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 6 months of treatment, venous malformation had decreased in size and lightened, as well as improved quality-of-life scores.

Mortality predictive factors in congenital hepatic hemangioma: a case-control study.

Congenital hepatic hemangiomas (CHHs) are benign vascular tumors whose clinical, histological, and genetic correlation has recently been described in patients with long-term survival, although no mortality risk factors have been identified to date. The aim of this study is to analyze predictors of mortality in patients with CHH. A retrospective single-center case-control study of consecutive CHH patients diagnosed in our institution between 1991 and 2021 was performed, who were classified into two groups according to their survival. Demographic, gestational, imaging, and laboratory data at diagnosis were collected and compared between both groups. A total of 29 patients were included (12 males; 17 females) of whom 5 died as a result of CHH evolution due to cardiac failure and coagulopathy, with a median age of 11 days until death. No differences in demographic or gestational data were reported. There were neither differences when comparing imaging tests, nor in location, number of affected liver segments, or CHH estimated volume. Upon laboratory data at diagnosis, deceased patients had a significant elevation of median liver enzymes [glutamic-oxaloacetic transaminase (359 u/L vs. 45 u/L; p < 0.01) and glutamic-pyruvic transaminase (313 u/L vs. 20 u/L; p < 0. 01)], as well as a decreased median platelet count (85,250/µL vs. 337,000/µL; p < 0.01), prothrombin activity (54% vs. 93%; p < 0.01), and fibrinogen (131 mg/dL vs. 284 mg/dL; p < 0.01), with no differences in blood count or biochemistry data. CONCLUSIONS: CHH clinical behavior can be innocuous or life-threatening. Thrombocytopenia, coagulation disorders, and increased liver enzymes at diagnosis seem to be the main predictors of mortality. WHAT IS KNOWN: • Congenital Hepatic Hemangiomas (CHHs) are benign vascular tumors whose clinical behavior can be innocuous or life-threatening. WHAT IS NEW: • Thrombocytopenia, coagulation disorders and increased liver enzymes at diagnosis seem to be the main predictors of mortality in these patients.

Undergrowth Of First Toe In PiK3CA-Related Overgrowth Spectrum (PROS).

BACKGROUND: PIK3CA-related overgrowth syndrome (PROS) include a heterogeneous group of disorders characterized by segmental overgrowth secondary to somatic mosaic activating variants in PIK3CA. Segmental undergrowth is more uncommon and has been less studied but pathogenic variants in PIK3CA have also been found. With this in mind, we have noticed a group of patients with PROS that present an undergrowth component associated with their focal overgrowth. METHODS: Retrospective review of patients with PROS presenting overgrowth of the lower limb and undergrowth of the ipsilateral first toe was performed. RESULTS: Six patients were included, 4 female and 2 male with a median age of 16.8 years. All patients presented a PROS phenotype with overgrowth of the lower limb and undergrowth of ipsilateral first toe. A PIK3CA pathogenic variant was confirmed in all patients. Patients underwent multiple treatments, currently all are receiving alpelisib with a mean duration of 15.8 months (1-39) and partial response in lipomatosis and vascular anomalies but no response in overgrowth and undergrowth so far. CONCLUSIONS: Pathogenic variants in the same gene can create different phenotypes depending on the time and place of the mutation. There is little information regarding opposing phenotpyes in the same patient with PROS. The presence of undergrowth in our series might be explained by genetic, embryogenic, maternal, or placental factors but needs to be further investigated.

Segmental undergrowth is associated with pathogenic variants in vascular malformation genes: A retrospective case-series study.

