The asymmetric limb (gigantism): diagnostic approachCatalina Wilches V.1

Andrea Gallo H.1

Gabriel Daza C.2

Mónica Tafur A.2

Óscar Rivero2

Gustavo Triana2

Summary: Diseases that present with asymmetric development of one of the extremitiesare unusual entities and are considered a diagnostic challenge for radiologists. Within thesegroup of entities, we could find Proteus syndrome, Maffucci syndrome , KlippelTrenaunayWebersyndrome and lipomatous macrodystrophy. It is important to recognizeradiological findings of the diseases that are characterized by gigantism in order to achievean accurate diagnosis.Key Words (MeSH)GigantismExtremityProteus1 Radiologist residente III. Departamento de RadiologÃa e Imágenes Diagnósticas, Fundación Santa Fe deBogotá. Bogotá, Colombia.2 Radiologist. Departamento de RadiologÃa e Imágenes Diagnósticas, Fundación Santa Fe de Bogotá. Bogotá,Colombia.1KlippelTrenaunayWeberIntroductionThere are diseases that cause overgrowth of an extremity or extremities, or parts of it, withthe consequent asymmetry in the size of the extremities, and that do not constitutecongenital malformations, but abnormalities that are developed during lifetime.Frequently we face the challenge of evaluating studies of patients with clear limbasymmetry, with excessive growth in some of their extremities, global or focal, associatedwith or without alteration in the morphology of soft tissues.Differential diagnosis is not broad, clinical history, physical examination and evaluation ofcomparative images are essential elements, in most cases it is possible to reach an adequatediagnosis. .Maffucci SyndromeMaffucci syndrome is an unusual condition, not inherited (1). It is a congenital mesodermaldysplasia (2), characterized by multiple enchondroma associated with cavernoushemangiomas, lymphangiomas are less often found in the soft tissues (3,4).

Enchondromas are benign cartilaginous tumors that can occur in any bone but mostcommonly occur in phalanges and long bones (2).In 25% of cases, symptoms appear duringchildhood or during the first year of life, in 45% the beginning of symptoms occur beforethe age of 6 years , and in 78% before puberty (1). The bone and vascular lesions in theextremities are usually asymmetrical in distribution, with a unilateral compromise in 50%2of patients. Hemangiomas are located in the subcutaneous tissue and are seen as bluishnodules, although there may also be visceral and mucous involvement. Bony lesions have apredilection for the tubular bones, with greater compromise in metacarpals and phalangesof hands. Enchondromas can also be found in the bones of the foot, tibia, fibula, radiusand ulna. They might present with painless swelling or pathological fractures in 26% ofcases (2,3).The prevalence of malignancy in the literature varies from 23% to 100%, wherechondrosarcoma is the most common tumor, with an incidence of 51% in patients withMaffucci syndrome (5). Other malignancies (1) as fibrosarcoma, hemangioendothelioma,hemangiosarcoma or lymphangiosarcoma could be found. Maffucci syndrome is alsoassociated with tumors in other organs such as CNS, gastrointestinal tract, pancreas andovary (3,4). Radiographically, the abnormalities are more evident in the hands and feet (2),and appear as radiolucent lesions with well defined borders, with expansive remodeling ofbone, cortical thinning and endosteal scalloping. In some cases it can be seen chondroidmatrix mineralization in arcs and rings. These changes cause bone deformity. In the softtissues are evident phleboliths and “popcorn” calcifications (1,3,6) (Figures. 1a, 1b).Magnetic resonance imaging (MRI) is useful for diagnosis and location of deephemangiomas (2,5,7). Maffucci syndrome treatment is largely symptomatic and patientsshould be followed periodically to detect malignant transformation. In some cases surgicalmanagement is indicated to correct the bone and soft tissue deformities especially if there is

