The Misguided Research on Klippel-Trenaunay Syndrome

Sir:FigureWe read with interest the article entitled “How Do the Type and Location of a Vascular Malformation Influence Growth in Klippel-Trénaunay Syndrome?” by Funayama et al.,1 in which the authors described the association of the type and location of certain vascular malformations with abnormal subcutaneous tissue, muscle, and bone growth in patients presumed to have Klippel-Trenaunay syndrome. We respectfully disagree with the authors with regard to several points in the design and findings of their study. First, Klippel-Trenaunay syndrome is best defined as combined slow-flow malformations—namely, capillary, venous, and lymphatic—in an overgrown limb. Reviewing the Patients and Methods section of the article, it seems that the authors either opted not to consider or were not aware of the key differences among the several forms of vascular anomalies that may affect the extremities. Klippel-Trenaunay syndrome, as a separate disease entity, was not defined by the authors, and the inclusion criteria were unnecessarily loose. Without any proper clinical, genetic, or imaging evidence, the authors collectively lumped different clinical entities under a larger composite diagnosis of Klippel-Trenaunay syndrome. Some of the patients included in the study may qualify for more appropriate diagnoses such as capillary malformation with overgrowth, venous malformation, or a combination of these malformations. The authors even included patients with tumors (tufted angioma) and arteriovenous malformation in their cohort. These disorders are vastly different from (and should not be confused with) Klippel-Trenaunay syndrome. Only three patients had the typical capillary, venous, and lymphatic anomalies of Klippel-Trenaunay syndrome. The authors adopted diagnostic criteria for Klippel-Trenaunay syndrome as proposed by Oduber and colleagues.2 Unfortunately, these diagnostic criteria are essentially flawed and misleading. Combining these unrelated diseases into one entity represents a major flaw in the study design and may result in ambiguous or wrong conclusions about the disease under study. Second, Klippel-Trenaunay syndrome is typically associated with limb overgrowth. The authors described only one patient with increased bone girth, in contrast to the experience at larger centers.3 In addition, leg bone circumferential hypoplasia was documented in half of the patients without specification of the age of patients at which leg bone hypoplasia was diagnosed. Although Klippel-Trenaunay syndrome is an overgrowth syndrome, atrophy can occasionally be seen in some older patients, probably secondary to underuse. Limb atrophy, however, is not a primary hallmark of Klippel-Trenaunay syndrome and is not as common as the authors claimed. Third, although the diagnosis of vascular malformations is largely clinical, advanced cross-sectional and interventional imaging techniques are crucial for reaching the correct diagnosis in many cases and for planning the management. The authors did not describe a systematic diagnostic approach to the osseous or soft-tissue changes. It is not clear how many patients underwent magnetic resonance imaging, computed tomography, venography, or angiography, or whether the findings were reviewed systematically by experienced radiologists. Plain radiographs play a limited role in evaluation for soft-tissue and intrinsic osseous changes. Fourth, Servelle-Martorell syndrome (or genuine diffuse phlebectasia of Bockenheimer) refers to an extensive venous anomaly of the limb. Contractures and atrophy of the leg are common. Commenting on this disease, the authors mentioned an arterial component and stated that it can be differentiated from Klippel-Trenaunay syndrome by the absence of limb bone overgrowth. These claims are unsupported by the literature, cannot be concluded based on the data presented, and have not been our experience with many patients with this disorder. Finally, the International Society for the Study of Vascular Anomalies adopted the classification of vacular anomalies as proposed by Mulliken and Glowacki4 in 1982. The classification stratifies the majority of vascular anomalies and overgrowth syndromes into certain simple or combined anomalies. Many overgrowth syndromes with complex vascular anomalies (such as Klippel-Trenaunay syndrome) can still be listed as having a combined form of anomalies (capillary, venous, and lymphatic). Given the above-mentioned contamination of the cohort under study, the authors' proposal to replace the term “overgrowth” with “abnormal growth” is not backed by the proper scientific evidence. The published literature on Klippel-Trenaunay syndrome is rife with confusing, bizarre, and poorly documented conditions. For example, a study reviewing the existing literature on the presumed association between Klippel-Trenaunay syndrome and spinal arteriovenous malformation was published recently. Alomari and colleagues5 reviewed the published cases and books and searched the large database of their vascular anomalies center. None of the reports of such an association reliably established the diagnosis of Klippel-Trenaunay syndrome in any of the patients. As there was not a single patient with this association in their large database, the authors concluded that the association between arteriovenous malformations and Klippel-Trenaunay syndrome is most likely erroneous. Overgrowth syndromes with vascular anomalies are rare and complex. In addition, the presence of multiple overlapping features contributes to complicated diagnosis and management of these conditions. Careful interpretation of clinical, genetic, and advanced imaging findings is essential for appropriate diagnosis of these conditions; otherwise, the literature will continue to repeatedly produce the same confusing, misguided research. Mohammad Reza Rajebi, M.D. Ahmad I. Alomari, M.D., M.Sc. Divisions of Vascular Radiology and Interventional Radiology, Children's Hospital Boston and, Harvard Medical School, Boston, Mass. DISCLOSURE Neither author has any relevant financial interests to disclose.