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Background
Postzygotic activating PIK3CA variants cause several phenotypes within the PIK3CA -related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007 PIK3CA...
Citations
... In humans, a great number of PIK3CA variants have been identified and found to exert varying effects on the recruitment of the AKT pathway. 25 To simulate a higher degree of AKT recruitment, we also created PIK3CA Tie2-HO mice that bear homozygous PIK3CA mutations in capillaries and venous endothelial cells. After Cre recombination, a more severe phenotype emerged, characterized by the rapid occurrence of disseminated and voluminous capillary venous malformations with reduced life expectancy ( Supplementary Fig. 7a-c). ...
Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK , an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA -related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations’ occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA ( n = 16) or TEK ( n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK -related capillary venous malformations.
... Besides NS, the RASopathy family includes neurofibromatosis type 1 (NF1), NS with multiple lentigines (previously known as LEOPARD syndrome), Costello Syndrome (CS), cardio-facio-cutaneous syndrome (CFCS), Legius syndrome, Mazzanti syndrome, capillary malformation-arteriovenous malformation syndrome (CM-AVM), and other emerging clinically related disorders [3,4]. Somatic variants in a number of the same genes (e.g., KRAS, HRAS and NRAS) underlie mosaic RASopathies, including oculoectodermal syndrome [5], encephalo-cranio-cutaneous lipomatosis [6], Schimmelpenning-Feuerstein-Mims syndrome [7], cutaneous skeletal hypophosphatemic syndrome (CSHS) [8], and vascular malformations [9][10][11][12][13][14][15][16]. Constitutional RASopathies have significant phenotypic overlap encompassing dysmorphic facial features, congenital heart defects (CHDs) and hypertrophic cardiomyopathy (HCM), growth failure, skeletal and ectodermal abnormalities, lymphatic dysplasia, cryptorchidism, bleeding diathesis, and various degrees of neurodevelopmental delay (NDD)/intellectual disability (ID). ...
The RASopathies are a group of syndromes caused by genetic variants that affect the RAS-MAPK signaling pathway, which is essential for cell response to diverse stimuli. These variants functionally converge towards the overactivation of the pathway, leading to various constitutional and mosaic conditions. These syndromes show overlapping though distinct clinical presentations and share congenital heart defects, hypertrophic cardiomyopathy (HCM), and lymphatic dysplasia as major clinical features, with highly variable prevalence and severity. Available treatments have mainly been directed to target the symptoms. However, repurposing MEK inhibitors (MEKis), which were originally developed for cancer treatment, to target evolutive aspects occurring in these disorders is a promising option. Animal models have shown encouraging results in treating various RASopathy manifestations, including HCM and lymphatic abnormalities. Clinical reports have also provided first evidence supporting the effectiveness of MEKi, especially trametinib, in treating life-threatening conditions associated with these disorders. Nevertheless, despite notable improvements, there are adverse events that occur, necessitating careful monitoring. Moreover, there is evidence indicating that multiple pathways can contribute to these disorders, indicating a current need to more accurate understand of the underlying mechanism of the disease to apply an effective targeted therapy. In conclusion, while MEKi holds promise in managing life-threatening complications of RASopathies, dedicated clinical trials are required to establish standardized treatment protocols tailored to take into account the individual needs of each patient and favor a personalized treatment.
... As a consequence, the decision about genetic testing is difficult as well, and reports on the increasing application of high throughput assays in diagnostics of these entities illustrate their genetic heterogeneity and the need to apply massive parallel sequencing (MPS) approaches (Brioude et al., 2019). Additionally, these deep sequencing assays also harbor the potential to address and identify mosaic constitutions (Shen et al., 2020;Mussa et al., 2022) (see below). ...
... Cellular mosaicism is a particular observation in overgrowth syndromes (e.g., in BWSp and PIK3CA-related overgrowth disorders) (Baker et al., 2021;Mussa et al., 2022), as several of them exhibit overgrowth only of parts of the body or even organs. As a consequence, routine genetic testing often reveals normal results as is it is conducted in peripheral lymphocytes. ...
