Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.

Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.

Common somatic alterations identified in maffucci syndrome by molecular karyotyping.

Maffucci syndrome (MS) is a rare congenital disorder characterized by multiple central cartilaginous tumors (enchondromas) in association with cutaneous spindle cell hemangiomas. These patients have a high incidence of malignant transformation. No familial case is known and the etiopathogenic cause remains unknown. In enchondromatosis (Ollier disease, OD), which is comprised of enchondromas only, 4 mutations in the PTHR1 gene have been identified in 4 patients; 3 were somatic and 1 was germline. No PTHR1 mutations have been detected in MS, whereas somatic IDH1 and, more rarely, IDH2 mutations have been observed in 77% of patients with MS and 81% of patients with OD. These genetic alterations are shared with other tumors, including glioma, leukemia and carcinoma. To search for underlying somatic genomic causes, we screened MS tissues using Affymetrix SNP-chips. We looked for CNVs, LOH and uniparental isodisomy (UPID) by performing pairwise analyses between allelic intensities in tumoral DNA versus the corresponding blood-extracted DNA. While common chromosomal anomalies were absent in constitutional DNA, several shared CNVs were identified in MS-associated tumors. The most frequently encountered somatic alterations were localized in 2p22.3, 2q24.3 and 14q11.2, implicating these chromosomal rearrangements in the formation of enchondromas and spindle cell hemangiomas in MS. In one chondrosarcoma specimen, large amplifications and/or deletions were observed in chromosomes 3, 6, 9, 10, 12, 13, and 19. Some of these genetic changes have been reported in other chondrosarcomas suggesting an etiopathogenic role. No LOH/UPID was observed in any Maffucci tissue. Our findings identify frequent somatic chromosomal rearrangements on 2p22.3, 2q24.3 and 14q11.2, which may unmask mutations leading to the lesions pathognomonic of MS.

Somatic uniparental isodisomy explains multifocality of glomuvenous malformations.

Inherited vascular malformations are commonly autosomal dominantly inherited with high, but incomplete, penetrance; they often present as multiple lesions. We hypothesized that Knudson's two-hit model could explain this multifocality and partial penetrance. We performed a systematic analysis of inherited glomuvenous malformations (GVMs) by using multiple approaches, including a sensitive allele-specific pairwise SNP-chip method. Overall, we identified 16 somatic mutations, most of which were not intragenic but were cases of acquired uniparental isodisomy (aUPID) involving chromosome 1p. The breakpoint of each aUPID is located in an A- and T-rich, high-DNA-flexibility region (1p13.1-1p12). This region corresponds to a possible new fragile site. Occurrences of these mutations render the inherited glomulin variant in 1p22.1 homozygous in the affected tissues without loss of genetic material. This finding demonstrates that a double hit is needed to trigger formation of a GVM. It also suggests that somatic UPID, only detectable by sensitive pairwise analysis in heterogeneous tissues, might be a common phenomenon in human cells. Thus, aUPID might play a role in the pathogenesis of various nonmalignant disorders and might explain local impaired function and/or clinical variability. Furthermore, these data suggest that pairwise analysis of blood and tissue, even on heterogeneous tissue, can be used for localizing double-hit mutations in disease-causing genes.

[Classification of superficial vascular anomalies]. / Classification des anomalies vasculaires superficielles.

