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PIK3CA-related overgrowth spectrum (PROS): New insight in known diseases
Síndromes de sobrecrecimiento relacionados con PIK3CA (PROS): Conocimiento nuevo de enfermedades conocidas
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Los números debajo de cada dominio corresponden a los aminoácidos de inicio y final para dichos dominios. Las estrellas corresponden a la ubicación de los tres <span class="elsevierStyleItalic">hotspots</span> indicados en el texto. Los dominios de la proteína son: i) ABD: <span class="elsevierStyleItalic">adaptor-binding domain</span>, se encarga de interaccionar con la proteína p85, reguladora de la vía; ii) RBD: <span class="elsevierStyleItalic">ras-binding domain</span>, lugar de interacción entre PI3K y la cascada de señalización RAS; iii) C2: dominio con estructura de sándwich β de función desconocida; iv) helicoidal: es un dominio con conformación tridimensional helicoidal de función desconocida; v) cinasa (quinasa): dominio catalítico responsable de fosforilar los efectores de la vía.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Adriana Iriarte Fuster, Pau Cerdà Serra, Antoni Riera-Mestre" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Adriana" "apellidos" => "Iriarte Fuster" ] 1 => array:2 [ "nombre" => "Pau" "apellidos" => "Cerdà Serra" ] 2 => array:2 [ "nombre" => "Antoni" "apellidos" => "Riera-Mestre" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020621005702" "doi" => "10.1016/j.medcle.2021.03.018" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020621005702?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775321003006?idApp=UINPBA00004N" "url" => "/00257753/0000015700000010/v1_202111140539/S0025775321003006/v1_202111140539/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2387020621005726" "issn" => "23870206" "doi" => "10.1016/j.medcle.2021.03.019" "estado" => "S300" "fechaPublicacion" => "2021-11-26" "aid" => "5680" "copyright" => "Elsevier España, S.L.U." 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array:20 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "<span class="elsevierStyleItalic">PIK3CA</span>-related overgrowth spectrum (PROS): New insight in known diseases" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "483" "paginaFinal" => "488" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Adriana Iriarte Fuster, Pau Cerdà Serra, Antoni Riera-Mestre" "autores" => array:3 [ 0 => array:3 [ "nombre" => "Adriana" "apellidos" => "Iriarte Fuster" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Pau" "apellidos" => "Cerdà Serra" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:4 [ "nombre" => "Antoni" "apellidos" => "Riera-Mestre" "email" => array:1 [ 0 => "ariera@bellvitgehospital.cat" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidad de HHT y otras Enfermedades Minoritarias Vasculares, Servicio de Medicina Interna, Hospital Universitari de Bellvitge, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Facultad de Medicina y Ciencias de la Salud, Universitat de Barcelona, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndromes de sobrecrecimiento relacionados con <span class="elsevierStyleItalic">PIK3CA</span> (PROS): Conocimiento nuevo de enfermedades conocidas" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1730 "Ancho" => 2175 "Tamanyo" => 178054 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Diagram of the canonical pathway of PI3K signaling activation and its intracellular signal transduction. The solid arrows indicate the pathway, and the dashed arrows point to negative feedback mechanisms. The stars mark known therapeutic targets for which drugs are available, which are outlined in cursive.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-related overgrowth syndromes, known as the <span class="elsevierStyleItalic">PIK3CA</span>-related overgrowth spectrum (PROS), are a heterogeneous group of rare diseases in which the presence of vascular malformations (VMs) is associated with segmental overgrowth of certain parts of the body.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The main characteristic shared by these diseases is that they are all caused by mutations in the gene encoding the alpha subunit of PI3K.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> It was when the genetic mechanisms underlying these diseases were discovered, in 2014, that the term PROS was first coined.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">This new spectrum of diseases was included in the latest update of the VMs classification of the International Society for the Study of Vascular Anomalies (ISSVA) in May 2018.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,5</span></a> At present, several diseases are included under the PROS concept, all of them with specific phenotypic features, but also with common characteristics that result in overlapping phenomena (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Their global epidemiological characteristics are poorly known, although it is estimated that these entities separately have prevalence rates of less than 1/1,000,000, with a male/female ratio of 1/1.3.<span class="elsevierStyleSup">1,2.</span> This low prevalence means that, despite encompassing several diseases, the PROS is considered a rare disease (ORPHA code 530313).