Are You Confident of the Diagnosis?
What you should be alert for in the history
As a rule, most people with Klippel-Trenaunay syndrome (KTS) are in good general health and will be able to deal adequately with their condition.
At first presentation, there will usually not be specific complaints. A good history will suffice to catch any possibly relevant medical problems. In children, asking for problems with motor development (and watching how the children move) will help to determine whether growth disturbances, if present, are mechanically relevant and need to be addressed.
Vascular malformations, if present, can cause local pain and swelling. If located in the deep venous system, they can interfere with function, causing symptoms of venous insufficiency such as restless legs.
It is recommended in adults to specifically ask for symptoms, pointing to thromboembolic events, as there are indications that pulmonary embolism, in particular, can occur in the context of KTS.
Phleboliths (calcified painful thrombi) and thrombophlebitis are also not uncommon in KTS patients, although these are self-limited and present no danger to general health.
Lymphatic malformations may present problems if they are superficial and cause lymphatic fluid to leak. In females of reproductive age, symptoms of pelvic congestion may be indicative of pelvic vascular malformations. Rarely, bloody stools or rectal bleeding may be a manifestation of intestinal vascular malformations. Diarrhea and failure to thrive may indicate loss of fluid through intestinal lymphatic malformations.
Characteristic findings on physical examination
Classically, KTS will present with a triad of overgrowth, capillary malformation, and visible varicose veins affecting one or both lower extremities in a mosaic pattern (Figure 1). Capillary malformations tend to be distributed along a Blaschko type 2 (checkerboard) mosaic pattern and have a purple to deep-purple hue. They can extend onto the pelvic area, and so can the overgrowth, which is disproportionate. The latter is a useful distinguishing characteristic, as some forms of vascular malformation deregulated growth (VM-DG) do not cause disproportionate overgrowth.
The abnormalities are present at birth; the disproportionate growth ceases when overall body growth stops. The pattern is highly variable, although megadactyly is rather frequent. The growth disturbance may manifest rather as hypoplasia, and the extent and nature of the vascular malformations may vary considerably, ranging from superficial varicose veins with a persisting embryonic (lateral) vein to deep venous malformations affecting muscles and sometimes bone.
Lymphatic malformations are often present and will, if superficial, appear as dark-purple sharply demarcated plaques with grey hyperkeratosis and lymphatic blebs filled with clear or hemorrhagic fluid that can ooze out of the lesion. Occasional findings include lipomas, epidermal nevi, and café au lait macules.
Expected results of diagnostic studies
KTS is first and foremost a clinical diagnosis. There are no diagnostic studies that can unequivocally confirm it. Considering that vascular malformations are responsible for most morbidity, duplex ultrasound, magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and various angiographic procedures are the most pertinent studies in KTS. Depending on the extent of the condition, these studies may demonstrate deep vascular (venous) malformations affecting muscle and, sometimes, even bone.
The differential diagnosis can be difficult and may require the consultation of experts in the field. In principle, all disorders combining vascular malformations with deregulated growth should be considered. In practice, the most important considerations are:
1. Phosphatase and tensin homolog (PTEN)-associated disorders such as Cowden disease (MIM 158350). This disease can manifest with vascular malformations, segmental overgrowth, and epidermal nevi due to loss of heterozygosity in the affected tissues, a presentation known as SOLAMEN (segmental overgrowth with lipomatosis, arteriovenous malformation, and epidermal nevi).
SOLAMEN is distinguished by the presence of typical Cowden manifestations such as macrocephaly, geographic tongue, and trichoepitheliomas. Patients are predisposed to developing certain types of cancer (breast, uterus, thyroid) and can have cerebral malformations such as hemimegalencephaly.
2. Proteus syndrome (PS, MIM 176920). The cardinal distinguishing feature of this characteristic syndrome is relentless asymmetric growth of the skeleton, connective tissue, and even organs, starting in the first year after birth. Overgrowth in KTS tends to keep pace with normal growth and stops after puberty. Frequent and typical manifestations are cerebriform connective tissue nevi (CCTN), in particular of the soles (CCTN), and linear verrucous epidermal nevus.
