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Vascular malformations
Part II: Associated syndromes
Maria C. Garzon, MD,a Jennifer T. Huang, MD,b Odile Enjolras, MD,c and Ilona J. Frieden, MDd New York, New York; Evanston, Illinois; Paris, France; and San Francisco, California
Cutaneous vascular malformations are rare disorders representing errors in vascular development. These lesions occur much less commonly but are often confused with the common infantile hemangioma. It is important to properly diagnose vascular malformations because of their distinct differences in morbidity, prognosis and treatment. Vascular malformations may be associated with underlying disease or systemic anomalies. Several of these syndromes are well dened and can often be distinguished on the basis of the ow characteristics of the associated vascular malformation. ( J Am Acad Dermatol 2007;56:541-64.) Learning objective: At the completion of this learning activity, participants should be able to better recognize underlying diseases or systemic anomalies that may be associated with vascular malformations. Participants should also better understand the various syndromes and conditions discussed and become more familiar with their management.

ascular malformations may be associated with underlying disease or systemic anomalies in select situations. Several syndromes are well dened and familiar to most physicians. In this section we will categorize these syndromes on the basis of the characteristics of the associated vascular malformation. In some syndromes, such as Proteus syndrome and Maffucci syndrome, more than one type of vascular anomaly can occur (Tables I-III).

Abbreviations used: ataxia-telangiectasia arteriovenous malformation Bannayan-Riley-Ruvalcaba syndrome cyclic AMP-response element binding protein CMTC: cutis marmorata telangiectatica congenita CNS: central nervous system CREB: cyclic AMP-response element binding CT: computed tomography HHT: hereditary hemorrhagic telangiectasia IHH: Indian hedgehog KTS: Klippel-Trenaunay syndrome M-CMTC: macrocephaly-CMTC (syndrome) MRI: magnetic resonance imaging PPV: phakomatosis pigmentovascularis PTHR1: parathyroid receptor type 1 PTHrP: parathyroid hormoneerelated protein TAR: thrombocytopeniaeabsent radius (syndrome) AT: AVM: BRRS: CBP:


Sturge-Weber syndrome Denition. Sturge-Weber syndrome (SWS) is a sporadic congenital disorder characterized by a dermal capillary malformation (port-wine stain) occurring in association with vascular malformations of the leptomeninges and the eye. The major

From the Departments of Dermatology and Pediatrics, Columbia University, New Yorka; Department of Dermatology, Northwestern University, Evanstonb; Childrens Hospital Armand Trousseau, Parisc; and the Departments of Dermatology and Pediatrics, University of California, San Francisco.d Funding sources: None. Conflicts of interest: None identified. Reprint requests: Maria C. Garzon, MD, Associate Professor of Clinical Dermatology and Clinical Pediatrics, Columbia University, 161 Fort Washington Ave, New York, NY 10032. E-mail: 0190-9622/$32.00 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2006.05.066

extracutaneous symptoms include seizures, hemiplegia, mental retardation, and glaucoma. Sturge1 first described a patient with epilepsy, a facial capillary malformation, and buphthalmos in 1879. He speculated that the patients seizures were caused by an underlying vascular anomaly of the brain. Subsequently, Kalischer verified the presence of the underlying vascular anomaly. Durck, Volland, Krabbe, and Parkes Weber better characterized the pattern and distribution of the characteristic intracranial calcifications.2 Since the initial descriptions, the syndrome has been variably dened in the literature. The complete 541

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Table I. Syndromes associated with vascular stains: Slow flow

Sturge-Weber Klippel-Trenaunay Servelle-Martorell CMTC MacrocephalyeCMTC Adams-Oliver Hemangiomatous branchial clefts, lip pseudoclefts Roberts/SC phocomelia Rubinstein-Taybi Thrombocytopeniaeabsent radius Beckwith-Wiedemann Nova Phakomatosis pigmentovascularis Cutaneous capillary-venous malformationecerebral capillary malformation Proteus* Hemihyperplasia multiple lipomatosis* Bannayan-Riley-Ruvalcaba*
CMTC, Cutis marmorata telangiectatica congenita. *Other types of vascular malformations may also occur.

Table II. Syndromes associated with vascular stains: Fast flow

Bonnet-Dechaume-Blanc/Wyburn-Mason Parkes Weber Capillary malformationearteriovenous malformation Cobb

Table III. Syndromes associated with venous, lymphatic, or mixed malformations

Blue rubber bleb nevus Proteus Hemihyperplasia multiple lipomatosis Bannayan-Riley-Ruvalcaba Maffucci Gorham Stout Bockenheimer

syndrome generally includes the triad of facial dermal capillary malformation (port-wine stain), ipsilateral central nervous system (CNS) vascular malformation (leptomeningeal angiomatosis), and vascular malformation of the choroid of the eye associated with glaucoma. Partial forms have been reported. Leptomeningeal and choroidal vascular malformations have been reported in the absence of a vascular stain and may represent a variant form of SWS.3 A dermal capillary stain associated with glaucoma in the absence of a CNS anomaly is considered by many authors to be a partial form of the syndrome.4 However, only patients with confirmed ocular choroidal and leptomeningeal involvement should be considered as having SWS. Cutaneous features The risk for SWS is determined by the distribution of the port-wine stain. Two large studies of patients with facial capillary malformations have shown that SWS occurs exclusively in patients whose capillary malformation is located in the distribution of the rst branch of the trigeminal nerve, although glaucoma is occasionally seen with lower lid stains. This conrmed earlier observations by Alexander5 who proposed that patients with supraocular lesions were at greatest risk of having a leptomeningeal abnormality. Enjolras and her coworkers found SWS to occur only in patients with some portion of the V1 distribution affected, although the stain could involve others (Fig 1). The (ophthalmic) first branch (V1) of the trigeminal nerve was defined according to the

classic neurologic drawing of the 3 sensory branches of the trigeminal nerve as innervating the upper lid, and the (maxillary) second branch (V2 dermatome), the lower lid.6 A subsequent study performed by Tallman et al7 found ocular and CNS abnormalities to occur exclusively in patients with port-wine stains involving the upper and lower lids (91%) or lower lids alone (9%). Therefore they had a larger portion of patients with port-wine stains in the distribution of V2 with leptomeningeal anomalies and glaucoma than the previous studies. Although their findings suggest that some patients with SWS may have V2-associated port-wine stains alone, this disparity in findings may be attributed to a difference in definition of the distribution of the V1 and V2 dermatomal areas, which is probably due to anatomic variability in the so-called watershed area of the upper and lower eyelids that can be innervated by either V1 or V28 (Fig 2). Regardless, the conclusion of both studies is the same; capillary malformations overlying the upper lids are associated with SWS. The overall incidence of ocular or CNS involvement in patients with capillary malformations located in the V1 and V2 areas is reported to be approximately 8% but is considerably higher when multiple dermatomes (V1, V2, V3) or bilateral stains are present (24%).7 The capillary malformation of the skin associated with SWS is present at birth. It may extend to mucosal surfaces with concomitant gingival hypertrophy, which may be even further accentuated in patients being treated with phenytoin for seizures. Some patients exhibit accelerated eruption of teeth.9 Patients with associated V2 port-wine stains may demonstrate maxillary hypertrophy. SWS is commonly


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Fig 1. Infant with widespread bilateral facial capillary malformation at risk for Sturge-Weber syndrome.

associated with port-wine stains on other areas of the body. Moreover, SWS may be seen in association with Klippel-Trenaunay syndrome (KTS).10,11 Contrary to popular assumption, leptomeningeal vascular malformations are rarely located in close proximity to the facial port wine stain. In fact, the frontal lobe is the least common location for CNS involvement. Leptomeningeal vascular malformations are most often located over the occipital lobes, followed by the temporal and parietal lobes.12-14 Extracutaneous features Neurologic. Seizures are the most common neurologic abnormality associated with SWS and occur in 55% to 90% of patients.15 Two studies found an 80% incidence of seizures in patients with SWS.16,17 Seizures were slightly more common in patients with bilateral port-wine stains than those with unilateral lesions. All patients with seizures had port-wine stains involving the V1 dermatome.16 Seizures are usually focal in type, but may become generalized.17 Seizures arise within the first year of life in 75% of patients; however, later onset may occur in some patients. Affected individuals with bihemispheric leptomeningeal capillary malformations demonstrate an earlier onset of seizures and more likely suffer from developmental delay and mental retardation.18 Rarely, diffuse early neurologic involvement is lethal during the first months of life, caused by uncontrolled epilepsy. Although cited in some literature, no retrospective or longitudinal studies have shown that early-onset seizures are more often associated with developmental delay.19,20 The risk of mental retardation has been variably reported between 50% and 65%.15,16,19 The higher reported rates of mental retardation may be attributed to those studies published in the neurologic literature in which patients present to neurologists

