Satoru Takahashi

The placenta produces a variety of steroid hormones through the catalytic activity of steroidogenic enzymes, including cytochrome P450 (CYP) hydroxylases and hydroxysteroid dehydrogenases (HSD). Large amounts of progesterone produced by the placenta are essential for the maintenance of pregnancy. Although androgens and estrogens are also elevated in maternal circulation during gestation, there are conflicting reports on whether de novo synthesis of these steroids occurs in the human placenta. To address this issue, we performed a comprehensive analysis of steroidogenic gene expression in early and term placenta. While none of the genes examined showed binary expression changes, 17β-HSDs, including HSD17B1 and AKR1C3, were markedly upregulated in the term placenta. CYP19A1 and HSD11B2 genes were also markedly upregulated. In contrast, CYP17A1, CYP21A2, CYP11B1, CYP11B2, and HSD17B3 were almost undetectable. Consistent with these findings, the plasma ratios of active to precursor sex steroids (estradiol/estrone and testosterone/androstenedione) were higher in pregnant than in non-pregnant women, although concentrations of all steroids increased. In contrast, plasma levels and profiles of 11-oxygenated androgens were unchanged. These results indicate that the human placenta does not significantly contribute to circulating levels of either classical or novel classes of androgens. Therefore, this study provides new insights into the tissue of origin and the physiological significance of sex steroids during gestation.

Background/Objectives: CDKL5 deficiency disorder (CDD) is a rare X-linked developmental and epileptic encephalopathy characterized by early onset refractory epilepsy and severe neurodevelopmental impairment with autistic features. Despite advances in genetic diagnosis, objective biomarkers reflecting disease mechanisms remain limited. Extracellular vesicles (EVs) circulating in the blood may contain disease-related proteins derived from the central nervous system. This study aimed to characterize the plasma EV proteome in CDD in a hypothesis-generating exploratory framework and identify the candidate molecular pathways associated with this disorder. Methods: Plasma samples from seven patients with genetically confirmed CDD and seven neurotypical developmental controls were analyzed. Extracellular vesicle-containing preparations (EVs-cp) were isolated via immunoprecipitation using antibodies against CD9, CD63, and CD81. Proteomic profiling was performed using data-independent mass spectrometry. Differentially expressed proteins were identified using Welch’s t-test with a false discovery rate correction. Functional enrichment, protein interaction network, and correlation analyses were performed using CDKL5 Clinical Severity Assessment (CCSA) scores. Results: In total, 5617 proteins were identified, of which 3510 were used for quantitative analysis. Compared to the controls, 2108 proteins were upregulated and 158 were downregulated in the CDD samples. Enrichment analysis revealed alterations in vesicle-mediated transport, cytoskeletal organization, and immune-related pathways. Several proteins were also correlated with clinical severity scores. Conclusions: Plasma EV proteomics revealed molecular alterations associated with CDD and provided a potential approach for biomarker discovery and mechanistic investigation.

Pyoderma gangrenosum (PG) is a noninfectious neutrophilic dermatosis that can occur either idiopathically or secondary to various systemic conditions. PG is rare in childhood and even rarer in infancy. Due to its rarity, the pathophysiological mechanisms remain unclear. Although systemic glucocorticoids are considered the first‐line therapy, no standardized second‐line or subsequent therapeutic approach has been established, particularly for refractory cases. In this report, we present a case of infantile idiopathic PG showing sustained clinical improvement after the addition of the anti–tumor necrosis factor (TNF)‐alpha antibody infliximab (IFX). In addition, we conducted multiplex cytokine analysis to explore the patient’s inflammatory profile and provide preliminary observations regarding the inflammatory milieu associated with this condition. The patient, a 9‐month‐old infant, developed multiple pustules and ulcerative skin lesions on the face and extremities following Bacillus Calmette–Guérin (BCG) vaccination. Pathogen investigations were all negative, and the diagnosis of PG was made based on clinical findings, supported by histological features and exclusion of other conditions. After initial treatment with glucocorticoids and cyclosporine, remission was achieved; however, repeated relapses occurred. IFX was subsequently initiated, resulting in significant clinical improvement. Serum cytokine profiling at the onset revealed a broad elevation of proinflammatory cytokines, including soluble TNF receptors 1 and 2, with a pattern partially overlapping with that observed in Kawasaki disease. The clinical course and cytokine analysis results suggest that IFX may be a viable treatment option for refractory PG, even in infants.

