Life-threatening Malformations Research Articles

Life-threatening Lymphatic Malformation With Somatic Activating NRAS Mutation Successfully Treated With Trametinib: A Case Study.

Kaposiform lymphangiomatosis (KLA) is a rare and aggressive subtype of complex lymphatic anomalies (CLA), characterized by abnormal lymphatic proliferation leading to distinct clinical manifestations. Despite the complexity of this condition, there is no established standard therapy, and treatment options such as sclerotherapy, laser therapy, and surgery remain variably effective and are limited to symptom management rather than curative. Sirolimus, an mTOR pathway inhibitor, has shown promise as a primary therapy, particularly in patients without a driver mutation. However, in some instances, the genetic landscape of KLA has revealed somatic mutations in the RAS-MAPK pathway, most notably the NRAS variant (c.182A>G, p.Q61R), representing a potential therapeutic target. We present a case of a 4-year-old male who presented with pericardial and pleural effusions without notable coagulopathy found to harbor an NRAS p.Gln61Arg gene mutation, diagnosed through next-generation sequencing (NGS) analysis. Initial therapy with sirolimus failed to provide optimal benefit with persistent pleural effusion. Subsequent treatment with the MEK inhibitor trametinib led to significant clinical improvement, evidenced by the resolution of effusions and removal of the chest tube. In the short term, no significant adverse effect was reported. Our findings underscore the value of genomic profiling in guiding personalized treatment strategies for rare and complex diseases presenting like KLA. This case highlights the potential of targeted therapies, such as trametinib, in improving clinical outcomes for patients with disease with activating NRAS variants, emphasizing the importance of ongoing research to validate and expand these therapeutic approaches in the management of vascular anomalies.

Синдром Бланда-Уайта-Гарланда: клинические особенности течения и лечения у пациентки молодого возраста

Bland-White-Garland syndrome (SBUG) is a rare, high–risk fatal outcome in infancy and sudden death in adults, an anomaly of the divergence of the left coronary artery (LCA) from the pulmonary artery (PA) (ALCAPA - abnormal left coronary artery arising from the pulmonary artery). In 85-90% of cases, children without radical surgical treatment do not live up to a year. In our clinical case, in a 36-year-old patient, the disease debuted with recurrent ventricular arrhythmias, Imaging diagnostic methods coronary angiography, spiral computed tomography, magnetic resonance imaging of the heart revealed in the patient, in addition to the pathology of the LCA, individual anatomical features of the coronary bed, which provided adequate myocardial perfusion and maintained sufficient myocardial reserve. A combined operation was performed on a patient at the "Federal Center for Cardiovascular Surgery" of Khabarovsk: prosthetics of the LCA trunk with a vascular prosthesis "Vascutek PTFE" № 6. Plastic surgery of the pulmonary trunk (PT) with a patch from the autopericardium. Mitral valve repair (MV) on the "MedInj" support ring № 28. The postoperative period was uneventful. The period of dynamic observation was 22 months. Currently, the patient is in a satisfactory condition and is able to work. Given the different clinical variants of SBUG, specialists providing primary health care - district pediatricians, internists, cardiologists - should be wary of this rare but life-threatening congenital malformation. Keywords: Bland-White-Garland syndrome, anomaly of the left coronary artery, ALCAPA.

Tracheal reconstructive surgery under ECMO for the treatment of congenital tracheal stenosis in the premature infant: case report

BackgroundCongenital tracheal stenosis (CTS) is a rare but life-threatening malformation of the trachea. Surgical reconstruction is the treatment of choice in symptomatic cases which is highly risky and is rarely performed in extremely premature infants. With this, reporting a case of CTS managed by tracheal reconstructive surgery under ECMO in a baby weighing 1.47 kg at 32 + 1 WOG was the first ever case in China.Case presentationA premature newborn with a very low birth weight (VLBW) was admitted to our institute for breathing difficulties, requiring mechanical ventilation, and experienced two unsuccessful attempts of extubation. The team performed tracheal reconstructive surgery supported by ECMO after identifying lower tracheal stenosis through a bronchoscopy examination. One month after the surgery, oxygen support was able to discontinue. The patient's entire hospitalization was incredibly challenging, marked by hemodynamic instability with persistent anemia, and disseminated intravascular coagulation (DIC), which were managed with great care. Despite the difficult stay, a follow-up bronchoscopy revealed no obstruction or tracheal stenosis, leading to a successful discharge.ConclusionAdvancements in diagnostic techniques and innovative management methods have made diagnosing and treating CTS easier, even in premature infants. Our case is the first in China to successfully undergo tracheal reconstructive surgery supported by ECMO, inspiring future achievements in the medical field.