All superficial vascular abnormalities are not angiomas even though this term continues - incorrectly - to be used. Because the suffix "oma" implies a tumor, it is necessary to differentiate true vascular tumors, such as infantile hemangioma, from vascular malformations. From a hemodynamic perspective, there are two types of vascular malformations: slow- and fast-flow. In addition to the functioning of the impaired or severely damaged vessels, we discuss slow-flow capillary, venous, or lymphatic malformations and rapid flow arterial and arteriovenous malformations. All combinations are possible. There are several types of childhood vascular tumors with different courses and different prognoses. Infantile hemangioma is by far the most frequent (8 to 10 children/100). The diverse other vascular tumors in children are sufficiently rare that they are described as orphan diseases. Since the end of the last century, a simple endothelial marker, GLUT-1, is available. This immunophenotype is present in all cases of infantile hemangioma at every stage and is negative in other tumors. Kasabach-Merritt syndrome and its accompanying severe thrombocytopenia never complicate childhood hemangioma, contrary to what has been said for nearly 60 years. When it is present, the tumor is either a tufted angioma or kaposiform hemangioendothelioma, and the GLUT1 marker can distinguish them from infantile hemangioma if the histologic diagnosis is uncertain (GLUT 1 is negative in both the latter cases). There are a wide variety of rare vascular tumors; many of them are benign, isolated, or limited; some are locally aggressive and recur after excision. A small number are low-grade malignant lesions with a risk of multivessel expansion, metastasis, and sometimes a fatal outcome. Major progress has been made in the imaging of these vascular abnormalities. Magnetic resonance imaging (MRI) in particular has revolutionized the non-invasive and especially the non-irradiating exploration of many of them. It provides information about the extent of the lesion and allows an etiological approach in many cases. Moreover, neuroradiologic evaluation of vascular cerebromeningeal lesions benefits not only from the now-standard diagnostic neurologic imaging methods of CT and MRI, but also from various advances in the techniques of functional imaging. Accordingly, for Sturge-Weber syndrome, functional imaging provides hope for an early prognosis, in particular cognitive, when these techniques are more widely used (SPECT, PET, especially the new advanced sequences of perfusion in MRI-DTI). Chronic - indeed lifelong - coagulation abnormalities, with phases of aggravation, occur in approximately half of the patients with venous malformations of the trunk and limbs, and more rarely in neck and face sites. This is not without consequences, but also not without therapeutic solutions: screening for it is therefore essential (measurement of dimer and fibrinogen levels). The discovery of gene mutations at the origin of some familial vascular malformations provides complementary data for the current classification of vascular abnormalities. It suggests that targeted therapy may be possible but probably not for quite a bit longer.

Nasal tip haemangiomas: guidelines for an early surgical approach.

The treatment of Cyrano nose haemangioma (CNH) is difficult because of its location and possible complications: psychological impact, severe skin infiltration and consequences on nasal growth. We suggest that the best treatment for nasal tip haemangiomas is an early surgery to remove the affected tissues and preserve the anatomy. A total of 39 children (32 females and seven males) underwent early surgery for the treatment of CNH. Mean age was 35 months. Skin infiltration was present in 15 cases. Cartilage lack or distortion was observed in 29 cases. Each patient was evaluated for global cosmetic appearance, reduction in volume of the tumour, improvement of skin texture and quality of the scar. Multiple surgical procedures were performed in 14 cases. The average postoperative follow-up was 48 months. Patients with low-volume tumours had only one surgery, whereas patients with large tumours underwent a mean of 1.9 surgeries. In 29 cases, distortion or lack of cartilaginous structures required dissection and approximation of the alar cartilages in their anatomical position. We could identify three types of CNH that lead to three distinct surgical approaches: type A (mild cases) is characterised by no cutaneous involvement, no misalignment of the cartilages and mild nasal volume increase; type B (moderate cases) entails partial cutaneous infiltration, misalignment of the cartilages and moderate nasal volume increase; and type C (severe cases) is characterised by cutaneous infiltration, misalignment of the cartilages and severe nasal volume increase.

Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.