Segmental overgrowth has been widely described in patients with congenital vascular anomalies. However, segmental undergrowth has been poorly characterized, and no large series of patients have been published. We present the clinical and molecular characteristics a cohort of 37 patients with vascular malformations and segmental undergrowth. True undergrowth was only considered when the musculoskeletal system was involved to avoid confusion with other causes of segmental reduction, as in lipodystrophy or the long-term osteopenia seen in patients with Servelle-Martorell syndrome. Deep high-throughput sequencing was performed in tissue samples from 20 patients using a custom panel. We identified three groups: undergrowth associated with (1) venous, (2) capillary-venous, and (3) lymphatic-capillary-venous malformations. Congenital or early childhood onset undergrowth can occur with or without associated overgrowth. Different likely pathogenic or pathogenic variants were detected in 13 of 20 (65%) tissue samples in the PIK3CA, TEK, GNAQ, or GNA11 genes. In conclusion, the eponymous Servelle-Martorell syndrome should not be used as a synonym for undergrowth. Segmental undergrowth should be considered a characteristic associated with vascular malformations. Patients with PIK3CA variants show all different combinations of overgrowth and undergrowth. Thus, the term PROS (PIK3CA-related overgrowth spectrum) does not cover the entire spectrum.

Venous malformations: what do phleboliths tell us in the pediatric population?

PURPOSE: Phleboliths are often observed within Venous malformations (VM) and frequently indicated as cause of morbidity. The aim of this study is to investigate independent risk factors for phleboliths in a pediatric population and to determine if its presence influences clinical management. METHODS: We retrospectively review data from patients diagnosed with VM in a vascular anomalies center during a 5-year period. Associations between phleboliths and potential risk factors were assessed. A multivariable analysis, was performed to assess the influence of phleboliths in the need for surgery. RESULTS: We included 88 patients with a mean age of 10 years. Phleboliths were found in 33.0%. In univariate analysis, there were no significant differences between the two groups regarding age or gender, location, dimension or depth of the VM, pain and laboratory parameters. Multivariable analysis could not detect any independent risk factor for phleboliths. In contrast, multivariable logistic analysis revealed that when phleboliths were present, the need for surgical extirpation was more likely (p = 0.031). CONCLUSIONS: This study showed that patients who have phleboliths within their VM seem to require surgery more frequently. This constitutes an entirely innovative thought that could raise awareness to a lower threshold for surgery in this group of patients.

Menstrual disorders associated with sirolimus treatment.

INTRODUCTION: Sirolimus has become a pillar in the treatment of vascular anomalies due to its inhibition of the mammalian target of rapamycin (mTOR). Adverse effects include metabolic and hematologic disorders among others, although menstrual disorders have not been well described. MATERIALS AND METHODS: Retrospective review of patients with vascular anomalies on sirolimus treatment was performed. Patients presenting menstrual alterations were included. MAIN RESULTS: One hundred and thirty-six patients with vascular anomalies on treatment with sirolimus were reviewed, finding seven women out of 74 (9.4%) who presented menstrual alterations attributable to the treatment. These seven patients presented with different vascular malformations and three showed pathogenic variants in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in affected tissue. Partial response in six and stability in one patient was obtained after treatment, administered for an average of 27.5 months (6-48). Five patients have completed treatment and two patients continue on after 12 and 15 months, respectively. All patients reported regular menstrual cycles prior to sirolimus treatment. One patient presented with amenorrhea for 4 months after treatment initiation that later spontaneously resolved. The other six patients presented with hypermenorrhea, four of them associating metrorrhagia. Most patients presented with mild menstrual alterations, without needing dose reduction or withdrawal, although one discontinued sirolimus due to hypermenorrhea, metrorrhagia, and hematuria. After sirolimus withdrawal, regular menstrual cycles were restored in five patients. CONCLUSION: Sirolimus treatment can produce menstrual disorders as adverse effects. Although mild and reversible upon dose reduction or cessation of treatment, patients and physicians should be aware on this potential side effect.

Reactivation of Kasabach-Merritt phenomenon in a young adult with a congenital kaposiform hemangioendothelioma.

We present the rare case of a young adult who developed late recurrence of Kasabach-Merritt phenomenon in a congenital kaposiform hemangioendothelioma that had been quiescent since infancy. We postulate that the extensive and infiltrative nature of our patient's tumor, combined with a recent history of direct microtrauma from acupuncture, contributed to the development of this late complication.