Fig 2. Anatomic distribution of branches of the trigeminal nerve. Darkly shaded area represents watershed area that may be supplied by either V1 or V2 dermatomes. (Reprinted with permission from Elsevier. Eicheneld L, Frieden I, Esterly N. Vascular stains, malformations and tumors. In: Textbook of neonatal dermatology. 1st ed. Philadelphia: Saunders; 2001. p. 332.)

with predominantly CNS complaints. Most patients achieve developmentally appropriate milestones during the first few months of life. Subsequently, about half of all patients with SWS will continue to be developmentally normal. Those with more extensive neurologic involvement, including bilateral leptomeningeal disease or seizures refractory to treatment, are at higher risk for developmental delay, mental retardation, or both. As stated earlier, earlyonset seizures have not been proven to increase ones risk for developmental delay.19,20 Hemiplegia has been reported in approximately 30% of patients with SWS, which may be an underestimation of this phenomenon as these episodes may be transient and of short duration.21 Headaches are reported more commonly in adults and are believed to be caused by hemodynamic alterations in the brain.22 Ophthalmologic. Glaucoma is the most common ophthalmologic abnormality seen in patients with SWS. It is associated with an ipsilateral vascular malformation of the choroidal vasculature of the eye. The vascular anomaly may be detected on funduscopic examination. As stated earlier, glaucoma is most commonly noted with a capillary malformation

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located in either or both of the rst two branches of the trigeminal nerve. Glaucoma may also be detected in the eye contralateral to the cutaneous capillary malformation. Glaucoma is present at birth in approximately two thirds of patients; but may arise as late as adulthood.16,23 Congenital and early-onset glaucoma may lead to buphthalmos. In an at-risk infant with V1 port-wine stains, a large cloudy cornea at birth is an indication of acute glaucoma, an ophthalmologic emergency. All patients with capillary malformations affecting the lids should be evaluated periodically for glaucoma because early identification and management may prevent loss of vision. Several mechanisms have been proposed to explain the pathogenesis of glaucoma in SWS. These include (1) hyperemia of the ciliary body secondary to the presence of the choroidal vascular malformation, leading to overproduction of aqueous uid; (2) anomalous chamber angle in early-onset glaucoma; (3) abnormal arteriovenous connections in episcleral vascular plexus, resulting in abnormally elevated venous pressures, and (4) premature aging of the normal trabecular meshwork in late-onset glaucoma.23,24 Pathogenesis The pathogenesis of SWS is still not clearly elucidated. Couly and Le Douarin25 analyzed the rostral limits of the cephalic neural crest using quail and chick chimeras. They demonstrated that the ectomesenchyme for the nasofrontal bud (forehead and upper lid) and pia mater (meninges) of the brain share a common progenitor in the anterior neural fold. The maxillomandibular dermis is also derived from the neural crest; however, the origin of these cells is topographically different than those in the forehead and upper lid. The former are derived from the hindbrain neural fold. Therefore it has been hypothesized that a somatic mutation occurring early in embryogenesis in the anterior neural fold results in SWS, whereas a similar mutation in the hindbrain neural fold does not, because meninges do not arise from this area.25 Radiologic ndings Radiographic evaluation is useful in conrming the diagnosis of SWS, delineating the extent of the ocular and CNS vascular anomalies, and detecting associated CNS abnormalities, including cerebral atrophy. However, routine radiologic evaluation in the absence of neurologic symptoms is controversial because it may not alter the course of treatment. Plain radiographs of the skull may detect intracranial calcications, revealing the classic tram-line

appearance, but calcications are often not present before 2 years of age. Newer radiographic techniques have made plain lms obsolete. After 1 year of age, computed tomography (CT) can detect calcications that are not visible on plain radiographs and is more sensitive for detecting calcications than magnetic resonance imaging (MRI).26 CT is also capable of detecting parenchymal volume loss and choroid plexus enlargement. Magnetic resonance studies with enhancement are very useful for detecting leptomeningeal and ocular vascular malformations earlier and they more sensitively demonstrate gray and white matter abnormalities and engorgement of the deep venous system than does CT (Fig 3).27-30 More specifically, spin-echo T1-weighted and T2-weighted images with administration of gadolinium contrast are recommended for a complete evaluation of intracranial involvement.20,31,32 In addition, single-photon emission CT may detect areas of hypoperfusion and, thus, latent vascular anomalies, which may not be visible with other imaging studies.33 A recent case report also suggests that blood-oxygen-level-dependent magnetic resonance venography may be useful in early detection of venous anomalies.34 Because of the advent of these newer imaging studies, the more invasive radiologic study of cerebral angiography is rarely necessary.35 Currently, MRI is recommended as the method of choice for the diagnosis of SWS. Radiographic studies will help to confirm the diagnosis and functional cerebral imaging systems, such as single-photon emission CT and positron emission tomography, help to determine the extent of neurologic involvement to assist in medical and surgical therapy.32,36 Diagnosis and management SWS should be suspected in all patients with facial capillary malformations involving the V1 dermatome, keeping in mind the watershed area of the trigeminal nerve. At-risk infants should undergo careful physical examination to determine the extent of the malformation. Initial ophthalmologic evaluation should be performed in the neonatal period because of the risk of congenital glaucoma. If the rst complete ophthalmologic evaluation is normal, it should be repeated frequently (some authors have suggested quarterly evaluations) for the rst 2 years of life. If the examination results remain normal, the vision should be re-evaluated at least annually throughout the patients lifetime. When ophthalmologic abnormalities are present, their management will need to be individualized. Neurologic development should be monitored carefully. Periodic evaluation by a pediatric neurologist is an essential


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Table IV. Differential diagnosis for cutaneous vascular anomaly and limb enlargement
Vascular malformations Vascular tumors

KTS Extensive venous malformation Parkes Weber syndrome Proteus syndrome Hemihyperplasia and multiple lipomas CMTC, macrocephaly-CMTC (rare; limb hypoplasia more common)

Infantile hemangioma Kaposiform hemangioendothelioma Tufted angioma

CMTC, Cutis marmorata telangiectatica congenita; KTS, KlippelTrenaunay syndrome.

for clinicians. The Sturge-Weber Foundation is an active support group for patients and families (Web site,
Fig 3. This magnetic resonance study shows gadolinium enhancement of the leptomeningeal vascular anomaly found in Sturge-Weber syndrome.

Klippel-Trenaunay syndrome Denition. KTS is characterized by a supercial vascular stain of the skin in association with soft tissue and bony hypertrophy of the affected limb, and varicose veins with or without deep venous anomalies (Fig 4). KTS should be distinguished from Parkes Weber syndrome, where the vascular stain is associated with limb overgrowth and significant arteriovenous shunting of the involved limb.37 Lymphatic anomalies of the affected limb may occur concurrently in both KTS (a slow-flow complex combined with vascular malformation) and Parkes Weber syndrome (a high-flow complex combined vascular malformation). The differential diagnosis for limb enlargement associated with a vascular lesion also includes other disorders that are listed in Table IV. KTS should also be differentiated from Servelle-Martorell syndrome, which is the association of capillary stains and varicose veins with relative undergrowth rather than overgrowth of the affected limb.38 Cutaneous features Klippel and Trenaunay published their initial case report followed by a review of 51 cases early in39 the twentieth century, further delineating the characteristics of these patients. The capillary malformation was noted to involve an entire limb. Varicose veins were present from birth or appeared during infancy and were associated with limb hypertrophy.37 Typically, the vascular stain is noted at birth and cases involving the lower extremity predominate (Fig 4). Involvement of both the upper and lower extremities may occur in 10% to 15% of cases and is usually ipsilateral. There are rare reports of crossed

Fig 4. Klippel-Trenaunay syndrome (capillary-venous malformation); note overgrowth of affected limb.