A rare case of polysplenia syndrome associated with atrioventricular canal defect and type four ileal atresia in a preterm neonate: A case report and literature review

Antenatal diagnosis of heterotaxy syndrome is only the tip of the iceberg. These neonates can have a myriad of multi-system anomalies, each of which requires anticipation and an individualized management plan. The spectrum of heterotaxy syndrome ranges from incidentally detected innocuous anomalies to major life-threatening congenital malformations such as atrioventricular canal defects and bowel atresia. Neonatal sepsis tends to be more fulminant and catastrophic in these neonates with complex anomalies and poor outcomes that necessitates better-informed antenatal counseling regarding the termination of such pregnancies.

Use of polygenic and clinical risk scores in wide spectrum congenital heart malformations: a diagnostic and therapeutic perspective

Worldwide, congenital heart defects (CHDs) are a leading cause of mortality and morbidity. Globally, the annual prevalence rate of CHDs is about 1.5 million. It is one of the most common life-threatening congenital malformations, with a visible difference between high-income countries (HICs) and developing countries. This difference may be attributed to the diagnostic facilities and interventions.1 Moreover, the use of genetic and clinical risk scores is less studied in this field compared to other diagnostic and therapeutic approaches. Thus, we comprehensively review the available literature on adult and pediatric syndromic or non-syndromic CHDs and propose limitations and future directions in this field. Risk factors for this fatal disease include genetic and environmental factors.2,3 Risk stratification based on prenatal diagnosis with genetic counseling has shown better clinical outcomes. The modified World Health Organization (mWHO) guidelines are among the first proposed for risk stratification based on clinical scores.4 The combination of polygenic risk scores (PRS) and clinical risk evaluation has been adopted in various populations as better diagnostic and therapeutic approaches for various diseases, including coronary artery disease,5 diabetes,6 obesity,7 and cancers.8,9 However, unlike these diseases, polygenic risk scores are rarely used for the genetic diagnosis of CHD patients. The clinical utility of polygenic risk scores for CHDs is still in the early stages and requires validation studies in different cohorts. Incorporating PRS into the clinical setting may improve CHD diagnosis and therapeutic strategies.10 Recently, an initial attempt was made to determine the clinical utility of polygenic risk scores in a large dataset of the European cohort. Data from this study suggested a high potential for PRS in distinguishing between clinical phenotypes (mild, moderate, and severe) of congenital heart malformations.11 Furthermore, this hypothesis was tested in patients with transposition of the great arteries (TGA) to assess the utility of risk stratification after arterial switch operation. The cumulative risk score was computed for single nucleotide polymorphisms (SNPs) that reached the threshold statistical significance of p<1×10−5 in the initial analysis. Combined clinical and polygenic risk scores showed improved risk stratification in mild, moderate, and severe TGA phenotypes.12 Similarly, in another European cohort, the risk allele frequency was higher in the diseased group compared to the control group. However, statistical analysis suggested a non-significant association with p>0.05. Interestingly, combined risk scores constructed for selected SNPs showed a significant association with the disease with a p-value of 0.002. This evidence further supports the hypothesis that the cumulative effect of polymorphisms has better diagnostic and therapeutic efficacy than individual SNPs.13 There are certain limitations to its clinical use. Firstly, social stigma and lack of awareness regarding this disease are major hurdles. Secondly, there is a need to recruit a large number of samples from different populations to validate the clinical utility of PRS. Additionally, a lack of resources in developing countries also contributes to fatal outcomes. We recommend conducting large cohort studies in different ethnic groups to predict better risk associations, develop better therapeutic strategies, and formulate management guidelines.

Neurosurgical strategy based on the type of occult spinal dysraphism in omphalocele-exstrophy-imperforate anus-spinal defects complex: A review of 10 cases.

Omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex is a rare, life-threatening congenital malformation primarily treated with abdominogenital repair. The optimal indication and timing of neurosurgical interventions for the associated spinal cord lesions remains insufficiently studied. We reviewed spinal dysraphism in OEIS to evaluate the best timing for neurosurgical intervention. We retrospectively reviewed 10 patients with OEIS, analyzing their clinical and imaging data, as well as surgical and pathological findings. Terminal myelocystocele (TMCC) and spinal lipomas were observed in 5 patients each. Of the spinal lipomas, one had a single filar lipoma, while four had double lipomas (3 caudal and dorsal; 1 filar and dorsal). TMCC manifested with severe lower limb motor dysfunction in addition to abdominogenital disorder at birth, with the cyst-induced lumbosacral mass increasing over time. Spinal lipomas were less symptomatic except for abdominogenital issues and demonstrated minimal growth of the intraspinal lipoma over time. Untethering surgery was performed in 8 patients (5 TMCC; 3 spinal lipomas) at a median age of 3 (range, 2-10) months for TMCC and 6 (range, 2-14) months for spinal lipomas. One TMCC patient (surgery at 10 months) experienced postoperative cerebrospinal fluid leakage, necessitating three reoperations. Magnetic resonance imaging is essential to diagnose spinal cord malformations accurately. The necessity and timing of surgical intervention differ between TMCC and spinal lipomas. Since TMCC lesions tend to enlarge, surgery should be performed as soon as the patient's abdominogenital condition stabilizes. For spinal lipomas, surgery should be considered carefully based on the patient's neurological condition.

Floyd Type II Congenital Tracheal Agenesis in a Preterm Neonate: A Rare Case Report

Tracheal agenesis is a rare and life-threatening airway malformation, and currently, there is no curative treatment available. The described case involves a preterm male newborn at 30 weeks of gestational age who could not be intubated during resuscitation, despite multiple attempts. However, the baby could be ventilated after oesophageal intubation. Tracheal stenosis/ atresia was suspected, and airway evaluation was performed using a thin, flexible fiberoptic bronchoscope. No tracheal opening could be identified, and upon introducing the bronchoscope into the oesophagus, a triluminal opening was found, through which the scope could not be further navigated. To further delineate the anatomy, a Contrast-enhanced Computed Tomography (CECT) thorax was performed, revealing the absence of a tracheal lumen and the communication of both bronchi at the carina with the oesophagus. Unfortunately, the baby succumbed to the illness after three days. Tracheal agenesis is an anatomical malformation that typically presents as respiratory distress and the absence of an audible cry at birth. Attempts to establish a definite airway are unsuccessful, which may result in early neonatal death. Oesophageal intubation may temporarily establish ventilation until palliative surgery is performed.

Мониторинг пороков развития умерших детей и плодов в Омской области

The article presents the dynamics of the overall indicator and the structure of the entire spectrum of malformations in deceased, stillborn children and fetuses eliminated for medical reasons in the Omsk Oblast from 2009 to 2023. Absolute values are determined and indicators of the overall frequency of malformations are calculated in three observation groups: in fetuses; in stillborn children; in live-born children who died after birth up to and including 17 years of age. With a moderate tendency to increase, the weighted average (cumulative) indicator of the frequency of malformations was 5.5 ± 0.11 per 1,000 pregnancies. The structure is dominated by defects incompatible with life in the circulatory system (22.0 ± 0.65 %), central nervous system (19.1 ± 0.61 %) and musculoskeletal system (14.9 ± 0.56 %). The rate of malformations showed the most pronounced upward tendency in the “Chromosomal abnormalities” group (16.6; p < 0.05). A pronounced downward tendency is observed in the “Genital malformations” and “Pulmonary airway malformations” groups. The entire set of malformations showed a moderate upward tendency in the rate of malformations (3.65; p < 0.05). The study of the dynamics of the rate and structure of malformations in fetuses, stillborn children and deceased children, in addition to monitoring malformations in live-born children, allows obtaining the most complete data for further objective assessment of the effectiveness of prenatal diagnostics and the system for preventing the birth of children with potentially life-threatening malformations.

Morphogenetic processes in the development and evolution of the arteries of the pharyngeal arches: their relations to congenital cardiovascular malformations.