Overgrowth disorders comprise a group of entities with a variable phenotypic spectrum ranging from tall stature to isolated or lateralized overgrowth of body parts and or organs. Depending on the underlying physiological pathway affected by pathogenic genetic alterations, overgrowth syndromes are associated with a broad spectrum of neoplasia predisposition, (cardio) vascular and neurodevelopmental anomalies, and dysmorphisms. Pathologic overgrowth may be of prenatal or postnatal onset. It either results from an increased number of cells (intrinsic cellular hyperplasia), hypertrophy of the normal number of cells, an increase in interstitial spaces, or from a combination of all of these. The underlying molecular causes comprise a growing number of genetic alterations affecting skeletal growth and Growth-relevant signaling cascades as major effectors, and they can affect the whole body or parts of it (mosaicism). Furthermore, epigenetic modifications play a critical role in the manifestation of some overgrowth diseases. The diagnosis of overgrowth syndromes as the prerequisite of a personalized clinical management can be challenging, due to their clinical and molecular heterogeneity. Physicians should consider molecular genetic testing as a first diagnostic step in overgrowth syndromes. In particular, the urgent need for a precise diagnosis in tumor predisposition syndromes has to be taken into account as the basis for an early monitoring and therapy. With the (future) implementation of next-generation sequencing approaches and further omic technologies, clinical diagnoses can not only be verified, but they also confirm the clinical and molecular spectrum of overgrowth disorders, including unexpected findings and identification of atypical cases. However, the limitations of the applied assays have to be considered, for each of the disorders of interest, the spectrum of possible types of genomic variants has to be considered as they might require different methodological strategies. Additionally, the integration of artificial intelligence (AI) in diagnostic workflows significantly contribute to the phenotype-driven selection and interpretation of molecular and physiological data.
... The rate of overgrowth is mainly influenced by the type of variant, as different variants can have diverse activating effects. The extent and type of tissues or organs involved, along with the activating capacity (referred to as "strength" or "oncogenicity") of the variant, ultimately determine the severity of the clinical manifestations [4]. In this context, PIK3CArelated disorder phenotypes are extremely heterogeneous, and it is not always easy to associate clinical findings with a specific condition. ...
... Sanger sequencing is usually not able to detect variants with a VAF lower than 15-20% and has a low sensitivity compared to NGS methods [16]. This was recently highlighted in a review of more than 1000 PROS cases, as 10 hot-spot variants cover 70% of PROS cases [4]; therefore, a rapid screening of recurrent hotspot variants may be a reasonable initial diagnostic approach particularly in cases such as macrodactyly, CLOVES syndrome and KTS. However, since such restricted choice potentially leaves out (a) thirty percent of subjects (1 out of 3) potentially bearing different genetic defects, and (b) a number of identifiable gene defects directly involved in cellular and tissue growth control and involved in the PI3K upstream/downstream pathway, a targeted exome sequencing panel including the following genes is strongly suggested: PIK3CA, CCND2, AKT1, AKT2, AKT3, PTEN, GNA11, GNAQ, RACE1, MTOR, PI3KCAa/d, PIK3R1, PIK3R2, PDK1, S6K1, TSC1, TSC2, UBF, TIF-IA, RPTOR, RICTOR, PI3KCD, TEK, CBL, RASA1, HRAS, KRAS, NRAS, SOS1, ARAF, CBL, RASA1, BRAF, MAP2K1, MEK, and PTPN11 [17,18]. ...
... A negative result is expected in a variable proportion of cases, ranging from 15 to 60%, as reported in recent papers on PROS cases [4]. This could be secondary to undetectable low level of mosaicism, the quality of the sample (especially in formalin-fixed paraffinembedded tissue), the type and site of sampling, and the sensitivity of the analytical method used. ...