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The low prevalence and great clinical variability of these syndromes entail a highly complex diagnosis, particularly in infrequent situations. This is a common issue in the field of rare diseases, in which case it is difficult to accumulate sufficient experience on the characteristics and natural course of a disease from a single site.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The creation of registries could contribute to overcoming these difficulties and, therefore, represent a priority in the management of rare disease.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9</span></a> The aim of this paper is to review the new view on PROS syndromes in order to contribute to the dissemination of these entities and, thus, to reach an optimal diagnosis of patients suffering them.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Pathophysiology</span><p id="par0020" class="elsevierStylePara elsevierViewall">Phosphatidylinositol-4,5-bisphosphate 3-kinases (PI3Ks) form a family of enzymes known for their role in the signal transduction that stimulates cell growth, proliferation, and migration.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> This family is comprised by eight isoforms that are divided into three classes (class I: α, β, γ, and δ; class II: α, β, and γ; and class III), each expressing in different cell types and with different functions, some of which remain unknown to date. Because of its role in the pathophysiology of certain solid tumors, the best known and most studied isoform is class I subtype α (known as PIK3CA or p110α), which is encoded by the <span class="elsevierStyleItalic">PIK3CA</span> gene.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> This PIK3CA isoform is involved in the PROS and consists of five domains. Most of its mutations (over 80%) affect three specific codons (called hotspots), which encode two glutamic acids located at positions 542 and 545, corresponding to the helical domain, and a histidine located at position 1,047, corresponding to the catalytic domain of the kinase (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Under normal conditions, stimulation of tyrosine kinase receptors (among others) in the cell membrane activates the phosphorylation of PI3K, which, in turn, catalyzes the conversion of phosphatidylinositol (3,4)-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-triphosphate (PIP3). This phospholipid acts as a second messenger by recruiting cytoplasmic proteins that amplify the signal until it reaches its effectors. Protein phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN) is a phosphatase that antagonizes the PI3K/AKT/mTOR (where AKT is a serine/threonine kinase also called protein kinase B, and mTOR is the mammalian target of rapamycin) signaling pathway by dephosphorylating PIP3 and thereby modulating the cell cycle progression. Mutations in PI3K facilitate sequestering the enzyme in the cell membrane, thus resulting in the constant production of PIP3 and, in turn, the permanent activation of the PI3K/AKT/mTOR signaling pathway.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,10</span></a> Although the molecular mechanics leading to the PROS phenotype are not yet well defined, they are well known in the fields of oncology or isolated vascular malformations and, therefore, assumed to be similar or even equivalent (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The mutations described are gain-of-function mutations in both cancer and the PROS.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,10</span></a> In fact, PI3K hyperactivation causes vascular overgrowth in conditions other than the PROS.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> For example, immunohistochemistry studies showed an <span class="elsevierStyleItalic">in situ</span> hyperactivation of PI3K in the telangiectases of patients with hereditary hemorrhagic telangiectasia (HHT).<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">However, although mutations in the <span class="elsevierStyleItalic">PIK3CA</span> gene have also been linked to cancer in adult patients, those with PROS syndromes exhibit approximately the same incidence of cancer as the general population, which is explained by the pathophysiological characteristics of the PROS. Moreover, it must be noted that in the PROS, although the <span class="elsevierStyleItalic">PIK3CA</span> mutations are somatic, as in the case of cancer—that is, not germline mutations and, therefore, not inherited—, they occur during embryogenesis. Thus, the amount of tissue affected and, as a result, the extent of the lesions depends on the time of embryogenesis at which they occur (earlier or later). Another relevant pathophysiological aspect that also contributes to determining the phenotype is the specific primary germ layer (ectoderm, mesoderm, or endoderm) in which the mutation occurs, as different tissues derive from each one of them. These two aspects are crucial, as the phenotype varies greatly depending on the time of embryonic development at which the mutations occur and the primary germ layer that they affect.