Mutations in the angiopoietin receptor TIE2/TEK have been identified as the cause for autosomal dominantly inherited cutaneomucosal venous malformation (VMCM). Thus far, two specific germline substitutions (R849W and Y897S), located in the kinase domain of TIE2, have been reported in five families. The mutations result in a fourfold increase in ligand-independent phosphorylation of the receptor. Here, we report 12 new families with TEK mutations. Although the phenotype is primarily characterized by small multifocal cutaneous vascular malformations, many affected members also have mucosal lesions. In addition, cardiac malformations are observed in some families. Six of the identified mutations are new, with three located in the tyrosine kinase domain, two in the kinase insert domain, and another in the carboxy terminal tail. The remaining six are R849W substitutions. Overexpression of the new mutants resulted in ligand-independent hyperphosphorylation of the receptor, suggesting this is a general feature of VMCM-causative TIE2 mutations. Moreover, variation in the level of activation demonstrates, to the best of our knowledge for the first time, that widely differing levels of chronic TIE2 hyperphosphorylation are tolerated in the heterozygous state, and are compatible with normal endothelial cell function except in the context of highly localized areas of lesion pathogenesis.

Role of Propranolol in the therapeutic strategy of infantile laryngotracheal hemangioma.

There are recent reports of effective treatment of cutaneous hemangiomas with Propranolol. The current study aims to assess efficacy of systemic Propranolol for subglottic hemangiomas and to discuss its place among the other available therapies. We report 2 infants with subglottic hemangiomas, which were resistant to other established medical treatments. One infant presented with PHACES association, the other with widespread cutaneous congenital hemangiomas. Both were subsequently treated with systemic Propranolol. Both patients' subglottic hemangiomas responded dramatically to systemic Propranolol. No side effects of the therapy occurred, and a safety protocol previously designed for Propranolol prescribed for other indications was applied to our patients. Propranolol appears to be an effective treatment for subglottic hemangiomas and should now be used as a first-line treatment in subglottic hemangiomas when intervention is required.

Coagulation disorders in patients with venous malformation of the limbs and trunk: a case series of 118 patients.

OBJECTIVE: To investigate the clinical characteristics of venous malformation of the limbs and trunk and known but poorly appraised associated coagulation disorders. Venous malformations are ubiquitous, slow-flow vascular anomalies known to be occasionally painful because of thrombotic episodes inside the lesion. DESIGN: Large case series, with screening of accepted standard coagulation tests. SETTING: Ambulatory multidisciplinary clinics for vascular anomalies. PATIENTS: This 2-year study (2003-2005) included 118 patients with clinical, radiological, and biological features informative for better defining venous malformation and associated coagulation abnormalities. MAIN OUTCOME MEASURES: The primary outcome was coagulation disorders associated with VM. Secondary measures include anatomic location, extent of lesion, localized pain, and impaired motion. RESULTS: The mean age of patients was 27 years, and there was a female preponderance of 64%. The venous malformation involved the upper extremity, lower extremity, and trunk in 30%, 58%, and 36% of patients, respectively; it was plurifocal in 22%. Intralesional pain (in 92% of patients) had a higher frequency in female (63%) than in male (47%) patients. Tissular involvement concerned the skin (65%), muscle (73%), bone (13%), joints (12%), and viscera (9%). According to our severity scoring system, cases of less gravity had a score of 2 or 3 (52%), cases of intermediate severity had a score of 4 or 5 (32%), and cases of major severity had a score of 6 to 9 (10%). The most frequent blood coagulation abnormality was a high plasma D-dimer level (> 0.5 microg/mL) (58% of patients), which was correlated with muscle involvement and high severity score and was more frequent in women. The factor VIII-von Willebrand factor complex was documented in 84 patients, and plasma von Willebrand factor level was decreased (<60%) in 23 (27%) of them; 10 of the 84 patients (12%) had more notably decreased levels (<50%). CONCLUSIONS: This study of a large case series of patients with pure venous malformation in the limbs and/or trunk highlights muscle involvement and frequency of pain. It validates that coagulation disorders, present in 58% of our patients, create thrombotic painful events. Under certain circumstances, these disorders entail a risk of hemorrhage because of the progression of localized intravascular coagulopathy to disseminated intravascular coagulopathy.

Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations.

