Reconstructive

RECONSTRUCTIVE

Differential Diagnosis of Lower Extremity Enlargement in Pediatric Patients Referred with a Diagnosis of Lymphedema

Carolyn C. Schook, B.A. Background: There are many causes for a large lower limb in the pediatric age John B. Mulliken, M.D. group. These children are often mislabeled as having lymphedema, and incor- Steven J. Fishman, M.D. rect diagnosis can lead to improper treatment. The purpose of this study was to Ahmad I. Alomari, M.D. determine the differential diagnosis in pediatric patients referred for lower Frederick D. Grant, M.D. extremity “lymphedema” and to clarify management. Arin K. Greene, M.D., Methods: The authors’ Vascular Anomalies Center database was reviewed be- M.M.Sc. tween 1999 and 2010 for patients referred with a diagnosis of lymphedema of Boston, Mass. the lower extremity. Records were studied to determine the correct cause for the enlarged extremity. Alternative diagnoses, sex, age of onset, and imaging studies were also analyzed. Results: A referral diagnosis of lower extremity lymphedema was given to 170 children; however, the condition was confirmed in only 72.9 percent of patients. Forty-six children (27.1 percent) had another disorder: microcystic/macrocystic lymphatic malformation (19.6 percent), noneponymous combined vascular malformation (13.0 percent), capillary malformation (10.9 percent), Klippel- Trenaunay syndrome (10.9 percent), hemihypertrophy (8.7 percent), posttraumatic swelling (8.7 percent), Parkes Weber syndrome (6.5 percent), lipedema (6.5 percent), venous malformation (4.3 percent), rheumatologic disorder (4.3 percent), infantile hemangioma (2.2 percent), kaposiform hemangioendothelioma (2.2 percent), or lipofibromatosis (2.2 percent). Age of onset in children with lymphedema was older than in patients with another diagnosis (p ϭ 0.027). Conclusions: “Lymphedema” is not a generic term. Approximately one-fourth of pediatric patients with a large lower extremity are misdiagnosed as having lymphedema; the most commonly confused causes are other types of vascular anomalies. History, physical examination, and often radiographic studies are required to differentiate lymphedema from other conditions to ensure the child is managed appropriately. (Plast. Reconstr. Surg. 127: 1571, 2011.)

ymphedema is the chronic, progressive swell- tial causes of congenital lower extremity over- ing of tissue caused by inadequate lymphatic growth, referring physicians likely are most Lfunction. Lymphedema may result from familiar with the term “lymphedema.” anomalous development (primary) or injury (sec- Lymphedema, however, is typically an adult dis- ondary) to lymph nodes or lymphatic vessels. Al- ease caused by lymphadenectomy and/or irradi- though lymphedema is a specific condition, chil- ation to the axilla or groin. Primary pediatric dren with a large lower limb are often labeled as lymphedema is rare; a child erroneously diag- having lymphedema, regardless of the underlying nosed with lymphedema may undergo unneces- cause. Because lymphedema is much more prev- sary tests and be given incorrect treatment. The alent in the general population than other poten- purposes of this study were to determine the ac- curacy of the term “lymphedema” for pediatric lower limb enlargement and to document other From the Departments of Plastic and Oral Surgery, Surgery, and Radiology, Vascular Anomalies Center, Children’s Hos- causes with which it is frequently confused. pital Boston, Harvard Medical School. Received for publication July 22, 2010; accepted October 11, 2010. Disclosure: The authors have no financial interest Copyright ©2011 by the American Society of Plastic Surgeons to declare in relation to the content of this article. DOI: 10.1097/PRS.0b013e31820a64f3