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> This is why PROS syndromes can manifest from an isolated macrodactyly to more complex syndromes such as the CLOVES syndrome, which combines overgrowth with VMs, skin lesions, and scoliosis (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Symptomatology</span><p id="par0040" class="elsevierStylePara elsevierViewall">Patients with PROS syndromes are characterized by presenting with segmental overgrowth of multiple tissues, with vascular (capillaries, veins, and lymphatic vessels) and adipose tissues being the most involved at a macroscopic level. Other characteristic findings are the presence of polydactyly, cutaneous syndactyly, renal and urinary tract anomalies (agenesis, hydronephrosis, ureteral duplication, or renal cysts), and the presence of ovarian cysts and testicular hydroceles.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> As shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, the spectrum of PROS syndromes can be divided into either complex syndromic phenotypes with a high degree of involvement or isolated forms. Although there was initially controversy surrounding the Klippel-Trenaunay syndrome, the detection of <span class="elsevierStyleItalic">PIK3CA</span> mutations in these patients has now been confirmed.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Symptoms associated with the PROS depend on the extent of the overgrowth and the anatomical site affected by it, with the lower limbs predominantly being affected, mostly unilaterally and following a distal to proximal pattern. Segmental overgrowth is often congenital, although it can manifest during the first year of life and subsequently progress into adulthood in some cases. The tissues that are mostly affected by this condition are the fibroadipose, vascular, nervous system, and musculoskeletal ones. Vascular malformations may be present in 43% of patients, including capillary, venous, arteriovenous, or lymphatic malformations, and different types might even present concomitantly in some patients.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Patients with PROS syndromes have a higher risk of developing thromboembolic complications due to blood stasis caused by the VM itself, the existence of localized intravascular coagulation characterized by high <span class="elsevierStyleSmallCaps">d</span>-dimer levels associated with fibrinogen and platelet consumption, and the limited mobility of the patients themselves as a result of their pain and the asymmetric overgrowth of their limbs.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16,17</span></a> In fact, elevation of D-dimer levels is characteristic of low-flow VMs, as opposed to high-flow or arteriovenous VMs, and translates into spontaneous thrombosis and thrombolysis phenomena secondary to venous stasis, which activates the coagulation cascade.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> This prothrombotic condition can be further aggravated after a surgical procedure. In this regard, a particular study analyzed thromboembolic events in patients with PROS syndromes and reported that 64% of pulmonary embolisms occurred following a surgical procedure or sclerotherapy.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Although <span class="elsevierStyleItalic">PIK3CA</span> mutations are very common in different types of tumors, an increased incidence of cancer among patients with this condition has not been documented. To date, the only malignant tumor reported in patients with the PROS has been Wilms' tumor (nephroblastoma). Although there is still not enough evidence to demonstrate that these patients are at an increased risk of developing these tumors, it is advised that serial abdominal ultrasound scans be performed every three to four months until the age of eight years for their early detection.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Diagnosis</span><p id="par0060" class="elsevierStylePara elsevierViewall">Due to the phenotypic variability of the syndromes included in the PROS, different diagnostic criteria have been proposed to help clinicians evaluate patients suffering from them. As they are congenital or early childhood onset disorders, they are characterized by an absence of a family history (sporadic cases) and a mosaic distribution. Overall, most patients present with a progressive disease and might manifest the full spectrum of clinical manifestations of the disease or only isolated ones. The diagnostic criteria are subdivided into mandatory common features and two main categories. To reach the diagnosis, the common characteristics must be present in association with at least two criteria from group A (syndromic forms) or one from group B (isolated forms) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Multiple phenotypes associated with mutations in the PI3K/AKT/mTOR pathway and leading to a spectrum of segmental overgrowth syndromes have been described. Therefore, other diseases should also be considered in the differential diagnosis of the PROS, such as the Proteus syndrome, which is characterized by an asymmetric overgrowth of the lower limbs and the growth of cerebriform nevi; PTEN hamartoma tumor syndrome, which is characterized by the existence of macrocephaly, skin lesions such as trichilemmomas, and the growth of lipomas and hamartomas in the gastrointestinal tract, the skin, and the thyroid gland; as well as tuberous sclerosis complex (TSC1/2), which presents with central nervous system involvement associated with characteristic skin lesions, such as facial angiofibromas and the growth of tumors in multiple organs (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). The Parkes-Weber syndrome, like other syndromes caused by mutations in the <span class="elsevierStyleItalic">RASA1</span> gene, is characterized by high-flow (arteriovenous) fistulas. Their main complication is heart failure associated with a high cardiac output and, although they also cause overgrowth of the affected limb, they should not be confused with a PROS syndrome.