Capillary malformation-arteriovenous malformation (CM-AVM) is a newly recognized autosomal dominant disorder, caused by mutations in the RASA1 gene in six families. Here we report 42 novel RASA1 mutations and the associated phenotype in 44 families. The penetrance and de novo occurrence were high. All affected individuals presented multifocal capillary malformations (CMs), which represent the hallmark of the disorder. Importantly, one-third had fast-flow vascular lesions. Among them, we observed severe intracranial AVMs, including vein of Galen aneurysmal malformation, which were symptomatic at birth or during infancy, extracranial AVM of the face and extremities, and Parkes Weber syndrome (PKWS), previously considered sporadic and nongenetic. These fast-flow lesions can be differed from the other two genetic AVMs seen in hereditary hemorrhagic telangiectasia (HHT) and in phosphatase and tensin homolog (PTEN) hamartomatous tumor syndrome. Finally, some CM-AVM patients had neural tumors reminiscent of neurofibromatosis type 1 or 2. This is the first extensive study on the phenotypes associated with RASA1 mutations, and unravels their wide heterogeneity.

Utility of radiofrequency ablation for haemorrhagic lingual lymphangioma.

Lymphangiomas of the mouth and tongue pose considerable therapeutic problems. Their complete exeresis is not feasible, and they can be a major functional impediment and cause face and jaw deformities. A risk of secondary growth is classically described after surgical reduction. Invasion of lingual mucosa, often papillomatous, results in accidental biting, recurrent bleeding and pain. Here, we report on 7 cases of children with haemorrhagic mucosal lingual lymphangiomas, one with noteworthy drop in the haemoglobin, treated by surface radiofrequency reduction. With a short follow-up (3-13 months), a functional improvement was observed in every case, as a complete disappearance of bleeding in 5/7 cases, and a moderate local relapse in 2/7 cases. This technique did not induce progressive regrowth. It provides a new therapeutic tool for the treatment of lingual microcystic lymphangioma.

Uncommon benign infantile vascular tumors.

Significant progress in the diagnosis of infantile vascular tumors has been achieved during the past 2 decades because of improvements in the recognition of clinical characteristics, radiologic features, and histopathologic analysis, as well as the discovery of important immunophenotypic markers such as GLUT-1. These recent advances make it possible to define more clearly the distinct clinical entities with their variable prognoses and to improve the management of lesions that, although histologically benign, infrequently may be lethal because of their invasive potential.

Vascular malformations. Part II: associated syndromes.

UNLABELLED: Cutaneous vascular malformations are rare disorders representing errors in vascular development. These lesions occur much less commonly but are often confused with the common infantile hemangioma. It is important to properly diagnose vascular malformations because of their distinct differences in morbidity, prognosis and treatment. Vascular malformations may be associated with underlying disease or systemic anomalies. Several of these syndromes are well defined and can often be distinguished on the basis of the flow characteristics of the associated vascular malformation. LEARNING OBJECTIVE: At the completion of this learning activity, participants should be able to better recognize underlying diseases or systemic anomalies that may be associated with vascular malformations. Participants should also better understand the various syndromes and conditions discussed and become more familiar with their management.

Vascular malformations: Part I.

UNLABELLED: Cutaneous vascular malformations are rare disorders representing errors in vascular development. These lesions occur much less commonly but are often confused with the common infantile hemangioma. It is important to properly diagnose vascular malformations because of their distinct differences in morbidity, prognosis and treatment. Vascular malformations may be associated with underlying disease or systemic anomalies. Several of these syndromes are well defined and can often be distinguished on the basis of the flow characteristics of the associated vascular malformation. LEARNING OBJECTIVE: At the completion of this learning activity, participants should have a better understanding of the different types of cutaneous vascular malformations. Because of the importance of proper diagnosis of these lesions, participants should also be better able to direct correct management and treatment.

Congenital plaque-type glomuvenous malformations presenting in childhood.

