Odile Enjolras

Congenital hemangioma: Evidence of accelerated involution

OBJECTIVE To study the course of hemangiomas that proliferate in utero, are fully grown at birth, and begin to regress during early infancy. DESIGN We analyzed retrospectively 31 infants with congenital hemangioma seen at Tarnier-Cochin Hospital (Paris) and Childrens Hospital (Boston). Diagnosis was made by clinical and radiologic examination and, if necessary, by biopsy. Age, gender, location, appearance, and evolution were noted for each infant. RESULTS Only 3 of 23 congenital hemangiomas were diagnosed in utero by ultrasonography. The three most common morphologic forms were raised violaceous tumor with ectatic veins (n = 8), raised grayish tumor with multiple tiny telangiectasias, surrounded by a pale halo (n = 8), and flat infiltrative tumor with violaceous overlying skin (n = 5). Two congenital hemangiomas had associated thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon). All the untreated congenital hemangiomas (n = 24) regressed by the time the infants were 14 months of age, leaving either atrophic skin or extra skin. Seven congenital hemangiomas required therapy for complications: three tumors responded to systemic corticosteroid administration and four were resected. CONCLUSION Hemangiomas can proliferate in utero and manifest as fully developed tumors at birth. These congenital hemangiomas can regress rapidly. This phenomenon raises new questions about the pathogenesis of this tumor.

Rapidly Involuting Congenital Hemangioma: Clinical and Histopathologic Features

We define the histopathologic findings and review the clinical and radiologic characteristics of rapidly involuting congenital hemangioma (RICH). The features of RICH are compared to the equally uncommon noninvoluting congenital hemangioma (NICH) and common infantile hemangioma. RICH and NICH had many similarities, such as appearance, location, size, and sex distribution. The obvious differences in behavior served to differentiate RICH, NICH, and common infantile hemangioma. Magnetic resonance imaging (MRI) of the three tumors is quite similar, but some RICH also had areas of inhomogeneity and larger flow voids on MRI and arterial aneurysms on angiography. The histologic appearance of RICH differed from NICH and common infantile hemangioma, but some overlap was noted among the three lesions. RICH was composed of small-to-large lobules of capillaries with moderately plump endothelial cells and pericytes; the lobules were surrounded by abundant fibrous tissue. One-half of the specimens had a central involuting zone(s) characterized by lobular loss, fibrous tissue, and draining channels that were often large and abnormal. Ancillary features commonly found were hemosiderin, thrombosis, cyst formation, focal calcification, and extramedullary hematopoiesis. With one exception, endothelial cells in RICH (as in NICH) did not express glucose transporter-1 protein, as does common infantile hemangioma. One RICH exhibited 50% postnatal involution during the 1st year, stopped regressing, was resected at 18 months, and was histologically indistinguishable from NICH. In addition, several RICH, resected in early infancy, also had some histologic features suggestive of NICH. Furthermore, NICH removed early (2–4 years), showed some histologic findings of RICH or were indistinguishable from RICH. We conclude that RICH, NICH, and common infantile hemangioma have overlapping clinical and pathologic features. These observations support the hypothesis that these vascular tumors may be variations of a single entity ab initio. It is unknown whether the progenitor cell for these uncommon congenital vascular tumors is the same as for common infantile hemangioma.

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. Hum Mutat 29(7), 959–965, 2008.

Kasabach-Merritt phenomenon : a retrospective study of treatment with vincristine

Purpose Kasabach-Merritt phenomenon (KMP) is characterized by profound thrombocytopenia, microangiopathic hemolytic anemia, a consumptive coagulopathy, and an enlarging vascular lesion. The syndrome develops in infancy and is associated with a high morbidity and mortality rate. The purpose of this study was to assess the effectiveness of vincristine in the treatment of KMP. Methods We retrospectively reviewed the clinical and laboratory data of 15 patients with KMP treated with vincristine at 9 institutions across the United States, South America, and Europe. Results All 15 patients had profound thrombocytopenia and consumption of fibrinogen at presentation. Ten patients had biopsies of their lesions, and results included five (33.3%) kaposiform hemangioendotheliomas, three (20%) tufted angiomas, one lesion (6.7%) with features of both kaposiform hemangioendothelioma and tufted angioma, and one (6.7%) unclassified vascular tumor. All 15 patients had an increase in platelet count of at least 20,000 with an average response time of 4.0 weeks after initiation of vincristine therapy. Thirteen patients had an increase in fibrinogen level of 50 mg/dL with an average response time of 3.4 weeks. In 13 patients there was a significant decrease in the size of the vascular lesion. The average duration of treatment was 21.5 (±12.6) weeks. Four patients (26%) relapsed. All four were successfully treated with a second course of vincristine. Complications included one patient with abdominal pain, one patient with transient loss of deep tendon reflexes, and one patient with irritability. Conclusion Vincristine presents a safe and sometimes effective treatment option in the management of KMP.

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.

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.

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.

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 Knudsons 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.

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.

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.