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PATIENTS AND METHODS Weber syndrome (6.5 percent), venous malforma- After approval from the Committee on Clini- tion (4.3 percent), infantile hemangioma (2.2 per- cal Investigation at Children’s Hospital Boston, cent), or kaposiform hemangioendothelioma (2.2 our Vascular Anomalies Center database was re- percent). Other conditions confused with viewed for patients sent between 1999 and 2010 lymphedema were hemihypertrophy (8.7 percent), labeled with lower extremity “lymphedema.” In- posttraumatic swelling (8.7 percent), lipedema (6.5 dividuals with disease onset after 21 years of age percent), rheumatologic disease (4.3 percent), and were excluded to ensure that only a pediatric co- lipofibromatosis (2.2 percent). hort was studied. The correct diagnosis was deter- Female patients constituted 62.1 percent of mined by history, physical examination, photo- patients (77 of 124) with lymphedema and 58.7 graphs, imaging studies, and/or histopathology. percent (27 of 46) of children without the disor- Alternative conditions, sex, and age-of-onset were der (p ϭ 0.68). Median age of onset in children recorded. The Mann-Whitney U test was used to with lymphedema was older [4 years (range, 0 to differentiate age of onset between patients with 12 years)] than in patients with another diagnosis lymphedema and children with other disorders. [0 years (range, 0 to 4 years)] (p ϭ 0.027). At least Age of onset was defined in years and, if present one imaging study was obtained in 84.7 percent before 12 months of age, was recorded as 0. Results (144 of 170) of children: magnetic resonance im- are presented as median with interquartile range aging in 93 (54.1 percent), ultrasonography in 78 (25th to 75th percentile). A two-tailed value of p (45.9 percent), plain film radiography in 53 (31.2 Ͻ 0.05 was considered significant. Statistical anal- percent), lymphoscintigraphy in 35 (20.6 per- ysis was performed using the SPSS software pack- cent), computed tomography in 27 (15.9 per- age (version 16.0; SPSS, Inc., Chicago, Ill.). cent), echocardiography in 13 (7.6 percent), and/or angiography in 12 patients (7.1 percent). RESULTS A referral diagnosis of lower extremity DISCUSSION lymphedema was identified in 170 children of Lymphedema is an often loosely used label for 9477 patients in the database (1.8 percent). an enlarged lower extremity in children, regard- Lymphedema was confirmed in 124 patients (72.9 less of the cause. Lymphedema is a precise term percent). The remaining 27.1 percent (46 of 170) that defines chronic, progressive swelling of sub- of patients referred with lymphedema had a dif- cutaneous tissue caused by abnormal develop- ferent diagnosis (Table 1). Seventy percent (32 of ment or injury to the lymphatic vasculature. Pri- 46) had another type of vascular anomaly: micro- mary lymphedema most commonly affects the cystic/macrocystic lymphatic malformation (19.6 lower extremity (Fig. 1). Patients have a significant percent), noneponymous combined vascular mal- risk of infection, and limb enlargement occurs formation (13.0 percent), diffuse capillary mal- over time from adipose deposition and fibrosis. formation with overgrowth (10.9 percent), Klip- Lymphedema can be differentiated from other pel-Trenaunay syndrome (10.9 percent), Parkes causes of extremity overgrowth by history and physical examination in approximately 90 percent of patients. The foot is always involved and swell- Table 1. Causes of an Enlarged Lower Extremity ing proceeds proximally. Edema becomes less pit- Referred with an Incorrect Diagnosis of Lymphedema ting over time as adipose and fibrous tissue are 1 No. (%) deposited. Definitive diagnosis of lymphedema Microcystic/macrocystic lymphatic requires lymphoscintigraphy, which is 92 percent malformation 9 (19.6) sensitive and 100 percent specific for the Noneponymous combined vascular disorder.2 Compromised lymphatic function is il- malformation 6 (13.0) Klippel-Trenaunay syndrome 5 (10.9) lustrated by delayed transit and/or cutaneous ac- Capillary malformation 5 (10.9) cumulation (dermal backflow) of radiolabeled Hemihypertrophy 4 (8.7) colloid injected into the feet. Posttraumatic swelling 4 (8.7) Parkes Weber syndrome 3 (6.5) Management of lymphedema requires daily Lipedema 3 (6.5) washing and moisturizing of the extremity to min- Venous malformation 2 (4.3) imize desiccation, skin breakdown, and subse- Rheumatologic disease 2 (4.3) Infantile hemangioma 1 (2.2) quent cellulitis. Patients should wear protective Kaposiform hemangioendothelioma 1 (2.2) clothing to prevent incidental trauma, which also Lipofibromatosis 1 (2.2) can lead to infection. Compression therapy using Total 46 (100) a custom-fitted garment and a pneumatic pump

