CONTINUING MEDICAL EDUCATION

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. Theselesions occur much less commonly but are often confused with the common infantile hemangioma. It isimportant to properly diagnose vascular malformations because of their distinct differences in morbidity,prognosis and treatment. Vascular malformations may be associated with underlying disease or systemicanomalies. Several of these syndromes are well defined and can often be distinguished on the basis of theflow 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 betterrecognize underlying diseases or systemic anomalies that may be associated with vascular malformations.Participants should also better understand the various syndromes and conditions discussed and becomemore familiar with their management.

541

Vascular malformations may be associatedwith underlying disease or systemic anoma-lies in select situations. Several syndromes

are well defined and familiar to most physicians.In this section we will categorize these syndromeson the basis of the characteristics of the associatedvascular malformation. In some syndromes, suchas Proteus syndrome and Maffucci syndrome, morethan one type of vascular anomaly can occur (TablesI-III).

SYNDROMES ASSOCIATED WITHVASCULAR STAINS: SLOW FLOWSturge-Weber syndrome

Definition. Sturge-Weber syndrome (SWS) is asporadic congenital disorder characterized by adermal capillary malformation (port-wine stain)occurring in association with vascular malforma-tions of the leptomeninges and the eye. The major

From the Departments of Dermatology and Pediatrics, Columbia

University, New Yorka; Department of Dermatology, North-

western University, Evanstonb; Children’s 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: mcg2@columbia.edu.

0190-9622/$32.00

ª 2007 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2006.05.066

extracutaneous symptoms include seizures, hemi-plegia, mental retardation, and glaucoma.

Sturge1 first described a patient with epilepsy,a facial capillary malformation, and buphthalmos in1879. He speculated that the patient’s seizures werecaused by an underlying vascular anomaly of thebrain. Subsequently, Kalischer verified the presenceof the underlying vascular anomaly. Durck, Volland,Krabbe, and Parkes Weber better characterized thepattern and distribution of the characteristic intra-cranial calcifications.2

Since the initial descriptions, the syndrome hasbeen variably defined in the literature. The complete

Abbreviations used:

AT: ataxia-telangiectasiaAVM: arteriovenous malformationBRRS: Bannayan-Riley-Ruvalcaba syndromeCBP: cyclic AMP-response element binding

proteinCMTC: cutis marmorata telangiectatica

congenitaCNS: central nervous systemCREB: cyclic AMP-response element bindingCT: computed tomographyHHT: hereditary hemorrhagic telangiectasiaIHH: Indian hedgehogKTS: Klippel-Trenaunay syndromeM-CMTC: macrocephaly-CMTC (syndrome)MRI: magnetic resonance imagingPPV: phakomatosis pigmentovascularisPTHR1: parathyroid receptor type 1PTHrP: parathyroid hormoneerelated proteinTAR: thrombocytopeniaeabsent radius

(syndrome)

J AM ACAD DERMATOL

APRIL 2007

542 Garzon et al

syndrome generally includes the triad of facialdermal capillary malformation (port-wine stain),ipsilateral central nervous system (CNS) vascularmalformation (leptomeningeal angiomatosis), andvascular malformation of the choroid of the eyeassociated with glaucoma. Partial forms have beenreported. Leptomeningeal and choroidal vascularmalformations have been reported in the absenceof a vascular stain and may represent a variant formof SWS.3 A dermal capillary stain associated withglaucoma in the absence of a CNS anomaly isconsidered by many authors to be a partial form ofthe syndrome.4 However, only patients with con-firmed ocular choroidal and leptomeningeal involve-ment should be considered as having SWS.

Cutaneous featuresThe risk for SWS is determined by the distribution

of the port-wine stain. Two large studies of patientswith facial capillary malformations have shown thatSWS occurs exclusively in patients whose capillarymalformation is located in the distribution of the firstbranch of the trigeminal nerve, although glaucomais occasionally seen with lower lid stains. This con-firmed earlier observations by Alexander5 who pro-posed that patients with supraocular lesions were atgreatest risk of having a leptomeningeal abnormal-ity. Enjolras and her coworkers found SWS to occuronly in patients with some portion of the V1 distri-bution affected, although the stain could involveothers (Fig 1). The (ophthalmic) first branch (V1) ofthe trigeminal nerve was defined according to the

Table I. Syndromes associated with vascularstains: Slow flow

Sturge-WeberKlippel-TrenaunayServelle-MartorellCMTCMacrocephalyeCMTCAdams-Oliver‘‘Hemangiomatous’’ branchial clefts, lip pseudocleftsRoberts/SC phocomeliaRubinstein-TaybiThrombocytopeniaeabsent radiusBeckwith-WiedemannNovaPhakomatosis pigmentovascularisCutaneous capillary-venous malformationecerebral

capillary malformationProteus*Hemihyperplasia multiple lipomatosis*Bannayan-Riley-Ruvalcaba*

CMTC, Cutis marmorata telangiectatica congenita.

*Other types of vascular malformations may also occur.

classic neurologic drawing of the 3 sensory branchesof the trigeminal nerve as innervating the upper lid,and the (maxillary) second branch (V2 dermatome),the lower lid.6 A subsequent study performed byTallman et al7 found ocular and CNS abnormalitiesto occur exclusively in patients with port-wine stainsinvolving the upper and lower lids (91%) or lowerlids alone (9%). Therefore they had a larger portionof patients with port-wine stains in the distributionof V2 with leptomeningeal anomalies and glaucomathan the previous studies. Although their findingssuggest that some patients with SWS may haveV2-associated port-wine stains alone, this disparityin findings may be attributed to a difference indefinition of the distribution of the V1 and V2dermatomal areas, which is probably due to anatomicvariability in the so-called ‘‘watershed area’’ of theupper and lower eyelids that can be innervated byeither V1 or V28 (Fig 2). Regardless, the conclusion ofboth studies is the same; capillary malformationsoverlying the upper lids are associated with SWS. Theoverall incidence of ocular or CNS involvement inpatients with capillary malformations located in theV1 and V2 areas is reported to be approximately8% but is considerably higher when multiple der-matomes (V1, V2, V3) or bilateral stains are present(24%).7

The capillary malformation of the skin associatedwith SWS is present at birth. It may extend to mucosalsurfaces with concomitant gingival hypertrophy,which may be even further accentuated in patientsbeing treated with phenytoin for seizures. Somepatients exhibit accelerated eruption of teeth.9

Patients with associated V2 port-wine stains maydemonstrate maxillary hypertrophy. SWS is commonly

Table II. Syndromes associated with vascularstains: Fast flow

Bonnet-Dechaume-Blanc/Wyburn-MasonParkes WeberCapillary malformationearteriovenous malformationCobb

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

Blue rubber bleb nevusProteusHemihyperplasia multiple lipomatosisBannayan-Riley-RuvalcabaMaffucciGorham StoutBockenheimer

J AM ACAD DERMATOL

VOLUME 56, NUMBER 4

Garzon et al 543

associated with port-wine stains on other areas ofthe body. Moreover, SWS may be seen in associationwith Klippel-Trenaunay syndrome (KTS).10,11

Contrary to popular assumption, leptomeningealvascular malformations are rarely located in closeproximity to the facial port wine stain. In fact, thefrontal lobe is the least common location for CNSinvolvement. Leptomeningeal vascular malformationsare most often located over the occipital lobes,followed by the temporal and parietal lobes.12-14

Extracutaneous featuresNeurologic. Seizures are the most common neu-

rologic abnormality associated with SWS and occurin 55% to 90% of patients.15 Two studies found an80% incidence of seizures in patients with SWS.16,17

Seizures were slightly more common in patients withbilateral port-wine stains than those with unilaterallesions. All patients with seizures had port-winestains involving the V1 dermatome.16 Seizures areusually focal in type, but may become generalized.17

Seizures arise within the first year of life in 75% ofpatients; however, later onset may occur in somepatients. Affected individuals with bihemisphericleptomeningeal capillary malformations demon-strate an earlier onset of seizures and more likelysuffer from developmental delay and mental retar-dation.18 Rarely, diffuse early neurologic involve-ment is lethal during the first months of life, causedby uncontrolled epilepsy. Although cited in someliterature, no retrospective or longitudinal studieshave shown that early-onset seizures are more oftenassociated with developmental delay.19,20

The risk of mental retardation has been variablyreported between 50% and 65%.15,16,19 The higherreported rates of mental retardation may be attrib-uted to those studies published in the neurologicliterature in which patients present to neurologists

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

with predominantly CNS complaints. Most patientsachieve developmentally appropriate milestonesduring the first few months of life. Subsequently,about half of all patients with SWS will continue to bedevelopmentally normal. Those with more extensiveneurologic involvement, including bilateral lepto-meningeal disease or seizures refractory to treat-ment, are at higher risk for developmental delay,mental retardation, or both. As stated earlier, early-onset seizures have not been proven to increaseone’s risk for developmental delay.19,20 Hemiplegiahas been reported in approximately 30% of patientswith SWS, which may be an underestimation of thisphenomenon as these episodes may be transient andof short duration.21 Headaches are reported morecommonly in adults and are believed to be caused byhemodynamic alterations in the brain.22

Ophthalmologic. Glaucoma is the most com-mon ophthalmologic abnormality seen in patientswith SWS. It is associated with an ipsilateral vascularmalformation of the choroidal vasculature of the eye.The vascular anomaly may be detected on fundu-scopic examination. As stated earlier, glaucoma ismost commonly noted with a capillary malformation

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

J AM ACAD DERMATOL

APRIL 2007

544 Garzon et al

located in either or both of the first two branches ofthe trigeminal nerve. Glaucoma may also be detectedin the eye contralateral to the cutaneous capillarymalformation. Glaucoma is present at birth in ap-proximately two thirds of patients; but may arise aslate as adulthood.16,23 Congenital and early-onsetglaucoma may lead to buphthalmos. In an at-riskinfant with V1 port-wine stains, a large cloudy corneaat birth is an indication of acute glaucoma, anophthalmologic emergency. All patients with capil-lary malformations affecting the lids should beevaluated periodically for glaucoma because earlyidentification and management may prevent lossof vision.

