Ectopic bone formation after joint replacement or brain injury in humans is a serious complication that causes immobility of joints and severe pain. However, mechanisms underlying such ectopic bone formation are not fully understood. Bone morphogenetic protein (BMPs) are defined as inducers of ectopic bone formation, and they are regulated by several types of inhibitors. ANA is an antiproliferative molecule that belongs to Tob/BTG family, but its activity in bone metabolism has not been known. Here, we examined the role of ANA on ectopic bone formation activity of BMP. In ANA-deficient and wild-type mice, BMP2 was implanted to induce ectopic bone formation in muscle. ANA deficiency increased mass of newly formed bone in vivo compared with wild-type based on 3D-μCT analyses. ANA mRNA was expressed in bone in vivo as well as in osteoblastic cells in vitro. Such ANA mRNA levels were increased by BMP2 treatment in MC3T3-E1 osteoblastic cells. Overexpression of ANA suppressed BMP-induced expression of luciferase reporter gene linked to BMP response elements in these cells. Conversely, ANA mRNA knockdown by small interference RNA enhanced the BMP-dependent BMP response element reporter expression. It also enhanced BMP-induced osteoblastic differentiation in muscle-derived C2C12 cells. Immunoprecipitation assay indicated that ANA interacts with Smad8. Thus, ANA is a suppressor of ectopic bone formation induced by BMP, and this inhibitory ANA activity is a part of the negative feedback regulation of BMP function.

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was originally reported as a responsible gene for generalized arterial calcification in infancy (GACI). Though the prognosis of GACI patients is poor because of myocardial infarction and heart failure in relation to medial calcification of the coronary arteries, some patients rescued by bisphosphonate treatment have been reported. Recently, ENPP1 is also reported as responsible for autosomal recessive hypophosphatemic rickets type 2. We show here a boy with homozygous ENPP1 mutations diagnosed as having GACI in early infancy. After the diagnosis, he was treated with etidronate disodium (EHDP) in combination with antihypertensive drugs. The calcification of major arteries was diminished and disappeared by the age of eight months. He also showed mild hypophosphatemia (2.6-3.7 mg/dl) from the age of one year. After the treatment with EHDP for five years, he showed genu valgum with hypophosphatemia (2.6 mg/dl). He was diagnosed as having hypophosphatemic rickets at the age of seven years. The findings that hyper-mineralization of the arteries and hypo-mineralization of the bone observed in the same patient are noteworthy. ENPP1 could be regarded as a controller of the calcification of the whole body at least in part.

Patients with vitamin D-dependent rickets type 1A (VDDR1A) are usually treated with alfacalcidol, an analog of vitamin D. Around puberty, an increased dose of alfacalcidol is recommended for these patients to avoid hypocalcemia and secondary hyperparathyroidism. However, no indicators of secondary hyperparathyroidism except for PTH are presently known. The aim of this study is to evaluate whether urinary calcium to creatinine ratio (U-Ca/Cr) is useful as a biomarker of secondary hyperparathyroidism in VDDR1A patients in order to determine the proper dose of alfacalcidol. Two brothers with VDDR1A were recruited who had null mutations of CYP27B1 which encodes 1-alpha-hydroxylase of vitamin D. We investigated the relationship between U-Ca/Cr and intact-PTH around puberty when the brothers showed hypocalcemia with secondary hyperparathyroidism. The results were compared to those of five patients with vitamin D deficiency (VDD). As a result, high intact-PTH levels were observed when U-Ca/Cr decreased to less than 0.1 (mg/mg) in both VDDR1A brothers. This relationship was also observed in the VDD patients. However, it is necessary to take into account body calcium status, either in depletion or in excess, to accurately evaluate the relationship between U-Ca/Cr and secondary hyperparathyroidism. First, low U-Ca/Cr was detected in situations with calcium depletion without hyperparathyroidism in the VDDR1A patients. Second, high U-Ca/Cr with hyperparathyroidism could be detected theoretically in a condition of excess calcium supply. In conclusion, a U-Ca/Cr ratio of less than 0.1 (mg/mg) in VDDR1A patients is useful to accurately evaluate calcium depletion and secondary hyperparathyroidism.

Abscess-forming cervical bacterial infections are rare and serious infections. Methods: We retrospectively examined the trends in abscess-forming cervical bacterial infections in children who required inpatient treatment in three periods before (January 2016 to June 2020), during (July 2020 to December 2022) and after the COVID-19 pandemic (January 2023 to June 2024). Results: The study included 96 patients with superficial cervical abscesses and 111 patients with deep cervical abscesses (34 with retropharyngeal abscesses, 51 with peritonsillar abscesses, and 26 with deep neck abscesses). Both decreased during the COVID-19 pandemic and increased significantly after the COVID-19 pandemic compared to before the COVID-19 pandemic (0.94 ± 0.92 vs. 0.50 ± 0.72 vs. 1.67 ± 1.11/month, 0.93 ± 0.96 vs. 0.60 ± 0.84 vs. 2.39 ± 1.70/month), which was related with the trends of respiratory viral infections. Bacteria were identified in 79 of the 97 cases in which punctures were performed; however, there were no significant differences between the three periods. No significant changes were found in the pharyngeal streptococcal antigen positivity rate, rate of oral antibiotic use before hospitalization, length of hospital stay, or duration of antibiotic administration before and after the COVID-19 pandemic. Conclusions: The COVID-19 pandemic has affected the epidemiology of cervical abscess-forming bacterial infections in children. Although the reemergence of respiratory viral infections after the COVID-19 pandemic may be a factor, the cause of the doubling in the number of neck abscesses after the COVID-19 pandemic remains unclear and requires further investigation.

Hypochondroplasia is an autosomal dominant genetic disorder due to a heterozygous pathogenic variant of the FGFR3 gene. The early diagnosis of hypochondroplasia is necessary, since growth hormone is effective for improving adult height. The genetic test for the FGFR3 gene could help the early diagnosis. The detailed characteristics of FGFR3 genotypes have not been widely investigated in Japan, except for a common pathogenic variant, p.Asn540Lys. This study retrospectively analyzed the FGFR3 genotypes of 35 patients from 30 families with hypochondroplasia (age, range 0–6 years, median 1 year) in Japan. The pathogenic variants of FGFR3 were identified in all the patients: p.Asn540Lys in 23 probands (76.7%), p.Lys650Gln in 2 (6.7%), p.Leu324His in 2 (6.7%), p.Leu324Val, p.Ser351Cys, and p.Lys650Thr in 1 each (3.2%). The median age at diagnosis, height SD score at diagnosis, or the severity of radiologic findings was not significantly different between probands with p.Asn540Lys and those with other variants. Intellectual disability or epilepsy was identified in seven patients with p.Asn540Lys, but none with other variants. The genetic test of FGFR3 can be useful for assessing the potential risk of neurological sequela in children with hypochondroplasia.