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Fig. 1. Images demonstrating primary lymphedema in a 2-year-old boy with left lower extremity swelling that had been present since birth (left). (Above, right) Lymphoscintig- raphy demonstrates dermal backflow and absent inguinal node drainage 21⁄2 hours after injection.(Below,right)AxialT2-weightedmagneticresonanceimagingwithfatsaturation shows a hyperintense reticular network of dilated subcutaneous channels between the dermis and fascial plane. helps to reduce the volume of the extremity and not more likely to have lymphedema than boys; slow progression. Patients with significant mor- therefore, sex should not be considered when dif- bidity who have failed conservative treatment ferentiating lymphedema from other conditions. may be considered for contour resection. We If the diagnosis remains equivocal following his- prefer suction-assisted lipectomy for moderately tory and physical examination, lymphoscintigra- enlarged extremities and staged skin/subcuta- phy will rule out lymphedema, and magnetic res- neous resection for patients with major over- onance imaging can confirm the diagnosis of growth and skin excess.3–6 another vascular anomaly. Approximately one-fourth of patients la- Diffuse capillary malformation with over- beled with lymphedema referred to our center growth can cause soft-tissue and skeletal enlarge- had another condition. The most commonly ment of a limb (Fig. 2). Patients are not at in- confused diagnoses were other vascular anom- creased risk for infection, and the progression of alies: single-vessel forms (capillary malformation, overgrowth is slow. The cutaneous stain is treated lymphatic malformation, venous malformation), by pulsed-dye laser. The circumferential over- combined malformations (capillary-venous, lym- growth may be improved with suction-assisted li- phatic-venous), and eponymous syndromes (Klip- pectomy; occasionally, axial enlargement can pel-Trenaunay, Parkes Weber). It is important to cause a leg-length discrepancy. separate these conditions from lymphedema be- Venous and noneponymous combined mal- cause their natural history, prognosis, and treat- formations (e.g., capillary-venous, lymphatic-ve- ment are very different. Like lymphedema, vascu- nous) are localized in more than 90 percent of lar anomalies are diagnosed by history and patients; 50 percent affect deep structures (e.g., physical examination in at least 90 percent of muscle, bone, joints, viscera) (Figs. 2 and 3).7,8 patients. Although primary lymphedema can pres- One-half of sporadic venous malformations have ent at birth, it also may develop later in childhood a somatic mutation in the TIE2 receptor.8 Venous or in adolescence. In contrast, most vascular malformations of the lower limb typically involve anomalies are obvious during infancy. Girls are the skin and/or muscles. If all tissues, including

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Fig. 2. Examples of patients with single-vessel type vascular malformations with a referring diagnosis of lymphedema. (Above, left) A 9-year-old boy with a diffuse capillary malformation and overgrowth of the left lower extremity; capillary malformation is not a component of lymphedema. (Below, left) Coronal T1-weighted magnetic resonance imaging shows thickening of the subcutaneous fat with normal blood channels. (Above, center) An 8-year-old girl with a venous malformation of the right lower extremity (lymphedema does not have cutaneous varicosities). (Below, center) Coronal T2-weighted magnetic resonance imaging scan showing deep intramuscular and cutaneous venous anomalies. (Above, right) A 12-month-old boy with a lymphatic malformation of the right lower limb. Although history and physical examination were consistent with lymphedema, macrocystic lymphatic malformation was diagnosed based on magnetic resonance imaging findings. (Below, right) Sagittal T2-weighted magnetic resonance imaging scan with fat saturation demonstrates fluid-filled lymphatic macrocysts within the intermuscular space. bone, are affected, the disorder is called phleb- Treatment of lower extremity venous malforma- ectasia of Bockenheimer.9 Extremity venous mal- tion includes compression garments, sclerother- formation can cause leg-length discrepancy, hyp- apy, and/or resection. oplasia resulting from disuse atrophy, fibrosis, Primary lymphedema differs from microcys- pain, pathologic fracture, hemarthrosis, and de- tic, macrocystic, and combined lymphatic mal- generative arthritis.10,11 A large venous malforma- formations because it is not cystic and involves tion involving the deep venous system is at risk for only the subcutaneous layer. Microcystic/mac- thrombosis and pulmonary embolism. Stagnation rocystic lymphatic malformation can affect all within a lesion can cause localized intravascular structures of the extremity, including muscle and coagulopathy and painful phlebothromboses. bone (Fig. 2). Several germ-line mutations cause