Several mechanisms have been proposed to ex-plain the pathogenesis of glaucoma in SWS. Theseinclude (1) hyperemia of the ciliary body secondaryto the presence of the choroidal vascular malforma-tion, leading to overproduction of aqueous fluid; (2)anomalous chamber angle in early-onset glaucoma;(3) abnormal arteriovenous connections in episcleralvascular plexus, resulting in abnormally elevatedvenous pressures, and (4) premature aging ofthe normal trabecular meshwork in late-onsetglaucoma.23,24

PathogenesisThe pathogenesis of SWS is still not clearly eluci-

dated. Couly and Le Douarin25 analyzed the rostrallimits of the cephalic neural crest using quail andchick chimeras. They demonstrated that the ecto-mesenchyme for the nasofrontal bud (forehead andupper lid) and pia mater (meninges) of the brainshare a common progenitor in the anterior neuralfold. The maxillomandibular dermis is also derivedfrom the neural crest; however, the origin of thesecells is topographically different than those in theforehead and upper lid. The former are derived fromthe hindbrain neural fold. Therefore it has beenhypothesized that a somatic mutation occurring earlyin embryogenesis in the anterior neural fold results inSWS, whereas a similar mutation in the hindbrainneural fold does not, because meninges do not arisefrom this area.25

Radiologic findingsRadiographic evaluation is useful in confirming

the diagnosis of SWS, delineating the extent of theocular and CNS vascular anomalies, and detectingassociated CNS abnormalities, including cerebralatrophy. However, routine radiologic evaluation inthe absence of neurologic symptoms is controversialbecause it may not alter the course of treatment.Plain radiographs of the skull may detect intracranialcalcifications, revealing the classic ‘‘tram-line’’

appearance, but calcifications are often not presentbefore 2 years of age. Newer radiographic tech-niques have made plain films obsolete. After 1 yearof age, computed tomography (CT) can detect cal-cifications that are not visible on plain radiographsand is more sensitive for detecting calcificationsthan magnetic resonance imaging (MRI).26 CT isalso capable of detecting parenchymal volume lossand choroid plexus enlargement. Magnetic reso-nance studies with enhancement are very usefulfor detecting leptomeningeal and ocular vascularmalformations earlier and they more sensitivelydemonstrate gray and white matter abnormalitiesand engorgement of the deep venous system thandoes CT (Fig 3).27-30 More specifically, spin-echoT1-weighted and T2-weighted images with adminis-tration of gadolinium contrast are recommendedfor a complete evaluation of intracranial involve-ment.20,31,32 In addition, single-photon emission CTmay detect areas of hypoperfusion and, thus, latentvascular anomalies, which may not be visible withother imaging studies.33 A recent case report alsosuggests that blood-oxygen-level-dependent mag-netic resonance venography may be useful in earlydetection of venous anomalies.34 Because of theadvent of these newer imaging studies, the moreinvasive radiologic study of cerebral angiography israrely necessary.35 Currently, MRI is recommendedas the method of choice for the diagnosis of SWS.Radiographic studies will help to confirm the diag-nosis and functional cerebral imaging systems, suchas single-photon emission CT and positron emissiontomography, help to determine the extent of neuro-logic involvement to assist in medical and surgicaltherapy.32,36

Diagnosis and managementSWS should be suspected in all patients with facial

capillarymalformations involving theV1dermatome,keeping in mind the watershed area of the trigem-inal nerve. At-risk infants should undergo carefulphysical examination to determine the extent ofthe malformation. Initial ophthalmologic evaluationshould be performed in the neonatal period be-cause of the risk of congenital glaucoma. If the firstcomplete ophthalmologic evaluation is normal, itshould be repeated frequently (some authors havesuggested quarterly evaluations) for the first 2 yearsof life. If the examination results remain normal,the vision should be re-evaluated at least annuallythroughout the patient’s lifetime. When ophthalmo-logic abnormalities are present, their managementwill need to be individualized. Neurologic develop-ment should be monitored carefully. Periodic eval-uation by a pediatric neurologist is an essential

J AM ACAD DERMATOL

VOLUME 56, NUMBER 4

Garzon et al 545

component of the management of SWS. Seizuresassociated with SWS are typically treated with anti-convulsant medications but may prove difficult tocontrol in some situations.

The capillary malformation of the skin can beeffectively lightened by using the pulsed-dye laserfor vascular lesions. On the other hand, the diagnosisand management of intracranial involvement and itsneurologic sequelae pose a more difficult challenge

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

Fig 3. This magnetic resonance study shows gadoliniumenhancement of the leptomeningeal vascular anomalyfound in Sturge-Weber syndrome.

for clinicians. The Sturge-Weber Foundation is anactive support group for patients and families (Website, http://www.sturge-weber.com/).

Klippel-Trenaunay syndromeDefinition. KTS is characterized by a superficial

vascular stain of the skin in association with softtissue and bony hypertrophy of the affected limb,and varicose veins with or without deep venousanomalies (Fig 4). KTS should be distinguished fromParkes Weber syndrome, where the vascular stainis associated with limb overgrowth and significantarteriovenous shunting of the involved limb.37

Lymphatic anomalies of the affected limb may occurconcurrently in both KTS (a slow-flow complexcombined with vascular malformation) and ParkesWeber syndrome (a high-flow complex combinedvascular malformation). The differential diagnosisfor limb enlargement associated with a vascularlesion also includes other disorders that are listedin Table IV. KTS should also be differentiatedfrom Servelle-Martorell syndrome, which is the asso-ciation of capillary stains and varicose veins withrelative undergrowth rather than overgrowth of theaffected limb.38

Cutaneous featuresKlippel and Trenaunay published their initial case

report followed by a review of 51 cases early in39 thetwentieth century, further delineating the character-istics of these patients. The capillary malformationwas noted to involve an entire limb. Varicose veinswere present from birth or appeared during infancyand were associated with limb hypertrophy.37

Typically, the vascular stain is noted at birth andcases involving the lower extremity predominate(Fig 4). Involvement of both the upper and lowerextremities may occur in 10% to 15% of cases and isusually ipsilateral. There are rare reports of ‘‘crossed

Table IV. Differential diagnosis for cutaneousvascular anomaly and limb enlargement

Vascular malformations Vascular tumors

KTS Infantile hemangiomaExtensive venous

malformationKaposiform

hemangioendotheliomaParkes Weber syndrome Tufted angiomaProteus syndromeHemihyperplasia and

multiple lipomasCMTC, macrocephaly-CMTC

(rare; limb hypoplasiamore common)

CMTC, Cutis marmorata telangiectatica congenita; KTS, Klippel-

Trenaunay syndrome.

J AM ACAD DERMATOL

APRIL 2007

546 Garzon et al

bilateral’’ involvement in which contralateral extrem-ities are affected.40 The stain commonly extends ontoadjacent truncal skin.41 The stain is typically large,but even on the affected extremity; some areasof skin may be spared. It may be distributed in aconfluent geographic pattern or more randomly onthe affected limb and adjacent trunk. A recent studysuggests that the presence of a geographic vascularstain is a predictor of the risk of both associatedlymphatic malformation and complications in pa-tients with KTS.42 The geographic vascular stain isred to violaceous and may darken, develop blebs(vesicles of lymphatic malformations), and bleedas the patient matures. Geographic stains are oftenlocated on the lateral aspect of the thigh, knee, andlower leg (Fig 5). Nongeographic stains are pink tored and scattered over the affected limb. In patientswith nongeographic stains, other KTS symptoms(varicose veins and overgrowth) manifest later inlife 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 childhoodor adolescence. One of the more common venousanomalies involves the full length of the lateral limb.It is thought to represent persistence of the embry-onic dorsal vein system that normally disappears inthe first trimester.40 Deep venous anomalies havebeen variably reported in the literature.37,43,44 Avariety of symptoms of varying clinical significancemay be associated with venous varicosities. These

Fig 5. Geographic capillary malformation in patientwith Klippel-Trenaunay syndrome. Sharply demarcatedborder signals an underlying lymphatic anomaly (capillary-venous-lymphatic malformation).

include pain, thrombophlebitis, cellulitis, venousstasis dermatitis, and ulcers.40 Cellulitis of the af-fected limb may manifest as fever and recurrentpainful swelling with sterile cultures. Cutaneousmanifestations include atrophy of the skin, verrucae,and hyperhidrosis.40 Venous varicosities are fre-quently disfiguring. Patients with lower extremityvaricosities may also experience rectal bleeding andhematuria.44-46 Life-threatening complications in-clude deep vein thrombosis, pulmonary embolism,gram-negative sepsis, and coagulopathy.47,48 SWSmay occur in association with KTS.49

Extracutaneous featuresOrthopedic. Limb hypertrophy is caused by

hypertrophy of the soft tissues and bones. When anassociated lymphatic malformation coexists, it willcontribute to the appearance of limb gigantism. Theaffected limb is usually longer and has an increasedcircumference when compared with the unaffectedlimb. The difference in limb length may be slightor quite dramatic. As the patient grows, the lengthdiscrepancy may become more prominent, but pro-gression is not predictable. Limb length enlargementwill cease when the child’s growth cycle is completeat the end of adolescence.40

PathogenesisThe origin of most cases of KTS is unknown. Early

theories suggested that venous changes developedas a consequence of a deep venous obstruction thatresulted in edema and hypertrophy of the limb.43

However, Baskerville, Ackroyd, and Browse50 foundthat few patients with KTS have true atresia of thedeep veins. They hypothesized that a mesodermaldefect affecting vascular development could causethis condition. Although KTS usually is a sporadiccondition, Aelvoet, Jorens, and Roelen51 reportedfamilial cases of KTS that were not inherited in aMendelian pattern. They noted that hemihypertro-phy and vascular lesions occurred more commonlyin some families of an individual with KTS. A multi-factorial inheritance of KTS was suggested. Happle52

subsequently suggested that paradominant inheri-tance of a single gene defect could explain thedevelopment of KTS as well as the occurrence ofboth familial and sporadic cases. He noted that thelesions of KTS were arranged in a mosaic pattern.Heterozygotes for a defective gene would be phe-notypically normal, but the defective allele could betransmitted throughout many generations. The syn-drome would only occur if a somatic mutationoccurred during embryogenesis that resulted in aloss of heterozygosity. This would result in a clonalpopulation of cells that were homozygous or

J AM ACAD DERMATOL

VOLUME 56, NUMBER 4

Garzon et al 547

hemizygous for the KTS mutation. Happle52 postu-lated that germline homozygous expression of thegenetic defect would likely be incompatible with life.

In 1995, a single case of KTS was associated with5:11 balanced translocation.53 Since then, moleculargenetic analysis has identified 5 of 130 patients withKTS who have overexpression of VG5Q, an impor-tant angiogenic factor that is located on chromosome5q13.3. More specifically, these 5 patients had agenomic mutation in E133K, acting by a gain-of-function mechanism and causing up-regulation ofVG5Q, resulting in increased angiogenesis.54 Inaddition, Timur et al55 recently reported identifica-tion of a de novo supernumerary ring chromosome18 in a patient with KTS, mild mental retardation,tapered digits, and elongated thin feet. Thesefindings suggest that KTS is likely a geneticallyheterogeneous disorder. However, these recentdevelopments may guide further research on thepathogenesis of sporadic causes of KTS.