CCTN is sufficient for the diagnosis of PS, if present. Patients can develop parotid gland adenomas or bilateral ovarian cystadenomas. PS can have a facial phenotype that is more common in those with cognitive deficits: dolichocephaly, minor down-slanting palpebral fissures, ptosis, flattening of the malar bones, relative lengthening of the face, a persistently open mouth at rest, and (cranio)facial distortion due to hyperostosis.
3. Congenital lipomatous overgrowth, vascular malformations and epidermal nevi (CLOVE, MIM 612918). This recently described entity is characterized by mostly truncal vascular malformations, overgrowth of adipose tissue, scoliosis, and enlarged, but not severely distorted, bony structures without progressive overgrowth. Broad hands and feet can be part of the phenotype. The distorted growth characteristic of Proteus syndrome is lacking and only occurs in body areas that have been subject to major trauma or surgery. It is not yet certain whether CLOVE is really distinct from the Cowden spectrum.
4. Capillary malformation-arteriovenous malformation (CM-AVM, MIM 608354). This disorder is caused by mutations in the RASA1 gene and typically manifests with atypical capillary malformations that are multiple, small, round to oval, and pinkish red. The phenotype may include arteriovenous malformations and overgrowth, in which case it may mimic KTS. Lack of venous malformations, and the atypical character of the capillary malformations when compared to those found in KTS, will usually allow distinction. When in doubt, genetic testing can help.
Other isolated or syndromic types of vascular malformation will usually present no differential diagnostic problems.
Who is at Risk for Developing this Disease?
Vascular malformation-deregulated growth syndrome (VM-DG) is not a single disorder, but is considered a spectrum, with isolated congenital vascular malformations at one end of the spectrum and Proteus syndrome at the other.
KTS is presently classified as VM-DG type 3 (Girth type). Isolated capillary malformations are quite common (“port wine stain,” “stork bite”) with an estimated frequency of 0.03%-0.05%. VM-DG type 3, on the other hand, is rare, with an estimated prevalence of 1:50,000 to 1:100,000. There are no known risk factors. Males and females are equally affected.
What is the Cause of the Disease?
The cause, if there is a single one, is presently unknown. Environmental factors have been proposed, but presently a genetic etiology is assumed. The abnormalities only affect a limited number of tissues, and it is thus thought that the genetic defect(s) must be present in a mosaic state, i.e., in the abnormal tissues only, having been acquired during embryogenesis. The earlier the defect arises, the more cells will be affected and the more extensive the eventual phenotype will be.
KTS and Sturge-Weber can co-occur in one patient, as predicted by this hypothesis. However, a single gene defect probably cannot account for the considerable phenotypic diversity observed in KTS.
To explain it, we recently introduced the concept of paradominant inheritance involving more than one gene. Paradominant inheritance in the present case means that a predisposition for KTS (and related VM-DG disorders) is transmitted as a single-gene mutation that does not cause a phenotype in the heterozygous state. The gene can therefore be transmitted unperceived through many generations. The trait becomes manifest only if in the developing embryo a second somatic mutation or other genetic event occurs that leads to loss of the remaining healthy allele (loss of heterozygosity). The effects of the inherited mutation then become manifest.
Polygenic paradominant inheritance proposes that KTS and related VM-DG syndromes are caused by simultaneous mutations or polymorphisms in two or more genes, of which one (or more) are involved in (lymph)angiogenesis and the other(s) in growth regulation. Individuals who have a germline mutation in only one of these genes do not show a complete VM-DG phenotype, but may have limited symptoms such as a venous malformation.
The trait can be transmitted over several generations, similar to single-gene paradominant inheritance. The complete syndrome will only become manifest if a second gene is mutated, either by inheritance from the other parent, or by a mutation after fertilization. If the latter occurs, the pattern of distribution of VM-DG features can be explained by the presence of the combined mutations, in a mosaic pattern, depending on timing and localization of the second mutation.
It is assumed that simultaneous presence of two germline mutations is lethal and the cells with the combination of mutations will survive only if they are close to cells not harboring both mutations (lethal gene theory). If a second mutation is inherited from the other parent, the embryo will not survive unless a backward mutation recovering the function of the gene would occur in some of the cells, again resulting in a mosaic pattern of abnormalities. The theory predicts that involvement of the entire body with KTS or a related VM-DG syndrome will not be observed because it is lethal.
