Purpose Somatic activating variants in the PI3K-AKT pathway cause vascular malformations with and without overgrowth. We previously reported an individual with capillary and lymphatic malformation harboring a pathogenic somatic variant in PIK3R1, which encodes three PI3K complex regulatory subunits. Here, we investigate PIK3R1 in a large cohort with vascular anomalies and identify an additional 16 individuals with somatic mosaic variants in PIK3R1. Methods Affected tissue from individuals with vascular lesions and overgrowth recruited from a multisite collaborative network was studied. Next-generation sequencing targeting coding regions of cell-signaling and cancer-associated genes was performed followed by assessment of variant pathogenicity. Results The phenotypic and variant spectrum associated with somatic variation in PIK3R1 is reported herein. Variants occurred in the inter-SH2 or N-terminal SH2 domains of all three PIK3R1 protein products. Phenotypic features overlapped those of the PIK3CA-related overgrowth spectrum (PROS). These overlapping features included mixed vascular malformations, sandal toe gap deformity with macrodactyly, lymphatic malformations, venous ectasias, and overgrowth of soft tissue or bone. Conclusion Somatic PIK3R1 variants sharing attributes with cancer-associated variants cause complex vascular malformations and overgrowth. The PIK3R1-associated phenotypic spectrum overlaps with PROS. These data extend understanding of the diverse phenotypic spectrum attributable to genetic variation in the PI3K-AKT pathway.

IMPORTANCEVaccine-derived and wild-type rubella virus (RuV) has been identified within granulomas in patients with inborn errors of immunity, but has not been described in granulomas of healthy adults.OBJECTIVE To determine the association between RuV and atypical granulomatous inflammation in immune-competent adults.DESIGN, SETTING, AND PARTICIPANTS This case series, conducted in US academic dermatology clinics from January 2019 to January 2021, investigated the presence of RuV in skin specimens using RuV immunofluorescent staining of paraffin-embedded tissue sections, real-time reverse-transcription polymerase chain reaction, whole-genome sequencing with phylogenetic analyses, and cell culture by the US Centers for Disease Control and Prevention. Rubella immunoglobulin G, immunoglobulin M enzyme-linked immunoassay, and viral neutralization assays were performed for the sera of immunocompetent individuals with treatment refractory cutaneous granulomas and histopathology demonstrating atypical palisaded and necrotizing granulomas. Clinical immune evaluation was performed.MAIN OUTCOMES AND MEASURES Identification, genotyping, and culture of vaccine-derived and wild-type RuV within granulomatous dermatitis of otherwise clinically immune competent adults. RESULTSOf the 4 total immunocompetent participants, 3 (75%) were women, and the mean (range) age was 61.5 (49.0-73.0) years. The RuV capsid protein was detected by immunohistochemistry in cutaneous granulomas. The presence of RuV RNA was confirmed by real-time reverse-transcription polymerase chain reaction in fresh-frozen skin biopsies and whole-genome sequencing. Phylogenetic analysis of the RuV sequences showed vaccine-derived RuV in 3 cases and wild-type RuV in 1. Live RuV was recovered from the affected skin in 2 participants. Immunology workup results demonstrated no primary immune deficiencies. CONCLUSIONS AND RELEVANCEThe case series study results suggest that RuV (vaccine derived and wild type) can persist for years in cutaneous granulomas in clinically immunocompetent adults and is associated with atypical (palisaded and necrotizing type) chronic cutaneous granulomas. These findings represent a potential paradigm shift in the evaluation, workup, and management of atypical granulomatous dermatitis and raises questions regarding the potential transmissibility of persistent live RuV.

Common variable immunodeficiency disorder is a primary immunodeficiency disorder characterized by reduced levels of serum immunoglobulins and impaired antibody response. This condition may be associated with development of noninfectious granulomatous dermatitis of the skin which may be disfiguring and destructive. There are no published guidelines for the treatment of cutaneous granulomas in this patient population. In recent studies, rubella virus–positive cells in granulomas were localized to M2 macrophages which have an important role in wound healing and the secretion of immunoregulatory cytokines. We present a case of treatment-refractory, disfiguring common variable immunodeficiency disorder–associated granulomatous dermatitis. Immunofluorescence microscopy of the biopsy specimen confirmed the presence of rubella vaccine capsid proteins in M2 macrophages within the granuloma, a newly recognized phenomenon in this patient population. This knowledge may serve to identify future therapeutic targets or preventative strategies for granulomatous dermatitis in patients with primary immunodeficiency disorder.

No abstract

No abstract

No abstract

The initial clinical presentation of infantile myofibromatosis can vary from subtle skin changes to large tumors. Here, we describe a case of congenital generalized infantile myofibromatosis which presented with diffuse hypopigmented macules, some with subtle atrophy and telangiectasia. Further workup revealed visceral involvement which led to treatment with systemic chemotherapy. Awareness of this rare clinical presentation is crucial to expedite workup and treatment given the poor prognosis in infants with visceral involvement.

cAMP response element-binding protein 1 (CREB) is a b-catenin-regulated transcription factor in squamous cell carcinoma (SCC) cells