Radiologic findingsSeveral radiographic studies are helpful in man-

agement. Echo/Doppler and duplex scans are thestudies of choice to evaluate for superficial and deepvenous anomalies, as well as arteriovenous shunting.Plain radiographs or ortho-roentenography (‘‘scan-ograms’’) can be used to evaluate for bony hyper-trophy, but in young patients the discrepancy may bea subtle radiographic finding. MRI of the lower limbwill delineate the extent of soft-tissue hypertrophy,bone involvement, and presence of an associatedlymphatic anomaly.56 MRI is also helpful in differen-tiating KTS from an extensive venous malformationof the extremities; KTS has no or only minor muscleinvolvement. Venography can be useful before treat-ment of varicose veins to assure the presence of apatent deep venous system.

Diagnosis and managementKTS should be suspected in all infants with cap-

illary malformations involving a limb. The differentialdiagnosis 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 withVenous Malformations, Lymphatic Malformations, orMixed Malformations’’ below) and isolated nonsyn-dromic capillary malformation of the skin. If KTS isdiagnosed, regular monitoring of leg lengths is man-datory. If significant differences (typically[2 cm) aredetected, or progressive lengthening occurs, pediat-ric orthopedic evaluation should be obtained. Themanagement of limb length discrepancy should be

individualized and will depend upon many factors,including the extent of the limb length difference, thepatient’s age, and limb function. Percutaneous epi-physeodesis is one method that has been used tocause growth arrest of the longer limb.

Physical examination of the patient with KTSshould include auscultation and palpation of theinvolved area to assess for the presence of anarteriovenous malformation (AVM) to rule out ParkesWeber syndrome. An arterialized component ofthe malformation should be suspected if unusualwarmth or pain is noted. Serial measurements of theextremity should be performed to assess for hyper-trophy. It is regarded as prudent to screen for Wilms’tumor with ultrasonography in patients with hemi-hypertrophy. However, recent studies have shownno increase in incidence of Wilms’ tumor in patientswho demonstrate hemihypertrophy occurring inassociation with KTS. Therefore screening is cur-rently not routinely recommended.57

Many patients with KTS can be managed conser-vatively with elastic support garments. These gar-ments protect the limb from trauma and decreasethe swelling associated with venous insufficiency.Patients with atresia of the deep venous system maycomplain of pain with compression. Surgery is gen-erally reserved for those patients with symptomaticsuperficial varicose veins. Detailed evaluation andanatomic mapping of the venous system of the limbis mandatory before surgery. Complete resection ofvaricose veins will not halt bony hypertrophy.44,48

Capillary malformations may be treated with thepulsed-dye laser, but results are less satisfactory thanfor facial and truncal lesions. Lymphatic bleedingblebs are difficult to eradicate and may requiretreatment with surgical excision or destructive lasertechniques.

Cutis marmorata telangiectatica congenitaDefinition. Cutis marmorata telangiectatica

congenita (CMTC) is an uncommon and distinctivecutaneous vascular malformation. First describedby van Lohuizen58 in 1922, CMTC is characterizedby a fixed reticulated vascular pattern on the skinthat resembles physiologic cutis marmorata. Variousnames have been used to describe this disorder,including nevus vascularis reticularis and congenitallivedo reticularis. CMTC is the preferred designa-tion.59,60 A few series have noted CMTC to have afemale preponderance.59,61,62

Cutaneous featuresCMTC is usually noted at birth and may have a

localized orgeneralizeddistribution.When localized,it often has a sharply segmental pattern (Fig 6).

J AM ACAD DERMATOL

APRIL 2007

548 Garzon et al

The reticulated pattern may be fine or coarse, withbroad streaks of discolored skin in a ‘‘tram-track-like’’ pattern. One may also see erythema andtelangiectases associated with the reticulated pat-tern. CMTC can be differentiated from physiologiccutis marmorata by its persistence after the infanthas been warmed and by the presence of lineardepressed lines, usually more prominent over thelimb joints. Atrophy of the skin and subcutaneoustissues that may manifest as hypoplasia of theaffected limb, has been reported, but is an inconstantfeature.60 Ulceration of the affected skin may also beseen in association with CMTC, particularly wheninvolving the skin overlying elbows and knees.59

CMTC may be seen in association with a port-winestain type of capillary malformation and discretesuperficial varicose veins. These malformations mayoccur distant to the area of CMTC or within the sameaffected area.59

Extracutaneous featuresCMTC occurs as an isolated anomaly in the major-

ity of localized cases; however, associated congenitalanomalies have been reported in 27% to 50%of cases.59,60 Associated abnormalities are morecommon in generalized cases of CMTC. The mostcommon associated congenital anomaly is limb hy-poplasia. Other rare associations include limb hyper-plasia, aplasia cutis congenita, congenital pigmentednevus, widespread dermal melanosis (mongolianspot), skull asymmetry, syndactyly, scoliosis, hypo-thyroidism, developmental delay, and anogenitalanomalies.59,60,62-66 Glaucoma has also been re-ported in association with facial CMTC overlyingthe lids.59,67 A clinically distinct condition has beendescribed that comprises CMTC and congenital mac-rocephaly together with prenatal and postnatal mac-rosomia, segmental overgrowth, CNS malformations,connective tissue abnormalities, and intellectualhandicap (see below).68,69 CMTC is also described

Fig 6. Cutis marmorata telangiectatica congenita involv-ing upper extremity. Note sharp cut-off of the affectedarea.

as a feature of Adams-Oliver syndrome and will bediscussed in following sections.

PathogenesisThe cause of CMTC is unknown. Histologic

examination of biopsy specimens obtained frompatients has shown inconsistent results. Some au-thors report dilated capillaries in the dermis andsubcutaneous tissue, whereas others could detect novascular anomaly. Sparse dermal perivascular lym-phocytic infiltrates and swelling of endothelial cellshas also been reported.59 Rogers and Poyzer70 fromAustralia reported a series of 4 infants with CMTC, allborn within a 20-km radius over an 18-month period;although they could not find any convincing evi-dence for an environmental or genetic factor, theysuggested the possibility of a common dysmorpho-genic environmental agent in the pathogenesis.Other authors have proposed that the segmentaldistribution, often with a sharp midline separation,suggests that CMTC may be a disorder characterizedby genetic mosaicism in which a lethal gene survivesby partial or mosaic expression.62,71

CMTC appears to occur sporadically; however, agenetic basis has been proposed in a few cases.72

One author suggests paradominant inheritance. Inother words, heterozygous individuals are pheno-typically normal. Therefore the mutation can betransmitted unperceived through many generations.This syndrome only becomes manifest when apostzygotic somatic mutation occurs during earlyembryogenesis, forming a mosaic population of cellsthat is homozygous for the mutation.73

Diagnosis and managementCMTC should be differentiated from other disor-

ders, including Bockenheimer syndrome (diffusephlebectasia). Some port-wine stain capillary mal-formations may also have a reticulated pattern,which makes distinguishing them from CMTC diffi-cult. It is important to distinguish CMTC from awidespread diffuse, generalized form of a ‘‘livedoid’’capillary malformation and is not associated withatrophy, ulceration, or limb hypoplasia. This type ofcapillary malformation is associated with a signifi-cant risk of associated visceral vascular anomalies(eye, brain, kidneys, and heart) and may representmacrocephaly-CMTC and requires evaluation andfollow-up (personal communication, O. Enjolras,MD, May 2000). CMTC should also be differentiatedfrom persistent true cutis marmorata that can beseen in trisomy 21, Cornelia de Lange syndrome,and homocystinuria.

Unlike port-wine stain capillary malformations,CMTC has a tendency to lighten with maturity in

J AM ACAD DERMATOL

VOLUME 56, NUMBER 4

Garzon et al 549

many, but not all, patients.74 Marked improvementis often noted in the first 2 years of life.62 Whenlightening occurs, it is rarely complete and may leaveresidual reticulate lesions.59,60,62 Patients with CMTCshould undergo careful physical examination toassess for other congenital anomalies. Measurementof limb length and girth should be performed at thetime of evaluation. Affected individuals should beinformed that the lesion may lighten with maturityand ulcerations should be treated with local support-ive care, including application of hydrocolloid dress-ings. If lesions persist, they may be treated with thepulsed-dye laser, although the response is variable.

Macrocephaly-CMTC syndromeMacrocephaly-CMTC syndrome (M-CMTC) is a

rare sporadic disorder that has recently been rec-ognized to be a distinct disorder that should bedifferentiated from CMTC. It is characterized by aCMTC-like vascular malformation occurring in asso-ciation with macrocephalic neonatal hypotonia anddevelopmental delay. The skin lesion is typically apatchy reticulated vascular stain and lacks the asso-ciated cutaneous atrophy that is often seen in typicalCMTC; therefore this vascular malformation is bettercategorized as a reticulated capillary malformationrather than true CMTC. A midline facial nevus flam-meus (capillary malformation) is also reportedto be present in most cases described in the litera-ture. Other associations include hydrocephalus,connective tissue defects (soft skin, joint hypermo-bility), toe syndactyly, frontal bossing, and, rarely,hemihypertrophy.68

Adams-Oliver syndromeAdams-Oliver syndrome is a rare disorder charac-

terized by CMTC occurring in association with aplasiacutis congenita of the scalp, and bony abnormalitiesof the limbs and cranium.75,76 Congenital cardiacmalformations are reported in some patients with thisdisorder.77 It has been suggested that Adams-Oliversyndrome represents a disorder that results from anearly embryologic vascular abnormality.78,79 Autoso-mal 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 associa-tion of capillary malformations, branchial clefts, lippseudoclefts, and unusual facial appearance in 1957,and several cases have been reported subsequently.Most commonly, patients are noted at birth to havecervical/infra-auricular skin defects that may appearaplastic or as vascular stains erroneously called‘‘hemangiomatous,’’ with draining sinus fistulas.

Rarely, these skin lesions may be supra-auricular.Anomalous retroverted ears, microphthalmia, naso-lacrimal duct obstruction, pseudocleft lip, cleft lip,or cleft palate are part of this unusual syndrome.84

Roberts/SC phocomelia syndromeRoberts/SC phocomelia syndrome is a rare auto-

somal recessive disorder characterized by severelimb defects and cleft palate. Some patients haveglabellar vascular stains.85,86 Patients who sharefeatures that overlap between thrombocytopeniaeabsent radius (TAR) syndrome and this disorder havebeen described (see ‘‘ThrombocytopeniaeAbsentRadius Syndrome,’’ below).87 Cytogenetic studiesof some patients have shown consistent chromo-somal abnormalities, including premature centro-mere separation and centromere splitting andpuffing.88,89 No genetic locus defect has yet beenidentified for this syndrome.