The variability of VM-DG syndromes can be explained by the number of the various genes involved in (lymph)angiogenesis and growth regulation, and the numerous possible combinations of mutated genes. The rarity of VM-DG follows automatically from the low prior probability of so many different gene defects coinciding in one individual.
The pathophysiology of the various KTS symptoms is unclear, the causative gene defect(s) being unknown. Varicose veins can arise from congenital absence of venous valves or as a consequence of altered intravascular pressures caused by, for example, vascular malformations. It has been proposed that the hypertrophic growth is caused by abnormal blood flow, but this explanation seems unlikely because hypoplasia can also occur in the context of KTS.
Systemic Implications and Complications
Except for thromboembolic complications, which are relatively rare, there are no systemic conditions specifically associated with KTS.
Patients often benefit from and need psychological counseling, which may be required lifelong.
There are no medical options yet for the visible manifestations of KTS. Most treatments are directed at the vascular component.
Some options for therapy include compression therapy, laser treatment, and sclerotherapy in the appropriate settings (performed by a vascular surgeon).
Due to the abnormal vascular nature of these lesions, the clinician can consider using low-dose aspirin or another anticoagulant to decrease the risk of thromboembolic disease. Consultations with a hematologist will be helpful to guide prophylactic therapy in this regard.
Optimal Therapeutic Approach for this Disease
Most patients do not require specific interventions. The most common problems and their preferred approaches are listed below. Any interventions that are considered must be planned and executed by an experienced multidisciplinary team, as multiple treatment modalities may be required for optimal results.
There is no medical need to treat capillary malformations, but patients may want treatment for cosmetic reasons. The preferred modality is pulsed dye laser. For lesions with a purple hue, Nd:YAG laser treatment may be more suitable. Intense pulsed light is not effective.
Some specialists advocate early treatment, particularly for facial capillary malformations as in Sturge-Weber. Others defer treatment until patients have reached an age at which they can decide for themselves. Arguments can be put forward for either approach. With the present state of knowledge, there is no medical reason to prefer one approach over the other.
Specific interventions here depend on the nature of the lesion and whether or not it causes any specific complaints. The mainstay of therapy for vascular malformations is compression therapy using properly fitted elastic stockings. The vast majority of patients are perfectly well treated with those. Depending upon the precise nature of the vascular malformations, other interventions can occasionally be of value.
Varicose veins may be treated with sclerotherapy or phlebectomy if they are associated with specific complaints and if there are no abnormalities in the deep venous system. Isolated vascular malformations are occasionally amenable to sclerotherapy or embolization, preferably preceded by direct punction contrast imaging to make sure that the lesion has no significant connections to critical structures. When such interventions are contemplated, one should enlist the aid of an interdisciplinary team experienced in such matters.
There are microcystic and macrocystic lymphatic malformations. Intervention may be required for malformations that leak fluid or interfere with (vital) functions. Treatment options include surgical resection, sclerotherapy, laser, radiofrequency ablation, and sometimes chemotherapy with agents such as rapamycin. Sclerotherapy works well for macrocystic malformations. Selection of options for microcystic malformations must be individualized.
Arteriovenous malformations may require treatment because of the complications they cause. These may include high-output cardiac failure in high-flow arteriovenous malformations, compromise of vital structures, hemorrhage, or ischemia of affected limbs. Intervention should be undertaken by a multidisciplinary team; treatment options include embolization, sclerotherapy or surgical resection.
In the majority of cases, the overgrowth requires no intervention. The most important consequence is a leg length discrepancy. If this remains smaller than about 3cm, no treatment is required. A simple insole in the shoe, worn on the unaffected side, will suffice to correct the inequality.
Larger differences can become cumbersome, or even invalidating, and must be addressed. Depending on the size, a discrepancy may still be addressed by proper orthopedic footwear; however, if a leg is growing very quickly and it is foreseen that it will become so much longer than the unaffected one that disability will result, growth may be halted, for instance, by surgical intervention. A child with leg length discrepancy must be followed at regular intervals by an experienced pediatric orthopedic surgeon so that treatment may be started in a timely manner when needed.