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> However, we now know that these other overgrowth syndromes manifest with other clinical characteristics that do not meet the criteria set for PROS syndromes and, above all, that they are due to other genetic causes.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Therefore, the identification of specific mutations in affected individuals is important because of the potential diagnostic and therapeutic implications they represent. However, reaching a genetic diagnosis for PROS syndromes is not straightforward and is challenging in several ways. This is because <span class="elsevierStyleItalic">PIK3CA</span> mutations occur as a postzygotic event, causing somatic mosaicism, owing to which pathogenic variants are usually undetectable in the blood or tissues of normal appearance, and consequently only detected in the affected organs. Because of this, the genetic diagnosis of a PROS syndrome involves the conduct of a biopsy, which is often complex because the lesions are hypervascularized.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In addition, which tissue is most likely to have the mutation should be determined. It should be noted that some biopsies from these patients may exhibit a very low level of mosaicism (<5%).</p><p id="par0075" class="elsevierStylePara elsevierViewall">Hence, either a molecular diagnosis with high-throughput sequencing techniques, such as next generation sequencing (NGS),<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> or the use of other more specific techniques, such as a Droplet Digital polymerase chain reaction (ddPCR) and customized restriction fragment length polymorphism (RFLP) assays, is required. The latter methods identify specific <span class="elsevierStyleItalic">PIK3CA</span> mutations and are able to detect very low percentages of mosaicism in the cells under study (0.5%–0.001%).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Because of these difficulties, one must bear in mind that a negative result does not rule out the diagnosis of a PROS syndrome in patients with compatible phenotypes.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Treatment</span><p id="par0085" class="elsevierStylePara elsevierViewall">The therapeutic approach for overgrowth syndromes has classically consisted in conservative management, limited to treating complications arising from the overgrowth through the use of compressive therapies, surgical excision, orthopedic surgery, sclerotherapy, and/or embolization. These strategies are probably insufficient, as the condition often progresses, and these patients tend to experience a relapse during their follow-up.</p><p id="par0090" class="elsevierStylePara elsevierViewall">The identification of the PIK3/AKT/mTOR activation pathway has been a therapeutic breakthrough for these patients. Because mTOR is a downstream effector of the PI3K signaling pathway, the use of a specific inhibitor, such as sirolimus, has proven to be an attractive therapeutic strategy in patients with PROS syndromes. Several studies performed to date have demonstrated its benefit in venous and lymphatic malformations in both pediatric and adult patients.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> A modest clinical and radiological improvement has been demonstrated particularly in PROS syndromes, although these treatments are not free of adverse effects.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In this regard, different PIK3 inhibitors have been approved for the treatment of several oncohematological diseases in which gain-of-function mutations are observed in this gene. A selective <span class="elsevierStyleItalic">PIK3CA</span> inhibitor, called alpelisib, has recently been approved in Spain for the treatment of locally advanced or metastatic breast cancer with a <span class="elsevierStyleItalic">PIK3CA</span> mutation. One particular study analyzed the compassionate use of alpelisib in 19 patients with various phenotypic expressions of the PROS, including six patients with CLOVES syndrome, two with macrocephaly-capillary malformation (MCAP) syndrome, and nine patients with localized overgrowth. All patients exhibited remarkable improvements, including a reduction in their capillary malformations and epidermal nevi, cessation of their chronic gastrointestinal bleeding, an improvement in their scoliosis, and an improvement in the cognitive function of the two patients with MCAP. In this patient cohort, alpelisib was well tolerated and caused few adverse effects.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Due to the complexity of these diseases and the wide range of complications that these patients can experience during their follow-up, specialized multidisciplinary units involved in the diagnosis, follow-up, and optimal management of patients affected by PROS syndromes should be created.