Rubinstein-Taybi syndromeRubinstein-Taybi syndrome was described in

1963.90 It is a rare sporadic condition characterizedby mental retardation, growth retardation, broadthumbs, broad, large toes, and a typical facial ap-pearance. Skin manifestations include hirsutism,capillary malformations, keloid and excessive scarformation, and, rarely, cafe au lait macules. Capillarymalformations are an inconstant feature of thissyndrome.91

The gene for this disorder has been localized tochromosome 16p13.3. Patients with growth retarda-tion, coloboma, capillary malformation, and hypo-tonia appear to be more likely to demonstrate adeletion in this region.92 This region contains thegene for the human cyclic AMP-response elementbinding (CREB) protein (CBP). The loss of functionof this gene eliminates expression of CBP, therebyabolishing histone acetyl transferase activity andimpairing the ability to transactivate CREB.93 Recentmouse studies suggest that some of the cognitive andphysiologic deficits observed in Rubinstein-Taybisyndrome are not simply due to the reduction ofCBP during development but may also result fromthe continued requirement throughout life for boththe CREB coactivation and histone acetylation func-tion of CBP.94 In addition, the long-term memorydefect in mice induced by loss of function of CBPhas been suggested to improve with enhancementof CREB function with drugs such as inhibitors ofphosphodiesterase 4.95

Thrombocytopeniaeabsent radius syndromeTAR syndrome is a rare autosomal recessive

disease characterized by hypomegakaryocytic

J AM ACAD DERMATOL

APRIL 2007

550 Garzon et al

thrombocytopenia and bilateral radial aplasia withnormal thumbs. Anemia, eosinophilia, leukemoidgranulocytosis, and lower limb abnormalities arecommon associated features.96,97 Many patients arenoted to have a capillary malformation of the fore-head. Ashinoff and Geronemus98 described a patientwith TAR syndrome and a widespread capillarymalformation involving the head and neck whoresponded poorly to treatment with the flash-lamppulsed-dye laser. Some studies suggest that defectivesignal transduction in the c-mpl pathway, preventingthrombopoietin-induced tyrosine phosphorylationof platelet proteins, may impair megakaryocytopoi-esis, contributing to some cases of TAR syndrome.99

No genetic locus defect has yet been identified forthis syndrome.

Beckwith-Wiedemann syndromeBeckwith-Wiedemann syndrome is characterized

by gigantism, omphalocele (exomphalos), and mac-roglossia.100 Posterior helical ear pits, hypoglycemia,predisposition for tumors (Wilms’, rhabdomyosar-coma, hepatoblastoma, adrenal tumors), and facial,usually centrofacial, capillary malformations alsooccur in this syndrome. These stains are virtuallyidentical to salmon patches (nevus simplex) butare more often persistent. The mode of inheritanceis complex. The majority of cases are sporadic,although there are several reports of families withautosomal dominant inheritance of this syndrome.Although inheritance of this genetic defect appearsto be autosomal dominant, recent studies suggestthat this syndrome is only phenotypically expressedwhen maternally inherited.

Cytogenetic analysis reveals dysregulation ofimprinted genes on chromosome 11p15. This regionis composed of two distinct domains with multipleimprinted genes regulated by two imprinting cen-ters. Among these imprinted genes, overexpressionof IGF2 (domain 1) and p57KIP2 (domain 2) areidentified to be involved in the pathogenesis ofBeckwith-Wiedemann syndrome. Identifiable muta-tions are rare and mostly involve the p57KIP2 gene,the majority identified in families with an autosomaldominant inheritance pattern. In addition, 40% ofcases involve activation of the normally silent ma-ternal allele p57KIP2 by loss of imprinting of LIT-1.101

Interestingly, up-regulation of insulin-like growthfactor 2 has been associated more often with Wilms’tumor, whereas a mutation in p57KIP2 may be relatedto embryonal tumor types, such as rhabdomyosar-coma and hepatoblastoma.102 Understanding thegenetic inheritance and specific mechanisms fortumorigenesis will assist in genetic counseling, earlytumor detection, and prognostic determination.

Nova syndromeNova syndrome is characterized by a capillary

malformation in the glabellar area, communicatinghydrocephalus, posterior fossa brain abnormalities,including Dandy-Walker malformation, agenesis ofthe cerebellar vermis, and mega cisterna magna.Occasionally, seizures are seen. Autosomal domi-nant inheritance has been suggested.103

Phakomatosis pigmentovascularisDefinition. Phakomatosis pigmentovascularis

(PPV) is the term used to describe a group ofdisorders that are characterized by the presence ofa capillary malformation and a ‘‘pigmented’’ nevus.First described in the Japanese dermatologic litera-ture, these associated anomalies are classified into4 subgroups. The classification of this disorder iscontroversial. Type I is characterized by the pres-ence of a capillary malformation (port-wine stain)and an epidermal nevus. Type II, the most commonform, is characterized by the presence of a port-winestain and aberrant mongolian spots. Type III isdefined as the presence of a port-wine stain andnevus spilus. Type IV includes a port-wine stain,nevus spilus, and aberrant mongolian spots. Nevusanemicus is a variable component of the latter 3types. Recently, it has been proposed that theassociation of CMTC with aberrant mongolianspots be classified as PPV type V.104 Hasegawa andYasuhura105 proposed a classification that furtherdivided these groups into localized (a) and systemic(b) forms. Recently Happle106 has proposed a sim-plified classification, based on the types of predom-inant skin lesions.

Clinical characteristicsPPV is rare and arises sporadically. It is slightly

more common in females than males.105 The vascu-lar birthmark is invariably a capillary malformation ofthe skin. It may be located on any part of the bodyand may affect large segments of the body. PPV typeII is the most common type of PPV and accounts formore than 80% of reported cases.107 The pigmentanomaly has been called an aberrant mongolian spotbecause it persists and the distribution differs fromthat seen in mongolian spots. Histologic examinationreveals dermal melanosis and melanocytosis. Notsurprisingly, several cases of SWS or KTS seen inassociation with oculocutaneous melanosis or nevusof Ota or Ito have been reported in the literature andare considered by some authors to be a form oftype II PPV.108-110 PPV types III and IV have been re-ported in association with nevus spilus. A variety ofextracutaneous abnormalities, such as selective IgA

J AM ACAD DERMATOL

VOLUME 56, NUMBER 4

Garzon et al 551

deficiency, endocrinopathies, granular cell tumors,iris mammillations, have been reported in associa-tion with PPV.111-113

PathogenesisThe pathogenesis of PPV is poorly understood.

An abnormality in morphogenesis that occurs earlyin development and affects cells that are precursorsto the vascular and pigment system has been postu-lated.108 Dunarti and Happle114 and Happle115 havehypothesized that PPV is due to so-called ‘‘twinspotting’’ whereby somatic mutations on neighbor-ing genes give rise to mosaic spots in close proximityto one another. Such a finding that has been seen inthe plant kingdom has not been confirmed in verte-brates.114-116 Another possible mechanism could beone or more somatic mutations causing dysregula-tion in multiple embryonic cell lines, includingmelanocytes and the fetal vasculature.

Diagnosis and managementThe diagnosis of PPV is established on the basis of

clinical findings. Patients with vascular birthmarksinvolving the face, trunk, and limbs should undergoevaluation for SWS or KTS. Ocular evaluation isessential to rule out glaucoma in those cases in whichthe pigment or vascular birthmark affects the peri-ocular skin.117

SYNDROMES ASSOCIATED WITHVASCULAR STAINS AND HIGH-FLOWLESIONS (AVM)Bonnet- Dechaume- Blanc syndromeor Wyburn-Mason syndrome

Definition and clinical characteristics. Wyburn-Mason syndrome (Bonnet-Dechaume-Blancsyndrome)was first reported by Bonnet and his coauthorsin 1937 and was later reported in the English-language literature by Wyburn in 1943.118,119 Theseterms are generally considered to be synonymous.This rare syndrome is characterized by cerebralAVMs that usually involve the midbrain, an ipsilateralretinal vascular malformation, and a red stain ofthe facial skin often misinterpreted as a capillarymalformation, in fact a quiescent Schobinger stage IAVM.120,121

The vascular malformation of the skin is aninconstant finding in Wyburn-Mason syndrome.When present, it either is unilateral and involvesthe skin innervated by the trigeminal nerve or it iscentrofacial, involving the mid forehead, glabella,nose, and upper lip. Bilateral capillary stains havebeen reported. Patients may present with ocular orCNS complaints, including headaches and seizures.

The degree of ocular and CNS involvement is relatedto the extent of the underlying malformations andpossible bleeding.

PathogenesisThe pathogenesis of this disorder is poorly un-

derstood. The constellation of features is believedto be the result of vascular dysgenesis that occursduring embryogenesis.

Diagnosis and managementRetinal vascular malformations may be detected

on funduscopic examination. Magnetic resonancestudies will help to define the extent of the ocularvascular malformation and CNS AVM. Cerebral angi-ography assists in characterizing the AVM and maybe performed to discuss whether a non-high-risktreatment is possible to consider (embolization).122

Wyburn-Mason syndrome should be differentiatedfrom SWS. The latter is characterized by the presenceof a capillary malformation of the face includingthe V1 area, a slow-flow leptomeningeal vascularmalformation, cerebral atrophy, and calcifications.Patients with hereditary hemorrhagic telangiectasia(HHT) may also present with CNS AVM or arteriove-nous fistula; however, telangiectases of the skinand mucosal surface are the typical cutaneousfindings.123

Parkes Weber syndromeParkes Weber syndrome is defined by the over-

growth of an extremity linked to the presence of anAVM with multiple arteriovenous fistulas along theaffected extremity, well evidenced by ultrasound/Doppler or magnetic resonance angiography, inaddition to a cutaneous red stain, which is a quies-cent Schobinger stage I AVM. Parkes Weber syn-drome more commonly affects the lower extremities(Fig 7). During childhood the angiogram oftenshows enlarged arteries and patchy areas of hyper-vascularization; arteriovenous fistulas usually de-velop around puberty or after trauma (includingany surgical procedure performed on the affectedlimb). This disease may be complicated by high-output congestive cardiac failure. Significant leglength discrepancy may require epiphyseodesis,but this should be in the least invasive form possible(percutaneous epiphyseodesis) to avoid worseningof the AVM.124 Lymphatic anomalies and lymphe-dema can be present. At the lower limb level, thesemay occur in association with hypertrophied digits,creating severe deformity, papillomatosis of thetoes, and recurrent infection, occasionally requiringamputation.