component of the management of SWS. Seizures associated with SWS are typically treated with anticonvulsant medications but may prove difcult to control in some situations. The capillary malformation of the skin can be effectively lightened by using the pulsed-dye laser for vascular lesions. On the other hand, the diagnosis and management of intracranial involvement and its neurologic sequelae pose a more difcult challenge

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include pain, thrombophlebitis, cellulitis, venous stasis dermatitis, and ulcers.40 Cellulitis of the affected limb may manifest as fever and recurrent painful swelling with sterile cultures. Cutaneous manifestations include atrophy of the skin, verrucae, and hyperhidrosis.40 Venous varicosities are frequently disfiguring. Patients with lower extremity varicosities may also experience rectal bleeding and hematuria.44-46 Life-threatening complications include deep vein thrombosis, pulmonary embolism, gram-negative sepsis, and coagulopathy.47,48 SWS may occur in association with KTS.49 Extracutaneous features Orthopedic. Limb hypertrophy is caused by hypertrophy of the soft tissues and bones. When an associated lymphatic malformation coexists, it will contribute to the appearance of limb gigantism. The affected limb is usually longer and has an increased circumference when compared with the unaffected limb. The difference in limb length may be slight or quite dramatic. As the patient grows, the length discrepancy may become more prominent, but progression is not predictable. Limb length enlargement will cease when the childs growth cycle is complete at the end of adolescence.40 Pathogenesis The origin of most cases of KTS is unknown. Early theories suggested that venous changes developed as a consequence of a deep venous obstruction that resulted in edema and hypertrophy of the limb.43 However, Baskerville, Ackroyd, and Browse50 found that few patients with KTS have true atresia of the deep veins. They hypothesized that a mesodermal defect affecting vascular development could cause this condition. Although KTS usually is a sporadic condition, Aelvoet, Jorens, and Roelen51 reported familial cases of KTS that were not inherited in a Mendelian pattern. They noted that hemihypertrophy and vascular lesions occurred more commonly in some families of an individual with KTS. A multifactorial inheritance of KTS was suggested. Happle52 subsequently suggested that paradominant inheritance of a single gene defect could explain the development of KTS as well as the occurrence of both familial and sporadic cases. He noted that the lesions of KTS were arranged in a mosaic pattern. Heterozygotes for a defective gene would be phenotypically normal, but the defective allele could be transmitted throughout many generations. The syndrome would only occur if a somatic mutation occurred during embryogenesis that resulted in a loss of heterozygosity. This would result in a clonal population of cells that were homozygous or

Fig 5. Geographic capillary malformation in patient with Klippel-Trenaunay syndrome. Sharply demarcated border signals an underlying lymphatic anomaly (capillaryvenous-lymphatic malformation).

bilateral involvement in which contralateral extremities are affected.40 The stain commonly extends onto adjacent truncal skin.41 The stain is typically large, but even on the affected extremity; some areas of skin may be spared. It may be distributed in a confluent geographic pattern or more randomly on the affected limb and adjacent trunk. A recent study suggests that the presence of a geographic vascular stain is a predictor of the risk of both associated lymphatic malformation and complications in patients with KTS.42 The geographic vascular stain is red to violaceous and may darken, develop blebs (vesicles of lymphatic malformations), and bleed as the patient matures. Geographic stains are often located on the lateral aspect of the thigh, knee, and lower leg (Fig 5). Nongeographic stains are pink to red and scattered over the affected limb. In patients with nongeographic stains, other KTS symptoms (varicose veins and overgrowth) manifest later in life than in patients affected with a geographic stain, whose KTS is usually obvious at birth. Venous varicosities may be noted in early infancy, but usually become prominent later in childhood or adolescence. One of the more common venous anomalies involves the full length of the lateral limb. It is thought to represent persistence of the embryonic dorsal vein system that normally disappears in the rst trimester.40 Deep venous anomalies have been variably reported in the literature.37,43,44 A variety of symptoms of varying clinical significance may be associated with venous varicosities. These


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hemizygous for the KTS mutation. Happle52 postulated that germline homozygous expression of the genetic defect would likely be incompatible with life. In 1995, a single case of KTS was associated with 5:11 balanced translocation.53 Since then, molecular genetic analysis has identified 5 of 130 patients with KTS who have overexpression of VG5Q, an important angiogenic factor that is located on chromosome 5q13.3. More specifically, these 5 patients had a genomic mutation in E133K, acting by a gain-offunction mechanism and causing up-regulation of VG5Q, resulting in increased angiogenesis.54 In addition, Timur et al55 recently reported identification of a de novo supernumerary ring chromosome 18 in a patient with KTS, mild mental retardation, tapered digits, and elongated thin feet. These findings suggest that KTS is likely a genetically heterogeneous disorder. However, these recent developments may guide further research on the pathogenesis of sporadic causes of KTS. Radiologic ndings Several radiographic studies are helpful in management. Echo/Doppler and duplex scans are the studies of choice to evaluate for supercial and deep venous anomalies, as well as arteriovenous shunting. Plain radiographs or ortho-roentenography (scanograms) can be used to evaluate for bony hypertrophy, but in young patients the discrepancy may be a subtle radiographic nding. MRI of the lower limb will delineate the extent of soft-tissue hypertrophy, bone involvement, and presence of an associated lymphatic anomaly.56 MRI is also helpful in differentiating KTS from an extensive venous malformation of the extremities; KTS has no or only minor muscle involvement. Venography can be useful before treatment of varicose veins to assure the presence of a patent deep venous system. Diagnosis and management KTS should be suspected in all infants with capillary malformations involving a limb. The differential diagnosis for KTS includes Parkes Weber syndrome, Servelle-Martorell syndrome, Proteus syndrome, hemihyperplasia and lipomata syndrome (see Hemihyperplasia Multiple Lipomatosis Syndrome under the main heading Syndromes Associated with Venous Malformations, Lymphatic Malformations, or Mixed Malformations below) and isolated nonsyndromic capillary malformation of the skin. If KTS is diagnosed, regular monitoring of leg lengths is mandatory. If significant differences (typically[2 cm) are detected, or progressive lengthening occurs, pediatric orthopedic evaluation should be obtained. The management of limb length discrepancy should be

individualized and will depend upon many factors, including the extent of the limb length difference, the patients age, and limb function. Percutaneous epiphyseodesis is one method that has been used to cause growth arrest of the longer limb. Physical examination of the patient with KTS should include auscultation and palpation of the involved area to assess for the presence of an arteriovenous malformation (AVM) to rule out Parkes Weber syndrome. An arterialized component of the malformation should be suspected if unusual warmth or pain is noted. Serial measurements of the extremity should be performed to assess for hypertrophy. It is regarded as prudent to screen for Wilms tumor with ultrasonography in patients with hemihypertrophy. However, recent studies have shown no increase in incidence of Wilms tumor in patients who demonstrate hemihypertrophy occurring in association with KTS. Therefore screening is currently not routinely recommended.57 Many patients with KTS can be managed conservatively with elastic support garments. These garments protect the limb from trauma and decrease the swelling associated with venous insufciency. Patients with atresia of the deep venous system may complain of pain with compression. Surgery is generally reserved for those patients with symptomatic supercial varicose veins. Detailed evaluation and anatomic mapping of the venous system of the limb is mandatory before surgery. Complete resection of varicose veins will not halt bony hypertrophy.44,48 Capillary malformations may be treated with the pulsed-dye laser, but results are less satisfactory than for facial and truncal lesions. Lymphatic bleeding blebs are difficult to eradicate and may require treatment with surgical excision or destructive laser techniques. Cutis marmorata telangiectatica congenita Denition. Cutis marmorata telangiectatica congenita (CMTC) is an uncommon and distinctive cutaneous vascular malformation. First described by van Lohuizen58 in 1922, CMTC is characterized by a fixed reticulated vascular pattern on the skin that resembles physiologic cutis marmorata. Various names have been used to describe this disorder, including nevus vascularis reticularis and congenital livedo reticularis. CMTC is the preferred designation.59,60 A few series have noted CMTC to have a female preponderance.59,61,62 Cutaneous features CMTC is usually noted at birth and may have a localized or generalized distribution. When localized, it often has a sharply segmental pattern (Fig 6).