functional impairment of the extremity or for cosmetic reasons (1.8).KlippelTrenaunayWebersyndrome3Described by Klippel and Trenaunay in 1900, it is considered a rare entity characterized bycombined capillary, vein and lymphatic malformations, and congenital hypertrophy of alower extremity (9). It occurs in 1 in 20 00040000 live births, and there are no genderdifferences (1013).ParkesWebersyndrome, which consists of varicose vein dilatation andmultiple congenital arteriovenous fistulas with secondary outgrowth of the limb that occursuntil epiphyseal closure is a similar condition.KlippelTrenaunayWebersyndrome etiology is unclear. There are three origin theories.Staple and Bliznak propose damage to the sympathetic ganglion or the lateral intermediatetract dilatation leading to microscopic arteriovenous anastomoses, resulting in venousabnormalities (15). Servelle suggests that blockage of the venous flow secondary to deepvenous abnormalities causes, venous hypertension and varicose dilatations. Baskervillesuggests that due to a mesodermal defect abnormal vascular communications occur (9,10,16).Venous malformations or varicose dilations occur in 72% of cases, and often the abnormalvenous flow is caused by persistent embryonic veins, agenesis, hypoplasia, valvularincompetence, or aneurysms of deep veins, and they occur in the superficial, deep andperforator venous systems (2.17 to 19). These vascular malformations are slow flowing,because there are no arterial compromise , associated lymphatic compromise, turns theskin blue or purple (Figures. 2a, 2b) (13,20,21).Hypertrophy of the extremity is due to the vascular malformations described and theincreased volume of the soft tissues and bone, usually in an asymmetric configuration, itoccurs in 95% of the cases .4Proteus SyndromeIt was described by Cohen and Hayden in the year of 1979. The name comes from

theGreek God Proteus who had the ability to change shape, and was proposed by Wiedemannin 1983 (3335).It is an entity of unknown cause, although it is believed that is caused by asomatic gene mutation, which has not been identified. It is a rare hamartomatous condition,characterized by a broad spectrum of malformations. Focal overgrowth of tissues derivedfrom all three germ layers is found, it is a multisystemic disease with a great clinicaldiversity (3638).In general, it is not apparent at birth, it develops in childhood and earlyadolescence after this time disease stabilizes. It has general and specific clinical diagnosticcriteria.General Clinical criterion:• Random distribution in the body• Progressive course of lesions• Sporadic Occurrence.Specific clinical criterion:• Category A: Cerebriform connective tissue nevus (pathognomonic but uncommon)(35.39).5• Category B: Linear squamous cell nevus, disproportionate, asymmetric overgrowth(compromise of one or more limbs, skull and vertebrae) (Figure. 3a), specific tumors(bilateral ovarian cystadenoma and monomorphic adenoma before or during the seconddecade), hemimegalencephaly, splenomegaly and fatty infiltration of the parotid gland,usually, in the right side, rarely occur. Increased subcutaneous fat and musclepseudohypertrophy on the affected side of face is observed (35.39).• Category C: Adipose tissue compromise : Lipoma or regional absence of fat, vascularmalformations, lung cysts and facial phenotype (may not be present: dolichocephaly, longface, mild ptosis, low nasal bridge, wide or inverted nostrils, mouth open at rest) (35.39).Diagnosis is made if one of the signs of A category two of the B category or 3 three inthe C category is present. (35.39).In plain films osteoporosis or hyperostosis is evident;macrodactyly (Figures. 3b, 3c) clinodactyly, polydactyly and syndactyly are occasionallyfound. In addition, malformed vertebral bodies and asymmetric cranial vault

thickening canbe observed (35). Computed tomography(CT) and MRI shows diffuse asymmetrichypertrophy of soft tissues, muscle and adipose tissue (Figures.3d3f),sometimesassociated with lymphatic, capillary and venous malformations, (35). Visceral compromiseis less common than musculoskeletal and soft tissue abnormalities, splenomegaly,asymmetric megalencephaly white matter abnormalities and nephromegalia could occur.Cases of pulmonary embolism and pulmonary cystic changes has been described (34, 40,41).6Lipomatous MacrodistrophyThis rare disease is characterized by overgrowth of all mesenchymal elements surroundingthe toes or fingers, associated or not to macrodactyly (4244).It is a nonhereditarydiseasethat can manifest in two ways: The first way of presentation is detectable from birth (staticform), asymmetry of the fingers of the affected limb, which grows synchronously with therest of the body is evident.(43). The second way of presentation (progressive form) isdetected in older age patients) disproportionate and progressive growth of the affected partis found (45). Generally growth stops at puberty, the lateral aspect of the upper extremity isusually affected (finding described by Golding in 1960) and the medial aspect of the lowerextremity (finding described by Feriz 1925) (43.46). It equally affects both gendersunilateral, lower limb compromise is predominant; second and third toes are more ofteninvolved (46). t the etiology of this disease is unknown , it is suspected that alterationsmay be linked to changes in uteru with growth factor or fetal circulation changes . Anothertheory relates to lipomatous degeneration (46, 47).Histology shows proliferation of a fibrous network and fat that normally surrounds thebones, tendons, muscles and nerves, especially in the palmar or plantar aspect of theaffected limb, resulting in extra deposit of bone material in the fingers, at the endosteumand periostium with subsequent overgrowth, this results in aesthetic deformity and