J AM ACAD DERMATOL

APRIL 2007

552 Garzon et al

Capillary malformationeAVM syndromeCapillary malformationeAVM syndrome is a

recently described hereditary disorder that is char-acterized by cutaneous capillary malformationoccurring in association with high-flow vascularlesions (AVMs or arteriovenous fistula). This condi-tion is caused by mutations in the RASA1 gene. Thisgene encodes for a protein that plays an importantrole in the signaling for growth factor receptorsinvolved in the proliferation migration and survivalof various cell types, including endothelial cells(as signaling pathway).125 Phenotypic variability isdescribed. The high-flow lesions may be located inthe skin and subcutaneous tissue, bone, muscle, orbrain. Some of these patients have the clinicalfeatures of Parkes Weber syndrome (see above).The capillary malformations are often small pink-redmacules that may be widely distributed over the skinsurface; a pale halo may be noted at their periphery.Larger solitary capillary malformations are alsoreported in this condition.126

Cobb syndromeCobb syndrome is a rare nonhereditary disorder

that involves the association of spinal ‘‘angiomas’’ orAVMs with congenital, cutaneous vascular lesions,not a true capillary malformation (port-wine stain),but a quiescent Schobinger stage I AVM in the samedermatome. The importance of this syndrome is therecognition that cutaneous vascular lesions may hintat an accompanying spinal cord angioma or AVM thatmay result in variable neurologic complications.

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

SYNDROMES ASSOCIATED WITHVENOUS MALFORMATIONS, LYMPHATICMALFORMATIONS, OR MIXEDMALFORMATIONSBlue rubber bleb nevus syndrome

Definition. Blue rubber bleb nevus syndrome(Bean syndrome) is a rare disorder characterized byvenous malformations of the skin and gastrointesti-nal tract. In 1860, Gascoyen first reported this con-stellation of features, which was then followed byscattered reports. Bean127 reported two additionalcases and reviewed the literature in 1958. He coinedthe term ‘‘blue rubber bleb nevus syndrome’’ todescribe the characteristic skin and gastrointestinalfeatures.

Clinical characteristicsBlue rubber bleb nevus syndrome occurs sporad-

ically; several reports of familial cases exist withproposed autosomal dominant inheritance pattern,but it seems that there was a confusion in theliterature with the more recently described venousmalformations, multiple cutaneous and mucosalsyndrome (OMIM 600195), an autosomal dominantvenous malformation syndrome linked to TIE2/TEKmutation, located on chromosome 9p21, a syndromewhich does not include visceral venous malforma-tions, and, in particular, no gastrointestinal tractlesions. Venous malformations are usually apparentat birth or during early childhood, although onsetof symptoms in adulthood has been reported.129

The most characteristic skin lesion is a compressibleblue subcutaneous nodule (Fig 8). Bean127 likenedthe appearance of this lesion after compression toa ‘‘rubber nipple.’’ Cutaneous venous malformationscan vary greatly in size and number and becomemore apparent as a patient matures. The first darkblue spot often appears on previously absolutelynormal skin soon after birth, and their numbersincrease over the years. They may be found on anysurface of the skin and mucosa, including the scalp,but are commonly located on the trunk and extrem-ities (palms and soles). Patients may report associ-ated tenderness with palpation or at rest. Localizedhyperhidrosis has been reported in association withpainful lesions.128 Venous malformations located onextremities may be associated with orthopedic com-plaints including painful ambulation when the solesare involved, bone deformities that occur as a con-sequence of direct compression, pathologic frac-tures, and extension of the venous malformation tothe underlying muscle or joint.128,130

Gastrointestinal tract venous malformations causethe most significant morbidity in blue rubber blebnevus syndrome. The entire bowel may be affected,

J AM ACAD DERMATOL

VOLUME 56, NUMBER 4

Garzon et al 553

but involvement of the small intestine and colonis most common. Symptoms may develop duringchildhood or adulthood. Patients may lack symp-toms of gastrointestinal involvement, but have ane-mia from chronic occult intestinal blood loss andmelena. Rectal bleeding and abdominal pain, whichmay be a consequence of intussusception and hem-orrhage, can also occur.129,131 In addition to anemia,consumptive coagulopathy is commonly observedin these patients, with high D-dimer levels and lowfibrinogen, responsible for severe hemorrhagesas early as infancy.132 Venous malformations mayalso be found in the CNS, orbit, and genitourinarytract.133-137 Bleeding, pain, and compression associ-ated with subcutaneous or visceral venous malfor-mations may result in functional impairment.

PathogenesisThe pathogenesis of blue rubber bleb nevus

syndrome has not been elucidated.

Diagnosis and managementBlue rubber bleb nevus syndrome should be

suspected in patients who present with cutaneousvascular malformations. The differential diagnosisfor this condition includes isolated venous malfor-mations of the skin or mucosa, HHT, multiple glomustumors (glomuvenous malformation), and Maffuccisyndrome. Patients should undergo evaluation foroccult gastrointestinal involvement and anemia.MRI and computed tomographic scans may assistin identifying the extent of lesions in muscles andviscera.131,138 Destructive modalities, including car-bon dioxide laser, sclerotherapy, and surgical exci-sion, have been used to treat cutaneous lesions.139

Symptomatic gastrointestinal venous malformationsmay be treated with argon or Nd:YAG laser ablationor surgical resection.140,141 Systemic steroids havebeen used with some success in controlling growthof intestinal lesions.142 Recent case reports haveshown treatment with interferon alfa to help withregression of coagulopathy and treatment withsubcutaneous octreotide to reduce bleeding ingastrointestinal lesions.143,144

PROTEUS SYNDROMEDefinition

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

Clinical characteristicsIn the initial description of this syndrome,

Weidemann, Burgio, and Aidenhoff proposed thefollowing criteria for diagnosis: gigantism of thehands and/or feet, pigmented nevi often associatedwith ‘‘raised and rough’’ skin, hemihypertrophy,subcutaneous masses, skull abnormalities, acceler-ated growth, and visceral abnormalities (Fig 9). Sincethen, patients reported in the literature with Proteussyndrome have had such variable clinical character-istics that concern had been expressed for misdiag-nosis and overreporting of this syndrome.146,147

Therefore, in 1998, a workshop on Proteus syn-drome was held by the National Institutes of Health,and recommendations of diagnostic criteria weredeveloped.148 In 2004, upon review of all reportedcases of Proteus syndrome in the literature andfurther inspection of confusion or misunderstandingof criteria, the diagnostic criteria were again slightlyrevised. Of note, of the 205 cases reported in theliterature, only 97 cases met the diagnostic criteriafor Proteus syndrome.149 Patients must meet boththe general and specific criteria to be accuratelydiagnosed with Proteus syndrome. The generalcharacteristics of a mosaic distribution of lesions,progressive clinical course, and sporadic occurrenceare considered mandatory. The diagnostic criteria forProteus syndrome are listed in Table V. The mostcharacteristic manifestation is a cerebriform thicken-ing of the palms and soles (connective tissue nevus)(Fig 10).150-152 Linear verrucous epidermal nevi arefrequently reported in affected individuals.153 Owingto the presence of widespread epidermal nevi,Proteus syndrome should be differentiated fromepidermal nevus syndrome (Solomon syndrome).Although the vascular anomalies described inProteus syndrome are not well characterized, clinicalexperience suggests that capillary, venous, lym-phatic, and combined slow-flow malformationsidentical to KTS may occur. Extremity deep venousthrombosis and pulmonary embolism may alsooccur. The presence of the more characteristic

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

J AM ACAD DERMATOL

APRIL 2007

554 Garzon et al

anomalies associated with Proteus syndrome estab-lishes the diagnosis.

Pulmonary abnormalities are reported in somepatients with Proteus syndrome. These includepulmonary cysts, which may be rapidly progressive,and lead to recurrent infections. Renal abnormalitiescan also be seen, including renal cysts, vascularanomalies, and diabetes insipidus.151 A characteristicfacial phenotype has been noted in patients withseizures and severe mental retardation. These pa-tients are noted to have dolichocephaly, long face,mild downslanting of the palpebral fissures, mildptosis, a low nasal bridge and an open mouth atrest.151 Structural malformations of the brain are seenwith increased frequency in Proteus syndrome.151

Seizures are also noted in approximately 13% ofpatients. Patients with Proteus syndrome usuallydemonstrate normal intelligence.

PathogenesisThe pathogenesis of Proteus syndrome is poorly

understood. Happle154 proposed that it represents adisorder caused by somatic mosaicism of a mutatedgene that would be lethal in its nonmosaic state Thistheory of a postzygotic mutation has been supportedby other authors, evidenced by the mosaic pattern ofcutaneous lesions and discordance in identical twinpairs.155 The mutated gene may result in an alterationof an important tissue growth factor or its recep-tor.153,156 Over the past few years, it has also beensuggested that PTEN tumor suppressor gene is

Fig 9. Proteus syndrome. Note significant hemihypertro-phy and deformity of the foot, in addition to capillarymalformation on abdomen.

defective in patients with Proteus and Proteus-likesyndrome.157 Turner, Cohen, and Biesecker149 havesince argued that, in analyzing these cases, thesepatients do not actually meet diagnostic criteria andsuggest that PTEN has no association with Proteussyndrome.

Diagnosis and managementThe diagnosis of Proteus syndrome is established

on the basis of clinical features. Recently, a study of

Table V. Diagnostic criteria for Proteus syndrome

For diagnosis: General criteria (mandatory) 1 specificcriteria (category signs)

General criteria: Specific criteria:Mosaic distribution

of lesionsEither one from A or two from B

or three from CProgressive courseSporadic occurrence

Category signs ManifestationsA 1. Connective tissue nevus

B 1. Epidermal nevus2. Disproportionate overgrowth

(one or more)3. Specific tumors before end of

second decade (either one)Bilateral ovarian cystadenomasParotid monomorphic adenoma

C 1. Dysregulated adipose tissue(either one) LipomasLipomasRegional absence of fa

2. Vascular malformations(one or more)Capillary malformationVenous malformationLymphatic malformation

3. Lung cysts4. Facial phenotype

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.

