Klippel-Trenaunay syndrome (Klippel-Trenaunay-Weber syndrome; angio-osteohypertrophy syndrome) is a developmental vascular abnormality of the extremities. Classically, there is the triad of cutaneous capillary malformations, dilated superficial veins or venous malformations, and overgrowth of the limb (local gigantism). Capillary-lymphaticovenous malformations are present in the deeper soft tissues in most of these patients as well. Typically, the abnormality involves a single lower extremity (95%); arm involvement is rare. Klippel-Trenaunay syndrome apparently is due to a disturbance in embryogenesis, with persistence of primitive arteriovenous communications within the developing limb bud. Abnormalities of superficial veins in these patients range from ectasia of small veins to large venous or lymphaticovenous malformations. Potential deep venous abnormalities include aplasia, hypoplasia, aneurysmal dilation, duplications, and valvular incompetence.^1–3

Klippel-Trenaunay syndrome has no gender or racial predilection. Most cases are sporadic. The clinical findings of Klippel-Trenaunay syndrome include superficial varices, port wine telangiectatic nevi, and hypertrophy of the soft tissues and bones of the extremity. The port wine skin lesions are usually evident early in infancy. Progressive dilation of superficial veins usually begins with ambulation. Various complications can eventually develop due to the abnormal venous and lymphatic drainage, including thrombophlebitis, edema, and ulcerations. Cutaneous vascular malformations may extend beyond the limb, but usually do not cross the midline. Visceral vascular malformations of the colon and urinary bladder occur in occasional patients. Extremity hypertrophy is the most variable of the 3 classic features of Klippel-Trenaunay syndrome. There may be osseous lengthening, soft tissue hypertrophy, or both. Other potential clinical manifestations include protein-losing enteropathy, thrombocytopenia (due to platelet sequestration), hematuria, hematochezia, systemic hypertension, and renal failure. Patients with Klippel-Trenaunay syndrome occasionally have ipsilateral cerebral hemihypertrophy.

Imaging studies of patients with Klippel-Trenaunay syndrome demonstrate osseous and soft tissue overgrowth in the affected extremity (Figure 64-1). The bones are elongated and widened, and there is a variable degree of cortical thickening. Phleboliths may be visible radiographically in venous malformations within the affected extremity or throughout the body. Venography of patients with Klippel-Trenaunay syndrome usually shows small size or absence of some or all of the major deep veins of the involved extremity. However, there is considerable variability in the deep venous anatomy in these patients. There are multiple dilated, tortuous, valveless superficial veins. Abnormal venous channels may extend between deep veins and the dilated superficial veins. Arteriography shows a normal arterial phase (or slight enlargement of the ipsilateral arteries), an irregular blush during the tissue phase, and dilated superficial veins on delayed images. The anomalous venous anatomy can also be evaluated with sonography, contrast-enhanced CT, MR, or contrast-enhanced MR angiography (Figure 64-2).^4,5

The Parkes Weber syndrome is a similar entity, with monomelic limb gigantism in combination with complex vascular malformations. The vascular anomalies of Klippel-Trenaunay syndrome are pure low-flow venous lesions, whereas Parkes Weber syndrome includes arteriovenous lesions. Most often there is a mixed character, with high-flow shunting intermixed with a capillary-lymphaticarteriovenous lesion. Large-volume shunting in these patients occasionally leads to infantile congestive heart failure or ischemic changes in the extremity.

The radiographic findings of Parkes Weber syndrome are similar to those of Klippel-Trenaunay syndrome, with enlargement of the soft tissues and osseous structures of the involved extremity. Angiography shows 1 or more areas of arteriovenous shunting. Most often, there is a large infiltrative vascular malformation of mixed consistency. The tissue phase shows multiple areas of irregular staining. As with Klippel-Trenaunay syndrome, the venous phase shows a paucity of deep veins in the involved extremity, and dilated superficial veins. Noninvasive documentation of arteriovenous shunting in these patients can often be achieved with Doppler sonography or MR angiography.⁴

Lymphedema refers to the accumulation of interstitial fluid as a result of lymph stasis. The interstitial fluid contains high molecular weight proteins. Extremity lymphedema can occur as a secondary phenomenon related to surgical, neoplastic, or infectious mechanisms, with interruption, obliteration, infiltration, or compression of lymphatics. The most common type of lymphedema, however, is primary. Primary lymphedema is the result of abnormal development of 1 or more portions of the lymphatic system. The etiology is unknown. Most instances of primary lymphedema are hereditary.^6–8

