Loss-of-function OGFRL1 variants identified in autosomal recessive cherubism families.

Cherubism (OMIM 118400) is a rare craniofacial disorder in children characterized by destructive jawbone expansion due to the growth of inflammatory fibrous lesions. Our previous studies have shown that gain-of-function mutations in SH3 domain-binding protein 2 (SH3BP2) are responsible for cherubism and that a knock-in mouse model for cherubism recapitulates the features of cherubism, such as increased osteoclast formation and jawbone destruction. To date, SH3BP2 is the only gene identified to be responsible for cherubism. Since not all patients clinically diagnosed with cherubism had mutations in SH3BP2, we hypothesized that there may be novel cherubism genes and that these genes may play a role in jawbone homeostasis. Here, using whole exome sequencing, we identified homozygous loss-of-function variants in the opioid growth factor receptor like 1 (OGFRL1) gene in 2 independent autosomal recessive cherubism families from Syria and India. The newly identified pathogenic homozygous variants were not reported in any variant databases, suggesting that OGFRL1 is a novel gene responsible for cherubism. Single cell analysis of mouse jawbone tissue revealed that Ogfrl1 is highly expressed in myeloid lineage cells. We generated OGFRL1 knockout mice and mice carrying the Syrian frameshift mutation to understand the in vivo role of OGFRL1. However, neither mouse model recapitulated human cherubism or the phenotypes exhibited by SH3BP2 cherubism mice under physiological and periodontitis conditions. Unlike bone marrow-derived M-CSF-dependent macrophages (BMMs) carrying the SH3BP2 cherubism mutation, BMMs lacking OGFRL1 or carrying the Syrian mutation showed no difference in TNF-ɑ mRNA induction by LPS or TNF-ɑ compared to WT BMMs. Osteoclast formation induced by RANKL was also comparable. These results suggest that the loss-of-function effects of OGFRL1 in humans differ from those in mice and highlight the fact that mice are not always an ideal model for studying rare craniofacial bone disorders.

Effect of delivery mode on postnatal platelet count dynamics in neonates born to mothers with immune thrombocytopenia.

We aimed to determine the effect of delivery mode on postnatal platelet count dynamics in neonates born to mothers with immune thrombocytopenia (ITP). This single-center, retrospective study included 41 mothers with ITP and their 65 infants born by vaginal delivery (VD, n = 30) and cesarean section (CS, n = 35) between January 1997 and March 2022. The median difference in platelet counts from day 0 to day 2 (ΔPlt [D 0-2]) was significantly lower in the VD group (- 39 × 109/L, interquartile range [IQR]: - 47 to - 24 × 109/L) than the CS group (15 × 109/L, IQR: - 6.5 to 33 × 109/L) (p < 0.001). The median ΔPlt (D 0-5) was significantly lower in the VD group (- 55 × 109/L, IQR: - 85 to - 31 × 109/L) than the CS group (33 × 109/L, IQR: 1-69 × 109/L) (p < 0.001). Multivariate analysis also showed a significant association of delivery mode with ΔPlt (D 0-2) and ΔPlt (D 0-5) (both p < 0.001). VD neonates with platelet counts ≥ 100 × 109/L at birth were significantly more likely than CS neonates to develop thrombocytopenia < 100 × 109/L at nadir (1/26 vs. 6/25) (p = 0.0496). Our findings indicate that mode of delivery is a useful predictor of postnatal platelet count dynamics in neonates born to mothers with ITP.

Incidence of Kawasaki disease before and during the COVID-19 pandemic: a retrospective cohort study in Japan.

Background: Epidemiological studies in Kawasaki disease (KD) have suggested infectious aetiology. During the COVID-19 pandemic, measures for mitigating SARS-CoV-2 transmission also suppress the circulation of other contagious microorganisms. The primary objective is to compare the number and incidence of KD before and during the COVID-19 pandemic in Japan, and the secondary objective is to investigate temporal association between the KD epidemiology and activities of SARS-CoV-2 and other viral and bacterial infections. Methods: A retrospective cohort study was conducted between 2016 and 2020 in Kobe, Japan. We collected information of hospitalised KD children in Kobe. Child population was identified through the resident registry system. Activity of COVID-19 and 11 other infectious diseases was derived from a public health monitoring system. Monthly change of KD incidence was analysed using a difference-in-difference regression model. Results: Throughout the study period, 1027 KD children were identified. KD had begun to decline in April 2020, coinciding with the beginning of the COVID-19 pandemic. The number of KD cases (n=66) between April and December 2020 was 40% of the average in the same period in 2016-2019 (165/year). Annual KD incidence was 315, 300, 353, 347 and 188/100 000 children aged 0-4 years in 2016-2020, respectively. The difference-in-difference value of KD incidence was significantly reduced in the fourth quarter in 2020 (-15.8, 95% CI -28.0 to -3.5), compared with that in 2016-2019. Sentinel surveillance showed a marked decrease of all infectious diseases except exanthema subitum after the beginning of the COVID-19 pandemic. There were 86 COVID-19 cases aged <10 years and no KD children associated with COVID-19. Conclusion: This study showed that the number and incidence of KD was dramatically reduced during the COVID-19 pandemic in Japan. This change was temporally associated with decreased activities of various infectious diseases other than COVID-19, supporting the hypothesis of infection-triggered pathogenesis in KD.