functional impairment. (47,48). Median and planter nerve compromise producecompression neuropathy. Plain radiography demonstrates focal macrodactyly secondary toincrease in thickness and length of the metacarpals or metatarsals and their phalanges, as7well as thickening of the soft tissues that surround them (Figures.4a, 4b) (44). It is commonto find degenerative changes in juxta articular regions, probably by an alteration of thenormal biomechanics of the limb, which leads to formation of osteophytes, subchondralcysts, joint space narrowing and subluxation, predominantly compromising the the ulnaraspect of (hands ) or the lateral aspect of foot) (Figures. 4c, 4d). Soft tissues show normalfat tissue lucency (46,47).CT shows negative attenuation coefficients in tissues surrounding bony structures (44.49).Due to increased fibrofatty tissue on fat saturation sequences, MRI could confirm the lipidnature of the tissue surrounding the affected fingers, and at the same time, could evaluatethe bone marrow infiltration of the phalanges, which shows high signal intensity insequences with T1 and T2 information, and decreased signal intensity on STIR(short timeinversion recovery) or FATSAT(fat saturation) sequences . Fibrous tissue has low signalintensity on all sequences (Figures.4e, 4f) (43.50).ConclusionConditions that produce asymmetry in the growth of the extremities are rare entitiesassociated with a variety of clinical and imaging findings, which allow differentiationbetween them. It is therefore important to recognize particular imaging findings of thesegroup of diseases that are characterized by gigantism, to achieve an accurate diagnosis.References81. Murphey MD, Fairbairn KJ, Parman LM, Bazter KG, Parsa MB y Smith WS.Musculoskeletal angiomatous lesions: radiologicpathologiccorrelation.Radiographics. 1995;15(4):893917.2. Lissa FC, Argente JS, Antunes GN, Basso Fde O, Furtado J. Maffucci syndrome andsoft tissue sarcoma: a case report. Int Semin Surg Oncol. 2009;6:2.3. Zwenneke Flach H, Ginai AZ, Wolter Oosterhuis J. Best cases from the AFIP.