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as a feature of Adams-Oliver syndrome and will be discussed in following sections. Pathogenesis The cause of CMTC is unknown. Histologic examination of biopsy specimens obtained from patients has shown inconsistent results. Some authors report dilated capillaries in the dermis and subcutaneous tissue, whereas others could detect no vascular anomaly. Sparse dermal perivascular lymphocytic inltrates and swelling of endothelial cells has also been reported.59 Rogers and Poyzer70 from Australia reported a series of 4 infants with CMTC, all born within a 20-km radius over an 18-month period; although they could not find any convincing evidence for an environmental or genetic factor, they suggested the possibility of a common dysmorphogenic environmental agent in the pathogenesis. Other authors have proposed that the segmental distribution, often with a sharp midline separation, suggests that CMTC may be a disorder characterized by genetic mosaicism in which a lethal gene survives by partial or mosaic expression.62,71 CMTC appears to occur sporadically; however, a genetic basis has been proposed in a few cases.72 One author suggests paradominant inheritance. In other words, heterozygous individuals are phenotypically normal. Therefore the mutation can be transmitted unperceived through many generations. This syndrome only becomes manifest when a postzygotic somatic mutation occurs during early embryogenesis, forming a mosaic population of cells that is homozygous for the mutation.73 Diagnosis and management CMTC should be differentiated from other disorders, including Bockenheimer syndrome (diffuse phlebectasia). Some port-wine stain capillary malformations may also have a reticulated pattern, which makes distinguishing them from CMTC difcult. It is important to distinguish CMTC from a widespread diffuse, generalized form of a livedoid capillary malformation and is not associated with atrophy, ulceration, or limb hypoplasia. This type of capillary malformation is associated with a signicant risk of associated visceral vascular anomalies (eye, brain, kidneys, and heart) and may represent macrocephaly-CMTC and requires evaluation and follow-up (personal communication, O. Enjolras, MD, May 2000). CMTC should also be differentiated from persistent true cutis marmorata that can be seen in trisomy 21, Cornelia de Lange syndrome, and homocystinuria. Unlike port-wine stain capillary malformations, CMTC has a tendency to lighten with maturity in

Fig 6. Cutis marmorata telangiectatica congenita involving upper extremity. Note sharp cut-off of the affected area.

The reticulated pattern may be fine or coarse, with broad streaks of discolored skin in a tram-tracklike pattern. One may also see erythema and telangiectases associated with the reticulated pattern. CMTC can be differentiated from physiologic cutis marmorata by its persistence after the infant has been warmed and by the presence of linear depressed lines, usually more prominent over the limb joints. Atrophy of the skin and subcutaneous tissues that may manifest as hypoplasia of the affected limb, has been reported, but is an inconstant feature.60 Ulceration of the affected skin may also be seen in association with CMTC, particularly when involving the skin overlying elbows and knees.59 CMTC may be seen in association with a port-wine stain type of capillary malformation and discrete superficial varicose veins. These malformations may occur distant to the area of CMTC or within the same affected area.59 Extracutaneous features CMTC occurs as an isolated anomaly in the majority of localized cases; however, associated congenital anomalies have been reported in 27% to 50% of cases.59,60 Associated abnormalities are more common in generalized cases of CMTC. The most common associated congenital anomaly is limb hypoplasia. Other rare associations include limb hyperplasia, aplasia cutis congenita, congenital pigmented nevus, widespread dermal melanosis (mongolian spot), skull asymmetry, syndactyly, scoliosis, hypothyroidism, developmental delay, and anogenital anomalies.59,60,62-66 Glaucoma has also been reported in association with facial CMTC overlying the lids.59,67 A clinically distinct condition has been described that comprises CMTC and congenital macrocephaly together with prenatal and postnatal macrosomia, segmental overgrowth, CNS malformations, connective tissue abnormalities, and intellectual handicap (see below).68,69 CMTC is also described


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many, but not all, patients.74 Marked improvement is often noted in the first 2 years of life.62 When lightening occurs, it is rarely complete and may leave residual reticulate lesions.59,60,62 Patients with CMTC should undergo careful physical examination to assess for other congenital anomalies. Measurement of limb length and girth should be performed at the time of evaluation. Affected individuals should be informed that the lesion may lighten with maturity and ulcerations should be treated with local supportive care, including application of hydrocolloid dressings. If lesions persist, they may be treated with the pulsed-dye laser, although the response is variable. Macrocephaly-CMTC syndrome Macrocephaly-CMTC syndrome (M-CMTC) is a rare sporadic disorder that has recently been recognized to be a distinct disorder that should be differentiated from CMTC. It is characterized by a CMTC-like vascular malformation occurring in association with macrocephalic neonatal hypotonia and developmental delay. The skin lesion is typically a patchy reticulated vascular stain and lacks the associated cutaneous atrophy that is often seen in typical CMTC; therefore this vascular malformation is better categorized as a reticulated capillary malformation rather than true CMTC. A midline facial nevus ammeus (capillary malformation) is also reported to be present in most cases described in the literature. Other associations include hydrocephalus, connective tissue defects (soft skin, joint hypermobility), toe syndactyly, frontal bossing, and, rarely, hemihypertrophy.68 Adams-Oliver syndrome Adams-Oliver syndrome is a rare disorder characterized by CMTC occurring in association with aplasia cutis congenita of the scalp, and bony abnormalities of the limbs and cranium.75,76 Congenital cardiac malformations are reported in some patients with this disorder.77 It has been suggested that Adams-Oliver syndrome represents a disorder that results from an early embryologic vascular abnormality.78,79 Autosomal recessive inheritance is reported.80,81 However, no genetic mutation has yet been identified.82 Hemangiomatous branchial clefts, lip pseudoclefts Harrison83 first reported the uncommon association of capillary malformations, branchial clefts, lip pseudoclefts, and unusual facial appearance in 1957, and several cases have been reported subsequently. Most commonly, patients are noted at birth to have cervical/infra-auricular skin defects that may appear aplastic or as vascular stains erroneously called hemangiomatous, with draining sinus fistulas.

Rarely, these skin lesions may be supra-auricular. Anomalous retroverted ears, microphthalmia, nasolacrimal duct obstruction, pseudocleft lip, cleft lip, or cleft palate are part of this unusual syndrome.84 Roberts/SC phocomelia syndrome Roberts/SC phocomelia syndrome is a rare autosomal recessive disorder characterized by severe limb defects and cleft palate. Some patients have glabellar vascular stains.85,86 Patients who share features that overlap between thrombocytopeniae absent radius (TAR) syndrome and this disorder have been described (see ThrombocytopeniaeAbsent Radius Syndrome, below).87 Cytogenetic studies of some patients have shown consistent chromosomal abnormalities, including premature centromere separation and centromere splitting and puffing.88,89 No genetic locus defect has yet been identified for this syndrome. Rubinstein-Taybi syndrome Rubinstein-Taybi syndrome was described in 1963.90 It is a rare sporadic condition characterized by mental retardation, growth retardation, broad thumbs, broad, large toes, and a typical facial appearance. Skin manifestations include hirsutism, capillary malformations, keloid and excessive scar formation, and, rarely, cafe au lait macules. Capillary malformations are an inconstant feature of this syndrome.91 The gene for this disorder has been localized to chromosome 16p13.3. Patients with growth retardation, coloboma, capillary malformation, and hypotonia appear to be more likely to demonstrate a deletion in this region.92 This region contains the gene for the human cyclic AMP-response element binding (CREB) protein (CBP). The loss of function of this gene eliminates expression of CBP, thereby abolishing histone acetyl transferase activity and impairing the ability to transactivate CREB.93 Recent mouse studies suggest that some of the cognitive and physiologic deficits observed in Rubinstein-Taybi syndrome are not simply due to the reduction of CBP during development but may also result from the continued requirement throughout life for both the CREB coactivation and histone acetylation function of CBP.94 In addition, the long-term memory defect in mice induced by loss of function of CBP has been suggested to improve with enhancement of CREB function with drugs such as inhibitors of phosphodiesterase 4.95 Thrombocytopeniaeabsent radius syndrome TAR syndrome is a rare autosomal recessive disease characterized by hypomegakaryocytic