The heart and aortic arch arteries in amniotes form a double circulation, taking oxygenated blood from the heart to the body and deoxygenated blood to the lungs. These major vessels are formed in embryonic development from a series of paired and symmetrical arteries that undergo a complex remodelling process to form the asymmetric arch arteries in the adult. These embryonic arteries form in the pharyngeal arches, which are symmetrical bulges on the lateral surface of the head. The pharyngeal arches, and their associated arteries, are found in all classes of vertebrates, but the number varies, typically with the number of arches reducing through evolution. For example, jawed vertebrates have six pairs of pharyngeal arch arteries but amniotes, a clade of tetrapod vertebrates, have five pairs. This had led to the unusual numbering system attributed to each of the pharyngeal arch arteries in amniotes (1, 2, 3, 4, and 6). We, therefore, propose that these instead be given names to reflect the vessel: mandibular (1st), hyoid (2nd), carotid (3rd), aortic (4th) and pulmonary (most caudal). Aberrant arch artery formation or remodelling leads to life-threatening congenital cardiovascular malformations, such as interruption of the aortic arch, cervical origin of arteries, and vascular rings. We discuss why an alleged fifth arch artery has erroneously been used to interpret congenital cardiac lesions, which are better explained as abnormal collateral channels, or remodelling of the aortic sac.

INDIAMAN-20 (INstant DIAgnosis of 20 Major ANomalies) protocol: application of IOTA diagnostic strategy to fetal anomalies.

To compile a list of instant diagnoses of major fetal anomalies, and to present their sonographic descriptors and test them in a retrospective series of fetuses with congenital anomalies managed at our center. The first step was to identify major anomalies that meet the following criteria: (1) can be diagnosed directly and unequivocally on the basis of a set of descriptors evident on a single sonographic view; (2) are among those more commonly diagnosed in utero; (3) represent major lethal or life-threatening malformations or anomalies for which no or only palliative surgery can be performed. For each of these anomalies, a sonographic descriptor was produced. The second step was to test the descriptors of the instant diagnoses in all cases with these anomalies evaluated since January 2000 in our Fetal Medicine Unit, retrieved from our electronic database. For each congenital anomaly-sonographic descriptor pair we then evaluated the presence vs absence of an unequivocal relationship between anomaly and descriptor, assessing: whether a particular descriptor in a set reference plane identified unequivocally the anomaly, i.e. the same descriptor could not be found in any other malformation; and whether a particular anomaly presented the corresponding descriptor in all cases. Finally, we evaluated whether the sonographic descriptors could be applied in all trimesters or only selectively, considering the natural history of the 20 instant diagnoses. Of the 20 instant diagnoses, five involved the central/peripheral nervous system (exencephaly/anencephaly, alobar/semilobar holoprosencephaly, cephalocele, open spinal dysraphism, complete agenesis of corpus callosum), five involved the heart (hypoplastic left heart syndrome, complete atrioventricular septal defect, severe Ebstein's anomaly, critical aortic stenosis, transposition of the great arteries), five involved the abdominal wall (left-sided congenital diaphragmatic hernia, exomphalos, gastroschisis, body-stalk anomaly) or gastrointestinal tract (duodenal atresia), and five involved the remaining systems (three urinary (autosomal recessive polycystic kidney disease, multicystic dysplastic kidney, lower urinary tract obstruction), two skeletal (transverse limb defect, radial ray defect)). All of the descriptors were found to identify unequivocally the related malformations, whereas four of the malformations were not associated with their reference descriptors in every case. For example, congenital diaphragmatic hernia (left-sided) presented without the stomach in the thorax in 42/93 (45.2%) cases. Due to the natural history of the condition, not all signs were recognizable in the first trimester, some becoming evident only from the second trimester onwards. We have defined sonographic descriptors that enable an unequivocal instant diagnosis for a list of 20 major congenital anomalies: the 'INDIAMAN-20' (INstant DIAgnosis of Major ANomalies) protocol. We believe that using this approach may facilitate focused training of less experienced operators and that it may be incorporated into artificial intelligence and deep learning protocols, further boosting the instant prenatal recognition of these lethal or life-threatening malformations. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Activity of a TIE2 inhibitor (rebastinib) in a patient with a life-threatening cervicofacial venous malformation.

