Rosai-Dorfman-Destombes (RDD) disease is a rare non-Langerhans cell histiocytosis typically characterized by massive lymphadenopathy. The purely cutaneous subtype (CRDD) is clinically polymorphic, mimicking various inflammatory or neoplastic conditions, making its diagnosis challenging. We present a case of a young phototype 4 Moroccan female with a 2-year history of a progressively enlarging violaceous tumor on her posterior thigh. Dermoscopy revealed structureless yellow areas with fine telangiectasias. Histological along with immunohistochemical examination showed a dense dermal infiltrate with large histiocytes exhibiting prominent emperipolesis confirming the diagnosis of CRDD. A comprehensive systemic workup was negative. No recurrence was detected after a 6 month follow up after surgical excision. This case highlights the importance of dermoscopic clues which correlates with the histological findings. In patients with higher phototypes, these findings are essential to guide the clinician toward a histiocytic disorder. Differential diagnoses such as Langerhans cell histiocytosis, juvenile xanthogranuloma, and sarcoidosis must be ruled out through immunohistopathology.

Ataxia telangiectasia and Rad3-related (ATR) initiates cell cycle checkpoints to maintain genome integrity in the presence of replication stress or various forms of DNA damage. However, how ATR is activated for checkpoint initiation remains incompletely understood. The canonical model suggests that binding of an ATR-activator protein relieves the autoinhibitory PIKK regulatory domain (PRD) within the kinase domain, thereby activating ATR by granting substrate access to the catalytic centre. To better understand the checkpoint initiation mechanism, we conducted a genetic screen in fission yeast that identified a charge-reversal mutation, E1369K, in the conserved FRAP-ATM-TRRAP (FAT) domain of Rad3, the ortholog of ATR. In vitro kinase assays show that the mutation converts Rad3 into a constitutively active form. This allows rescue of the Rad3 kinase signaling defect in cells lacking the phosphorylation of the Rad9-Rad1-Hus1 (9-1-1) complex specifically in the DNA replication checkpoint, not the damage checkpoint pathway. Since the mutation is not in the kinase domain and is away from the PRD, these findings show that, in addition to the canonical mechanism, Rad3 may also be activated allosterically via the FAT domain, a mechanism likely conserved in higher eukaryotes.

To examine the relationship between oral handicap, clinical characteristics, psychosocial status, and quality of life in patients with systemic sclerosis (SSc). This cross-sectional study included 99 patients with SSc. Oral handicap was assessed using the Mouth Handicap in Systemic Sclerosis Scale (MHISS). Social appearance anxiety, anxiety/depression symptoms, resilience, and quality of life were evaluated using the Social Appearance Anxiety Scale, Hospital Anxiety and Depression Scale, Brief Resilience Scale, and World Health Organization Quality of Life-BREF (WHOQOL-BREF), respectively. Statistical and hierarchical multiple regression analyses were also performed. Oral handicap was associated with female sex (rho = 0.220, p = 0.029) and diffuse cutaneous SSc subtype (rho =  - 0.482, p < 0.001). Oral handicap showed strong positive correlations with the facial and total modified Rodnan Skin Score (rho = 0.851 and rho = 0.737; both p < 0.001). Positive associations were also observed for gastrointestinal (GI) involvement, calcinosis, telangiectasia, Scl-70 positivity, and digital ulcers (p < 0.002 for all). MHISS scores were positively correlated with anxiety, depression, and social appearance anxiety, and negatively correlated with all WHOQOL-BREF domains (p < 0.001 for all). In the regression analyses, mRSS (β = 0.484, p < 0.001), GI involvement (β = 0.210, p = 0.006), and anxiety scores (β = 0.183, p = 0.036) remained independently associated with oral impairment. The clinical model explained an additional 54% of variance, with a further 5% contributed by psychosocial variables. Oral impairment in SSc reflects both clinical disease burden and psychosocial distress, underscoring its multifactorial nature.

Hereditary Hemorrhagic Telangiectasia (HHT) may present with symptoms arising from multiple organ systems. In this case report, the focus is on cardiovascular manifestations, including total blood volume, cardiac function, and the potential role of the sympathetic nervous system (SNS) in the clinical picture. The commonly held supposition that the cardiac hyperdynamic state in HHT is associated with increased SNS activity is examined by combining spectral analysis of heart rate variability with carbon monoxide-based measurement of total blood volume and transthoracic echocardiography. The observations are consistent with Guytonian venous return physiology and suggest a circulation characterized by low venous return resistance.

Macular telangiectasia (MacTel) is characterised by perifoveal capillary abnormalities, which can progress to retinal layer loss and cavitation-like changes. Though it occurs predominantly in isolation, a genetic association of MacTel has been noted. Our report aims to demonstrate one such association causing an alteration in serine metabolism leading to neuropathy and maculopathy secondary to Muller cell degeneration.