Risk factors for sequelae after surgery for lymphatic malformations in children.

OBJECTIVE: The first-line treatment of lymphatic malformations (LMs) is pharmacological or interventional; however, surgery is still necessary in selected cases. Our aim was to identify factors associated with the occurrence of permanent postoperative complications. METHODS: This was a case series study of children operated on for LMs between 2001 and 2021 and followed-up in our institution. Patients who presented sequelae derived from surgical treatment (cases) and those who did not (controls) were compared. RESULTS: We included 112 children who underwent surgery for LMs in different centers. Forty-nine cases and 63 controls were included (58% male), with a mean age of 34 months. Patients younger than 1 year presented more complications than older children, 59% (n = 29/49) vs 41% (n = 24/49), respectively (P = .02). LMs were in the cervicofacial region in seven patients in the control group compared with 30 of the cases (P ≤ .001), with microcystic malformations the most associated with sequelae (n = 11/15; P = .019). Concerning permanent complications, 88% were neurological (n = 43/49), mainly peripheral facial palsy (n = 17). There was greater postoperative residual disease in controls compared with cases (65% vs 14%, respectively; P ≤ .0001). However, following a second procedure in the control group, there was no significant difference in long-term cure rates (P = .38). CONCLUSIONS: The risk of sequelae following surgery for LM increases significantly in patients younger than 12 months in cervicofacial and microcystic malformations. Because non-radical resections are associated with fewer complications and an optimal long-term cure rate, we consider that aggressive surgical approaches should be avoided if the absence of sequelae is not guaranteed.

Lymphatic Malformations in Parkes Weber's Syndrome: Retrospective Review of 16 Cases in a Vascular Anomalies Center.

INTRODUCTION: Parkes Weber's syndrome (PWS) is a rare genetic disorder characterized by overgrowth and vascular malformations, primarily affecting the extremities. While PWS is known to be associated with arteriovenous and capillary malformations, the potential involvement of lymphatic malformations (LMs) has not been previously reported. The objective of this study is to investigate the presence of lymphatic anomalies in PWS patients and their role in the development of limb asymmetry. MATERIALS AND METHODS: This is a retrospective study of patients diagnosed with PWS in a Vascular Anomalies Center from 1994 to 2020. Clinical data were obtained from medical records including diagnostic imaging, lymphoscintigraphy, and genetic testing. The Institutional Review Board and Ethics Committee have approved this study. RESULTS: A total of 16 patients aged 18 interquartile range 14.7 years diagnosed with PWS were included (50% female). Six of the 16 patients with PWS had clinical and imaging data suggestive of LM (37.5%) and 3 of them had genetic variants in RASA1 (2/3) or KRAS (1/3). Limb asymmetry was greater in patients with isolated PWS (2.6 ± 0.8 cm) than in the PWS-lymphatic anomalies population (2 ± 0.7 cm), although not significant (p = 0.247). One in 6 patients with PWS-LM required amputation (16.6%) versus 1 in 10 in isolated PWS (10%). CONCLUSION: Lymphatic anomalies may be present in a significant number of patients with PWS and could have a role in limb asymmetry and outcomes. It is paramount to investigate their existence and distinguish them from true overgrowth.

Successful Sirolimus Treatment for Recurrent Pericardial Effusion in a Large Cervicomediastinal Provisionally Unclassified Vascular Anomaly: A Case Report.