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Fig. 3. Example of a noneponymous combined vascular malformation with a referring diagnosis of lymphedema. (Left) A 15-year-old girl with a capillary-venous malformation of the right lower limb; a lymphedematous lower extremity typically has normal overlying skin. (Right) Axial T2-weighted magnetic resonance imaging scan shows dilated veins within the subcutaneous fat underlying the capillary stain. primary lymphedema (VEGFR3, FOXC2, SOX18, of the lower extremity with overgrowth. Parkes and CCBE1).12–15 In contrast, microcystic/macro- Weber syndrome can be caused by a mutation in cystic lymphatic malformations are thought to re- RASA1, and patients with multiple capillary malfor- sult from paradominant inheritance; an individual mations are likely on the spectrum of capillary mal- with a predisposed inherited mutation develops a formation-arteriovenous malformation.17 Patients somatic second hit in the same gene that causes are at risk for congestive heart failure because of expression of the lesion.16 Symptomatic microcys- extensive arteriovenous shunting. Genetic counsel- tic/macrocystic lymphatic malformations of the ing is required for children with capillary malfor- lower extremity are managed by compression, mation-arteriovenous malformation because it is an sclerotherapy, and/or resection. autosomal dominant condition. Symptomatic pa- The eponymous vascular malformations, Klippel- tients are managed by embolization; epiphysiodesis Trenaunay and Parkes Weber syndrome, usually or amputation may be necessary. are more problematic than lymphedema (Fig. 4). Lipedema is commonly misdiagnosed as Klippel-Trenaunay syndrome is a capillary-lympha- lymphedema (Fig. 5). It is characterized by bilat- tic-venous malformation of the lower extremity with eral, fatty hypertrophy of the lower extremities in overgrowth. Patients are at risk for infections, disproportion to the rest of the body.18 Pubertal deep venous thrombosis, pulmonary embolism, female patients are primarily affected, and a pos- leg-length discrepancy, and difficulty with ambu- itive family history may be reported. Unlike lation. Large embryonal veins are removed to pre- lymphedema, the foot is not involved, pain is com- vent venous thrombosis. A shoe lift or epiphys- mon, and patients are not at an increased risk for iodesis may be necessary to correct leg-length infection. Lipedema can be differentiated from discrepancy. Occasionally, selective amputation is lymphedema by history and physical examination. required to permit footwear and to facilitate am- Magnetic resonance imaging shows increased sub- bulation. Soft-tissue overgrowth can be improved cutaneous adipose tissue without stranding or with staged skin/subcutaneous resection. Parkes thickened skin; lymphoscintigraphy is normal. Weber syndrome is a capillary-arteriovenous or The size of the limb can be reduced by suction- capillary-lymphatic-arteriovenous malformation assisted lipectomy.

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Fig. 4. Examples of children with eponymous combined vascular anomalies with a re- ferringdiagnosisoflymphedema.(Above,left)An18-year-oldfemalepatientwithKlippel- Trenaunay syndrome of the left lower extremity. The capillary malformation, venous varicosities, and cutaneous lymphatic vesicles were not consistent with lymphedema. (Below,left)AxialT2-weightedmagneticresonanceimagingscanwithfatsaturationdem- onstrates a marginal venous system and subcutaneous lymphatic malformation with subfascial involvement. (Above, right) A 6-month-old with Parkes Weber syndrome. A cutaneous stain and warm extremity indicated a fast-flow malformation. Diagnosis was confirmed by magnetic resonance angiography (below, right), demonstrating enlargement of the arteries and early opacification of the dilated veins.

