Laurence M. Boon

Vascular Dysmorphogenesis Caused by an Activating Mutation in the Receptor Tyrosine Kinase TIE2

Venous malformations (VMs), the most common errors of vascular morphogenesis in humans, are composed of dilated, serpiginous channels. The walls of the channels have a variable thickness of smooth muscle; some mural regions lack smooth muscle altogether. A missense mutation resulting in an arginine-to-tryptophan substitution at position 849 in the kinase domain of the receptor tyrosine kinase TIE2 segregates with dominantly inherited VM in two unrelated families. Using proteins expressed in insect cells, we demonstrate that the mutation results in increased activity of TIE2. We conclude that an activating mutation in TIE2 causes inherited VMs in the two families and that the TIE2 signaling pathway is critical for endothelial cell-smooth muscle cell communication in venous morphogenesis.

Infantile Hemangiomas: Current Knowledge, Future Directions. Proceedings of a Research Workshop on Infantile Hemangiomas

Ilona J. Frieden, M.D.,* Anita N. Haggstrom, M.D.,† Beth A. Drolet, M.D.,‡ Anthony J. Mancini, M.D.,§ Sheila Fallon Friedlander, M.D.,¶ Laurence Boon, M.D., Ph.D.,** Sarah L. Chamlin, M.D.,§ Eulalia Baselga, M.D.,†† Maria C. Garzon, M.D.,‡‡ Amy J. Nopper, M.D.,§§ Dawn H. Siegel, M.D.,* Erin W. Mathes, M.D.,* Deborah S. Goddard, M.D.,¶¶ Joyce Bischoff, Ph.D.,¶¶ Paula E. North, M.D., Ph.D.,*** and Nancy B. Esterly, M.D.†††

Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome

Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.

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.

Complications of systemic corticosteroid therapy for problematic hemangioma

Systemic corticosteroid therapy has been used to treat hemangiomas for 30 years; yet, there are no studies of possible complications. We reviewed the database of the Vascular Anomalies Center at the Boston Childrens Hospital and gathered information on short- and long-term side effects in children who were given systemic corticosteroids for problematic hemangiomas. In addition, a questionnaire regarding early and late consequences was sent to the families of children who were treated with corticosteroids from 1983 to 1997. Of 300 patients with hemangiomas, 80 children were identified as having received a full course of systemic corticosteroids for problematic tumors. Complete data were collected on 62 of these children. The response rate to the questionnaire was 78 percent (n = 62 of 80). The initial dose of corticosteroid varied from 2 to 3 mg/kg/ day. Duration of therapy ranged from 2 to 21 months (mean, 7.9 months; median, 6.5 months). The follow-up interval from the cessation of therapy ranged from 6 months to 15 years (mean, 4 years; median, 3 years). Short-term complications included cushingoid facies (n = 44; 71 percent), personality changes (n = 18; 29 percent), gastric irritation (n = 13; 21 percent), fungal (oral or perineal) infection (n = 4; 6 percent), and diminished gain of height (n = 22; 35 percent) and weight (n = 26; 42 percent). A total of 91 percent of children who had diminished gain of height (n = 20) returned to their pretreatment growth curve for height by 24 months of age. One child, who was treated at another institution with a dose of 20 mg/kg/day for 6.5 months that was slowly tapered over 18 months, was petite 6 years after ending therapy. Another child treated with an initial dose of 2 mg/kg/day for 5 months was smaller than predicted at the age of 6 years, but she was born prematurely and was on ventilatory support for respiratory distress. Three children treated with the standard dose and duration were at a low percentile for weight 4, 5, and 10 years after the cessation of therapy. Statistical analysis showed a correlation between diminished gain of height with duration of therapy and age at initiation of treatment. One child had corticosteroid myopathy that resolved with cessation of therapy. We found no evidence for immunologic suppression, i.e., there was no increase in the number of bacterial infections during corticosteroid administration. In conclusion, systemic corticosteroids can be safely given to treat endangering hemangiomas in infants at doses of 2 to 3 mg/kg/day, which are slowly tapered and stopped before the age of 1 year. Short-term side effects were minor and transient, and no serious long-term complications occurred.

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.