Purpose: Atrial function is associated with exercise tolerance and survival in patients with Fontan circulation. Although atrial function is often evaluated using strain parameters, changes in atrial pressure are also important but have not been well studied. This study aimed to investigate the atrial pressure–strain relationship in patients with Fontan circulation using data from cardiac catheterization and MRI.Methods: We retrospectively included 16 patients (median age: 12 years) who underwent cardiac MRI between 2020 and 2026, and 10 control patients (median age: 8.5 years). Atrial strain values were evaluated from 4-chamber cine MRI images. Pulmonary artery wedge pressure waveforms were used as a surrogate for atrial pressure. The pressure–strain index was calculated as an integrated measure of atrial pressure and strain.Results: The 2 groups showed no significant differences in age or body size. Patients with Fontan circulation had higher central venous pressure (CVP) and a lower cardiac index (CVP: 11.5 vs. 4.0 mmHg, P < 0.001; cardiac index: 2.9 vs. 3.8 L/min/m2, P = 0.007). Reservoir and conduit strains were lower in the Fontan group (reservoir strain: 16.7 vs. 26.2%, P < 0.001; conduit strain: 6.2 vs. 18.7%, P < 0.001); however, no significant difference was observed in pump strain between the groups. No significant difference was also noted in pressure–strain index between the 2 groups (0.2 vs. 0.2, P = 0.417).Conclusion: In patients with Fontan physiology, reservoir and conduit strain were lower than in controls. In contrast, atrial pressure–strain relationship was not clearly associated with conventional Fontan hemodynamic parameters. These findings suggest that the physiological significance of atrial pressure–strain relationship in the Fontan circulation remains uncertain.

The phosphatidylinositol‐3‐kinase (PI3K)‐AKT‐mTOR pathway plays a central role in cellular growth and survival, and somatic activating variants in PIK3CA cause PIK3CA‐related overgrowth spectrum (PROS). Because these variants arise postzygotically, affected individuals exhibit somatic mosaicism, making molecular diagnosis challenging, particularly when only peripheral blood is available. We report an infant with PROS presenting with hemimegalencephaly, facial infiltrating lipomatosis, epidermal nevi, and unilateral woolly hair. A hotspot PIK3CA variant (c.1633G>A, p.Glu545Lys) was identified in the resected brain tissue but not in the peripheral blood. Notably, the variant was detected in DNA extracted from hair follicles of curly hair on the affected side of the scalp, whereas it was absent in follicles from straight hair on the contralateral side. Droplet digital PCR demonstrated variant allele fractions of 24.7%–27.6% in brain tissue and 32.3% in curly hair. These findings highlight the utility of hair follicles as a minimally invasive and accessible source of DNA for detecting somatic mosaic variants in PROS. The spatial concordance between genotype and hair phenotype suggests a possible association between PIK3CA mosaicism and localized hair abnormalities, although causality remains to be established.

Digital clubbing is typically linked to pulmonary or cardiovascular diseases. There have been no reported cases of systemic lupus erythematosus (SLE) where the initial complaint was solely foca digital clubbing and a chilblain-like rash on the ngers. A 13-year-old girl experienced digital clubbing for 3 months. Physical examination revealed focal digital clubbing of the thumb, index nger, and middle nger on her right hand, along with slight blotchy erythema assessed as a chilblain-like rash. Laboratory data showed hypocomplementemia and a high anti-double-stranded DNA antibody titer. She was also positive for antiphospholipid antibodies, had prolonged prothrombin time and activated partial thromboplastin time, and elevated anti-prothrombin antibody levels. She was diagnosed with SLE complicated by hypoprothrombinemia associated with lupus anticoagulant. Prednisolone treat ment resolved the digital clubbing and laboratory abnormalities. Digital clubbing may be an initial symptom of SLE. Screening for autoimmune diseases should be considered when a patient presents with digital clubbing not associated with pulmonary or cardiovascular diseases or malignant tumors. Cite this article as: Sato M, Nagamori T, Kurisawa MJ, Tsuda J, Ishibazawa E, Takahashi S. Focal digital clubbing as an initial symptom of adolescent-onset systemic lupus erythematosus: a case report. Eur J Rheumatol. 2025, 12(4), 0075, doi:10.5152/eurjrheum.2025.24075.

Loss‐of‐function mutations of AVPR2 and L1CAM result in nephrogenic diabetes insipidus (NDI) and L1 syndrome. These diseases are inherited in an X‐linked recessive manner. Females with heterozygous variants can be affected owing to skewed X‐chromosome inactivation (XCI). A 3‐year‐old girl with normal development was presented with polydipsia and polyuria, and diagnosed of NDI through an improper response to water restriction and desmopressin administration. A targeted genome capture sequencing for X chromosome confirmed Xq28 microdeletion involving AVPR2 and L1CAM, derived from mother with mosaicism of the deletion. No pathogenic variants were identified in the paternal X allele nor in AQP2, another causative gene of NDI. XCI was exclusively skewed toward the maternal X chromosome in hair, oral mucosa, and blood, while it was random in nails and renal tubular epithelial cells (RTECs). Both AVPR2 and L1CAM mRNA expression in the patient's RTECs were significantly reduced compared to those of controls, with AVPR2 showing a more pronounced decrease. Thus, we demonstrated for the first time that NDI can develop in a female with a AVPR2 deletion despite of random XCI. Moreover, the absence of L1 syndrome in the female patient was caused most probably through organ‐dependent skewed XCI in the deletion allele.