Tumor resistance to radiotherapy continues to be a significant problem in improving cancer patient outcomes. To overcome radioresistance, drugs that sensitize cancer cells to ionizing radiation (IR) have been tested. In theory, radiosensitizers should increase irradiated tumor kill and improve patient outcomes. However, in practice, the clinical utility of such drugs is curtailed by radiosensitization of peri-tumoral normal tissues causing toxicities. To target radiosensitizer delivery to tumors, we developed an activatable cell penetrating peptide (ACPP) drug conjugate for spatially tumor-restricted delivery of the potent ataxia-telangiectasia mutated kinase inhibitor (ATMi) AZD0156. The ACPP scaffold cloaks a cell penetrating peptide-drug conjugate until it is unmasked within tumors through tumor-associated matrix metalloproteinase thus promoting preferential tumor uptake. Using clinically validated antibody-drug conjugate linker chemistry, we conjugated AZD0156 to ACPP (ACPP-AZD0156) and evaluated its immune stimulating and therapeutic activity with IR in immune-competent murine cancer models. Transcriptomic profiling revealed combining ACPP-AZD0156 with IR enhanced radiation-induced immune activation programs, including type I interferon signaling and leukocyte activation network. Importantly, ACPP-AZD0156 combined with IR stimulated intratumoral CD8[+] T cell infiltration and improved tumor control compared to non-targeted ATM inhibitor. Mechanistically, the therapeutic effect of ACPP-AZD0156 + IR was abrogated by CD8[+] T-cell depletion, establishing a role for adaptive immunity engagement by ACPP-AZD0156 radiosensitization. Finally, the combination of IR and ACPP-AZD0156 with PD-1 blockade resulted in durable tumor control and long-term survival. Taken together, these data provide a basis for tumor-targeted ATMi delivery as a precision oncology based immunogenic radiosensitization strategy.

Intralesional triamcinolone acetonide (TAC) remains the standard nonsurgical treatment for keloids but is limited by steroid-related adverse effects. Intralesional vitamin D has recently emerged as a potential alternative. This meta-analysis evaluated the comparative efficacy and safety of vitamin D versus TAC in keloid management. A systematic search of PubMed, Embase, and the Cochrane library identified randomized controlled trials comparing these treatments. The primary outcome was scar improvement assessed using validated scales, while secondary outcomes included lesion flattening and treatment-related adverse events. Four trials were included. TAC demonstrated superior efficacy in improving scar severity (MD = -9.72; 95% CI -17.41 to -2.02; p = 0.013) and lesion flattening (RR = 0.68; 95% CI 0.48 to 0.96; p = 0.028). Vitamin D was associated with significantly lower risks of pigmentation changes (RR = 0.23; 95% CI 0.07 to 0.78; p = 0.018) and skin atrophy (RR = 0.51; 95% CI 0.32 to 0.82; p = 0.006), with no significant differences in pain, erythema, telangiectasia, or blister formation. While TAC appeared more effective for scar regression and lesion flattening, vitamin D was associated with a more favorable safety profile, particularly regarding skin atrophy and dyspigmentation. Vitamin D may be considered in selected patients who are particularly concerned about steroid-related adverse effects or lesions located in cosmetically sensitive areas, although these findings should be interpreted cautiously given the limited evidence base.

Telangiectasia macularis eruptiva perstans (TMEP) is a rare vascular phenotype of cutaneous mastocytosis predominantly reported in adults; pediatric cases are exceptional and are particularly difficult to recognize in darker skin phototypes. We report the case of a 4-year-old girl who presented with subtle brown macules and faint telangiectasias, in whom dermoscopy and histopathology confirmed TMEP despite a normal serum tryptase level. Symptomatic management with antihistamines and topical tacrolimus achieved a favorable clinical outcome. This case highlights the diagnostic challenges of TMEP in skin of color and underscores the need for structured long-term surveillance.

Multiple myeloma (MM) is characterized by genomic instability and therapeutic resistance. Emerging evidence indicates that germline DNA damage response (DDR) mutations, including BRCA1/2, ATM, and CHEK2 variants, contribute to MM susceptibility, clonal evolution, and treatment response. Inherited DDR defects promote chromosomal instability, reshape the immune microenvironment, and facilitate therapy-driven disease progression. Recent advances in multiomics profiling, single-cell sequencing, and liquid biopsy have improved the functional interpretation and clinical monitoring of DDR alterations. Moreover, DDR-associated vulnerabilities provide opportunities for precision therapies, including PARP inhibitor-based synthetic lethality strategies. This review summarizes the mechanistic and clinical significance of germline DDR alterations in MM and highlights their translational potential in precision oncology.

Growth differentiation factor 2 (GDF2), also known as bone morphogenetic protein-9 (BMP9), is a key member of the transforming growth factor-beta (TGF-β) superfamily, playing a pivotal role in pulmonary vascular regulation and remodeling. Dominant variants in GDF2 are known to cause hereditary hemorrhagic telangiectasia type 5 (HHT5), a condition characterized by telangiectases and arteriovenous malformations (AVMs). More recently, recessive variants in GDF2 have been reported to cause pulmonary arterial hypertension (PAH) with or without features of HHT5. In this study, we identified a founder variant in GDF2 that potentially causes semidominant PAH in a cohort of 13 patients ranging in age from pediatric to middle-aged adults. Careful clinical evaluation revealed a wide range of ages of onset and disease severity. However, lack of HHT manifestations was a consistent clinical feature. Our results lend further support to GDF2 as a bona fide disease gene in the context of non-syndromic PAH and demonstrate the power of founder variants to reveal the full spectrum of disease variability.