J AM ACAD DERMATOL

VOLUME 56, NUMBER 4

Garzon et al 555

24 patients showed that the number of cutaneousmanifestations predicted the extent of extracutane-ous abnormalities, possibly predicting prognosis.158

Management to date is largely supportive.

Hemihyperplasia multiple lipomatosissyndrome

This syndrome was reported by Biesecker et al159

who described a group of patients that had previ-ously been designated to have Proteus syndromebut did not meet the diagnostic criteria and did notappear to have distinct features. In addition, thesepatients showed more overgrowth than is typicallyseen in KTS. These individuals present with hemi-hyperplasia at birth and moderate overgrowth withsubcutaneous lipomas, which remains relativelystable from infancy through preadolescence in mostpatients. Superficial capillary malformations arereported in some of these patients. Affected personslack deep vascular malformations, epidermal nevi,connective tissue nevi, and bony exostoses thatcharacterize Proteus syndrome. Moreover, they alsolack the features of Bannayan-Riley-Ruvalcaba syn-drome (BRRS), including cutaneous pigmentedmacules and macrocephaly (see following section).A provisional designation has been given to thissyndrome because once the genetics of this orderare elucidated, it may prove to represent a milderform of Proteus syndrome.

Bannayan-Riley-Ruvalcaba syndromeDefinition and clinical characteristics. BRRS

represents a disorder that had previously been clas-sified under the eponyms Bannayan-Zonana syn-drome, Riley-Smith syndrome, and Ruvalcaba-Myhresyndrome. This is an autosomal dominant conditionwith a variable clinical phenotype. The predominantclinical features are macrocephaly, developmentaldelay, pseudopapilledema, pigmented macules onthe glans penis, and hamartomatous growths, in-cluding subcutaneous and visceral lipomas, gastro-intestinal polyposis, and what are often described as‘‘hemangiomas’’ (capillary malformations and com-bined malformations).160,161 Subcutaneous lipomasand hyperpigmented macules on the glans penis aretwo of the most common cutaneous manifestationsin this syndrome. Affected persons may also have anincreased number of cafe au lait macules. Vascularanomalies are present in only 10% of patients.161

The associated vascular anomalies have been poorlycharacterized in the literature and erroneously calledhemangiomas. They are reported to persist intoadulthood in some patients. It is likely that they arecapillary malformations or combined malformations.Other less common manifestations include testicular

enlargement, thyroiditis, hyperextensible joints,pectus excavatum, and scoliosis.161

PathogenesisSeveral patients with overlapping features of

Cowden syndrome and BRRS have been reported inthe medical literature.162 In 1997, evaluation of twofamilies with BRRS revealed mutations in the PTENgene, a tumor suppressor gene that had previouslybeen recognized as the gene mutated in Cowdensyndrome.163-165 Since then, there have been multi-ple families reported to have members with bothsyndromes.166 This association suggests that BRRSand Cowden syndrome are allelic conditions.167

Diagnosis and managementThe diagnosis of BRRS should be considered in

children with macrocephaly, pigmented lesions onthe genitalia (males), lipomas, and vascular growths.A careful family history should be obtained forfeatures that would be suggestive of Cowden dis-ease. Proteus syndrome should be considered in thedifferential diagnosis, but is usually associated withmore significant overgrowth and thickened palmsand soles. Neurologic and gastrointestinal assess-ments should be performed in patients in whomthe diagnosis is suspected. Recently, it has been sug-gested that, because of the close association withCowden disease, patients with BRRS should bescreened for the malignant tumors commonly asso-ciated with that disorder. Although clear guidelinesdo not exist, physicians caring for these patientsshould be aware of this potential.167

Maffucci syndromeDefinition. First described by Angelo Maffucci

in 1881, Maffucci syndrome is a rare sporadic geneticdisorder typically comprising enchondromas andvascular anomalies (both nodules of venous malfor-mations and of a distinctive tumor, the spindle cellhemangioendothelioma).168

Clinical characteristicsApproximately 160 cases have been reported

worldwide, 100 of which have been from theUnited States. There is no observed sex or racialpreference. Affected persons appear normal at birth.The disease usually manifests in early childhood,when multiple superficial and deep venous malfor-mations appear as asymmetric blue or purple, soft,occasionally tender nodules, sometimes masses,usually in the distal extremities (Fig 11). Oralor intra-abdominal vascular anomalies, includingvenous and lymphatic anomalies, may also befound.169,170 Simultaneously enchondromas develop

J AM ACAD DERMATOL556 Garzon et al

that present as hard nodular lesions, most frequentlyin the phalanges and long bones. Complicationsinclude phlebolith formation within vascular malfor-mations, short stature, bone irregularities, such asshortened long bones and pathologic fractures, withsubsequent distortion of limbs, and malignant trans-formation of enchondromas into chondrosarcomas.Approximately 30% to 40% of enchondromas trans-form into chondrosarcomas. Although chondrosar-comas are by far the most common neoplasmencountered, Maffucci syndrome is associated withmany other malignancies. There have been severalreports of associations with breast, ovarian, pancre-atic, parathyroid, and pituitary tumors.171,172 Thespindle-cell hemangioendothelioma (also desig-nated spindle-cell hemangioma in the literature), avascular tumor, is commonly found either besidethe venous nodules, as a cutaneous mass, or inter-mingled with the venous malformation on patho-logic sections in Maffucci syndrome. Patients withMaffucci syndrome usually have normal life expec-tancy if no malignant transformation occurs.

PathogenesisThis disease appears to develop from mesodermal

dysplasia early in life, with no obvious inheritancepattern. Although there is no genetic locus identifiedto cause all of the clinical features of Maffuccisyndrome, a mutation in the Indian hedgehog/parathyroid hormoneerelated protein (IHH/PTHrP)pathway is suggested to be responsible for thedevelopment of enchondromatosis. IHH promoteschondrocyte proliferation, whereas PTHrP is nor-mally responsible for delaying hypertrophic dif-ferentiation of proliferating chondrocytes. Mutantparathyroid receptor type 1 (PTHR1) has beenshown to cause enchondroma-like lesions in trans-genic mice.173 Two patients with enchondromatosishave also been found to have an activating mutationin PTHR1 in tumor specimens. However, recentgenetic investigations of 31 patients with enchon-dromatosis revealed no abnormalities in the IHH/PTHrP pathway.174

Fig 11. Maffucci syndrome. Venous malformations andenchondromas.

Diagnosis and managementPlain films are usually performed to confirm

suspicion of enchondromas; they also reveal thepresence of phleboliths. MRI is the best tool toinvestigate the lesions of venous malformation inthe distal extremities or in the head. Regular physicalexaminations are necessary to monitor for anychanges that may suggest the development of chon-drosarcomas. Radiologic evaluation of suspect areaswith plain films, computed tomography, and/or MRIshould be conducted. Evidence of malignant trans-formation includes cortical destruction, endostealcortical erosion, and zones of lucency within apreviously mineralized area. A needle biopsy shouldthen be performed on these suspect areas of thebone. Chondrosarcomas are diagnosed with thehistologic finding of poorly differentiated pleomor-phic chondrocytes. Venous malformations are man-aged conservatively unless symptomatic.

Gorham-Stout syndromeDefinition and clinical characteristics. Gor-

ham-Stout syndrome (disappearing bone disease,phantom bone disease, diffuse skeletal hemangio-matosis) is a very rare syndrome that was firstdescribed in 1838 by Jackson; it was designated asa syndrome upon publication of a 24-case review in1955 by Gorham and Stout. It is characterized byvascular malformations and intraosseous, vascularmalformations, and osteolysis.175 Although venous,lymphatic, and capillary malformations are reportedin this syndrome, the most common finding seems tobe a lymphatic malformation.176 Cutaneous vascularmalformations are rare in Gorham syndrome butmay occur. Patients with this disorder often presentduring childhood with an antecedent history ofminor trauma resulting in a pathologic fracture. It isequally common in males and females. The truncalbones and upper extremities are most commonlyaffected. The vascular malformation may be local-ized or diffuse, and the degree of bone resorption isvariable. Complete resorption of the bone has beenreported in several cases.175

PathogenesisHistologic evaluation of the bone reveals intraos-

seous, anomalous vascular channels and fibroustissue. Acid phosphatase cytochemistry suggeststhat mononuclear phagocytes, multinuclear osteo-clasts, and the vascular endothelium are involved inbone resorption in this disease.177 Recent histochem-ical evaluation of osteoclast activity in this diseasehas shown an increase in the sensitivity of osteoclastprecursors to humoral factors that promote osteo-clast formation and bone resorption.178

APRIL 2007

J AM ACAD DERMATOL

VOLUME 56, NUMBER 4

Garzon et al 557

ManagementRadiotherapy has been used for pain relief and

cessation of osteolysis, with moderate success forsome patients. Biphosphonates and some antiangio-genic drugs are under evaluation.

Bockenheimer syndromeGenuine diffuse phlebectasia, or Bockenheimer

syndrome, is a rare disorder characterized by a bluenetwork of dilated veins. This venous malformationinvolves more commonly upper, but also lower,extremities. The lesions are present at birth and areprogressive. MRI will reveal the extent of the lesions,usually without the involvement of muscles andbones. Because of the distribution of lesions andmorphologic appearance, the differential diagnosisincludes common extensive venous malformationsof the limbs and KTS. Treatment includes supportivecare, such as sclerocompression of the lower ex-tremities and, if necessary, percutaneous sclerother-apy or resection.179

Cutaneous capillary venousmalformationsecerebral capillarymalformation

Small, localized cutaneous hyperkeratotic capil-laryevenous malformations are present in a smallpercentage of persons with inherited cerebral capil-lary malformations. Inherited cerebral capillarymalformations are associated with mutations in theCCM-1 gene that encodes for the KRIT1 protein.This protein is involved in the Ras signaling pathway(see ‘‘Capillary Malformation-AVM Syndrome’’ sec-tion). The skin lesions are dark red hyperkeratoticplaques that are localized. Histology reveals hyper-keratotic epidermis, and dilated capillary and ve-nous-like channels in the dermis and hypodermis.Cerebral capillary malformations cause headaches,seizures, and intracranial hemorrhage. It is hypoth-esized that the KRIT1 protein plays an important rolein cerebral and cutaneous vascular development.180

OTHER SYNDROMES ASSOCIATED WITHCUTANEOUS VASCULAR LESIONSHereditary hemorrhagic telangiectasia

Definition. Hereditary hemorrhagic telangiecta-sia (HHT), also known as Osler-Rendu-Weber syn-drome, is a genetically heterogeneous, autosomaldominant disorder characterized by mucocutaneousand visceral telangiectases and AVMs.