BACKGROUND: Glomuvenous malformations (GVMs) are now considered a separate entity from venous malformations. The rarest type of GVM is the generalized congenital plaque-type GVM. OBSERVATIONS: We present 10 new cases of congenital plaque-type GVM and describe their clinical progression and treatment. Mutations in the glomulin gene were found in those patients who participated in the genetic study. CONCLUSIONS: Congenital plaque-type GVMs are unique in their congenital nature, extensive distribution, difficult to diagnose and treat, and progressive involvement after birth. Most cases are familial, yet affected relatives usually have only minor lesions. The lesions of congenital plaque-type GVM are severe, visible at birth, and usually mistaken for extensive venous malformations. Vascular malformations are divided by hemodynamic type into slow-flow and fast-flow lesions. Slow-flow lesions are subcategorized as capillary, lymphatic, and venous.(1) Capillary malformations are flat, sharply demarcated, red-pink vascular stains of the skin commonly referred to as port-wine stains. These persist throughout life and are characterized histologically by dilated capillaries within the dermis. They slowly increase in size with age. Lymphatic malformations are spongelike collections of abnormal channels and spaces that contain clear lymphatic fluid, causing an excess of fluid to accumulate and dilate the lymphatic channels. This results in swelling of the affected area and, if extensive, can cause enlargement of soft tissues and bones.

Auricular arteriovenous malformation: evaluation, management, and outcome.

BACKGROUND: The external ear is the second most common site for extracranial arteriovenous malformation in the head and neck. METHODS: This retrospective review of 41 patients with auricular arteriovenous malformation was based on medical records, imaging studies, and photographs. Data were collected on natural history, progression, and outcome; patients were questioned about quality of life after treatment. RESULTS: The median age at initial presentation was 26 years (range, 1 to 55 years), and Schobinger stage was I in two patients, II in 19 patients, and III in 20 patients. No patients had a Schobinger stage of IV. Expansion occurred during childhood in seven patients, adolescence in 14 patients, pregnancy in 10 patients, and adulthood in 10 patients. Distribution of auricular and extra-auricular arteriovenous malformation was not limited to "watershed" areas between vascular territories (angiosomes). Twelve patients were untreated (follow-up, 0.5 to 6 years). Mean follow-up time for the 29 treated patients was 5.19 years (range, 1 to 18.75 years). Proximal ligation in nine patients caused progression: eight of them underwent amputation and one had embolization. Fifteen patients had embolization only: the arteriovenous malformation worsened and amputation was necessary in six patients; in the remaining nine patients, two improved, four persisted, and three worsened. Of 20 patients who had auricular amputation, 16 (80 percent) were controlled, three (15 percent) improved, and one had unresectable, residual cervicofacial arteriovenous malformation. Of 22 of 29 treated patients surveyed, 81 percent were satisfied with their management. Hearing was either unaffected (n = 15) or diminished (n = 5); two patients noted decreased sound localization. CONCLUSIONS: The authors recommend periodic evaluation for stage I to II auricular arteriovenous malformation and intervention if there is evolution to stage III. Preoperative embolization and partial or total amputation effectively control auricular and para-auricular arteriovenous malformation. Embolization can be palliative in children or in patients who are not psychologically prepared for amputation. Extensive extra-auricular arteriovenous malformation requires individualized endovascular therapy and resection.

Vascular anomalies and the growth of limbs: a review.