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="par0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">PIK3CA</span>-related overgrowth spectrum syndromes are a group of very phenotypically diverse entities caused by mutations in the gene encoding PIK3CA and are globally considered a rare disease (ORPHA code 530313). Knowledge of the clinical characteristics of patients with PROS syndromes, as well as the use of clinical and molecular diagnostic strategies, is important for reaching an early diagnosis and preventing potential associated complications. Further delving into these aspects will contribute to obtaining necessary tools to develop new therapeutic strategies for patients with PROS syndromes.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Funding sources</span><p id="par0110" class="elsevierStylePara elsevierViewall">This study was partially funded by the Carlos III Health Institute (<span class="elsevierStyleItalic">Instituto de Salud Carlos III</span>) through project PI17/00669 (co-financed by the European Regional Development Fund [ERDF], “A way of doing Europe”). It was also partially funded by a 2019–2021 research grant from the Research Committee of <span class="elsevierStyleItalic">Hospital Universitari de Bellvitge</span> (Barcelona, Spain).</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflicts of interest</span><p id="par0115" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres1639957" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1462304" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1639956" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1462303" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Pathophysiology" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Symptomatology" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Diagnosis" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Treatment" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Funding sources" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-12-24" "fechaAceptado" => "2021-03-23" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1462304" "palabras" => array:4 [ 0 => "<span class="elsevierStyleItalic">PIK3CA-</span>related overgrowth spectrum (PROS)" 1 => "Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K)" 2 => "Vascular malformation" 3 => "Rare diseases" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1462303" "palabras" => array:4 [ 0 => "Síndromes de sobrecrecimiento relacionados con <span class="elsevierStyleItalic">PIK3CA</span> (PROS)" 1 => "fosfatidilinositol-4,5-bifosfato 3-cinasa (PI3K)" 2 => "Malformaciones vasculares" 3 => "Enfermedades minoritarias" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">The overgrowth syndromes related to phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) are grouped under the concept of PROS (<span class="elsevierStyleItalic">PIK3CA</span>-related overgrowth spectrum). It is a heterogeneous group of diseases, considered a rare disease (ORPHA: 530,313), which combines the presence of vascular malformations with segmental overgrowth of some parts of the body. All these diseases are caused by mutations in the gene that encodes for the alpha subunit of PI3K. These mutations are somatic and take place during the embryonic stage. Depending on the stage of embryonic development and the affected germ layers, the phenotype will be very different, from syndromes with extensive involvement to isolated forms. Although there are clinical criteria, identification of the mutation by biopsy, although complex, confirms the diagnosis. The objective of the present study is to review the pathophysiological, clinical, diagnostic, and therapeutic aspects of PROS, in order to optimize its identification.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Los síndromes de sobrecrecimiento relacionados con la fosfatidilinositol-4,5-bifosfato 3-cinasa (PI3K), se agrupan bajo el concepto de PROS (<span class="elsevierStyleItalic">PIK3CA</span>-<span class="elsevierStyleItalic">related overgrowth spectrum</span>). Son un grupo heterogéneo de entidades, considerado una enfermedad minoritaria (ORPHA: 530313), que combina la presencia de malformaciones vasculares con el sobrecrecimiento segmentario de algunas partes del cuerpo. Todas estas enfermedades están causadas por mutaciones en el gen que codifica la subunidad alfa de la PI3K. Estas mutaciones son somáticas y tienen lugar durante la embriogénesis. Dependiendo del momento del desarrollo embrionario que se produzcan y a qué hoja precursora afecten, el fenotipo será muy distinto, desde síndromes con extensa afectación a formas aisladas. Aunque existen unos criterios clínicos, la identificación de la mutación mediante realización de una biopsia, aunque compleja, confirma el diagnóstico. El objetivo del presente trabajo es revisar los aspectos fisiopatológicos, clínicos, diagnósticos y terapéuticos del PROS, con el fin de optimizar su identificación.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as: A. Iriarte Fuster, P. Cerdà Serra and A. Riera-Mestre, Síndromes de sobrecrecimiento relacionados con <span class="elsevierStyleItalic">PIK3CA</span> (PROS): Conocimiento nuevo de enfermedades conocidas. Med Clin (Barc). 2021;157:483–488.</p>" ] ] "multimedia" => array:6 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 348 "Ancho" => 2508 "Tamanyo" => 51230 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Schematic image of the PI3K protein with the identified domains. The numbers below each domain correspond to the initial and final amino acids of said domains. The stars correspond to the location of the three hotspots described in the text. The domains of the protein are: i) the adaptor-binding domain (ABD), which is responsible for interacting with pathway regulatory protein p85; ii) the ras-binding domain (RBD), corresponding to the site of interaction between PI3K and the RAS signaling cascade; iii) C2, a domain of unknown function with a β sandwich structure; iv) the helical domain of unknown function with a three-dimensional helical conformation; and v) the kinase catalytic domain responsible for phosphorylating the pathway effectors.