Clinical characteristicsHHT is reported in many ethnic groups. The

prevalence varies among populations. Recurrentepistaxis from mucosal telangiectasia is a common

presenting feature, often reported within the firsttwo decades of life, and frequently occurs beforethe appearance of cutaneous telangiectasia.181 It isbleeding from lesions of the nasal mucosa that resultsin epistaxis, which may be severe. Telangiectases arealso located on the lips, oral mucosa, upper extrem-ities, nail beds, and trunk (Fig 12). Cutaneous telan-giectases rarely cause significant bleeding, althougha recent study suggests this occurrence is morefrequent than previously thought.182 Gastrointestinaltract telangiectases and AVMs result in significantbleeding in 16% of patients.183 Pulmonary AVMs areestimated to occur in 15% of patients with HHT,leading to respiratory complaints and neurologiccomplications, including emboli and stroke. Otherneurologic findings include CNS AVMs resulting inmigraines and seizures.184 AVMs are also found in theliver.

PathogenesisAnalysis of dysplastic vasculature in HHT reveals

direct arteriolar to venular connections and loss ofnormal intervening capillary segments.184 Geneticlinkage analysis of families with HHT has revealed atleast two loci. The first and more common formmaps to a locus on chromosome 9q33-34. Subse-quent analysis identified this to be the site of the ENGgene encoding for endoglin, a transforming growthfactor b binding protein.185 Several different muta-tions in this gene have been reported.186 A secondlocus is on chromosome 12q11-14 and is the site ofthe ALK1 gene, the product of which is an activin-like tyrosine kinase-1.187 Both genes encode ahomodimeric integral membrane glycoprotein ex-pressed mainly on vascular endothelial cells as thesurface receptor for the transforming growth factorb superfamily, which mediates vascular remodelingthrough effects on extracellular matrix production.188

Fig 12. Hereditary hemorrhagic telangiectasia. Multiplefacial telangiectases in affected adult.

J AM ACAD DERMATOL

APRIL 2007

558 Garzon et al

Mice deficient in endoglin or activin-like tyrosinekinase-1 die by mid-gestation from failure to formnormal vascular beds.189-191 Mutations of ENG morelikely result in pulmonary AVMs, whereas mutations inALK1 are associated with a more benign course. In alarge pedigree, HHTassociated with extensive hepaticAVMs did not map to either previously reported locus,suggesting additional genetic heterogeneity.192 Inaddition, it appears that the presence of epigeneticfactors and modifier genes is also required for expres-sion of this disease, based on reduced penetranceof the phenotype in heterozygous animals.193

Diagnosis and managementThe diagnosis of HHT is established when 3 of

the following features are present: (1) epistaxis: spon-taneous, recurrent nose bleeds; (2) telangiectases:multiple, at characteristic sites (lips, oral cavity, fin-gers, nose); (3) visceral lesions: such as gastrointes-tinal telangiectasia (with or without bleeding),pulmonary AVM, hepatic AVM, cerebral AVM, spinalAVM; and (4) family history: a first-degree relativewith HHT. Meeting two criteria suggests a possible orsuspected case.194 The differential diagnosis for HHTincludesCRESTsyndrome (calcinosis cutis, Raynaud’sphenomenon, esophageal dysfunction, sclerodac-tyly, and telangiectasia). Establishing the diagnosisof HHT in childhood is difficult. Factors that compli-cate early diagnosis include the observation thatvisceral involvement may not manifest until maturityand that scattered telangiectases may arise on thehead and neck of children who do not have HHT.Although this is problematic, HHT should be sus-pected in children in whom multiple lesions developon the skin and mucosa; further evaluation mayinclude genetic testing tohelp establish thediagnosis.

Once the diagnosis of HHT is suspected, patientsshould be carefully evaluated for pulmonary in-volvement. Patients with a family history of HHTwith pulmonary disease are at greatest risk of havingpulmonary AVMs. MRI is useful for assessing CNSinvolvement.184 The HHT Foundation is a usefulresource for patients and families with HHT (Website URL: http://www.hht.org/web/).

Ataxia-TelangiectasiaDefinition. Ataxia-telangiectasia (AT) is an

autosomal recessive disorder characterized bycerebellar degeneration, immunodeficiency, cancerpredisposition, chromosomal instability, radiosensi-tivity, and conjunctival and facial telangiectases.195

Clinical characteristicsThe disease usually becomes evident in early

childhood with the development of progressive

ataxia. Conjunctival telangiectases are a frequentearly manifestation and may also be noted on thefacial skin. Noninfectious persistent cutaneous gran-ulomatous plaques that often ulcerate are the othercutaneous finding in AT. Progeric changes of the hairand skin can also be seen. Humoral and cellularimmunodeficiency often manifests as recurrentsinopulmonary infections. Affected persons are atan increased risk of developing malignancies, mostcommonly lymphoreticular malignancy. Patientsalso exhibit growth retardation, elevated seruma-fetoprotein levels, chromosomal instability, andsensitivity to ionizing radiation. Affected personshave a shortened life expectancy, with death usuallyoccurring in the second or third decade of life.Heterozygotes (carriers)manifest an increased cancerpredisposition and radiosensitivity.196 Female car-riers are at a significantly increased risk of developingbreast cancer than the general population.196,197

PathogenesisFour complementation groups have been de-

scribed in AT based on measurements of radioresis-tant DNA synthesis. The ATM (ataxia telangiectasiamutated) gene is located on chromosome 11q22-23.Mutations in this gene are noted in patients from all4 complementation groups, suggesting that it is thesole gene responsible for this disorder. The geneproduct is similar to phosphotidylinositol-39 kinase,is believed to play an important role in signaltransduction and cellular responses to DNA damageand cell cycle control; it has also been shown to bepivotal in neurologic development.198,199 Little cor-relation exists between the level of ATM protein andthe type of underlying mutation, clinical phenotype,or radiophenotype. Recent work suggests that ATMprotein may be associated with dysregulation of theimmunoglobulin gene superfamily, which includesgenes for T-cell receptors. The normal switch fromthe production of IgM to IgG, IgA, and IgE isdefective, and the same may apply to the switchfrom immature T cells that express the g/d ratherthan the a/b receptors. This dysregulation mayexplain the frequency of infections and hematologicmalignancies. Accelerated telomere loss may beresponsible for neurologic disease, thymus aplasia,telangiectases, growth retardation, and impairedorgan mutation.200

Diagnosis and managementAT is diagnosed clinically, on the basis of relevant

clinical signs and symptoms as well as significantfamily history. Laboratory studies, including a-feto-protein, carcinoembryonic antigen, chromosomal

J AM ACAD DERMATOL

VOLUME 56, NUMBER 4

Garzon et al 559

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

REFERENCES

1. Sturge WA. A case of partial epilepsy apparently due a lesion

of one of the vasomotor centers of the brain. Clin Soc Trans

1879;12:162-7.

2. Mulliken JB, Young AE, editors. Vascular birthmarks and

hemangiomas: capillary (port-wine) and other telangiectatic

stains. Philadelphia: WB Saunders; 1988.

3. Ambrosetto P, Ambrosetto G, Michelucci R, Bacci A. Sturge-

Weber syndrome without port-wine facial nevus. Report of

2 cases studied by CT. Childs Brain 1983;10:387-92.

4. Demis DJ, Dobson RL, Maguire J, editors. Clinical dermatol-

ogy. Philadelphia: JB Lippincott & Co; 1995.

5. Alexander GL. Sturge Weber syndrome. In: Vinken PJ, Bruyn

GW, editors. Handbook of clinical neurology. The phako-

matoses. Amsterdam: North-Holland Publishing; 1972. pp.

223-40.

6. Enjolras O, Riche MC, Merland JJ. Facial port-wine stains and

the Sturge-Weber syndrome. Pediatrics 1985;76:48-51.

7. Tallman B, Tan OT, Morelli JG, Piepenbrink J, Stafford TJ,

Trainor S, et al. Location of port-wine stains and the like-

lihood of ophthalmic and/or central nervous system com-

plications. Pediatrics 1991;87:323-7.

8. Enjolras O, Mulliken JB. The current management of vascular

birthmarks. Pediatr Dermatol 1993;10:311-33.

9. Wilson S, Venzel JM, Miller R. Angiography, gingival hyper-

plasia and Sturge-Weber syndrome: report of case. J Dent

Child 1986;53:283-6.

10. Furukawa T, Igata A, Toyakura Y. Sturge-Weber and Klippel

Trenaunay syndrome with nevus of Ota and Ito. Arch

Dermatol 1970;102:640-5.

11. Leung AK, Lowry RB, Mitchell I, Martin S, Cooper DM. Klippel-

Trenaunay and Sturge-Weber syndrome with extensive Mon-

golian spots, hypoplastic larynx and subglottic stenosis. Clin

Exp Dermatol 1988;13:128-32.

12. Griffiths PD, Blaser S, Boodram MB, Armstrong D, Har-

wood-Nash D. Choroid plexus size in young children

with Sturge-Weber syndrome. Am J Neuroradiol 1996;17:

175-80.

13. Griffiths PD. Sturge-Weber syndrome revisited: the role of

neuroradiology. Neuropediatrics 1996;27:284-94.

14. Griffiths PD, Boodram MB, Blaser S, Armstrong D, Gilday DL,

Harwood-Nash D. 99mTechnetium HMPAO imaging in

children with the Sturge-Weber syndrome: a study of nine

cases with CT and MRI correlation. Neuroradiology 1997;39:

219-24.

15. Paller AS. The Sturge -Weber syndrome. Pediatr Dermatol

1987;4:300-4.

16. Sujansky E, Conradi M. Sturge-Weber syndrome: age of onset

of seizures and glaucoma and prognosis for affected chil-

dren. J Child Neurol 1995;10:49-58.

17. Pascual-Castroviejo I, Diaz-Gonzalez C, Garcia-Melian RM,

Gonzalez-Casado I, Munoz-Hiraldo E. Sturge-Weber syn-

drome: study of 40 patients. Pediatr Neurol 1993;9:

283-8.

18. Bebin EM, Gomez MR. Prognosis in Sturge-Weber disease:

comparison of unihemispheric and bihemispheric involve-

ment. J Child Neurol 1988;3:181-4.

19. Sujansky E, Conradi S. Outcome of Sturge-Weber syndrome

in 52 adults. Am J Med Genet 1995;57:35-45.

20. Thomas-Sohl KA, Vaslow DF, Maria BL. Sturge-Weber syn-

drome: a review. Pediatr Neurol 2004;30:303-10.

