We conducted a randomized phase 3 study to investigate the efficacy and safety of GH treatment in prepubertal Japanese patients with short stature due to SHOX deficiency. The patients were randomly allocated to the GH-GH group (n = 10), in which the patients were treated with GH (0.35 mg/kg/wk) subcutaneously once daily for 24 mo, or the no-treatment (NT)-GH group (n = 9), in which the patients were untreated for the first 12 mo and then administered the same dosage of GH for the next 12 mo. At month 12, the ∆height standard deviation score (SDS) for chronological age (CA) and serum IGF-1 level were significantly higher in the GH-GH group than those in the NT-GH group. In contrast, bone age (BA) and ΔBA/ΔCA were numerically higher in the GH-GH group but were not statistically significant. At month 24, these parameters were comparable between the two groups. The height velocity was significantly larger in the GH-GH group during the first year and in the NT-GH group during the second year. No serious adverse drug reactions were observed; however, one patient in the GH-GH group exhibited increased insulin resistance at month 24. These results indicated that GH is a promising treatment option for short stature in patients with SHOX deficiency.

Noonan syndrome (NS) is caused by pathogenic variants in genes encoding components of the RAS/MAPK pathway and presents with a number of symptoms, including characteristic facial features, congenital heart diseases, and short stature. Advances in genetic analyses have contributed to the identification of pathogenic genes in NS as well as genotype-phenotype relationships; however, updated evidence for the detection rate of pathogenic genes with the inclusion of newly identified genes is lacking in Japan. Accordingly, we examined the genetic background of 116 individuals clinically diagnosed with NS and the frequency of short stature. We also investigated genotype-phenotype relationships in the context of body mass index (BMI). Genetic testing revealed the responsible variants in 100 individuals (86%), where PTPN11 variants were the most prevalent (43%) and followed by SOS1 (12%) and RIT1 (9%). The frequency of short stature was the lowest in subjects possessing RIT1 variants. No genotype-phenotype relationships in BMI were observed among the genotypes. In conclusion, this study provides evidence for the detection rate of pathogenic genes and genotype-phenotype relationships in Japanese patients with NS, which will be of clinical importance for accelerating our understanding of the genetic backgrounds of Japanese patients with NS.

Type 1 diabetes mellitus (T1DM) adversely affects gonadal function. This study aimed to define the characteristics and factors associated with menstrual cycle abnormalities and polycystic ovary syndrome (PCOS) in Japanese patients with T1DM. Our study enrolled 157 patients, including 55 with oligomenorrhea (prolonged menstrual cycle) and 102 without oligomenorrhea. LH/FSH ratio (p = 0.04) and total testosterone levels (p = 0.03) were significantly higher in the oligomenorrhea group than in the non-oligomenorrhea group. No significant differences were found between the two groups regarding age at menarche, age at T1DM diagnosis, treatment, glycated hemoglobin, or total daily insulin dose. Of the 55 patients in the oligomenorrhea group, 27 were diagnosed with PCOS based on the Rotterdam criteria. We concluded that female patients with T1DM, as well as abnormal menstrual cycles and hyperandrogenism, may suffer from undiagnosed PCOS and should be referred to a gynecologist for full assessment, diagnosis, and treatment.

We encountered a Chinese girl with pseudohypoparathyroidism type 1A (PHP1A) and her mother with pseudopseudohypoparathyroidism (PPHP). Sequencing analysis of GNAS-Gsα revealed a heterozygous c.212+2T>C variant (NM_000516.4) affecting the canonical splice donor site of intron 2 in the girl and her mother. RT-PCR performed on mRNA samples obtained from cycloheximide-treated and cycloheximide-untreated lymphoblastoid cell lines of this girl revealed the utilization of an alternative splice donor site at 33–34 bp from the boundary between exon 2 and intron 2 and the production of an aberrant mRNA with a retention of a 32 bp intronic sequence between exon 2 and exon 3 (p.(Gly72Lysfs*39)), which satisfied the condition for the occurrence of nonsense-mediated mRNA decay, as predicted by SpliceAI. This study revealed the molecular consequences of disruption of the canonical splice donor site and confirmed the clinical utility of SpliceAI.

A 10-yr-old female was referred due to prolonged bleeding lasting for a week following tooth extraction. She had heavy periods since she was 9. Her height was < 0.4th centile. Tanner staging was breast stage B3-4, axillary hair A1, and pubic hair P1. Thyroid function tests showed elevated TSH, low free T4, and negative anti-TPO antibodies. Gonadotrophins showed high FSH and a prepubertal LH. Prolactin was high and ovarian cysts were found on ultrasound. Further investigations revealed low von Willebrand factor (vWF) antigen levels, leading to a diagnosis of acquired von Willebrand disease. She was started on levothyroxine therapy, with normalization of vWF antigen levels, prolactin levels, cessation of her menstrual periods and resolution of ovarian cysts.