</p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1730 "Ancho" => 2175 "Tamanyo" => 178054 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Diagram of the canonical pathway of PI3K signaling activation and its intracellular signal transduction. The solid arrows indicate the pathway, and the dashed arrows point to negative feedback mechanisms. The stars mark known therapeutic targets for which drugs are available, which are outlined in cursive.</p>" ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1253 "Ancho" => 2274 "Tamanyo" => 128067 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Diagram showing how somatic mutations occurring at different moments of embryonic development can result in varying phenotypes and topographic distributions in both fetuses and adults. The sooner they occur, the more tissues and more cells of each tissue are affected.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PROS syndromes \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical manifestations \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Syndromic forms</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>CLOVES syndrome (<span class="elsevierStyleItalic">congenital lipomatous overgrowth, vascular malformations, epidermal nevi, skeletal/spinal anomalies and/or scoliosis)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lipomatous overgrowths on the trunk and limbs, low-flow vascular malformations, epidermal nevi, scoliosis and/or spinal deformities \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Klippel-Trenaunay syndrome (KTS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Several combinations of capillary, venous, and lymphatic malformations associated with limb overgrowth \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Macrocephaly-capillary malformation (MCAP or M-CM) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Megalencephaly or hemimegalencephaly, polymicrogyria, cerebellar tonsil herniation, ventriculomegaly, vascular malformations (facial midline), segmental overgrowth, syndactyly, polydactyly, and connective tissue disorders \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Fibroadipose overgrowth (FAO) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Progressive segmental overgrowth of the subcutaneous, muscular, and visceral fibroadipose tissue, together with skeletal overgrowth, peripheral nerve enlargement, cutaneous capillary malformations, testicular or epididymal cysts, and hydroceles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hemihyperplasia-multiple lipomatosis (HHML) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Congenital overgrowth and asymmetry, vascular skin anomalies, and recurrent subcutaneous lipomas \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Facial infiltrating lipomatosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hemifacial overgrowth associated with soft-tissue infiltration, bone hypertrophy, macrodontia, hemimacroglossia, early dental development, and mucosal neuromas \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Isolated forms</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Macrodactyly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Overgrowth of one or more fingers \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hemimegalencephaly, dysplastic megalencephaly, focal cortical dysplasia (FCD) type IIa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Malformations of the cerebral cortex that are normally associated with epileptic seizures \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Muscular hemihyperplasia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Localized and non-progressive muscle overgrowth \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Isolated lymphatic malformations \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dilated or cystic lymphatic vessels at any location \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Skin pathologies, such as epidermal nevi and seborrheic keratosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign epithelial lesions caused by an overgrowth of cells in the outermost layer of the skin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Benign lichenoid keratosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign, isolated skin lesions in the form of a brown or reddish papule or plaque \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2794089.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Spectrum of syndromic or isolated overgrowths associated with the <span class="elsevierStyleItalic">PIK3CA</span> gene.</p>" ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">To reach the diagnosis, the common features must be present in association with at least two criteria from group A or one from group B. Table adapted from Keppler et al.