluded, all patients were evaluated for efficacy and safety. Microbiological efficacy as well as clinical cure were secondarily evaluated in 2 patients for whom MRSA was isolated from blood. Clinical efficacy rate was 76.5% (13/17) and number of cases in judgments of excellent, good, fairly improved and no change were 12, 1, 3 and 1 cases respectively. The patients for whom MRSA was isolated from blood were judged as MRSA eradicated case and cured without any additional anti-MRSA drugs. Adverse events were reported in 2 neonates and 3 pediatric patients. Possibly related adverse events to study drug (adverse drug reactions) were: 1 case of respiratory disorder, thrombocythemia, gamma-GTP increased, GOT increased and GPT increased in 3 pediatrics. These results suggest that an application of overseas dose regimen of TEIC for neonate and pediatrics is appropriate in Japan.