Hemihypertrophy, the idiopathic enlarge- most common tumor of infancy, is usually local- ment of an area compared with the contralateral ized and easily distinguished from lymphedema. A side, may be confused with lymphedema (Fig. 6).19 diffuse, reticular form may involve the lower ex- Hemihypertrophy is usually a diagnosis of exclu- tremity and present with hypertrophy.21 Reticular sion. Lymphoscintigraphy is normal and magnetic hemangioma is differentiated from lymphedema resonance imaging demonstrates enlargement of because it appears shortly after birth, proliferates, all components of the extremity (i.e., adipose, and then involutes. The tumor is infiltrative and muscle, bone) without pathologic findings. Un- can involve fascia or muscle. In addition, reticular like lymphedema, there is overgrowth of the tis- hemangioma often ulcerates and is associated with sues below the muscle fascia. Occasionally, sym- ventral-caudal malformative anomalies.21 Manage- metry may be improved with suction-assisted ment may require corticosteroid treatment for re- lipectomy of the subcutaneous compartment. In calcitrant ulceration or congestive heart failure; contrast to other causes of extremity overgrowth, imaging is necessary to rule out underlying struc- children with hemihypertrophy are at risk for tural disorders. Wilms tumor and require screening.20 Kaposiform hemangioendothelioma is a rare A lower extremity tumor can be mistaken for vascular neoplasm that is locally aggressive but lymphedema (Fig. 7). Infantile hemangioma, the does not metastasize.22,23 Although one-half of le-

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Fig.5. Exampleofapatientwithlipedemareferredwithamistakendiagnosis of lymphedema. (Left) The patient was a 34-year-old woman who had had enlarged lower extremities since adolescence. Because the feet were not involved,lipedemawasdiagnosedbyphysicalexaminationandconfirmedwith imaging. The lymphoscintigram was normal (prompt tracer uptake into ab- dominal nodes bilaterally) (above, right), and coronal T1-weighted magnetic resonance imaging showed circumferential overgrowth of the subcutaneous fat (below, right). sions are present at birth, onset can occur in in- growth is the predominant finding. Lipofibroma- fancy or childhood.24 The tumor is often diffuse, tosis can involve the subfacial compartments and and an extremity is affected in approximately one- cause bony overgrowth; the foot may be spared. third of patients.24,25 The skin is reddish purple Diagnosis is confirmed by histopathologic exam- and pain is common. In addition, 50 percent of ination showing abundant adipose tissue, spin- patients have Kasabach-Merritt phenomenon dled fibroblasts, focal fascicular growth, and lim- [thrombocytopenia (Ͻ25,000/mm3), petechiae, ited mitotic activity.30,31 Suction-assisted lipectomy bleeding].22,26,27 Kaposiform hemangioendotheli- can improve limb contour.31 oma enlarges in early childhood and then partially Posttraumatic swelling is erroneously labeled regresses after 2 years of age into mid childhood. lymphedema in some children. Prolonged edema Usually, there is residual tumor and fibrosis that of the lower extremity can occur following injury, causes chronic pain and stiffness.28 Kaposiform particularly after a severe sprain or fracture. Un- hemangioendothelioma also has a lymphatic like lymphedema, the lymphatic function of the component, which stains positive for the lym- extremity is normal. If the diagnosis is equivocal, phatic marker D2-40.25 First-line treatment is lymphoscintigraphy will demonstrate intact lym- vincristine to control Kasabach-Merritt phe- phatic flow. Some patients will have a ligamentous nomenon and pain; resection is rarely possible tear or small fracture that can be identified by because the tumor involves multiple tissue plain film and/or magnetic resonance imaging. planes and important structures.29 Rarely, rheumatologic disorders can cause Lipofibromatosis is a rare, slow-growing neo- chronic lower extremity swelling in children. plasm that, when diffuse, can cause enlargement Lymphedema and other conditions are ruled out of the lower limb.30,31 It is not aggressive and does by lymphoscintigraphy and magnetic resonance not metastasize. The leg usually is enlarged at birth imaging. If there is no history of trauma and no or by early childhood; subcutaneous fatty over- other potential cause of the swelling can be

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Fig. 6. Example of a child with hemihypertrophy with a referring diagnosis of lymphedema. (Left) An 11-year-old boy with right lower extremity enlargement present since birth. History and physical examination potentially were consistent with lymphedema. (Right) Axial pilot magnetic reso- nanceimagingscandemonstratedovergrowthofthelowerextremity,includingsubcutaneousfat, muscle, and bone. Because lymphedema affects only the skin and subcutaneous tissue, and a vascular abnormality was not present, hemihypertrophy was diagnosed.