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thrombocytopenia and bilateral radial aplasia with normal thumbs. Anemia, eosinophilia, leukemoid granulocytosis, and lower limb abnormalities are common associated features.96,97 Many patients are noted to have a capillary malformation of the forehead. Ashinoff and Geronemus98 described a patient with TAR syndrome and a widespread capillary malformation involving the head and neck who responded poorly to treatment with the flash-lamp pulsed-dye laser. Some studies suggest that defective signal transduction in the c-mpl pathway, preventing thrombopoietin-induced tyrosine phosphorylation of platelet proteins, may impair megakaryocytopoiesis, contributing to some cases of TAR syndrome.99 No genetic locus defect has yet been identified for this syndrome. Beckwith-Wiedemann syndrome Beckwith-Wiedemann syndrome is characterized by gigantism, omphalocele (exomphalos), and macroglossia.100 Posterior helical ear pits, hypoglycemia, predisposition for tumors (Wilms, rhabdomyosarcoma, hepatoblastoma, adrenal tumors), and facial, usually centrofacial, capillary malformations also occur in this syndrome. These stains are virtually identical to salmon patches (nevus simplex) but are more often persistent. The mode of inheritance is complex. The majority of cases are sporadic, although there are several reports of families with autosomal dominant inheritance of this syndrome. Although inheritance of this genetic defect appears to be autosomal dominant, recent studies suggest that this syndrome is only phenotypically expressed when maternally inherited. Cytogenetic analysis reveals dysregulation of imprinted genes on chromosome 11p15. This region is composed of two distinct domains with multiple imprinted genes regulated by two imprinting centers. Among these imprinted genes, overexpression of IGF2 (domain 1) and p57KIP2 (domain 2) are identified to be involved in the pathogenesis of Beckwith-Wiedemann syndrome. Identifiable mutations are rare and mostly involve the p57KIP2 gene, the majority identified in families with an autosomal dominant inheritance pattern. In addition, 40% of cases involve activation of the normally silent maternal allele p57KIP2 by loss of imprinting of LIT-1.101 Interestingly, up-regulation of insulin-like growth factor 2 has been associated more often with Wilms tumor, whereas a mutation in p57KIP2 may be related to embryonal tumor types, such as rhabdomyosarcoma and hepatoblastoma.102 Understanding the genetic inheritance and specific mechanisms for tumorigenesis will assist in genetic counseling, early tumor detection, and prognostic determination.

Nova syndrome Nova syndrome is characterized by a capillary malformation in the glabellar area, communicating hydrocephalus, posterior fossa brain abnormalities, including Dandy-Walker malformation, agenesis of the cerebellar vermis, and mega cisterna magna. Occasionally, seizures are seen. Autosomal dominant inheritance has been suggested.103 Phakomatosis pigmentovascularis Denition. Phakomatosis pigmentovascularis (PPV) is the term used to describe a group of disorders that are characterized by the presence of a capillary malformation and a pigmented nevus. First described in the Japanese dermatologic literature, these associated anomalies are classied into 4 subgroups. The classication of this disorder is controversial. Type I is characterized by the presence of a capillary malformation (port-wine stain) and an epidermal nevus. Type II, the most common form, is characterized by the presence of a port-wine stain and aberrant mongolian spots. Type III is dened as the presence of a port-wine stain and nevus spilus. Type IV includes a port-wine stain, nevus spilus, and aberrant mongolian spots. Nevus anemicus is a variable component of the latter 3 types. Recently, it has been proposed that the association of CMTC with aberrant mongolian spots be classied as PPV type V.104 Hasegawa and Yasuhura105 proposed a classification that further divided these groups into localized (a) and systemic (b) forms. Recently Happle106 has proposed a simplified classification, based on the types of predominant skin lesions. Clinical characteristics PPV is rare and arises sporadically. It is slightly more common in females than males.105 The vascular birthmark is invariably a capillary malformation of the skin. It may be located on any part of the body and may affect large segments of the body. PPV type II is the most common type of PPV and accounts for more than 80% of reported cases.107 The pigment anomaly has been called an aberrant mongolian spot because it persists and the distribution differs from that seen in mongolian spots. Histologic examination reveals dermal melanosis and melanocytosis. Not surprisingly, several cases of SWS or KTS seen in association with oculocutaneous melanosis or nevus of Ota or Ito have been reported in the literature and are considered by some authors to be a form of type II PPV.108-110 PPV types III and IV have been reported in association with nevus spilus. A variety of extracutaneous abnormalities, such as selective IgA


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deficiency, endocrinopathies, granular cell tumors, iris mammillations, have been reported in association with PPV.111-113 Pathogenesis The pathogenesis of PPV is poorly understood. An abnormality in morphogenesis that occurs early in development and affects cells that are precursors to the vascular and pigment system has been postulated.108 Dunarti and Happle114 and Happle115 have hypothesized that PPV is due to so-called twin spotting whereby somatic mutations on neighboring genes give rise to mosaic spots in close proximity to one another. Such a finding that has been seen in the plant kingdom has not been confirmed in vertebrates.114-116 Another possible mechanism could be one or more somatic mutations causing dysregulation in multiple embryonic cell lines, including melanocytes and the fetal vasculature. Diagnosis and management The diagnosis of PPV is established on the basis of clinical ndings. Patients with vascular birthmarks involving the face, trunk, and limbs should undergo evaluation for SWS or KTS. Ocular evaluation is essential to rule out glaucoma in those cases in which the pigment or vascular birthmark affects the periocular skin.117

The degree of ocular and CNS involvement is related to the extent of the underlying malformations and possible bleeding. Pathogenesis The pathogenesis of this disorder is poorly understood. The constellation of features is believed to be the result of vascular dysgenesis that occurs during embryogenesis. Diagnosis and management Retinal vascular malformations may be detected on funduscopic examination. Magnetic resonance studies will help to dene the extent of the ocular vascular malformation and CNS AVM. Cerebral angiography assists in characterizing the AVM and may be performed to discuss whether a non-high-risk treatment is possible to consider (embolization).122 Wyburn-Mason syndrome should be differentiated from SWS. The latter is characterized by the presence of a capillary malformation of the face including the V1 area, a slow-flow leptomeningeal vascular malformation, cerebral atrophy, and calcifications. Patients with hereditary hemorrhagic telangiectasia (HHT) may also present with CNS AVM or arteriovenous fistula; however, telangiectases of the skin and mucosal surface are the typical cutaneous findings.123 Parkes Weber syndrome Parkes Weber syndrome is dened by the overgrowth of an extremity linked to the presence of an AVM with multiple arteriovenous stulas along the affected extremity, well evidenced by ultrasound/ Doppler or magnetic resonance angiography, in addition to a cutaneous red stain, which is a quiescent Schobinger stage I AVM. Parkes Weber syndrome more commonly affects the lower extremities (Fig 7). During childhood the angiogram often shows enlarged arteries and patchy areas of hypervascularization; arteriovenous fistulas usually develop around puberty or after trauma (including any surgical procedure performed on the affected limb). This disease may be complicated by highoutput congestive cardiac failure. Significant leg length discrepancy may require epiphyseodesis, but this should be in the least invasive form possible (percutaneous epiphyseodesis) to avoid worsening of the AVM.124 Lymphatic anomalies and lymphedema can be present. At the lower limb level, these may occur in association with hypertrophied digits, creating severe deformity, papillomatosis of the toes, and recurrent infection, occasionally requiring amputation.


Bonnet- Dechaume- Blanc syndrome or Wyburn-Mason syndrome Denition and clinical characteristics. WyburnMason syndrome (Bonnet-Dechaume-Blanc syndrome) was rst reported by Bonnet and his coauthors in 1937 and was later reported in the Englishlanguage literature by Wyburn in 1943.118,119 These terms are generally considered to be synonymous. This rare syndrome is characterized by cerebral AVMs that usually involve the midbrain, an ipsilateral retinal vascular malformation, and a red stain of the facial skin often misinterpreted as a capillary malformation, in fact a quiescent Schobinger stage I AVM.120,121 The vascular malformation of the skin is an inconstant nding in Wyburn-Mason syndrome. When present, it either is unilateral and involves the skin innervated by the trigeminal nerve or it is centrofacial, involving the mid forehead, glabella, nose, and upper lip. Bilateral capillary stains have been reported. Patients may present with ocular or CNS complaints, including headaches and seizures.