Patient management must be individualized and strongly depends on age—the younger the patient, the more frequent the follow-up. Patients without functionally significant overgrowth and who otherwise have no problems can be seen once yearly or on as-needed basis.
Patients who have experienced thromboembolic events in the past can be monitored by D-dimer levels. There is no consensus yet in this regard. Patients should be instructed to visit when they have complaints (such as sudden swelling of an extremity). If there is a sudden onset of excesssive swelling or pain, a venous duplex should be considered to rule out a deep venous thrombosis.
Patients may need psychological support to help them cope with their deformities. Caregivers should be cognizant of the fact that malformations can be a heavy psychological burden to patients and their family. They should be alert and not be afraid to discuss such issues at an early stage.
Unusual Clinical Scenarios to Consider in Patient Management
Profuse hemorrhaging of bleeding varicosities can scare patients and healthcare providers. . Hemorrhaging can occur as a result of trauma or may start spontaneously. A rather infrequent complication, it can be easily treated by local compression. Instruct patients to take a clean towel and use it to apply pressure to the bleeding vessel for 30 minutes. Afterwards, these patients should visit their physicians so it can be determined if something can be done (sclerotherapy, phlebectomy, surgical ligation) to prevent recurrence.
What is the Evidence?
Biesecker, L. “The challenges of Proteus syndrome: diagnosis and management”. Eur J Hum Genet. vol. 14. 2006. pp. 1151-7. (How to diagnose and manage Proteus syndrome, written by one of the most prominent specialists in the field)
Caux, F, Plauchu, H, Chibon, F, Faivre, L, Fain, O, Vabres, P. “Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygosity”. Eur J Hum Genet. vol. 15. 2007. pp. 767-73. (Delineation of the SOLAMEN syndrome, which can cause diagnostic confusion)
Dompmartin, A, Vikkula, M, Boon, LM. “Venous malformation: update on aetiopathogenesis, diagnosis and management”. Phlebology. vol. 25. 2010. pp. 224-35. (This recent review discusses current knowledge on etiopathogenesis, diagnosis, and therapeutic management of venous malformations.)
Gloviczki, P, Duncan, A, Kalra, M, Oderich, G, Ricotta, J, Bower, T. “Vascular malformations: an update”. Perspect Vasc Surg Endovasc Ther. vol. 21. 2009. pp. 133-48. (An up-to-date review on management of vascular malformations, including lymphatic ones)
Happle, R. “Mosaicism in human skin”. Understanding the patterns and mechanisms. Arch Dermatol. vol. 129. 1993. pp. 1460-70. ( A relatively old but still very pertinent review that discusses the concept of genetic mosaicism, written by the dermatologist who introduced it to the fields of human genetics and dermatology)
Lobo-Mueller, E, Amaral, JG, Babyn, PS, Wang, Q, John, P. “Complex combined vascular malformations and vascular malformation syndromes affecting the extremities in children”. Semin Musculoskelet Radiol. vol. 13. 2009. pp. 255-76. (An overview of diagnostic procedures pertinent to vascular malformation syndromes)
Oduber, CE, van der Horst, CM, Sillevis Smitt, JH, Smeulders, MJ, Mendiratta, V, Harper, JI. “A proposal for classification of entities combining vascular malformations and deregulated growth”. Eur J Med Genet. 2011 Feb 25. (This paper describes the new classification for KTS and allied disorders)
Oduber, CE, van der Horst, CM, Hennekam, RC. “Klippel-Trenaunay syndrome: diagnostic criteria and hypothesis on etiology”. Ann Plast Surg. vol. 60. 2008. pp. 217-23. (An up-to-date overview of diagnostic criteria for KTS )
Sapp, JC, Turner, JT, van de Kamp, JM, van Dijk, FS, Lowry, RB, Biesecker, L. “Newly delineated syndrome of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) in seven patients”. Am J Med Genet A 2007 Dec. vol. 143A. 15. pp. 2944-58. (Delineation of CLOVE, which is often confused with KTS and similar disorders)
Steijlen, PM, van Steensel, MA. “Paradominant inheritance, a hypothesis explaining occasional familial occurrence of sporadic syndromes”. Am J Med Genet. vol. 85. 1999. pp. 359-6. (An explanation of the principles behind paradominant inheritance)
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