PIK3CA-related disorders encompass many rare and ultra-rare conditions caused by somatic genetic variants that hyperactivate the PI3K-AKT-mTOR signaling pathway, which is essential for cell cycle control. PIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations and PIK3CA-related non-vascular lesions. Phenotypes are extremely heterogeneous and overlapping. Therefore, diagnosis and management frequently involve various health specialists. Given the rarity of these disorders and the limited number of centers offering optimal care, the Scientific Committee of the Italian Macrodactyly and PROS Association has proposed a revision of the most recent recommendations for the diagnosis, molecular testing, clinical management, follow-up, and treatment strategies. These recommendations give insight on molecular diagnosis, eligible samples, preferable sequencing, and validation methods and management of negative results. The purpose of this paper is to promote collaboration between health care centers and clinicians with a joint shared approach. Finally, we suggest the direction of present and future research studies, including new systemic target therapies, which are currently under evaluation in several clinical trials, such as specific inhibitors that can be employed to downregulate the signaling pathway.
... Till now, dozens of mutations have been identified in patients with vascular malformation and the mutation spectrum has been well delineated. However, most studies on large case series were performed in countries different from China [24][25][26]. Only a limited number of vascular malformations with a definitive pathogenic mutation were previously reported in Chinese population [27][28][29]. ...
Background
Somatic mutations of cancer driver genes are found to be responsible for vascular malformations with clinical manifestations ranging from cutaneous birthmarks to life-threatening systemic anomalies. Till now, only a limited number of cases and mutations were reported in Chinese population. The purpose of this study was to describe the somatic mutation spectrum of a cohort of Chinese pediatrics with vascular malformations.
Methods
Pediatrics diagnosed with various vascular malformations were collected between May 2019 and October 2020 from Beijing Children’s Hospital. Genomic DNA of skin lesion of each patient was extracted and sequenced by whole-exome sequencing to identify pathogenic somatic mutations. Mutations with variant allele frequency less than 5% were validated by ultra-deep sequencing.
Results
A total of 67 pediatrics (33 males, 34 females, age range: 0.1–14.8 years) were analyzed. Exome sequencing identified somatic mutations of corresponding genes in 53 patients, yielding a molecular diagnosis rate of 79.1%. Among 29 PIK3CA mutations, 17 were well-known hotspot p.E542K, p.E545K and p.H1047R/L. Non-hotspot mutations were prevalent in patients with PIK3CA-related overgrowth spectrum, accounting for 50.0% (11/22) of detected mutations. The hotspot GNAQ p.R183Q and TEK p.L914F mutations were responsible for the majority of port-wine stain/Sturge–Weber syndrome and venous malformation, respectively. In addition, we identified a novel AKT1 p.Q79K mutation in Proteus syndrome and MAP3K3 p.E387D mutation in verrucous venous malformation.
Conclusions
The somatic mutation spectrum of vascular malformations in Chinese population is similar to that reported in other populations, but non-hotspot PIK3CA mutations may also be prevalent. Molecular diagnosis may help the clinical diagnosis, treatment and management of these pediatric patients with vascular malformations.
... The following types of tissue samples were used for molecular confirmation: epidermal nevus (n = 3), skin and subcutaneous fat obtained by biopsy needle (n = 6), and surgically obtained fat (n = 9). Previous studies reported that the detection rate of mutations in blood samples was extremely low in non-central nervous system (CNS) disorders [12], so we only used tissue samples for analysis. A total of eight PIK3CA mutations were detected in tissues isolated from sixteen (89%) patients with variant allele fractions (VAFs) ranging from 2.35% to 26.50%, and the average VAF was 12.76%. ...
... Recent studies have shown that nonhotspot mutations occur more frequently in CLOVES syndrome [35], and some less common mutant loci have been observed only in MCAP [36,37], while some mutations possessing strong oncogenic capacity were detected in somatic segmental overgrowth disorders [27]. Another recent study that included many cases yielded the same conclusion [12]. CLOVES is a systemic syndrome that includes a variety of manifestations: congenital lipomatous overgrowth (CLO), vascular malformation (V), epidermal nevi (E), and scoliosis/spinal malformation (S) [9]. ...