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Blue rubber bleb nevus syndrome Denition. Blue rubber bleb nevus syndrome (Bean syndrome) is a rare disorder characterized by venous malformations of the skin and gastrointestinal tract. In 1860, Gascoyen rst reported this constellation of features, which was then followed by scattered reports. Bean127 reported two additional cases and reviewed the literature in 1958. He coined the term blue rubber bleb nevus syndrome to describe the characteristic skin and gastrointestinal features. Clinical characteristics Blue rubber bleb nevus syndrome occurs sporadically; several reports of familial cases exist with proposed autosomal dominant inheritance pattern, but it seems that there was a confusion in the literature with the more recently described venous malformations, multiple cutaneous and mucosal syndrome (OMIM 600195), an autosomal dominant venous malformation syndrome linked to TIE2/TEK mutation, located on chromosome 9p21, a syndrome which does not include visceral venous malformations, and, in particular, no gastrointestinal tract lesions. Venous malformations are usually apparent at birth or during early childhood, although onset of symptoms in adulthood has been reported.129 The most characteristic skin lesion is a compressible blue subcutaneous nodule (Fig 8). Bean127 likened the appearance of this lesion after compression to a rubber nipple. Cutaneous venous malformations can vary greatly in size and number and become more apparent as a patient matures. The first dark blue spot often appears on previously absolutely normal skin soon after birth, and their numbers increase over the years. They may be found on any surface of the skin and mucosa, including the scalp, but are commonly located on the trunk and extremities (palms and soles). Patients may report associated tenderness with palpation or at rest. Localized hyperhidrosis has been reported in association with painful lesions.128 Venous malformations located on extremities may be associated with orthopedic complaints including painful ambulation when the soles are involved, bone deformities that occur as a consequence of direct compression, pathologic fractures, and extension of the venous malformation to the underlying muscle or joint.128,130 Gastrointestinal tract venous malformations cause the most signicant morbidity in blue rubber bleb nevus syndrome. The entire bowel may be affected,

Fig 7. Parkes Weber syndrome. AVM of the extremity associated with limb overgrowth.

Capillary malformationeAVM syndrome Capillary malformationeAVM syndrome is a recently described hereditary disorder that is characterized by cutaneous capillary malformation occurring in association with high-ow vascular lesions (AVMs or arteriovenous stula). This condition is caused by mutations in the RASA1 gene. This gene encodes for a protein that plays an important role in the signaling for growth factor receptors involved in the proliferation migration and survival of various cell types, including endothelial cells (as signaling pathway).125 Phenotypic variability is described. The high-flow lesions may be located in the skin and subcutaneous tissue, bone, muscle, or brain. Some of these patients have the clinical features of Parkes Weber syndrome (see above). The capillary malformations are often small pink-red macules that may be widely distributed over the skin surface; a pale halo may be noted at their periphery. Larger solitary capillary malformations are also reported in this condition.126 Cobb syndrome Cobb syndrome is a rare nonhereditary disorder that involves the association of spinal angiomas or AVMs with congenital, cutaneous vascular lesions, not a true capillary malformation (port-wine stain), but a quiescent Schobinger stage I AVM in the same dermatome. The importance of this syndrome is the recognition that cutaneous vascular lesions may hint at an accompanying spinal cord angioma or AVM that may result in variable neurologic complications.


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but involvement of the small intestine and colon is most common. Symptoms may develop during childhood or adulthood. Patients may lack symptoms of gastrointestinal involvement, but have anemia from chronic occult intestinal blood loss and melena. Rectal bleeding and abdominal pain, which may be a consequence of intussusception and hemorrhage, can also occur.129,131 In addition to anemia, consumptive coagulopathy is commonly observed in these patients, with high D-dimer levels and low fibrinogen, responsible for severe hemorrhages as early as infancy.132 Venous malformations may also be found in the CNS, orbit, and genitourinary tract.133-137 Bleeding, pain, and compression associated with subcutaneous or visceral venous malformations may result in functional impairment. Pathogenesis The pathogenesis of blue rubber bleb nevus syndrome has not been elucidated. Diagnosis and management Blue rubber bleb nevus syndrome should be suspected in patients who present with cutaneous vascular malformations. The differential diagnosis for this condition includes isolated venous malformations of the skin or mucosa, HHT, multiple glomus tumors (glomuvenous malformation), and Maffucci syndrome. Patients should undergo evaluation for occult gastrointestinal involvement and anemia. MRI and computed tomographic scans may assist in identifying the extent of lesions in muscles and viscera.131,138 Destructive modalities, including carbon dioxide laser, sclerotherapy, and surgical excision, have been used to treat cutaneous lesions.139 Symptomatic gastrointestinal venous malformations may be treated with argon or Nd:YAG laser ablation or surgical resection.140,141 Systemic steroids have been used with some success in controlling growth of intestinal lesions.142 Recent case reports have shown treatment with interferon alfa to help with regression of coagulopathy and treatment with subcutaneous octreotide to reduce bleeding in gastrointestinal lesions.143,144

Fig 8. Blue rubber bleb nevus syndrome, a venous malformation located on the palm.

Denition Proteus syndrome was so named by Weidemann, Burgio, and Aidenhoff145 in 1983 to describe a rare sporadic disorder that is characterized by soft tissue and bony hypertrophy of the hands and feet, hemihypertrophy, exostosis, cranial hyperostosis, visceral hamartomas including lipomas, vascular anomalies, and epidermal nevi.

Clinical characteristics In the initial description of this syndrome, Weidemann, Burgio, and Aidenhoff proposed the following criteria for diagnosis: gigantism of the hands and/or feet, pigmented nevi often associated with raised and rough skin, hemihypertrophy, subcutaneous masses, skull abnormalities, accelerated growth, and visceral abnormalities (Fig 9). Since then, patients reported in the literature with Proteus syndrome have had such variable clinical characteristics that concern had been expressed for misdiagnosis and overreporting of this syndrome.146,147 Therefore, in 1998, a workshop on Proteus syndrome was held by the National Institutes of Health, and recommendations of diagnostic criteria were developed.148 In 2004, upon review of all reported cases of Proteus syndrome in the literature and further inspection of confusion or misunderstanding of criteria, the diagnostic criteria were again slightly revised. Of note, of the 205 cases reported in the literature, only 97 cases met the diagnostic criteria for Proteus syndrome.149 Patients must meet both the general and specific criteria to be accurately diagnosed with Proteus syndrome. The general characteristics of a mosaic distribution of lesions, progressive clinical course, and sporadic occurrence are considered mandatory. The diagnostic criteria for Proteus syndrome are listed in Table V. The most characteristic manifestation is a cerebriform thickening of the palms and soles (connective tissue nevus) (Fig 10).150-152 Linear verrucous epidermal nevi are frequently reported in affected individuals.153 Owing to the presence of widespread epidermal nevi, Proteus syndrome should be differentiated from epidermal nevus syndrome (Solomon syndrome). Although the vascular anomalies described in Proteus syndrome are not well characterized, clinical experience suggests that capillary, venous, lymphatic, and combined slow-flow malformations identical to KTS may occur. Extremity deep venous thrombosis and pulmonary embolism may also occur. The presence of the more characteristic

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Table V. Diagnostic criteria for Proteus syndrome

For diagnosis: General criteria (mandatory) 1 specific criteria (category signs) General criteria: Specific criteria: Mosaic distribution Either one from A or two from B of lesions or three from C Progressive course Sporadic occurrence Category signs A B Manifestations 1. Connective tissue nevus 1. Epidermal nevus 2. Disproportionate overgrowth (one or more) 3. Specific tumors before end of second decade (either one) Bilateral ovarian cystadenomas Parotid monomorphic adenoma 1. Dysregulated adipose tissue (either one) Lipomas Lipomas Regional absence of fa 2. Vascular malformations (one or more) Capillary malformation Venous malformation Lymphatic malformation 3. Lung cysts 4. Facial phenotype

Fig 9. Proteus syndrome. Note signicant hemihypertrophy and deformity of the foot, in addition to capillary malformation on abdomen.

anomalies associated with Proteus syndrome establishes the diagnosis. Pulmonary abnormalities are reported in some patients with Proteus syndrome. These include pulmonary cysts, which may be rapidly progressive, and lead to recurrent infections. Renal abnormalities can also be seen, including renal cysts, vascular anomalies, and diabetes insipidus.151 A characteristic facial phenotype has been noted in patients with seizures and severe mental retardation. These patients are noted to have dolichocephaly, long face, mild downslanting of the palpebral fissures, mild ptosis, a low nasal bridge and an open mouth at rest.151 Structural malformations of the brain are seen with increased frequency in Proteus syndrome.151 Seizures are also noted in approximately 13% of patients. Patients with Proteus syndrome usually demonstrate normal intelligence. Pathogenesis The pathogenesis of Proteus syndrome is poorly understood. Happle154 proposed that it represents a disorder caused by somatic mosaicism of a mutated gene that would be lethal in its nonmosaic state This theory of a postzygotic mutation has been supported by other authors, evidenced by the mosaic pattern of cutaneous lesions and discordance in identical twin pairs.155 The mutated gene may result in an alteration of an important tissue growth factor or its receptor.153,156 Over the past few years, it has also been suggested that PTEN tumor suppressor gene is

Adapted with permission from Turner JT, Cohen MM, Biesecker LG. Reassessment of the Proteus syndrome literature: application of diagnostic criteria to published cases. Am J Med Genet 2004; 130A:111-22.