Fig. 7. Examples of patients with tumors erroneously labeled as lymphedema on referral. (Left) A 3-month-old with a reticular infantile hemangioma of the left lower extremity that appeared shortly after birth. The red appearance of the skin and rapid postnatal progression were inconsistent with lymphedema but typical for infantile hemangioma. (Center) A 3-month-old with kaposiform hemangioendothelioma diagnosed by history, physical examination, and laboratory findings. The patient suffered from diffuse discoloration of the extremity, bruising, and thrombocytopenia, which do not occur with lymphedema. (Right) A 5-year-old with lipofibromatosis. History and physical examination possibly were consistent with lymphedema.Becauseimagingstudieswereinconclusive,biopsyspecimenswereobtainedandthediagnosiswasmade histopathologically.

1578 Volume 127, Number 4 • Pediatric Lower Limb Enlargement identified, children are referred for rheumatologic consultation. Additional conditions may cause lower extremity asymmetry in children but were excluded

from this study because patients were not errone- Edema‡ F Nonspecific Subcutaneous/ ously diagnosed with lymphedema (Fig. 8). For ϭ adolescence subfascial edema condition

example, CLOVES syndrome (congenital lipoma- 1 Treat underlying tosis overgrowth, vascular malformations, epider- mal nevi, and scoliosis) represents a newly de- scribed overgrowth disorder.32,33 Rare vascular tumors, such as nonkaposiform hemangioendo- theliomas can involve the lower limb. Finally, con-

ditions that reduce the size of one lower extremity, Klippel-Trenaunay syndrome, Parkes Weber such as hemiatrophy, may cause the contralateral FM

limb to appear enlarged. Adipose/muscle/bone ϭ (normal vasculature) operative 1 Wilms tumor screening, CONCLUSIONS Approximately one-fourth of pediatric patients with a large lower extremity are misdiagnosed as having lymphedema. The most commonly confused causes are other types of vascular anomalies, lipedema, and hemihypertrophy. Al- FM ϭ though history and physical examination usually (enhancing lesion) operative are sufficient to differentiate lymphedema from Tumor-specific other conditions, lymphoscintigraphy and/or , increased.

magnetic resonance imaging may be necessary if 1 the cause is unclear (Table 2 and Fig. 9). If lymphedema is suspected, a lymphoscintigram is Subcutaneous adipose 1 Operative Pharmacotherapy, , with or without; Ϯ , without; Vascular Ϫ FF M Malformation* Lipedema Tumor† Hemihypertrophy ϭ embolization, operative , with; Abnormal vasculature Sclerotherapy, ϩ ϪϪ Ϫ ϮϪϮϪϪ Ϯ ϩϮϪϮϮ Ϫ ϮϩϪϩϪ Ϯ ϪϮϪϮϪ Ϫ ϪϪϪϪϩ Ϫ ϩϪϪϪϪ Ϫ ϪϩϪϩϪ FM Lymphedema Subcutaneous ϭ adipose/edema operative 1

Fig. 8. An infant with CLOVES syndrome, an additional cause of lower extremity asymmetry in children, diagnosed by physical examination. Foot anomalies and lipomatosis of the trunk do not OnsetFamilial transmission LateralityFoot/hand involvement Cutaneous changes Abnormal blood tests Risk for Wilms tumor Lymphoscintigraphy MRI findings Infancy/adolescence InfancyDiagnostic Unilateral/bilateral histopathology Management Unilateral Adolescence Compression, Bilateral Infancy Unilateral Infancy Unilateral Infancy/childhood/ Unilateral/bilateral Male-to-female incidence M occur with lymphedema. Table 2. Typical Characteristics of Conditions Causing Lower Extremity Enlargement in the Pediatric Age Group M, male; F, female;*Capillary MRI, malformation, lymphatic magnetic malformation, resonance venous malformation,syndrome, imaging; combined CLOVES vascular malformation syndrome). (e.g., lymphatic-venous†Infantile malformation, hemangioma, kaposiform hemangioendothelioma,‡Posttraumatic, lipofibromatosis. rheumatologic, and systemic fluid overload (e.g., cardiac, hepatic, renal disease).