... Nevertheless, the patient's body parts below the neck are usually uninvolved, and the blood and biochemical tests are within the normal range, so FIL should be considered an isolated and sporadic lesion. In other PIK3CA mutation-associated sporadic overgrowth diseases, p.Glu542Lys, p.Glu545Lys, and p.His1047Arg were responsible for the majority of cases [12]. For example, macrodactyly is caused by the overgrowth of bone and adipose tissues, and more than 90% of cases are caused by these three hotspot mutations [38]; similar proportions have been found in segmental overgrowth of limbs involving muscle and bone [39]. ...
Background:
Facial infiltrating lipomatosis (FIL) is a rare congenital disorder characterized by unilateral facial swelling, for which surgery is the prevailing therapeutic option. Several studies have shown that the development of FIL is closely associated with PIK3CA mutations. This study aimed to further identify rare clinical features and underlying molecular variants in patients with FIL.
Results:
Eighteen patients were included in this study, and all patients presented with infiltrating adipose tissues confirmed by magnetic resonance imaging. Macrodactyly, polydactyly, hemimegalencephaly and hemihyperplasia were also observed in patients with FIL. In total, eight different PIK3CA mutations were detected in tissues obtained from sixteen patients, including the missense mutations p.His1047Arg (n = 4), p.Cys420Arg (n = 2), p.Glu453Lys (n = 2), p.Glu542Lys (n = 2), p.Glu418Lys (n = 1), p.Glu545Lys (n = 1), and p.His1047Tyr (n = 1) and the deletion mutation p.Glu110del (n = 3). Furthermore, the GNAQ mutation p.Arg183Gln was detected in the epidermal nevus tissue of one patient. Imaging revealed that several patients carrying hotspot mutations had more severe adipose infiltration and skeletal deformities.
Conclusions:
The abundant clinical presentations and genetic profiles of FIL make it difficult to treat. PIK3CA mutations drive the pathogenesis of FIL, and PIK3CA hotspot mutations may lead to more extensive infiltration of lipomatosis. Understanding the molecular variant profile of FIL will facilitate the application of novel PI3K-targeted inhibitors.
... The heterogeneity of these conditions reflects both the kind of tissue affected and the body extension of the overgrown area. These factors are connected with the timing of onset during fetal development of the somatic causative PIK3CA pathogenic variants reflecting the degree of mosaicism and the combination of tissues involved [9,10]. Different gain-of-function variants in PIK3CA determine a variable degree of hyperactivation of the phosphatidylinositol 3 kinase (PI3K)/AKT/mTOR pathway [11], leading to a different severity in the abnormal proliferation of mesodermal and/or ectodermal tissues from embryogenesis onwards [10]. ...
... In spite of the advances in the knowledge of the PROS across the last decade, a consistent fraction of these phenotypes still remains orphan of a molecular diagnosis due to several factors: these include inappropriate tissue DNA sampling, very low-level mosaicism difficult to be detected, molecular mechanisms still to be unraveled. Some of the cases with PROS-like or overlapping phenotypes have recently shown to be caused by variants in genes of the same signal cascade (i.e., AKT1, AKT3, mTOR [9,[12][13][14][15]) or crosstalking molecular pathways (i.e., RAS/MAPK [16,17], or vascular proliferation pathway [18,19],). However, still nearly 30% of cases remain undiagnosed [9]. ...
... Some of the cases with PROS-like or overlapping phenotypes have recently shown to be caused by variants in genes of the same signal cascade (i.e., AKT1, AKT3, mTOR [9,[12][13][14][15]) or crosstalking molecular pathways (i.e., RAS/MAPK [16,17], or vascular proliferation pathway [18,19],). However, still nearly 30% of cases remain undiagnosed [9]. ...
PIK3CA pathogenic variants are responsible for a group of overgrowth syndromes, collectively known as PIK3CA-Related Overgrowth Spectrum (PROS). These gain-of-function variants arise postzygotically, and, according to time of onset, kind of embryonal tissue affected and regional body extension, give rise to heterogeneous phenotypes. PROS rarity and heterogeneity hamper the correct estimation of its epidemiology. Our work represents the first attempt to define the prevalence of PROS according to the established diagnostic criteria and molecular analysis and based on solid demographic data. We assessed the prevalence in Piedmont Region (Italy), including in the study all participants diagnosed with PROS born there from 1998 to 2021. The search identified 37 cases of PROS born across the 25-year period, providing a prevalence of 1:22,313 live births. Molecular analysis was positive in 81.0% of participants. Taking into account the cases with a detected variant in PIK3CA (n = 30), prevalence of molecularly positive PROS was 1:27,519.