Hepatic vascular anomalies in infancy: A twenty-seven-year experience

OBJECTIVE Infantile hemangioma and arteriovenous malformation (AVM) of the liver have a similar presentation but a different natural history, and therefore require different treatment. This study was undertaken to clarify differential diagnosis and management of these two biologically distinct vascular disorders. STUDY DESIGN We retrospectively analyzed the records of 43 children with hepatic vascular anomalies treated during the past 27 years. RESULTS Ninety percent were hemangiomas (n = 39); 10% were AVM (n = 4). Infants with AVM or large solitary hemangioma had hepatomegaly, congestive heart failure, and anemia as presenting symptoms at birth. Multiple hepatic hemangiomas manifested at 1 to 16 weeks of age with the same clinical triad, plus multiple cutaneous lesions (19/23). The mortality rate after treatment of hepatic AVM was 50% (2/4). The mortality rates after treatment of liver hemangiomas were as follows: resection of solitary lesions, 20% (2/10); embolization, 43% (3/7); corticosteroids, 30% (3/10); and interferon alfa-2a, 15% (2/13). CONCLUSION Solitary hepatic hemangioma cannot always be distinguished from hepatic AVM without radiologic studies. Multiple hepatic hemangiomas are differentiated from hepatic AVM by coexistence of multiple cutaneous hemangioma and by radiologic imaging. We recommend combined embolization and surgical resection for hepatic AVM and for solitary symptomatic hemangioma, if drug therapy fails. Pharmacologic treatment is used for symptomatic multiple liver hemangiomas. Embolization allows interim control of heart failure. A decreased mortality rate after interferon alfa-2a therapy is encouraging.

Association of Localized Intravascular Coagulopathy With Venous Malformations

OBJECTIVE To determine which venous malformations (VMs) are at risk for coagulopathy. Venous malformations are slow-flow vascular malformations present at birth, and localized intravascular coagulopathy (LIC) causes pain and thrombosis within a lesion and severe bleeding during surgical procedures. DESIGN Prospective convenience sample accrued from 2 multidisciplinary sites in Brussels, Belgium, and Caen, France. PARTICIPANTS The study population comprised 140 patients with clinical data and coagulation parameters. Magnetic resonance imaging was performed for 110 patients. MAIN OUTCOME MEASURE Measurement of D-dimer levels. RESULTS Of the 140 participants, 59 (42%) showed high D-dimer levels, 36 (61%) of whom had levels higher than 1.0 microg/mL. Six of the participants had low fibrinogen levels. In univariate analysis, large surface, presence of palpable phleboliths, and truncal localization were associated with high D-dimer levels. In the multivariate analysis, only large surface area and presence of phleboliths remained independently associated with high D-dimer levels. Severe LIC, characterized by concomitant low fibrinogen level, was associated with extensive venous malformations of the extremities. CONCLUSIONS Localized intravascular coagulopathy is statistically significantly associated with large and/or deep venous malformations that affect any location, which can have a palpable phlebolith. These patients are at risk of local pain due to thrombosis. Lesions with elevated D-dimer levels associated with low fibrinogen levels (severe LIC) commonly affect an extremity and have a high risk of hemorrhage. Low-molecular-weight heparin can be used both to treat the pain caused by LIC and to prevent decompensation of severe LIC to disseminated intravascular coagulopathy.

Venous malformation: update on aetiopathogenesis, diagnosis and management

The aim of this review was to discuss the current knowledge on aetiopathogenesis, diagnosis and therapeutic management of venous malformations (VMs). VMs are slow-flow vascular anomalies. They are simple, sporadic or familial (cutaneomucosal VMs or glomuvenous malformations), combined (e.g. capillaro-venous and capillaro-lymphaticovenous malformations) or syndromic (Klippel–Trenaunay, blue rubber bleb naevus and Maffucci). Genetic studies have identified causes of familial forms and of 40% of sporadic VMs. Another diagnostic advancement is the identification of elevated d-dimer level as the first biomarker of VMs within vascular anomalies. Those associated with pain are often responsive to low-molecular-weight heparin, which should also be used to avoid disseminated intravascular coagulopathy secondary to intervention, especially if fibrinogen level is low. Finally, development of a modified sclerosing agent, ethylcellulose–ethanol, has improved therapy. It is efficient and safe, and widens indications for sclerotherapy to sensitive and dangerous areas such as hands, feet and periocular area.

Molecular basis of vascular anomalies.

Vascular anomalies comprise a heterogeneous group of disorders that are divided into tumors (hemangiomas) and malformations. Recent advances in biomedical research provide insights into the molecular basis of these disorders and a deeper understanding of vascular morphogenesis. In the future, this emerging knowledge will contribute to novel ways to treat vascular anomalies and to regulate pathologic angiogenesis.