The clinical manifestations of lymphedema are the result of inadequate regional lymphatic transport capacity for the volume of interstitial fluid. High oncotic pressure due to the presence of proteins leads to accumulation of additional water. An inflammatory reaction ensues. The major clinical manifestation of lymphedema is regional soft tissue swelling, usually with a slowly progressive character. The most common initial manifestation is subtle asymmetry of an extremity. In the legs, swelling may begin in the foot and progress proximally. With severe disease, the extremity enlargement can be disabling. Congested dermal lymphatics lead to skin thickening and a peau d’orange appearance.

Although abnormalities of the lymphatic system are presumably present at birth in children with primary lymphedema, clinical manifestations often do not occur until later in childhood or in adulthood. Primary lymphedema is classified according to the age of presentation as follows: congenital (present at birth), praecox (clinical presentation before the age of 35), and tarda (presentation after the age of 35). The praecox form is most common, accounting for 65% to 80% of cases. Primary lymphedema is more common in females (M:F = 3:1). The peak age of presentation is around the time of puberty. Most often, the clinical manifestations predominate in a single lower extremity, although subclinical abnormalities of the lymphatic system are usually present in the contralateral lower extremity as well. There is an unexplained predilection for involvement of the left lower extremity. Involvement of the upper extremities is unusual. Upper extremity primary lymphedema can accompany lower extremity disease or occur as an isolated abnormality.

Milroy disease refers to hereditary congenital lymphedema. There is an autosomal dominant pattern of inheritance. The responsible gene is VEGFR3. Milroy disease accounts for 2% of primary lymphedema cases. These children typically present in infancy with lower extremity lymphedema. In some infants, edema is detectable at birth. Manifestations of developmental lymphatic system anomalies elsewhere in the body are sometimes present, for example, protein-losing enteropathy due to lymphangiectasia of the bowel, chylous ascites, and chylous pleural effusion.^9,10

Meige disease refers to hereditary lymphedema praecox, most often presenting around puberty. This disorder is inherited as an autosomal dominant trait and may represent a later presentation of the same genetic abnormality that causes Milroy disease. VEGFR3 mutations are often present in these patients; abnormalities of FOXC2 and possibly additional genes may also be important. The expression of the dominant VEGFR3 gene mutation is approximately 50%. Gene expression is higher in girls than in boys. Most instances of lymphedema tarda are apparently caused by mutations of the FOXC2 gene.

Some patients with a developmental abnormality of the lymphatic system have 1 of several potentially associated syndromes. Hyperplastic lymphedema occurs in some patients with neurofibromatosis type 1. Lymphatic maldevelopment is an occasional component of Noonan and Turner syndromes, for example, extremity lymphedema, pulmonary lymphangiectasia, and intestinal lymphangiectasia.

Primary lymphedema occurs in both hypoplastic and hyperplastic forms. The hypoplastic type is most common. In this type, contrast lymphography shows a subnormal number and caliber of lymphatic vessels in the involved extremity. With severe obstruction, filling of dermal collateral lymphatics (dermal backflow) is often demonstrated. With hyperplastic lymphedema, lymphography shows an increased number of lymphatic vessels in isolation or, more commonly, accompanied by lymphatic enlargement and tortuosity. The dilated lymphatics often lack normal valves.

Radiographic lymphography is a moderately invasive and technically challenging procedure in children. Lymphoscintigraphy is a safe and simple procedure that often provides sufficient information for the diagnosis and treatment of children with lymphedema. Technetium-labeled particles are injected into the subcutaneous tissues in the dorsum of the feet, and sequential images are obtained of the lower extremities and pelvis. Because the expression of disease is nearly always asymmetric, the clinically less involved extremity serves as an internal standard for assessing the rate of tracer ascent in the lymphatics. The appearance of dermal backflow is that of glove-like staining in the superficial soft tissues.