Provisionally unclassified vascular anomalies (PUVA) are a group of diseases with unique characteristics that make them unclassifiable within vascular tumors or malformations. We describe a PUVA as the cause of recurrent pericardial effusion and its response to sirolimus. A 6-year-old girl was referred with a cervicothoracic vascular anomaly, a violaceous, and irregular lesion in the neck and upper chest, diagnosed as "hemangioma". She had pericardial effusion at the neonatal age that required pericardiocentesis, propranolol, and corticosteroids. She remained stable for 5 years, when she presented with a severe pericardial effusion. A magnetic resonance visualized a diffuse vascular image in the cervical and thoracic region with mediastinal extension. The pathological study showed a vascular proliferation in the dermis and hypodermis with positive staining for Wilms' Tumor 1 Protein (WT1) and negative for Glut-1. Genetic testing found a variant in GNA14 , for which the diagnosis of PUVA was established. When a pericardial drain was placed without response, treatment with sirolimus was started with resolution of the effusion. Sixteen months later, the malformation is stable and there has been no recurrence of pericardial effusion. In a significant group of patients, definitive diagnosis is not possible despite pathological and genetic analysis. Mammalian target of rapamycin inhibitors may become a therapeutic option if symptoms are severe enough, with a low rate of reported side effects.

Thoracic venous malformation: a particular form of a visceral variant.

A teenage boy was admitted due to a thoracic mass with previous respiratory infections. The CT scan showed phleboliths in a cystic lesion with large draining channels. He also presented a mild thrombocytosis, elevated fibrinogen and D-dimer. Arteriogram revealed no abnormal arterial supply but venography proved venous draining channels as the major components of the lesion. The most important venous pedicle was embolised. However, 6 months later, CT scan showed no reduction in lesion size. Surgical resection was performed. Anatomopathological study described a venous malformation (VM) with a lymphatic component, and genetic testing found a typical mutation in PIK3CA and genetic variant in MAP3K3 This case reports a very rare pattern of thoracic vascular tumour. The authors aim to highlight the importance of genetic studies of VM with atypical presentation in order to achieve a definitive diagnosis.

Clinical Factors in Trunk Capillary Malformations in the Neonate: When to Suspect Other Associated Malformations? A Case-Control Study.

INTRODUCTION: Capillary malformations (CMs) can be sporadic or syndromic, in association with other underlying venous malformation (VM) or lymphatic malformation (LM). The objective of this study is to describe the clinical patterns in the neonate that allow us to differentiate sporadic CMs from those associated with other vascular malformations. MATERIALS AND METHODS: A case-control study was performed in neonates with CM located in the trunk, followed at our institution between 2008 and 2018. The patients were divided into two groups: group A (cases: CM associated with VM or LM) and group B (controls: sporadic CM without associated malformations). Demographic and clinical variables collected in the clinical history were evaluated (color, location, multifocality, bilaterality, position regarding the vascular axis, and involvement of the midline). RESULTS: Thirty-eight patients were included (18 cases and 20 controls) without differences in gender and age. In group A, the totality of patients presented CM with uniform color and lateral location (p < 0.001). In this group, bilateral and multifocal involvements were lower than in group B, without significant differences between both groups. The distribution of CMs in group A was always parallel to the vascular axis and the midline was always respected, without observing these characteristics in the group B (p < 0.001). CONCLUSION: The presence of a CM in the trunk of a neonate with uniform color, lateral location, parallel position to the vascular axis, and absence of involvement of the midline should make us suspect other underlying vascular malformations, which should be studied with complementary tests.

Congenital hepatic hemangiomas: Clinical, histologic, and genetic correlation.

BACKGROUND: The guide for monitoring and treatment of congenital hepatic hemangiomas (CHH) will depend on the subtype and the postnatal clinical behavior. Our aim is to present a series of CHH and characterize its clinical, histologic and genetic correlation, compared to cutaneous congenital hemangiomas (CCH). MATERIAL AND METHODS: A retrospective review of CHH patients diagnosed between 1991 and 2018 was performed. Clinical, morphological and histological data were analyzed and deep high-throughput sequencing was performed. MAIN RESULTS: Sixteen patients with CHH were included. Five patients were followed up with serial ultrasounds while pharmacological treatment (corticosteroids and propranolol) was decided in five. Surgical resection was performed in five owing to hemorrhage and suspicion of malignancy, and the last patient underwent embolization. Histologic analysis was available in 7 patients and confirmed CHH, showing two different histological patterns that could be associated with the presence of somatic pathogenic variants in GNAQ and/or PIK3CA detected in the genetic testing. Review of 7 samples of CCH revealed some histologic differences compared to CHH. CONCLUSION: CHH resemble its cutaneous homonym with similar clinical behavior. Histologic analysis can differentiate two subgroups while genetic testing can confirm mutations in GNAQ and in PIK3CA in a subset of CHH. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: IV.