Targeted therapy has become the first therapeutic option in many patients with vascular anomalies. A male 28-year-old patient presented a severe cervicofacial venous malformation involving half-lower face, anterior neck, and oral cavity with progression despite multiple previous treatments, with a somatic variant in TEK (endothelial-specific protein receptor tyrosine kinase) (c.2740C>T; p.Leu914Phe). The patient had facial deformity, daily episodes of pain and inflammation needing massive amount of medication, and difficulty in speech and swallowing, so rebastinib (a TIE2 kinase inhibitor) was approved for compassionate use. After 6months of treatment, venous malformation had decreased in size and lightened, as well as improved quality-of-life scores.

Overcoming roadblocks in clinical innovation via high fidelity simulation: use of a phantom simulator to achieve FDA and IRB approval of a clinical trial of fetal embolization of vein of Galen malformations

BackgroundVein of Galen malformation (VOGM) is a rare, life-threatening vascular malformation in neonates and is treated with embolization. However, even at the most experienced centers, patients face high mortality and...

Risk factors for adverse outcomes following surgical repair of esophageal atresia. A retrospective cohort study.

Esophageal atresia (EA) is a life-threatening congenital malformation of the esophagus. Despite considerable recent advances in perinatal resuscitation and neonatal care, EA remains an important cause of mortality and morbidity, especially in low-income countries. The aim of this study was to assess risk factors for adverse outcomes following surgical repair of EA at a single center in Tunisia. We performed a retrospective analysis using medical records of neonates with surgical management of EA at our institution from 1 January 2007 to 31 December 2021. In total, 88 neonates were included with a mortality rate of 25%. There were 29 girls and 59 boys. The diagnosis of EA was suspected prenatally in 19 patients. The most common associated anomalies were congenital heart diseases. Prematurity, low birth weight, outborn birth, age at admission >12hours, congenital heart disease, postoperative sepsis, and anastomotic leak were risk factors for mortality following surgical repair of EA. Anastomotic tension was the only factor associated with short-term complications and the occurrence of short-term complications was predictive of mid-term complications. This study provides physicians and families with contemporary information regarding risk factors for adverse outcomes following surgical repair of EA. Thus, any effort to reduce these risk factors would be critical to improving patient outcomes and reducing cost. Future multi-institutional studies are needed to identify, investigate, and establish best practices and clinical care guidelines for neonates with EA.

Morphogenesis of the Mammalian Aortic Arch Arteries.

The major vessels in mammals that take blood away from the heart and deliver it to the arms and the head take their origin from the aortic arch and are derived from the arteries formed within the embryonic pharyngeal arches. These pharyngeal arch arteries, initially symmetrical, form in a cranial to caudal sequence within the pharyngeal mesenchyme. They then undergo a complex process of remodeling to produce the asymmetrical brachiocephalic arteries as seen in the adult. A complex interaction between the tissues of the pharyngeal arches and the genes they express is required to ensure that arterial formation and remodeling is able to proceed normally. If this process is disrupted, life-threatening congenital cardiovascular malformations can occur, such as interruption of the aortic arch, isolation of individual arteries, or so-called vascular rings. Here, using state-of-the-art imaging techniques, we describe the morphogenesis of the arteries in humans and mice and the cardiovascular defects in the Tbx1 mutant mouse model. We provide details of the process of remodeling, clarifying also the morphogenesis of the external carotid artery and the so-called “migration” of the left subclavian artery.

Bilateral giant cervical cystic lymphangioma in an infant

Cystic Hygroma is a rare congenital lymphatic malformation; more so rare is the bilateral cystic Hygroma. Bilateral Giant cystic Hygroma is a potential life-threatening congenital malformation as it may cause airway obstruction, difficulties in nursing and feeding and failure to thrive. We present a case of a female infant with bilateral giant cystic hygroma. Keywords: cystic hygroma; bilateral; giant.

A Large Fetal Venous Malformation

A 28-year-old woman was referred to our institution at 35 weeks after an ultrasound diagnosis of an oral fetal lesion. Magnetic resonance showed a mass originating from the anterior part of the tongue with some areas of internal heterogeneity, possibly representing vascular structures. The multidisciplinary team decided to perform a cesarean delivery at 38 weeks. A large, well-defined bluish/purple exophytic mass arising from the apex of the tongue was confirmed right after birth, and a vascular anomaly was suspected. Precocious complete surgical excision and oral motor rehabilitation and feeding were performed. According to the 2018 International Society for the Study of Vascular Anomalies Classification (ISSVA), histological analysis confirmed a venous vascular malformation. Although rare, venous malformations represent the most common type of congenital vascular malformation. They are considered simple and slow-flow vascular malformations. Airway compromise may be a major concern when aerodigestive system involvement is present. Anatomic deformities and their functional and psychosocial impact are also important concerns. Herein, prompt recognition of an oral fetal mass allowed cautious delivery and postnatal management. It highlights the importance of careful prenatal diagnosis in managing potentially life-threatening congenital malformations.