With most cases of hypoplastic primary lymphedema, lymphoscintigraphy shows subnormal ascent of tracer, ranging from lack of detectable flow from the injection site to mild delay in flow relative to the contralateral extremity (Figure 64-3). In most patients, the lymphatic vessels and nodes in the affected extremity are poorly visualized. With severe obstruction, dermal backflow is present. In the hyperplastic form of lymphedema, lymphoscintigraphy shows slow ascent of tracer and prominent accumulation in dilated lymphatics in the affected extremity. Regional lymph nodes are often somewhat enlarged. Lymphoscintigraphy in instances of secondary lymphedema due to prior surgery or injury usually demonstrates dilation of the lymphatic vessels proximal to the obstruction. Dermal backflow may occur in this area. Leakage of lymph into the thoracic or abdominal cavities due to spontaneous rupture or traumatic/surgical disruption can also be documented by this technique.¹¹

Proteus syndrome refers to a group of congenital hamartomatous disorders that include localized gigantism of the hands and feet, hemihypertrophy, pigmented nevi, subcutaneous hamartomas, bony exostoses, and macrocephaly. The name is derived from the Greek god Proteus, who could change his appearance at will. The most common manifestation of Proteus syndrome is localized overgrowth of multiple tissues, including epidermis, dermal connective tissue, adipose tissue, vascular connective tissue, and bone. An important clinical and radiographic hallmark of Proteus syndrome is a random or mosaic distribution of manifestations throughout the body. Infants with Proteus syndrome often appear normal or have only mild asymmetric development. There is usually rapid progression of disease during childhood, and subsequent stabilization early during adolescence. There is considerable overlap in the features of Proteus syndrome with those of other disorders, such as Klippel-Trenaunay syndrome, neurofibromatosis type 1, and hemihypertrophy-multiple lipomatosis syndrome.^12–14

Common radiographic manifestations of Proteus syndrome include macrodactyly, clinodactyly, asymmetric limb overgrowth, scoliosis, hyperostosis, limb bowing, focal calvarial thickening, soft tissue masses, asymmetric fat distribution, and vascular malformations. Overgrowth of bone typically has an irregular and dysplastic character. Exostoses may arise from involved skeletal structures. The limbs are asymmetric, and lipomas are common. Lymphangiomatous hamartomas, lymphatic malformations, and vascular malformations can occur. Most patients have macrodactyly. Typically, there are varying degrees of involvement of individual bones in the hands and feet. There is often calcaneal enlargement and distortion. Patients with scoliosis often have multiple enlarged and distorted vertebrae. Skin abnormalities include nevi, hyper-keratoses, and other pigmented lesions.^15–18

Potential craniofacial manifestations of Proteus syndrome include craniosynostosis, unilateral condylar hyperplasia, hyperostosis, diploic widening, and exostoses. About half of patients with Proteus syndrome have macrocephaly, often with bony exostoses and hyperostosis. Other potential head and neck manifestations include macrophthalmia, retinal detachment, ear malformations, mandibular prognathism, and a depressed nasal bridge.

Hemihyperplasia (hemihypertrophy) is an asymmetric overgrowth of structures on 1 side of the body. The extremity overgrowth involves soft tissue and bone. Hemihyperplasia can occur as an isolated process or in association with various malformation syndromes, including Beckwith-Wiedemann syndrome, neurofibromatosis type 1, Klippel-Trenaunay-Weber syndrome, and Proteus syndrome (Table 64-1). Although the term hemihypertrophy is in general use, the overgrowth is due to cellular hyperplasia; therefore, the term hemihyperplasia is more appropriate. The estimated prevalence is 1 per 86,000 livebirths. There is a 2:1 female predominance. Almost all cases of hemihyperplasia are sporadic.^19,20

Radiographic evaluation demonstrates unilateral overgrowth of otherwise normal-appearing structures (Figure 64-4). There is a right-sided predominance (1.4:1). In some patients, the entire half of the body is involved, that is, total hemihyperplasia. The segmental form involves a single extremity or 1 side of the face and head. Asymmetry of the brain or abdominal organs may or may not be present (Figure 64-5). Occasionally, a crossed form of hemihyperplasia occurs, such as with involvement of 1 upper extremity and the contralateral lower extremity.