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34. Wiedemann HR, Burgio GR, Aldenhoff P, Kunze J, Kaufmann HJ, Schirg E. Theproteus syndrome: partial gigantism of the hands and/or feet, nevi, hemihypertrophy,subcutaneous tumors, macrocephaly or other skull anomalies and possible acceleratedgrowth and visceral affections. Eur J Pediatr. 1983;140(1):512.35. JamisDowC, Turner J, Biesecker LG, Choike PL. Radiologic manifestations ofproteus syndrome. RadioGraphics. 2004;24(4):105168.36. Cohen MMJr. Proteus syndrome: clinical evidence for somatic mosaicism and selectivereview. Am J Med Genet. 1993;47(5):64552.37. Levine C. The imaging of body asymmetry and hemihypertrophy. Crit Rev DiagnImaging. 1990;31(1):180.1238. Demir MK. Case 131: Proteus syndrome. Radiology. 2008;246(3): 9749.39. Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL, et al.Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation.Am J Med Genet. 1999;84(5):38995.40. Eberhard DA. Twoyearoldboy with Proteus syndrome and fatal pulmonarythromboembolism. Pediatr Pathol. 1994;14(5):7719.41. Kransdorf MJ, Jelinek JS, Moser RP, Utz JA, Brower AC, Hudson TM, et al. Softtissue masses: diagnosis using MR imaging. AJR. 1989;153(3):5417.42. Silverman TA, Enzinger FM. Fibrolipomatous hamartoma of nerve. Aclinicopathologic analysis of 26 cases. Am J Surg Pathol. 1985;9(1):714.43. Blacksin B, Barnes FJ, Lyons MM. MR diagnosis of macrodystrophia lipomatosa. AJR.1992;158(6):12957.44. Sone M, Ehara Sh, Tamakawa Y, Nishida J, Honjoh S. Macrodystrophia lipomatosa:CT and MR Findings. 2000;18(2):12932.45. D’Costa H, Hunter JD, O’Sullivan, O'Keefe D, Jenkins JP, Hughes PM. Magneticresonance imaging in macromelia and macrodactyly. Br J Radiol . 1996;69(822):5027.46. Turkington JR, Grey AC. MR imaging of macrodystrophia lipomatosa. Ulster Med J.2005;74(1):4750.47. Soler R, Radriguez E, Bargiela A, MartÃnez C. MR findings of macrodystrophialipomatosa. Clin Imaging. 1997;21(2):1357.48. Wang YC, Jeng CM, Marcantonio DR, Resnick D. Macrodystrophia lipomatosa: MRimaging in 3 patients. Clin Imaging. 1997;21(5):3237.1349. Aisen AM, Martel W, Braunstein EM, McMillin KI, Phillips WA, Kling TF. MRI and

CT evaluation of primary bone and softtissuetumors. AJR. 1986;146(4):74956.50. Cohen JM, Weinreb JC, Redman HC. Arteriovenous malformations of the extremities:MR imaging. Radiology. 1986;158(2):4759.FiguresFigs. 1a, 1b. Maffucci syndrome. Radiographs of upper limbs in two patients. Maffuccisyndrome, popcorn vascular calcifications are evident in the soft tissues. Enchondroma inthe fourth and fifth finger in the first patient.Figs. 2a, 2b. KlippelTrenaunayWebesyndromer. Clinical photographs of two patients,the lower limb edema , venous congestion and echymotic vascular markings on the skin.Figs. 2c, 2d. KlippelTrenaunayWebersyndrome. Radiography of the foot and right legvenography of a different patient, there is asymmetric enlargement of the first finger andabsence of the deep venous system, with a large draining superficial vein.Figs. 2e, 2f, 2g. KlippelTrenaunayWebersyndrome . Venography , coronal and axialMR images of a patient with multiple serpintiginos tubular images corresponding tosuperficial venous dilatations .14Fig. 3a. Proteus Syndrome. Clinical photograph of a patient with Proteus syndrome, whichshows exagerated increase in size of the second finger of right hand.Figs. 3b, 3c. Radiographs of hands and feet of another patient who presented macrodactylyof the third finger and third toe uf the right foot. Figures. 3d, 3e, 3f. Coronal gradient echoMR images, DP and 3D reconstruction in a patient with amputation of the fourth finger,macrodactyly and subluxation of the distal interphalangeal joint of the third finger, withulceration of the dorsal region and a fluid collection due to repetitive trauma in thatlocation.Fig. 4a.Lipomatous Macrodistrophy . Radiographs of patient with macrodactyly, asymmetricalthird and fourth fingers of the feet with prominence of the soft tissues.Fig. 4b. Lipomatous macrodistrophy detected from birth affecting the first finger Figs. 4(cd).Same patient. Significant degenerative changes in the distal interphalangeal

joints:fusion of the fourth and fifth fingers, surgical absence of phalanges of the second and thirdfingers. (E) T1 MR images ( same patient), shows signal intensity similar to subcutaneousfat in the tissues surrounding macrodactyly of the fourth and fifth toes. signal intensity ofthe bony structures is slightly lower than in normal bone.Fig. 4f. fat saturation sequence in the same patient, homogeneous decrease of signalintensity of bone marrow and soft tissues confirming its fatty nature.15ContactCatalina WilchesCarrera 51 No. 123A53,apto. 304Bogotá, Colombia

cwilches30@hotmail,comReceived for evaluation: September 12th, 2009Accepted for publication: November 18th, 200916