Hereditary Hemorrhagic Telangiectasia in a Geriatric Patient: A Case of Treatment Resistance

Hereditary hemorrhagic telangiectasia (HHT) is a condition known for frequent and severe epistaxis, telangiectasias that form along various surfaces of the body, and potentially life-threatening arteriovenous malformations (AVMs) that may develop in major organ systems. Management of this condition begins with prompt diagnosis, followed by careful screening for systemic complications, and care to minimize morbidity associated with blood loss. We hereby describe a case of treatment-resistant HHT in a geriatric patient who suffers from recurrent and severe epistaxis warranting frequent hospitalizations and blood transfusions. The case underscores the need to recognize HHT early, begin treatment promptly, and closely follow these patients to minimize the risk of hospital readmission.

Surgical Treatment of Patients with Full Tracheal Rings: Our Experience.

Introduction: Complete tracheal rings are a rare pathology occurring in 1 out of 100,000 live births. It is rare isolated tracheal or tracheobronchial anomaly resulting from abnormal cartilage growth, forming a complete ring, and leading to airway stenosis. A sliding tracheoplasty, primarily described by Tsang et al. and later widely presented by Grillo et al., overlaps the tracheal stenosing segments and shortens the trachea itself, and thus increases the diameter and circumference of the stenosing area double up. Materials and Methods: We have performed four slide tracheoplasties in the period between February 2019 and December 2020 in children who underwent medical treatment in the department of thoracic surgery in our center. Median age was 10 ± 5.5 months (2 months-1 year 6 months). Median weight was 6.9 ± 1.9 kg (4.5-9 kg). Slide tracheoplasty was performed using central venoarterial extracorporeal membrane oxygenation in 3 cases and using cardiopulmonary bypass in 1 case. Results: Patients were on artificial lung ventilation for 2-6 days in the postoperative period. Patients were discharged 14-18 days after the surgery. There were no lethal outcomes in our study. Discussion: Long segment congenital tracheal stenosis is an often and serious life-threatening anatomical malformation that bounded the length of trachea >50%. There is no unique treatment strategy for patients with such pathology. Sliding tracheoplasty can be recommended for all, but not for the shortest segments of stenosis, as it creates permissible voltage fluctuations during tracheal anastomosis. Excellent results in management of such severe patients can be achieved only through the collaboration of multidisciplinary team of specialists sharing organized and consistent patient-oriented approach.

Vascular Birthmarks as a Clue for Complex and Syndromic Vascular Anomalies.

Vascular birthmarks are common in neonates (prevalence: 20–30%) and mostly incidental findings sometimes with spontaneous regression (salmon patch and nevus simplex). Capillary malformations are found in about 1% and infantile hemangiomas are found in 4% of mature newborns. Vascular malformations are classified according to their most prominent vessel type. The term “capillary malformation” (port wine stain) includes a wide range of vascular lesions with different characteristics; they may be isolated or part of specific syndromic conditions. Part of the infantile hemangiomas and of the vascular malformations may require treatment for functional or cosmetic reasons, and in rare cases, investigations are also necessary as they represent a clue for the diagnosis of complex vascular malformation or tumors associated with extracutaneous abnormalities. Complex vascular malformations are mostly mosaicism due to early somatic mutations. Genetic advances have led to identify the main pathogenic pathways involved in this disease group. Diffuse capillary malformation with overgrowth, Klippel–Trenaunay syndrome, CLAPO syndrome, CLOVES syndrome, and megalencephaly-capillary malformation belong to the PIK3CA-related overgrowth. Capillary malformation–arteriovenous malformation underlies a fast-flow vascular malformation, sometimes manifesting as Parkes–Weber syndrome. Recognition of these different types of capillary vascular stains is sometimes difficult; however, associated findings may orient the clinicians while genetic testing may confirm the diagnosis. Lymphatic malformation frequently manifests as large masses that compress and/or infiltrate the surrounding tissues, representing a neonatal emergency when airways are involved. Infantile hemangiomas may cause functional and/or permanent esthetical damage, depending on their localization (such as periorbital area, lip, nose); large (more than 5 cm) infantile hemangiomas with a segmental distribution can be associated with obstruction or malformations of the underneath organs with complications: PHACE syndrome, LUMBAR/SACRAL syndrome, and beard infantile hemangioma. In our review, we discuss controversies regarding the international classification and emerging concepts in the field of vascular anomalies. Finally, we discuss potential developments of new, non-invasive diagnostic techniques and repurposing of target therapies from oncology. Complex and/or life-threatening vascular tumors and malformations are extremely rare events and they represent a considerable therapeutic challenge. Early recognition of clinical signs suggestive for a specific disease may improve therapeutic outcomes and avoid severe complications.

PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib.

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term referring to various clinical entities, which share the same pathogenetic mechanism. These conditions are caused by somatic gain-of-function mutations in PIK3CA, which encodes the 110-kD catalytic α subunit of PI3K (p110α). These PIK3CA mutations occur as post-zygotic events and lead to a gain of function of PI3K, with consequent constitutional activation of the downstream cascades (e.g., AKT/mTOR pathway), involved in cellular proliferation, survival and growth, as well as in vascular development in the embryonic stage. PIK3CA-related cancers and PROS share almost the same PIK3CA mutational profile, with about 80% of mutations occurring at three hotspots, E542, E545, and H1047. These hotspot mutations show the most potent effect on enzymatic activation of PI3K and consequent downstream biological responses. If present at the germinal level, these gain-of-function mutations would be lethal to the embryo, therefore we only see them in the mosaic state. The common clinical denominator of PROS disorders is that they are sporadic conditions, presenting with congenital or early childhood onset overgrowth with a typical mosaic distribution. However, the severity of PROS is highly variable, ranging from localized and apparently isolate overgrowth to progressive and extensive lipomatous overgrowth associated with life-threatening vascular malformations, as seen in CLOVES syndrome. Traditional therapeutic approaches, such as sclerotherapy and surgical debulking, are often not curative in PROS patients, leading to a recrudescence of the overgrowth in the treated area. Specific attention has been recently paid to molecules that are used and studied in the oncogenic setting and that are targeted on specific alterations of the pathway PI3K/AKT/mTOR. In June 2018, Venot et al. showed the effect of Alpelisib (BYL719), a specific inhibitor for the p110α subunit of PI3K, in patients with PROS disorders who had severe or life-threatening complications and were not sensitive to any other treatment. In these cases, dramatic anatomical and functional improvements occurred in all patients across many types of affected organ. Molecular testing in PROS patients is a crucial step in providing the conclusive diagnosis and then the opportunity for tailored therapy. The somatic nature of this group of diseases makes challenging to reach a molecular diagnosis, requiring deep sequencing methods that have to be performed on DNA extracted from affected tissue. Moreover, even analyzing the DNA extracted from affected tissue there is no guarantee to succeed in detection of the casual somatic mutation, since the affected tissue itself is highly heterogeneous and biopsy approaches can be burdened by incorrect sampling or inadequate tissue sample. We present an 8-year-old girl with CLOVES syndrome, born with a large cystic lymphangioma involving the left hemithorax and flank, multiple lipomas, and hypertrophy of the left foot and leg. She developed severe scoliosis. Many therapeutic approaches have been attempted, including Sildenafil treatment, scleroembolization, laser therapy, and multiple debulking surgeries, but none of these were of benefit to our patient's clinical status. She then started treatment with Rapamycin from May 2019, without significant improvement in both vascular malformation and leg hypertrophy. A high-coverage Whole Exome Sequencing analysis performed on DNA extracted from a skin sample showed a mosaic gain-of-function variant in the PIK3CA gene (p.H1047R, 11% of variant allele frequency). Once molecular confirmation of our clinical suspicion was obtained, after a multidisciplinary evaluation, we decided to discontinue Sirolimus and start targeted therapy with Alpelisib (50 mg/day). We noticed a decrease in fibroadipose overgrowth at the dorsal level, an improvement in in posture and excellent tolerability. The treatment is still ongoing.