As with other overgrowth syndromes, individuals with isolated hemihyperplasia are at an increased risk for intra-abdominal tumors. The tumor frequency in isolated hemihyperplasia is 5.9% as compared with 7.5% in Beckwith-Wiedemann syndrome. The most common tumors (in descending order of frequency) are Wilms tumor, adrenocortical carcinoma, hepatoblastoma, pheochromocytoma, testicular carcinoma, and undifferentiated sarcoma. Because of the increased risk of tumor development, patients with isolated hemihyperplasia should be intermittently screened (typically with abdominal sonography every 3 months until age 8).^21–24

Macrodystrophia lipomatosa is a rare developmental form of localized gigantism. This most often involves a single digit of the hand or foot (macrodactyly); only rarely are more extensive portions of the extremity affected. There is overgrowth of the mesenchymal elements, with disproportionate prominence of fibroadipose tissue. Radiographs show soft tissue overgrowth, osseous overgrowth, and osseous deformities (Figure 64-6). The phalanges are broad and, frequently, splayed distally. The distal phalanx often has a mushroom shape. The cortical surfaces are sometimes irregular. Clinodactyly is common. In some patients, the deformity is progressive and leads to secondary degenerative joint disease. Cross-sectional imaging studies show prominent fibrofatty tissue (Figure 64-7). In some instances, enlarged nerve roots are visible.^25–29

Congenital generalized lipodystrophy is a rare autosomal recessive disorder that results in a generalized lack of body fat. Alterations in body habitus due to absence of most adipose tissue are evident at birth. Other potential clinical features include hirsutism (in females), acromegalic features, and acanthosis nigricans. Most patients develop diabetes and dyslipidemia around the time of puberty, apparently due to amyloidosis within the pancreatic islets. The pathogenesis may involve deficient differentiation of mesodermal stem cells into metabolically active adipocytes. The prevalence is less than 1 per 12 million individuals.³⁰

MRI is useful for demonstrating the distribution of fat in patients with congenital generalized lipodystrophy. Fat is absent in the subcutaneous tissues and bone marrow. Likewise, most intrathoracic and intra-abdominal fat is absent. Relative preservation of fat is common in the orbits, tongue, buccal regions, palms, soles, scalp, perineum, periarticular areas, renal margins, epidural space, and crista galli. There is generalized skeletal signal alteration due to diminished marrow fat. Focal radiographically lucent bone lesions are present in some patients. The lesions are hyperintense on T2-weighted MR images (± fluid–fluid levels), and have peripheral enhancement.³¹

Familial partial lipodystrophy is a rare autosomal dominant disorder, with an estimated prevalence of less than 1 in 15 million individuals. In contradistinction to the autosomal recessive form, this type of lipodystrophy generally does not become clinically manifest until puberty. Some areas of the body are usually spared, depending on the specific subtype. The fat loss in patients with familial partial lipodystrophy tends to be most apparent in the extremities.³² Lipodystrophy also occurs in acquired forms; these are classified as generalized, partial, and localized. MR is the optimal imaging technique for characterization of the fat deficiency in all forms of lipodystrophy.³³

Juvenile dermatomyositis is an acquired autoimmune nonsuppurative systemic inflammatory disease that predominantly involves the skin, subcutaneous tissues, and skeletal muscles. This is the most common idiopathic inflammatory myopathy in children (Table 64-2). Juvenile polymyositis has similar clinical features, but lacks cutaneous involvement; this disorder is 10 to 20 times less common than dermatomyositis. Overlap myositis refers to the condition in which patients have features of idiopathic inflammatory myopathy in conjunction with those of a second connective tissue disease (e.g., juvenile idiopathic arthritis, scleroderma, systemic lupus erythematosus); this occurs with a similar frequency to that of juvenile dermatomyositis (Figure 64-8).^34–37

Patients with juvenile dermatomyositis most often present with a rash that is soon followed by muscle tenderness and weakness. The onset of the disease may be either acute or insidious (most common). There is usually a characteristic heliotrope facial rash that involves the eyelids and nasal bridge. Erythematous papules may develop along the extensor surfaces of the small joints of the hands, and sometimes at the elbows, knees, and ankles. Frequently, manifestations of muscle involvement are more prominent in proximal groups than in distal groups. Muscle enzyme levels may be elevated. Other potential clinical findings include contractures, dysphagia, abdominal pain, skin necrosis, interstitial lung disease, myocardial involvement, transient retinal exudates, optic atrophy, renal abnormalities, and a skin rash (Figure 64-9).