We report the case of a patient with osteogenesis imperfecta (OI) who developed pulmonary hemorrhage 4 d after pamidronate disodium (PA) administration, despite a relatively stable respiratory status. Bisphosphonates are introduced to reduce osteoclast activity and are now widely used in patients with OI. Bisphosphonates are typically well-tolerated in children, and the standard of care involves cyclic intravenous administration of PA. However, in practice, there is limited experience with the use of PA for severe OI during the neonatal period, and its safety remains uncertain. This report aimed to describe the respiratory events potentially associated with PA in a neonatal patient with OI type 2, suggesting that serious life-threatening complications of pulmonary hemorrhage may occur after PA administration. Further studies are required to assess the relationship between pulmonary hemorrhage and PA administration, aiming to enhance prophylaxis measures.

Central sleep apnea (CSA) is rare in older children. Although CSA mostly arises from neurological diseases such as Chiari malformation, the frequency of CSA is significantly higher in obese children. Herein, we describe the case of a 14-yr-old boy who presented with CSA secondary to severe obesity and a history of traumatic lateral medullary syndrome at 8 yr of age. Polysomnography revealed severe sleep apnea syndrome with apnea-hypopnea index of 41.4 per hour and central apnea index of 8.9 per hour. Magnetic resonance imaging of the head showed no new brainstem or cerebellar infarcts; however, old changes in the cerebellar infarction persisted. Obesity is primarily associated with obstructive sleep apnea. However, obesity can result in CSA through pharyngeal collapse and the reduction of oxygen reserves caused by reduced thoracic volume, which suppresses respiratory center stimulation. Because the respiratory center disorder owing to head injury sequelae improved after the acute stage, obesity was deemed the cause of CSA in this case. Hence, children with severe obesity may require CSA monitoring.

We present the case of a young male patient (height, 158.1 cm [+3.3 standard deviation (SD)]; weight, 63.7 kg [body mass index, 25.5]) with diabetes mellitus and severe insulin resistance associated with a heterozygous pathogenic insulin receptor substrate 1 (IRS1) frameshift mutation. The patient also had severe acanthosis nigricans. Notably, the patient’s father was undergoing treatment with high doses of insulin for diabetes mellitus, and had been experiencing angina pectoris. Laboratory data showed a fasting plasma glucose level of 88 mg/dL, hemoglobin A1C (HbA1c) of 7.4%, fasting insulin level of 43.1 µg/mL, and a homeostasis model assessment-insulin resistance (HOMA-IR) score of 9.36, indicating hyperinsulinism. Oral glucose tolerance test revealed a diabetic pattern and insulin hypersecretion. In addition, the patient had hyperlipidemia. Genetic studies revealed a heterozygous frameshift variant of IRS1 [NM_005544.3:c.1791dupG:p.(His598Alafs*13)] in the patient and his father, which can impair the binding and activation of phosphoinositide 3 (PI-3) kinase and defectively mediate the translocation of glucose transporter type 4 (GLUT4) in adipose tissues, possibly leading to glucose intolerance. Therefore, this variant may be disease causing. After confirming IRS1 mutation, metformin was administered, and physical exercise and dietary management were initiated; metformin was well tolerated, and optimal glycemic control was maintained.

Most patients with resistance to thyroid hormone (RTH) test negative in newborn screening (NBS) for congenital hypothyroidism (CH). Here, we present a case of RTH diagnosed through NBS. The patient presented to us after her NBS for CH revealed high TSH (23.4 µIU/mL) and free T4 (FT4) (5.40 ng/dL) levels. Apart from tachycardia, she exhibited no other manifestations related to excess or deficiency of thyroid hormones. A confirmatory test replicated the findings, showing elevated serum TSH levels (35.7 µIU/mL) along with high FT4 levels (5.84 ng/dL). Ultrasonography showed marked thyroid gland enlargement (> +4 SD). Targeted next-generation sequencing of genes associated with genetic thyroid disorders revealed a previously reported THRB variant, p.Gly345Cys. Unexpectedly, two biallelic DUOX2 variants (p.His678Arg and p.Arg1334Trp) were also detected. At her last visit, no significant issues were observed with neurological development, growth, bone maturation, or gastrointestinal symptoms related to thyroid function at the age of 1 year, without treatment for RTH and CH. During follow-up, the TSH and FT4 levels gradually decreased. In conclusion, we report a patient with simultaneous RTH and DUOX2 defects, demonstrating the value of conducting a comprehensive analysis of multiple genes associated with thyroid diseases to better comprehend the pathogenesis in patients with atypical thyroid-related phenotypes.