Akira Ishiguro

Severe congenital protein C (PC) deficiency is a rare inherited coagulation disorder that can be difficult to control with conventional medical treatment alone. We report a single‐center case series of three pediatric patients with severe congenital PC deficiency who underwent liver transplantation (LT). In all patients, plasma PC activity levels exceeded 64% after LT and remained stable without anticoagulation treatment or PC supplementation. Two patients were followed for more than 10 years, representing the longest reported outcomes to date. Stable anticoagulant function persisted despite rejection, graft dysfunction, and subsequent surgery, demonstrating durable restoration of physiological anticoagulant function after LT.

Background/Aims: The incidence of perianal lesions (PL) in children with Crohn’s disease (CD) is higher in East Asia than in Western countries. Early intervention for PL is essential to prevent sphincter dysfunction and ostomy placement. In this study, we aimed to investigate the clinical features, treatment, and consequences of pediatric CD with PL. Methods: We retrospectively reviewed a cohort of children diagnosed with CD from 2010 to 2020 at a Japanese children’s hospital. Demographics, treatments, and outcomes were evaluated and compared among subgroups. Results: Among 112 pediatric patients with CD, 36 (32.1%) had experienced PL during the observational period. The median ages at diagnosis and follow-up periods were 131 and 70 months, respectively. Six (85.7%) patients in the very early-onset (VEO) group (CD diagnosed before 6 years old) and 24 (82.8%) in the older age group had PL upon diagnosis of CD (P= 0.851). Biologics were given to 94.4% of patients: infliximab (67.7%), adalimumab (58.8%), ustekinumab (44.1%), risankizumab (11.8%), and vedolizumab (5.9%). Biologics were introduced within 1 year in 89.5% and 40.0% of patients diagnosed in 2016–2020 and 2010–2016, respectively (P= 0.002). Seton was frequently used in the older age group (87.5 vs. 42.9%, P= 0.190). Ostomy was frequently required in the VEO group (42.9% vs. 0.0%, P= 0.006). Conclusions: Patients with VEO-CD and PL had a notably high risk of ostomy placement. The earlier introduction of biologics and surgical interventions reduced corticosteroids use and ostomy placement in pediatric CD patients with PL.

CYCS encodes somatic cytochrome c, which plays a central role in the electron transport chain and oxidative phosphorylation. We report nine cases of autosomal dominant, non-syndromic CYCS-related thrombocytopenia in three Japanese families. Patients showed no or mild bleeding tendency, with preserved platelet size and morphology, and without other abnormalities in blood cell lineages. Using targeted gene sequencing for congenital thrombocytopenia, we identified pathogenic missense variants in CYCS, shared by all affected individuals in each family. Two were previously reported: c.274A > G,p.(Arg92Gly) and c.309C > T,p.(Thr103Ile); one was novel: c.212A > C,p.(Asn71Thr). Genetic testing should be considered in unexplained familial thrombocytopenia.

Summary: Ankyrin repeat domain 26 ( ANKRD26 )‐related thrombocytopenia ( ANKRD26 ‐RT) is an autosomal dominant disorder caused by variants in the 5′‐untranslated region of the ANKRD26 gene, leading to its overexpression and impaired megakaryocyte maturation. We identified a novel ANKRD26 variant (c.‐129_‐112del) and investigated its transcriptional impact, platelet function, and haematopoietic effects. We analysed ANKRD26 transcription in megakaryocytes derived from 21 ANKRD26 ‐RT patients using quantitative reverse transcription droplet digital polymerase chain reaction (PCR). Furthermore, platelet function, megakaryocyte morphology and RNA sequencing were assessed. The novel variant exhibited significantly higher ANKRD26 transcription levels than previously reported variants ( p < 0.001), but did not show any characteristic clinical phenotypes. Megakaryocytes with the novel variant showed reduced proplatelet formation and lower nuclear ploidy. RNA sequencing revealed upregulation of cell proliferation genes, including dedicator of cytokinesis 2 ( DOCK2) , cluster of differentiation ( CD38) and interleukin‐1 receptor accessory protein ( IL1RAP) . No platelet‐related or megakaryocyte‐related genes other than ANKRD26 were detected in these variants. The new variant disrupted the runt‐related transcription factor 1 (RUNX1)‐binding site, leading to ANKRD26 overexpression and possible haematopoietic abnormalities, though it did not directly correlate with clinical severity. However, genes linked to cell proliferation ( CD38, DOCK2 and IL1RAP ) showed increased expression. Our results suggested a potential link to leucocytosis, although further research is required to confirm this.

Introduction: Idiopathic short stature (ISS) refers to non-syndromic growth failure without chronic disorders. The molecular basis of ISS remains largely unknown. Although a variable number of tandem repeats (VNTR) of 57 nucleotides in ACAN is known to correlate with the height of people in the general population, the role of this genetic variant in the etiology of ISS has not been studied. Methods: We studied 128 Japanese patients with ISS, including 63 patients with prenatal and postnatal growth failure (small-for-gestational age-SS, SGA-SS), and 100 control individuals. To examine the repeat numbers of ACAN VNTR, we amplified the VNTR-containing genomic region and analyzed the PCR products by gel electrophoresis. The accuracy of the results was confirmed by long-read next-generation sequencing. Results: The repeat numbers of the patient group were similarly distributed to those of the control group, and no patient had a very small number. Moreover, the repeat numbers of the shorter and longer alleles in each individual, as well as the average number of the two alleles, were comparable between the two groups. The height standard deviation scores obtained from 106 patients did not correlate with the repeat numbers. There was no difference in the repeat numbers between the SGA-SS or non-SGA ISS groups, and the control group. Conclusion: The results of this study indicate that reduced repeat numbers of ACAN VNTR do not represent a monogenic cause or a major contributing factor for ISS. Our findings await further validation.