Fig 10. Thickened soles in patient with Proteus syndrome.

defective in patients with Proteus and Proteus-like syndrome.157 Turner, Cohen, and Biesecker149 have since argued that, in analyzing these cases, these patients do not actually meet diagnostic criteria and suggest that PTEN has no association with Proteus syndrome. Diagnosis and management The diagnosis of Proteus syndrome is established on the basis of clinical features. Recently, a study of


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24 patients showed that the number of cutaneous manifestations predicted the extent of extracutaneous abnormalities, possibly predicting prognosis.158 Management to date is largely supportive. Hemihyperplasia multiple lipomatosis syndrome This syndrome was reported by Biesecker et al159 who described a group of patients that had previously been designated to have Proteus syndrome but did not meet the diagnostic criteria and did not appear to have distinct features. In addition, these patients showed more overgrowth than is typically seen in KTS. These individuals present with hemihyperplasia at birth and moderate overgrowth with subcutaneous lipomas, which remains relatively stable from infancy through preadolescence in most patients. Superficial capillary malformations are reported in some of these patients. Affected persons lack deep vascular malformations, epidermal nevi, connective tissue nevi, and bony exostoses that characterize Proteus syndrome. Moreover, they also lack the features of Bannayan-Riley-Ruvalcaba syndrome (BRRS), including cutaneous pigmented macules and macrocephaly (see following section). A provisional designation has been given to this syndrome because once the genetics of this order are elucidated, it may prove to represent a milder form of Proteus syndrome. Bannayan-Riley-Ruvalcaba syndrome Denition and clinical characteristics. BRRS represents a disorder that had previously been classied under the eponyms Bannayan-Zonana syndrome, Riley-Smith syndrome, and Ruvalcaba-Myhre syndrome. This is an autosomal dominant condition with a variable clinical phenotype. The predominant clinical features are macrocephaly, developmental delay, pseudopapilledema, pigmented macules on the glans penis, and hamartomatous growths, including subcutaneous and visceral lipomas, gastrointestinal polyposis, and what are often described as hemangiomas (capillary malformations and combined malformations).160,161 Subcutaneous lipomas and hyperpigmented macules on the glans penis are two of the most common cutaneous manifestations in this syndrome. Affected persons may also have an increased number of cafe au lait macules. Vascular anomalies are present in only 10% of patients.161 The associated vascular anomalies have been poorly characterized in the literature and erroneously called hemangiomas. They are reported to persist into adulthood in some patients. It is likely that they are capillary malformations or combined malformations. Other less common manifestations include testicular

enlargement, thyroiditis, hyperextensible joints, pectus excavatum, and scoliosis.161 Pathogenesis Several patients with overlapping features of Cowden syndrome and BRRS have been reported in the medical literature.162 In 1997, evaluation of two families with BRRS revealed mutations in the PTEN gene, a tumor suppressor gene that had previously been recognized as the gene mutated in Cowden syndrome.163-165 Since then, there have been multiple families reported to have members with both syndromes.166 This association suggests that BRRS and Cowden syndrome are allelic conditions.167 Diagnosis and management The diagnosis of BRRS should be considered in children with macrocephaly, pigmented lesions on the genitalia (males), lipomas, and vascular growths. A careful family history should be obtained for features that would be suggestive of Cowden disease. Proteus syndrome should be considered in the differential diagnosis, but is usually associated with more signicant overgrowth and thickened palms and soles. Neurologic and gastrointestinal assessments should be performed in patients in whom the diagnosis is suspected. Recently, it has been suggested that, because of the close association with Cowden disease, patients with BRRS should be screened for the malignant tumors commonly associated with that disorder. Although clear guidelines do not exist, physicians caring for these patients should be aware of this potential.167 Maffucci syndrome Denition. First described by Angelo Maffucci in 1881, Maffucci syndrome is a rare sporadic genetic disorder typically comprising enchondromas and vascular anomalies (both nodules of venous malformations and of a distinctive tumor, the spindle cell hemangioendothelioma).168 Clinical characteristics Approximately 160 cases have been reported worldwide, 100 of which have been from the United States. There is no observed sex or racial preference. Affected persons appear normal at birth. The disease usually manifests in early childhood, when multiple supercial and deep venous malformations appear as asymmetric blue or purple, soft, occasionally tender nodules, sometimes masses, usually in the distal extremities (Fig 11). Oral or intra-abdominal vascular anomalies, including venous and lymphatic anomalies, may also be found.169,170 Simultaneously enchondromas develop

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Fig 11. Maffucci syndrome. Venous malformations and enchondromas.

that present as hard nodular lesions, most frequently in the phalanges and long bones. Complications include phlebolith formation within vascular malformations, short stature, bone irregularities, such as shortened long bones and pathologic fractures, with subsequent distortion of limbs, and malignant transformation of enchondromas into chondrosarcomas. Approximately 30% to 40% of enchondromas transform into chondrosarcomas. Although chondrosarcomas are by far the most common neoplasm encountered, Maffucci syndrome is associated with many other malignancies. There have been several reports of associations with breast, ovarian, pancreatic, parathyroid, and pituitary tumors.171,172 The spindle-cell hemangioendothelioma (also designated spindle-cell hemangioma in the literature), a vascular tumor, is commonly found either beside the venous nodules, as a cutaneous mass, or intermingled with the venous malformation on pathologic sections in Maffucci syndrome. Patients with Maffucci syndrome usually have normal life expectancy if no malignant transformation occurs. Pathogenesis This disease appears to develop from mesodermal dysplasia early in life, with no obvious inheritance pattern. Although there is no genetic locus identied to cause all of the clinical features of Maffucci syndrome, a mutation in the Indian hedgehog/ parathyroid hormoneerelated protein (IHH/PTHrP) pathway is suggested to be responsible for the development of enchondromatosis. IHH promotes chondrocyte proliferation, whereas PTHrP is normally responsible for delaying hypertrophic differentiation of proliferating chondrocytes. Mutant parathyroid receptor type 1 (PTHR1) has been shown to cause enchondroma-like lesions in transgenic mice.173 Two patients with enchondromatosis have also been found to have an activating mutation in PTHR1 in tumor specimens. However, recent genetic investigations of 31 patients with enchondromatosis revealed no abnormalities in the IHH/ PTHrP pathway.174

Diagnosis and management Plain lms are usually performed to conrm suspicion of enchondromas; they also reveal the presence of phleboliths. MRI is the best tool to investigate the lesions of venous malformation in the distal extremities or in the head. Regular physical examinations are necessary to monitor for any changes that may suggest the development of chondrosarcomas. Radiologic evaluation of suspect areas with plain films, computed tomography, and/or MRI should be conducted. Evidence of malignant transformation includes cortical destruction, endosteal cortical erosion, and zones of lucency within a previously mineralized area. A needle biopsy should then be performed on these suspect areas of the bone. Chondrosarcomas are diagnosed with the histologic finding of poorly differentiated pleomorphic chondrocytes. Venous malformations are managed conservatively unless symptomatic. Gorham-Stout syndrome Denition and clinical characteristics. Gorham-Stout syndrome (disappearing bone disease, phantom bone disease, diffuse skeletal hemangiomatosis) is a very rare syndrome that was rst described in 1838 by Jackson; it was designated as a syndrome upon publication of a 24-case review in 1955 by Gorham and Stout. It is characterized by vascular malformations and intraosseous, vascular malformations, and osteolysis.175 Although venous, lymphatic, and capillary malformations are reported in this syndrome, the most common finding seems to be a lymphatic malformation.176 Cutaneous vascular malformations are rare in Gorham syndrome but may occur. Patients with this disorder often present during childhood with an antecedent history of minor trauma resulting in a pathologic fracture. It is equally common in males and females. The truncal bones and upper extremities are most commonly affected. The vascular malformation may be localized or diffuse, and the degree of bone resorption is variable. Complete resorption of the bone has been reported in several cases.175 Pathogenesis Histologic evaluation of the bone reveals intraosseous, anomalous vascular channels and brous tissue. Acid phosphatase cytochemistry suggests that mononuclear phagocytes, multinuclear osteoclasts, and the vascular endothelium are involved in bone resorption in this disease.177 Recent histochemical evaluation of osteoclast activity in this disease has shown an increase in the sensitivity of osteoclast precursors to humoral factors that promote osteoclast formation and bone resorption.178


