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Mosaicism is the presence of two or more genetically distinct cell lineages originating from a single zygote. The skin frequently marks mosaic conditions through migration patterns of a population of mutant cells during embryogenesis. Somatic mutations in genes of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway can result in segmental overgrowth, hamartomas, and malignant tumors, given the crucial role of this axis in cell growth. Mosaicism for activating mutations in AKT1 and PIK3CA is responsible for Proteus syndrome and PIK3CA-Related Overgrowth Spectrum, respectively. These frequently exemplify Happle’s patterns of cutaneous mosaicism. Postzygotic mutations in PTEN and TSC1/TSC2 result in mosaic forms of the PTEN Hamartoma Tumor Syndrome and tuberous sclerosis complex, which may present as disseminated or segmental disease. Distinct features observed in these mosaic conditions may be attributed to differences in embryological timing or tissue type harboring the mutant cells. Deep sequencing methods of affected tissue is often necessary to diagnosis these disorders. Oral mTORC1 inhibitors, such as sirolimus and everolimus, are useful for treating tuberous sclerosis complex, and drugs targeting mTORC1 or other points along this signaling pathway are in clinical trials to treat several of these disorders.

Purpose: To determine if mosaic tuberous sclerosis complex (TSC) can be stratified into subtypes that correspond with prognosis and extent of disease. Methods: Next-generation sequencing of skin tumor and other samples was used to identify patients with mosaic pathogenic variants in TSC1 or TSC2 . Extent of disease, onset age, and family history of TSC were determined through retrospective analysis of patient records. Results: The median number of disease findings and age at penetrance differed between mosaic patients with asymmetrically distributed facial angiofibromas (4 findings, 24y, n=7), mosaic patients with bilaterally symmetric facial angiofibromas (8 findings, 10y, n=12), and germline TSC patients (10 findings, 4y, n=29). Cutaneous and internal organ involvement positively correlated in mosaic (R=0.62, p=0.005), but not germline (R=−0.24, p=0.24) TSC. Variant allele fraction (VAF) in the blood (range: 0-19%) positively correlated with the number of major features (R=0.55, p=0.028). Five had a TSC2 variant identified in the skin that was below detection in the blood. One of 12 children from a mosaic parent had TSC. Conclusion: The phenotype of mosaic TSC ranged from mild to indistinguishable from germline disease. Patients with mosaicism and asymmetric facial angiofibromas exhibited fewer findings, later onset, and lower VAF in the blood.

The AORPA from the aorta is a rare but important entity, necessitating a scrupulous preoperative and intraoperative evaluation. The techniques employing autologous tissues for enlarging and lengthening the AORPA seem to be associated with better results in terms of postoperative restenosis.

Proteus syndrome is a life-threatening segmental overgrowth syndrome caused by a mosaic gain-of-function AKT1 variant. There are no effective treatments for Proteus syndrome. Miransertib is an AKT1 inhibitor that, prior to this study, has been evaluated only in adult oncology trials. We designed a non-randomized, phase 0/1 pilot study of miransertib in adults and children with Proteus syndrome to identify an appropriate dosage starting point for a future efficacy trial using a pharmacodynamic endpoint. The primary endpoint was a 50% reduction in the tissue levels of AKT phosphorylation from biopsies in affected individuals. We also evaluated secondary efficacy endpoints. We found that a dose of 5 mg/m 2 /day (1/7 the typical dose used in oncology) led to a 50% reduction in phosphorylated AKT (pAKT) in affected tissues from five of six individuals. This dose was well tolerated. Two of the six efficacy endpoints (secondary objectives) suggested that this agent may be efficacious. We observed a decrease in a cerebriform connective tissue nevus and a reduction in pain in children. We conclude that 5 mg/m 2 /day of miransertib is an appropriate starting point for future efficacy trials and that this agent shows promise of therapeutic efficacy in children with Proteus syndrome.

Background Oral mechanistic target of rapamycin (mTOR) inhibitors have been shown to reduce visceral tumor volume in tuberous sclerosis complex (TSC) patients. Objective To evaluate the cutaneous response to oral sirolimus in TSC patients with an indication for systemic treatment, including long-term effects. Methods A retrospective analysis of fourteen adult TSC patients prescribed sirolimus to treat lymphangioleiomyomatosis (LAM) was performed. Serial photographs of angiofibromas, shagreen patches and ungual fibromas taken before, during and after the treatment period were blinded, then assessed using the Physician’s Global Assessment of Clinical Condition (PGA). Microscopic and molecular studies were performed on skin tumors harvested before and during treatment. Results Sirolimus significantly improved angiofibromas (median treatment duration: 12 months; median PGA: 4.5 [range 1.5–5]; Wilcoxon signed-rank test, p= 0.018) and shagreen patches (10; 4.5 [3.5–5]; p=0.039), whereas ungual fibromas improved in some patients (6.5; 4.66 [2.75–5]; p=0.109). Clinical, immunohistochemical or molecular evidence of resistance was not observed (range 5 to 64 months of treatment). Limitations This was a retrospective analysis limited to adult women with LAM. Conclusion Oral sirolimus is an effective long-term therapy for TSC skin tumors, particularly angiofibromas, in patients for whom systemic treatment is indicated.

Effective valve repair in patients with mitral regurgitation (MR) demands an understanding of its mechanism. In patients with ischemic heart disease and functional MR, which doubles late mortality, normal leaflets are apically displaced. This reflects an altered balance of forces acting on the leaflets: increased tethering forces restricting closure, resulting from an altered geometry of leaflet attachments, and decreased ventricular forces acting to close the leaflets. Extensive evidence confirms a central and predominant role of tethering as the final common pathway inducing functional MR; left ventricular (LV) pressure dynamically modulates the orifice area. Because ischemic MR is a disease of the entire mitral complex, including the remodeling LV, reducing annular size alone is often ineffective. Undersizing rings attempts to compensate for tethering; new and potentially more effective strategies directly address tethering by infarct plication, papillary muscle repositioning with a localized patch, or basal chordal cutting to increase coaptational surface area without prolapse. A comprehensive understanding of the valve in its ventricular context, therefore, provides new opportunities for successful valve repair in patients.