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Common characteristics (<span class="elsevierStyleItalic">required</span>)</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Existence of a somatic PIK3CA mutation<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Congenital or early childhood onset overgrowth</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sporadic cases (absence of a family history) and mosaic distribution</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Characteristics described in group A or B</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">A. Syndromic forms (two or more affected individuals)</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">B. Isolated forms</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1. Adipose, musculoskeletal, and nervous system overgrowth \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1. Isolated lymphatic malformations \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2. Capillary, venous, arteriovenous, and/or lymphatic vascular malformations \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2. Isolated macrodactyly or feet/hand/limb overgrowth \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3. Epidermal nevi \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3. Truncal adipose overgrowth \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4. Megalencephaly/focal cortical dysplasia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5. Epidermal nevi \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6. Seborrheic keratosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7. Benign lichenoid keratosis \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2794090.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">If no mutation is identified, it should be considered as a potential PROS syndrome.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Generally progressive. It may manifest as scoliosis (kyphosis), limb overgrowth, central nervous system anomalies (hydrocephalus, cerebellar tonsillar ectopia, Chiari malformation, megalencephaly, or mega-corpus callosum), regional lipomatosis associated with overgrowth, infiltrative lipomatosis, Wilms’ tumor, or ovarian cystadenoma.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Established clinical criteria for the diagnosis of patients with <span class="elsevierStyleItalic">PIK3CA</span>-related overgrowth spectrum.</p>" ] ] 5 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0030" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase class I subtype α. AKT: a serine/threonine kinase also called protein kinase B. PKB: protein kinase B. PKBA: protein kinase B alpha. PKBB: protein kinase B beta. PKBG: protein kinase B gamma. PTEN: phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. mTOR: mammalian target of rapamycin. TSC: tuberous sclerosis complex.</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Table adapted from Keppler et al.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PI3K/AKT/mTOR pathway component \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Overgrowth syndromes \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical manifestations \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">PIK3CA</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">PIK3CA</span>-related overgrowth spectrum (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">AKT</span> (PKB) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AKT1 (PKBA): Proteus syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Overgrowth, usually affecting the lower limbs \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AKT2 (PKBB): lipodystrophy-hypoglycemia syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recurrent severe fasting hypoglycemia, decreased level of consciousness, seizures, and asymmetric growth \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AKT3 (PKBG): megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (MPPH2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">In utero</span> onset; megalencephaly, polymicrogyria, postaxial polydactyly \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">mTOR</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Focal cortical dysplasia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Malformation of the cerebral cortex characterized by dysmorphic neurons associated with refractory epilepsy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">PTEN</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PTEN hamartoma tumor syndrome (Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and PTEN-related Proteus syndrome) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Benign and malignant neoplasms; brain overgrowth and neurodevelopmental anomalies, asymmetrical bones and soft-tissue overgrowth \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">TSC1/2</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tuberous sclerosis complex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypopigmented macules, facial angiofibromas, ash leaf spots, nail fibromas, cortical tubercles, subependymal nodules, and subependymal giant cell astrocytomas, seizures, and intellectual disability/developmental delay \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2794091.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Differential diagnosis of PROS syndromes <span class="elsevierStyleItalic">versus</span> other somatic overgrowth disorders associated with the PI3K/AKT/mTOR pathway.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:23 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K.M. 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