Oral Sirolimus: An Option in the Management of Neonates with Life-Threatening Upper Airway Lymphatic Malformations.

Background: Mechanistic target of rapamycin (mTOR) inhibitors are being used off-label showing promising results in patients with vascular anomalies. Children with lymphatic malformations (LMs) involving the airway benefit from sirolimus therapy soon after birth, reducing the need of tracheostomy. Available information about efficacy and side effects in neonates remains poor. We present seven newborns with severe head and neck LM showing response to sirolimus with no significant toxicity. Methods and Results: We performed a retrospective review of neonates with head and neck LM who received sirolimus between January 2014 and May 2018 with upper airway involvement needing ventilatory support. We analyzed type of LM, involved anatomical area, symptoms and response to sirolimus, including dosage, blood levels, response, side effects, and complications. Seven neonates received primary treatment with sirolimus in the context of cervical LM. Sirolimus was started at the recommended dose of 0.8 mg/m2/12 h and adjusted to maintain blood levels between 4 and 12 ng/mL. Median follow-up was 32 months (4-43) with a median treatment duration of 12 months (3-43). One patient had complete resolution of the malformation, one had complete resolution of symptoms, and five had partial resolution of the malformation with significant improvement in their respiratory conditions. Two patients required additional subtotal surgical resection and one tracheostomy. Four patients remain under treatment. Toxicity was not observed. Conclusions: Sirolimus is a safe drug in neonates and can be considered the first therapeutical option in newborns at high risk of respiratory failure before sclerosis or surgery. Close follow-up is mandatory to identify side effects at long-term use.

Alpelisib Treatment for Genital Vascular Malformation in a Patient with Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, and Spinal/Skeletal Anomalies and/or Scoliosis (CLOVES) Syndrome.

BACKGROUND: Most patients with phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA)-related overgrowth spectrum become symptomatic early in life and need treatment before puberty. Recently, the specific inhibition of PIK3CA pathways has been proposed as a therapeutic option for these patients improving their surgical options and quality of life. Alpelisib, a specific alpha fraction inhibitor, has shown promising results. CASE: A 17-year-old girl presented with severe involvement of her external genitalia with a combined vascular malformation in the context of congenital, lipomatous, overgrowth, vascular malformations, epidermal nevi and spinal/skeletal anomalies and/or scoliosis syndrome, needing frequent blood transfusions for anemia due to vaginal bleeding and use of a crutch for walking. After failure of treatment with rapamycin, compassionate treatment with alpelisib was started with excellent response. SUMMARY AND CONCLUSION: PIK3CA inhibitors might become a new option of treatment for PIK3CA-related overgrowth spectrum patients.

Iatrogenic Compartment Syndrome Secondary to Burn Dressing in a 2-Year-Old Child.

We report a severe case of compartment syndrome due to a compressive burn dressing. An otherwise healthy 2-year-old girl presented at her local health center with a superficial partial-thickness thermal burn on the dorsum of the mid phalanx of the second finger of her right hand. A compressive dressing was applied solely to the affected finger. Forty-eight hours afterward, the patient presented in the emergency room with severe pain of the finger. After removal of the dressing, a circular constrictive eschar was observed at the base of the finger, secondary to ischemia due to the compressive dressing. Emergent lateral escharotomies were performed, with immediate recovery of distal perfusion. One week afterward, the patient underwent surgical debridement of the burn on the dorsum of her finger and escharectomy of the ischemic eschar at the base. The lesions were covered with partial-thickness skin grafts. This case shows that acute compartment syndrome can lead to severe sequelae, such as the loss of an extremity or body segment. We must take utmost care in all our actions to avoid any (negligent) act that could lead to severe or permanent damage to our patients.