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Fig. 9. Diagnostic algorithm for pediatric lymphedema. the first imaging test ordered. A patient thought 4. Brorson H, Svensson H. Liposuction combined with con- to have a condition other than lymphedema on trolled compression therapy reduces arm lymphedema more history and physical examination usually under- effectively than controlled compression therapy alone. Plast Reconstr Surg. 1998;102:1058–1067; discussion 1068. goes magnetic resonance imaging evaluation to 5. Greene AK, Slavin SA, Borud L. Treatment of lower extrem- confirm the suspected diagnosis and/or to define ity lymphedema with suction-assisted lipectomy. Plast Reconstr the extent of disease. Magnetic resonance imaging Surg. 2006;118:118e–121e. also is commonly used as a secondary imaging 6. Brorson H, Ohlin K, Olsson G, Svensson B, Svensson H. study if lymphoscintigraphy is negative. Correct Controlled compression and liposuction treatment for lower diagnosis is important because the natural history extremity lymphedema. Lymphology 2008;41:52–63. and management of lymphedema are very differ- 7. Boon LM, Mulliken JB, Enjolras O, Vikkula M. Glomuvenous malformation (glomangioma) and venous malformation: ent compared with other lower extremity diseases Distinct clinicopathologic and genetic entities. Arch Dermatol. in children. 2004;140:971–976. 8. Limaye N, Wouters V, Uebelhoer M, et al. Somatic muta- Arin K. Greene M.D., M.M.Sc. tions in angiopoietin receptor gene TEK cause solitary and Department of Plastic Surgery multiple sporadic venous malformations. Nat Genet. 2009; Vascular Anomalies Center 41:118–124. Children’s Hospital Boston 300 Longwood Avenue 9. Kubiena HF, Liang MG, Mulliken JB. Genuine diffuse phle- Boston, Mass. 02115 bectasia of Bockenheimer: Dissection of an eponym. Pediatr [email protected] Dermatol. 2006;23:294–297. 10. Hein KD, Mulliken JB, Kozakewich HP, Upton J, Burrows PE. Venous malformations of skeletal muscle. Plast Reconstr Surg. ACKNOWLEDGMENT 2002;110:1625–1635. The authors thank David Zurakowski, Ph.D., for 11. Upton J, Coombs CJ, Mulliken JB, Burrows PE, Pap S. Vas- statistical expertise. cular malformations of the upper limb: A review of 270 patients. J Hand Surg Am. 1999;24:1019–1035. REFERENCES 12. Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. 1. Brorson H. Adipose tissue in lymphedema: The ignorance of Congenital hereditary lymphedema caused by a mutation adipose tissue in lymphedema. Lymphology 2004;37:175–177. that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet. 2. Gloviczki P, Calcagno D, Schirger A, et al. Noninvasive eval- 2000;67:295–301. uation of the swollen extremity: Experiences with 190 lym- 13. Irrthum A, Devriendt K, Chitayat D, et al. Mutations in the phoscintigraphic examinations. J Vasc Surg. 1989;9:683–689; transcription factor gene SOX18 underlie recessive and discussion 690. dominant forms of hypotrichosis-lymphedema-telangiecta- 3. Miller TA, Wyatt LE, Rudkin GH. Staged skin and subcuta- sia. Am J Hum Genet. 2003;72:1470–1478. neous excision for lymphedema: A favorable report of long- 14. Finegold DN, Kimak MA, Lawrence EC, et al. Truncating term results. Plast Reconstr Surg. 1998;102:1486–1498; discus- mutations in FOXC2 cause multiple lymphedema syn- sion 1499–1501. dromes. Hum Mol Genet. 2001;10:1185–1189.