... ), a testing approach which is commonly used in other conditions characterized by overgrowth and localized mosaicism [35]. In fact, an improvement in diagnostic performance has been documented by analyzing DNA from overgrowth tissue in these conditions, and the greater level of invasiveness in this situation would not only be justified by allowing a differential diagnosis towards other forms of overgrowth (e.g., PIK3CA-related overgrowth spectrum, vascular phenotype overlapping PIK3CA-related overgrowth spectrum with mutations in other genes) or body asymmetry (e.g., Silver-Russell syndrome) [35][36][37], but also by the opportunity to apply more precisely a targeted cancer screening [31] or management [38,39] based on the molecular lesion found within the BWSp. Further studies are needed to test this hypothesis and assess the best approach in such a condition, as well as the increase in the diagnostic yield by this approach. ...
Simple Summary
Beckwith-Wiedemann syndrome (BWSp) has recently been renamed to spectrum to reflect its diverse presentation and clinical features. In 2018, an international consensus developed a diagnostic approach and redefined clinical criteria, establishing a score above which a diagnosis can be made in case of a negative genetic test. We described a cohort of 831 patients to validate the efficacy of the 2018 consensus score for BWSp diagnosis, and to gather data on the performance of previous and current scoring systems, as well as the relationship between BWSp features, molecular tests, and the risk of cancer development.
Abstract
Different scoring systems for the clinical diagnosis of the Beckwith–Wiedemann spectrum (BWSp) have been developed over time, the most recent being the international consensus score. Here we try to validate and provide data on the performance metrics of these scoring systems of the 2018 international consensus and the previous ones, relating them to BWSp features, molecular tests, and the probability of cancer development in a cohort of 831 patients. The consensus scoring system had the best performance (sensitivity 0.85 and specificity 0.43). In our cohort, the diagnostic yield of tests on blood-extracted DNA was low in patients with a low consensus score (~20% with a score = 2), and the score did not correlate with cancer development. We observed hepatoblastoma (HB) in 4.3% of patients with UPD(11)pat and Wilms tumor in 1.9% of patients with isolated lateralized overgrowth (ILO). We validated the efficacy of the currently used consensus score for BWSp clinical diagnosis. Based on our observation, a first-tier analysis of tissue-extracted DNA in patients with <4 points may be considered. We discourage the use of the consensus score value as an indicator of the probability of cancer development. Moreover, we suggest considering cancer screening for negative patients with ILO (risk ~2%) and HB screening for patients with UPD(11)pat (risk ~4%).
... 12 Mosaic gain-of-function postzygotic somatic gene variants in PIK3CA underlie most HNLM and head and neck PROS, allowing targeted medical therapy. Large reviews of genotype-phenotype correlation in PIK3CA-related diseases typically distinguish between involvement of central nervous system vs involvement of extra-central nervous system and major diagnostic category but do not specifically identify individuals whose PROS includes the head and neck. 2 Mussa et al 13 identified that 70% of individuals with PIK3CA-related diseases have 1 of 10 pathogenic variants, with the remaining 30% have 81 other variants. The most common variants in lymphatic malformations are p.His1047Arg, p.Glu542Lys, and p.Glu545Lys. 3 Previously, empirical use of the mTOR inhibitor, sirolimus (Rapamune), a downstream inhibitor of the PI3K pathway, was used to treat a variety of lymphatic conditions, including postoperative lymphorrhea. ...