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Management Radiotherapy has been used for pain relief and cessation of osteolysis, with moderate success for some patients. Biphosphonates and some antiangiogenic drugs are under evaluation. Bockenheimer syndrome Genuine diffuse phlebectasia, or Bockenheimer syndrome, is a rare disorder characterized by a blue network of dilated veins. This venous malformation involves more commonly upper, but also lower, extremities. The lesions are present at birth and are progressive. MRI will reveal the extent of the lesions, usually without the involvement of muscles and bones. Because of the distribution of lesions and morphologic appearance, the differential diagnosis includes common extensive venous malformations of the limbs and KTS. Treatment includes supportive care, such as sclerocompression of the lower extremities and, if necessary, percutaneous sclerotherapy or resection.179 Cutaneous capillary venous malformationsecerebral capillary malformation Small, localized cutaneous hyperkeratotic capillaryevenous malformations are present in a small percentage of persons with inherited cerebral capillary malformations. Inherited cerebral capillary malformations are associated with mutations in the CCM-1 gene that encodes for the KRIT1 protein. This protein is involved in the Ras signaling pathway (see Capillary Malformation-AVM Syndrome section). The skin lesions are dark red hyperkeratotic plaques that are localized. Histology reveals hyperkeratotic epidermis, and dilated capillary and venous-like channels in the dermis and hypodermis. Cerebral capillary malformations cause headaches, seizures, and intracranial hemorrhage. It is hypothesized that the KRIT1 protein plays an important role in cerebral and cutaneous vascular development.180

Fig 12. Hereditary hemorrhagic telangiectasia. Multiple facial telangiectases in affected adult.

presenting feature, often reported within the rst two decades of life, and frequently occurs before the appearance of cutaneous telangiectasia.181 It is bleeding from lesions of the nasal mucosa that results in epistaxis, which may be severe. Telangiectases are also located on the lips, oral mucosa, upper extremities, nail beds, and trunk (Fig 12). Cutaneous telangiectases rarely cause significant bleeding, although a recent study suggests this occurrence is more frequent than previously thought.182 Gastrointestinal tract telangiectases and AVMs result in significant bleeding in 16% of patients.183 Pulmonary AVMs are estimated to occur in 15% of patients with HHT, leading to respiratory complaints and neurologic complications, including emboli and stroke. Other neurologic findings include CNS AVMs resulting in migraines and seizures.184 AVMs are also found in the liver. Pathogenesis Analysis of dysplastic vasculature in HHT reveals direct arteriolar to venular connections and loss of normal intervening capillary segments.184 Genetic linkage analysis of families with HHT has revealed at least two loci. The first and more common form maps to a locus on chromosome 9q33-34. Subsequent analysis identified this to be the site of the ENG gene encoding for endoglin, a transforming growth factor b binding protein.185 Several different mutations in this gene have been reported.186 A second locus is on chromosome 12q11-14 and is the site of the ALK1 gene, the product of which is an activinlike tyrosine kinase-1.187 Both genes encode a homodimeric integral membrane glycoprotein expressed mainly on vascular endothelial cells as the surface receptor for the transforming growth factor b superfamily, which mediates vascular remodeling through effects on extracellular matrix production.188


Hereditary hemorrhagic telangiectasia Denition. Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Rendu-Weber syndrome, is a genetically heterogeneous, autosomal dominant disorder characterized by mucocutaneous and visceral telangiectases and AVMs. Clinical characteristics HHT is reported in many ethnic groups. The prevalence varies among populations. Recurrent epistaxis from mucosal telangiectasia is a common

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Mice deficient in endoglin or activin-like tyrosine kinase-1 die by mid-gestation from failure to form normal vascular beds.189-191 Mutations of ENG more likely result in pulmonary AVMs, whereas mutations in ALK1 are associated with a more benign course. In a large pedigree, HHT associated with extensive hepatic AVMs did not map to either previously reported locus, suggesting additional genetic heterogeneity.192 In addition, it appears that the presence of epigenetic factors and modifier genes is also required for expression of this disease, based on reduced penetrance of the phenotype in heterozygous animals.193 Diagnosis and management The diagnosis of HHT is established when 3 of the following features are present: (1) epistaxis: spontaneous, recurrent nose bleeds; (2) telangiectases: multiple, at characteristic sites (lips, oral cavity, ngers, nose); (3) visceral lesions: such as gastrointestinal telangiectasia (with or without bleeding), pulmonary AVM, hepatic AVM, cerebral AVM, spinal AVM; and (4) family history: a rst-degree relative with HHT. Meeting two criteria suggests a possible or suspected case.194 The differential diagnosis for HHT includes CREST syndrome (calcinosis cutis, Raynauds phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia). Establishing the diagnosis of HHT in childhood is difficult. Factors that complicate early diagnosis include the observation that visceral involvement may not manifest until maturity and that scattered telangiectases may arise on the head and neck of children who do not have HHT. Although this is problematic, HHT should be suspected in children in whom multiple lesions develop on the skin and mucosa; further evaluation may include genetic testing to help establish the diagnosis. Once the diagnosis of HHT is suspected, patients should be carefully evaluated for pulmonary involvement. Patients with a family history of HHT with pulmonary disease are at greatest risk of having pulmonary AVMs. MRI is useful for assessing CNS involvement.184 The HHT Foundation is a useful resource for patients and families with HHT (Web site URL: Ataxia-Telangiectasia Denition. Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeciency, cancer predisposition, chromosomal instability, radiosensitivity, and conjunctival and facial telangiectases.195 Clinical characteristics The disease usually becomes evident in early childhood with the development of progressive

ataxia. Conjunctival telangiectases are a frequent early manifestation and may also be noted on the facial skin. Noninfectious persistent cutaneous granulomatous plaques that often ulcerate are the other cutaneous nding in AT. Progeric changes of the hair and skin can also be seen. Humoral and cellular immunodeciency often manifests as recurrent sinopulmonary infections. Affected persons are at an increased risk of developing malignancies, most commonly lymphoreticular malignancy. Patients also exhibit growth retardation, elevated serum a-fetoprotein levels, chromosomal instability, and sensitivity to ionizing radiation. Affected persons have a shortened life expectancy, with death usually occurring in the second or third decade of life. Heterozygotes (carriers) manifest an increased cancer predisposition and radiosensitivity.196 Female carriers are at a significantly increased risk of developing breast cancer than the general population.196,197 Pathogenesis Four complementation groups have been described in AT based on measurements of radioresistant DNA synthesis. The ATM (ataxia telangiectasia mutated) gene is located on chromosome 11q22-23. Mutations in this gene are noted in patients from all 4 complementation groups, suggesting that it is the sole gene responsible for this disorder. The gene product is similar to phosphotidylinositol-39 kinase, is believed to play an important role in signal transduction and cellular responses to DNA damage and cell cycle control; it has also been shown to be pivotal in neurologic development.198,199 Little correlation exists between the level of ATM protein and the type of underlying mutation, clinical phenotype, or radiophenotype. Recent work suggests that ATM protein may be associated with dysregulation of the immunoglobulin gene superfamily, which includes genes for T-cell receptors. The normal switch from the production of IgM to IgG, IgA, and IgE is defective, and the same may apply to the switch from immature T cells that express the g/d rather than the a/b receptors. This dysregulation may explain the frequency of infections and hematologic malignancies. Accelerated telomere loss may be responsible for neurologic disease, thymus aplasia, telangiectases, growth retardation, and impaired organ mutation.200 Diagnosis and management AT is diagnosed clinically, on the basis of relevant clinical signs and symptoms as well as signicant family history. Laboratory studies, including a-fetoprotein, carcinoembryonic antigen, chromosomal


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studies, and a quantitative immunoglobulin panel, are useful for both diagnosis and prognosis.
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