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15. Alders M, Hogan BM, Gjini E, et al. Mutations in CCBE1 analysis of pediatric vascular tumors reveals positivity in kaposi- cause generalized lymph vessel dysplasia in humans. Nat form hemangioendothelioma. Mod Pathol. 2005;18:1454–1460. Genet. 2009;41:1272–1274. 26. Mulliken JB, Anupindi S, Ezekowitz RA, Mihm MC Jr. Case 16. Brouillard P, Vikkula M. Genetic causes of vascular malfor- records of the Massachusetts General Hospital. Weekly clin- mations. Hum Mol Genet. 2007;16:R140–R149. icopathological exercises. Case 13-2004. A newborn girl with 17. Revencu N, Boon LM, Mulliken JB, et al. Parkes Weber a large cutaneous lesion, thrombocytopenia, and anemia. N syndrome, vein of Galen aneurysmal malformation, and Engl J Med. 2004;350:1764–1775. other fast-flow vascular anomalies are caused by RASA1 mu- 27. Sarkar M, Mulliken JB, Kozakewich HP, Robertson RL, Bur- tations. Hum Mutat. 2008;29:959–965. rows PE. Thrombocytopenic coagulopathy (Kasabach-Mer- 18. Rudkin GH, Miller TA. Lipedema: A clinical entity distinct ritt phenomenon) is associated with Kaposiform hemangio- from lymphedema. Plast Reconstr Surg. 1994;94:841–847; dis- endothelioma and not with common infantile hemangioma. cussion 848–849. Plast Reconstr Surg. 1997;100:1377–1386. 19. Ballock RT, Wiesner GL, Myers MT, Thompson BH. Hemi- 28. Enjolras O, Mulliken JB, Wassef M, et al. Residual lesions hypertrophy: Concepts and controversies. J Bone Joint Surg after Kasabach-Merritt phenomenon in 41 patients. JAm Am. 1997;79:1731–1738. Acad Dermatol. 2000;42:225–235. 29. Karnes JC, Lee BT, Phung T, Alomari AI, Mulliken JB, 20. Greene AK, Kieran M, Burrows PE, Mulliken JB, Kasser J, Greene AK. Adult-onset kaposiform hemangioendothelioma Fishman SJ. Wilms tumor screening is unnecessary in Klippel- in a posttraumatic site. Ann Plast Surg. 2009;62:456–458. Trenaunay syndrome. Pediatrics 2004;113:e326–e329. 30. Fetsch JF, Miettinen M, Laskin WB, Michal M, Enzinger FM. 21. Mulliken JB, Marler JJ, Burrows PE, Kozakewitch HP. Retic- A clinicopathologic study of 45 pediatric soft tissue tumors ular infantile hemangioma of the limb can be associated with with an admixture of adipose tissue and fibroblastic ele- ventral-caudal anomalies, refractory ulceration, and cardiac ments, and a proposal for classification as lipofibromatosis. overload. Pediatr Dermatol. 2007;24:356–362. Am J Surg Pathol. 2000;24:1491–1500. 22. Zukerberg LR, Nickoloff BJ, Weiss SW. Kaposiform heman- 31. Greene AK, Karnes J, Padua HM, Schmidt BA, Kasser JR, gioendothelioma of infancy and childhood: An aggressive Labow BI. Diffuse lipofibromatosis of the lower extremity neoplasm associated with Kasabach-Merritt syndrome and masquerading as a vascular anomaly. Ann Plast Surg. 2009; lymphangiomatosis. Am J Surg Pathol. 1993;17:321–328. 62:703–706. 23. Kasabach H, Merritt K. Capillary hemangioma with extensive 32. Sapp JC, Turner JT, van de Kamp JM, van Dijk FS, Lowry RB, purpura: Report of a case. Am J Dis Child. 1940;59:1063–1070. Biesecker LG. Newly delineated syndrome of congenital li- 24. Lyons LL, North PE, Mac-Moune Lai F, Stoler H, Folpe AL, pomatous overgrowth, vascular malformations, and epider- Weiss SW. Kaposiform hemangioendothelioma: A study of 33 mal nevi (CLOVE syndrome) in seven patients. Am J Med cases emphasizing its pathologic, immunophenotypic, and Genet A. 2007;143A:2944–2958. biologic uniqueness from juvenile hemangioma. Am J Surg 33. Alomari AI. Characterization of a distinct syndrome that Pathol. 2004;28:559–568. associates complex truncal overgrowth, vascular, and acral 25. Debelenko LV, Perez-Atayde AR, Mulliken JB, Liang MG, Ar- anomalies: A descriptive study of 18 cases of CLOVES syn- chibald TH, Kozakewitch HP. D2-40 immunohistochemical drome. Clin Dysmorphol. 2009;18:1–7.

Contacting the Editorial Office To reach the Editorial Office, please use the following contact information: Plastic and Reconstructive Surgery௡ Rod J. Rohrich, M.D., Editor-in-Chief UT Southwestern Medical Center 5959 Harry Hines Boulevard POB1, Suite 300 Dallas, Texas 75390-8820 Tel: 214-645-7790 Fax: 847-709-7534 E-mail: [email protected]

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