Purpose
PIK3CA-related overgrowth spectrum (PROS) conditions of the head and neck are treatment challenges. Traditionally, these conditions require multiple invasive interventions, with incomplete malformation removal, disfigurement, and possible dysfunction. Use of the PI3K inhibitor alpelisib, previously shown to be effective in PROS, has not been reported in PIK3CA-associated head and neck lymphatic malformations (HNLMs) or facial infiltrating lipomatosis (FIL). We describe prospective treatment of 5 children with PIK3CA-associated HNLMs or head and neck FIL with alpelisib monotherapy.
Methods
A total of 5 children with PIK3CA-associated HNLMs (n = 4) or FIL (n = 1) received alpelisib monotherapy (aged 2-12 years). Treatment response was determined by parental report, clinical evaluation, diary/questionnaire, and standardized clinical photography, measuring facial volume through 3-dimensional photos and magnetic resonance imaging.
Results
All participants had reduction in the size of lesion, and all had improvement or resolution of malformation inflammation/pain/bleeding. Common invasive therapy was avoided (ie, tracheotomy). After 6 or more months of alpelisib therapy, facial volume was reduced (range 1%-20%) and magnetic resonance imaging anomaly volume (range 0%-23%) were reduced, and there was improvement in swallowing, upper airway patency, and speech clarity.
Conclusion
Individuals with head and neck PROS treated with alpelisib had decreased malformation size and locoregional overgrowth, improved function and symptoms, and fewer invasive procedures.
... Of note, Martinez-Glez et al. recently described PIK3CA mutations in individuals presenting segmental undergrowth of musculoskeletal tissues together with vascular malformations, with or without associated overgrowth 22 . There are some other individuals who are clinically diagnosed with some of the so-called PROS conditions (that is, Klippel-Trenaunay syndrome (KTS), diffuse capillary malformation with overgrowth (DCMO) and megalencephalycapillary malformation (MCAP) syndrome) but are not associated with mutations in PIK3CA 23,24 . These observations indicate that the understanding of PIK3CA-related congenital disorders is in its infancy and that the current classification may need to be revisited in the future. ...
... The PIK3CA mutations that cause PROS are the very same ones that cause cancer, including the so-called cancer hotspots (p.Glu542Lys, p.Glu545Lys and p.His1047Arg). However, mutations in gene locations other than the common hotspots are more frequent in PROS than in cancer 23 . Given that PIK3CA is a gene widely associated with cancer, an intriguing aspect is whether individuals with PROS have an increased risk of developing cancer. ...
... The implementation of nextgeneration sequencing into clinical practice for PROS diagnosis has allowed us to study and follow large cohorts of individuals. Indeed, these genetic data have provided substantial evidence that there is not always a clear correlation between the type of cell lineages carrying the mutation, the VAF of the mutation in the affected tissue, and the severity of the clinical outcome 23 . In fact, some individuals develop an isolated, but very severe lesion and other individuals have widespread overgrowth but lower severity. ...
PIK3CA encodes the class I PI3Kα isoform and is frequently mutated in cancer. Activating mutations in PIK3CA also cause a range of congenital disorders featuring asymmetric tissue overgrowth, known as the PIK3CA-related overgrowth spectrum (PROS), with frequent vascular involvement. In PROS, PIK3CA mutations arise postzygotically, during embryonic development, leading to a mosaic body pattern distribution resulting in a variety of phenotypic features. A clear skewed pattern of overgrowth favoring some mesoderm-derived and ectoderm-derived tissues is observed but not understood. Here, we summarize our current knowledge of the determinants of PIK3CA-related pathogenesis in PROS, including intrinsic factors such as cell lineage susceptibility and PIK3CA variant bias, and extrinsic factors, which refers to environmental modifiers. We also include a section on PIK3CA-related vascular malformations given that the vasculature is frequently affected in PROS. Increasing our biological understanding of PIK3CA mutations in PROS will contribute toward unraveling the onset and progression of these conditions and ultimately impact on their treatment. Given that PIK3CA mutations are similar in PROS and cancer, deeper insights into one will also inform about the other. In this Review, the authors provide an overview of the pathogenic effects of somatic activating PIK3CA mutations in congenital disorders and discuss how the interplay between genetics, cell identity and the environment explains the onset, progression and severity of these disorders with a special focus on the vasculature.