Growth of the limb in a child can be impaired, with the coexistence of a vascular malformation. In these vascular bone syndromes, altered growth is manifest as overgrowth or hypotrophy. The vascular malformation is usually complex and gets progressively worse with time. The two types of vascular anomalies in limbs, fast-flow and slow-flow, can be associated with limb length discrepancies. The fast-flow vascular malformations together with arteriovenous fistulae are part of Parkes Weber syndrome, characterized by congenital red cutaneous staining, hypertrophy in girth and increasing of limb length, lymphedema, increasing skin alterations due to a distal vascular steal, and pain, all of which develop during childhood. Treatment is generally conservative. An affected lower extremity can be complicated by pelvic tilting and scoliosis because leg length discrepancy may reach 10 cm. To avoid such a course, stapling epiphysiodesis of the knee cartilages is often performed, but this orthopedic procedure may augment the worsening of the arterial venous malformation in the limb. Therefore, less aggressive orthopedic management is preferable. Slow-flow vascular anomalies associated with limb growth alteration include (1) a diffuse capillary malformation (port-wine stain) with congenital hypertrophy of the involved extremity which is non-progressive; (2) purely venous malformations invading skin, muscles and joints, with pain, functional impairment, a chronic localized intravascular coagulopathy requiring distinctive management, and usually a slight undergrowth of the affected extremity and progressing amyotrophy; (3) the triad of a port-wine stain, anomalous veins and overgrowth of the limb, often known as Klippel-Trenaunay syndrome, which requires orthopedic management to decide the optimal timing for epiphysiodesis (i.e. when leg length discrepancy is >2.5 cm). Varicose veins are sometimes surgically removed after ultrasonographic and Doppler evaluation has confirmed a normal deep venous system. Capillary malformations can be effectively treated with pulsed dye laser, but results are usually poor in distal extremities.

Glomuvenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities.

OBJECTIVES: To develop clinical criteria that permit clinical distinction between inherited glomuvenous malformation (GVM), known as glomangioma, and inherited cutaneomucosal venous malformation and to test these criteria on sporadic lesions. DESIGN: Clinical data were compiled for 1685 patients with inherited or sporadic cutaneous venous anomalies. Based on a cohort of patients with a mutation in the TIE2 or glomulin gene or a histologic diagnosis, we defined clinical criteria for inherited GVM and cutaneomucosal venous malformation. We then applied these criteria to sporadic cases in a blinded manner and genetically or histologically confirmed this clinical diagnosis whenever possible. RESULTS: Glomuvenous malformations accounted for 5.1% of venous anomalies and were frequently inherited (63.8%), whereas venous malformations were rarely familial (1.2%). Glomuvenous malformations were nodular and scattered, or plaque-like and segmental, with color varying from pink to purplish dark blue, whereas most venous malformations (VMs) were soft, blue, and often localized vascular lesions. Glomuvenous malformations were mainly located on the extremities and involved skin and subcutis, whereas VMs commonly affected muscles and joints (P<.001). Glomuvenous malformations had a distinct raised, often hyperkeratotic cobblestone-like appearance and could not be completely emptied by compression, unlike VMs. Glomuvenous malformations were painful by compression, whereas VMs were painful on awakening, after activity, or with hormonal changes. Elastic compressive garments aggravated pain in GVMs, in contrast to VMs. CONCLUSIONS: This large series of patients with superficial venous anomalies established clinical features that distinguish VMs and GVMs. This differential diagnosis is essential, as the outcome and the treatment for GVMs differ.

Congenital hemangiomas and infantile hemangioma: missing links.

Rapid postnatal growth and slow involution in childhood characterize the common infantile hemangioma. There are other rare vascular tumors that present fully grown at birth and behave quite differently, as designated by the acronyms: rapidly involuting congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH). RICH and NICH have similarities in appearance, location, size, equal sex ratio, and both have overlapping radiologic and histologic features with infantile hemangioma. However, neither type of congenital tumor immunostains for glucose transporter-1 protein, a marker of infantile hemangioma. This raises the question of whether these congenital vascular lesions are variations in a spectrum of hemangioma or are entirely different tumors. We describe two groups of patients that suggest a linkage between postnatal and congenital vascular tumors: Link I (n=5), children who had either RICH or NICH coexisting with infantile hemangioma, and Link II (n=10), children initially diagnosed as having RICH, but regression was incomplete and the residuum was that of NICH. We conclude that these infants exhibit "missing links" between the rare RICH and NICH, and the common infantile hemangioma.