21. Peterman AF, Hayles AB, Dockerty MB, Love JG.

Encephalotrigeminal angiomatosis (Sturge-Weber syn-

drome). Clinical study of thirty-five cases. JAMA 1958;

167:2169-76.

22. Cambon H, Truelle JL, Baron JC, Chiras J, Tran Dinh S, Chatel

M. Focal chronic ischemia and concomitant migraine: an

atypical form of Sturge-Weber angiomatosis? Rev Neurol

(Paris) 1987;143:588-94.

23. Greenwald MJ, Weiss A. Ocular manifestations of neuro-

cutaneous syndromes. Pediatr Dermatol 1984;2:98-117.

24. Cibis GW, Tripathi R, Tripathi BJ. Glaucoma in Sturge-Weber

syndrome. Ophthalmology 1984;91:1061-71.

25. Couly GF, Le Douarin NM. Mapping of the early neural

primordium in quail-chick chimeras. II. The prosencephalic

neural plate and neural folds: implications for the genesis

of cephalic human congenital abnormalities. Dev Biol 1987;

120:198-214.

26. Marti-Bonmati L, Menor F, Poyatos C, Cortina H. Diagnosis

of Sturge-Weber syndrome: comparison of the efficacy of

CT and MR imaging in 14 cases. Am J Roentgenol 1992;158:

867-71.

27. Welch K, Naheedy MH, Abroms IF, Strand RD. Computed

tomography of Sturge-Weber syndrome in infants. J Comput

Assist Tomogr 1980;4:33-6.

28. Stimac GK, Solomon MA, Newton TH. CT and MR of

angiomatous malformations of the choroid plexus in

patients with Sturge-Weber disease. Am J Neuroradiol

1986;7:623-7.

29. Chamberlain MC, Press GA, Hesselink JR. MR imaging and

CT in three cases of Sturge-Weber syndrome: prospective

comparison. Am J Neuroradiol 1989;10:491-6.

30. Sperner J, Schmauser I, Bittner R, Henkes H, Bassir C, Sprung

C, et al. MR-imaging findings in children with Sturge-Weber

syndrome. Neuropediatrics 1990;21:146-52.

31. Elster AD, Chen MY. MR imaging of Sturge-Weber

syndrome: role of gadopentetate dimeglumine and gra-

dient-echo techniques. AJNR Am J Neuroradiol 1990;

11685-9.

32. Chugani HT, Dietrich RB. Sturge-Weber syndrome. Recent

developments in neuroimaging and surgical consider-

ations. In: Fukuyama Y, Suzuki Y, Kamoshita S, Casear P,

editors. Fetal and perinatal neurology. Basel: Karger; 1992.

pp. 187-96.

33. Adamsbaum C, Pinton F, Rolland Y, Chiron C, Dulac O,

Kalifa G. Accelerated myelination in early Sturge-Weber

syndrome: MRI-SPECT correlations. Pediatr Radiol 1996;26:

759-62.

34. Mentzel HJ, Dieckmann A, Fitzek C, Brandl U, Reichenbach

JR, Kaiser WA. Early diagnosis of cerebral involvement in

Sturge-Weber syndrome using high-resolution BOLD MR

venography. Pediatr Radiol 2005;35:85-90. Epub 2004

Oct 6.

35. Vogl TJ, Stemmler J, Bergman C, Pfluger T, Egger E, Lissner J.

MR and MR angiography of Sturge-Weber syndrome. AJNR

Am J Neuroradiol 1993;14:417-25.

36. Griffiths PD. Sturge-Weber syndrome revisited: the role of

neuroradiology. Neuropediatrics 1996;27:284-94.

37. Young AE. Combined vascular malformations. In: Mulliken JB,

Young AE, editors. Vascular birthmarks and hemangiomas:

capillary (port-wine) and other telangiectatic stains. Phila-

delphia: WB Saunders; 1988. pp. 246-74.

38. Mattassi R. Differential diagnosis in congenital vascular-bone

syndromes. Semin Vasc Surg 1993;6:233-44.

39. Klippel LM, Trenaunay P. Du naevus variqueux oste ohyper-

trophique. Arch Gen Med (Paris) 1900;185:641-72.

J AM ACAD DERMATOL

APRIL 2007

560 Garzon et al

40. Gloviczki P, Hollier LH, Telander RL, Kaufman B, Bianco AJ,

Stickler GB. Surgical implications of Klippel Trenaunay syn-

drome. Ann Surg 1983;197:353-62.

41. Telander RL, Kaufman BH, Gloviczki P, Stickler GB, Hollier LH.

Prognosis and management of lesions of the trunk in

children with Klippel-Trenaunay syndrome. J Pediatr Surg

1984;19:417-22.

42. Maari C, Frieden IJ. Klippel-Trenaunay syndrome: the impor-

tance of ‘‘geographic stains’’ in identifying lymphatic disease

and risk of complications. J Am Acad Dermatol 2004;51:

391-8.

43. Servelle M. Klippel and Trenaunay’s syndrome. Ann Surg

1985;201:365-73.

44. Gloviczki P, Stanson AW, Stickler GB, Johnson CM, Toomey

BJ, Meland NB, et al. Klippel Trenaunay syndrome: the risks

and benefits of vascular interventions. Surgery 1991;110:

469-79.

45. Viljoen D, Saxe N, Pearn J, Beighton P. The cutaneous

manifestations of the Klippel-Trenaunay-Weber syndrome.

Clin Exp Dermatol 1987;12:12-7.

46. Baskerville PA, Ackroyd JS, Lea Thomas M, Browse NL.

The Klippel-Trenaunay syndrome: clinical radiological and

haemodynamic features and management. Br J Surg 1985;

72:232-6.

47. Bird LM, Jones MC, Kuppermann N, Huskins WC. Gram-

negative bacteremia in four patients with Klippel-Trenaunay-

Weber syndrome. Pediatrics 1996;97:739-41.

48. Neubert AG, Golden MA, Rose NC. Kasabach-Merritt coagu-

lopathy complicating Klippel-Trenaunay-Weber syndrome

in pregnancy. Obstet Gynecol 1995;85:831-3.

49. Vissers W, Van Steensel M, Steijlen P, Renier W, Van De

Kerkhof P, Van Der Vleuten C. Klippel-Trenaunay syndrome

and Sturge-Weber syndrome: variations on a theme? Eur J

Dermatol 2003;13:238-41.

50. Baskerville PA, Ackroyd JS, Browse NL. The etiology of Klippel

Trenaunay syndrome. Ann Surg 1985;202:624-7.

51. Aelvoet GE, Jorens PG, Roelen LM. Genetic aspects of the

Klippel-Trenaunay syndrome. Br J Dermatol 1992;126:

603-7.

52. Happle R. Klippel-Trenaunay syndrome: is it a paradominant

trait? Br J Dermatol 1992;128:465.

53. Whelan AJ, Watson MS, Porter FD. Klippel-Trenaunay syn-

drome associated with a 5:11 balanced translocation.

Am J Med Genet 1995;59:492-4.

54. Tian XL, Kadaba R, You SA, Liu M, Timur AA, Yang L, et al.

Identification of an angiogenic factor that when mutated

causes susceptibility to Klippel-Trenaunay syndrome. Nature

2004;427:640-5.

55. Timur AA, Sadgephour A, Graf M, Schwartz S, Libby ED,

Driscoll DJ, et al. Identification and molecular characteriza-

tion of a de novo supernumerary ring chromosome 18 in a

patient with Klippel-Trenaunay syndrome. Ann Hum Genet

2004;68:353-61.

56. Kanterman RY, Witt PD, Hsieh PS, Picus D. Klippel-Trenaunay

syndrome: findings and percutaneous intervention. AJR Am J

Roentgenol 1996;167:989-95.

57. Greene AK, Kieran M, Burrows PE, Mulliken JB, Kasser J,

Fishman SJ. Wilms tumor screening is unnecessary in Klippel-

Trenaunay syndrome. Pediatrics 2004;113:e326-9.

58. Van Lohuizen CHJ. Uber eine seltene ange borne Hautano-

malie (Cutis marmorata telangiectatica congenita). Acta Derm

Venereol (Stockh) 1922;3:202-11.

59. Picascia DD, Esterly NB. Cutis marmorata telangiectatica

congenita: report of 22 cases. J Am Acad Dermatol 1989;

20:1098-104.

60. South DA, Jacobs AH. Cutis marmorata telangiectatica

congenita (congenital generalized phlebectasia). Pediatrics

1978;93:944-9.

61. Way BH, Herrmann J, Gilbert EF, Johnson SA, Opitz JM.

Cutis marmorata telangiectatica congenita. J Cutan Pathol

1974;1:10-25.

62. Devillers ACA, de Waard-van der Spek FB, Oranje AP. Cutis

marmorata telangiectatica congenita. Clinical features in

35 cases. Arch Dermatol 1999;135:34-8.

63. Petrozzi JW, Rahn EK, Mofenson H, Greensher J. Cutis

marmorata telangiectatica congenita. Arch Dermatol 1970;

101:74-7.

64. Del Giudice SM, Nydorf ED. Cutis marmorata telangiectatica

congenita with multiple congenital anomalies. Arch Derma-

tol 1986;122:1060-1.

65. Powell ST, Su WP. Cutis marmorata telangiectatica congenita:

report of nine cases and review of the literature. Cutis

1984;34:305-12.

66. Pehr K, Moroz B. Cutis marmorata telangiectatica congenita:

long-term follow-up, review of the literature, and report of a

case in conjunction with congenital hypothyroidism. Pediatr

Dermatol 1993;10:6-11.

67. Weilepp AE, Eichenfield LF. Association of glaucoma with

cutis marmorata telangiectatica congenita: a localized ana-

tomic malformation. J Am Acad Dermatol 1996;35:276-8.

68. Robertson SP, Gattas M, Rogers M, Ades LC. Macrocephalye

cutis marmorata telangiectatica congenita: report of five

patients and a review of the literature. Clin Dysmorphol

2000;9:1-9.

69. Lapunzina P, Gairi A, Delicado A, Mori MA, Torres ML, Goma

A, et al. Macrocephaly-cutis marmorata telangiectatica con-

genita: report of six new patients and a review. Am J Med

Genet A 2004;130:45-51.

70. Rogers M, Poyzer KG. Cutis marmorata telangiectatica con-

genita. Arch Dermatol 1982;118:895-9.

71. Kennedy C, Oranje AP, Keizer K, van den Heuvel MM,

Catsman-Berrevoets CE. Cutis marmorata telangiectatica

congenita. Int J Dermatol 1992;31:249-52.

72. Kurczynski TW. Hereditary cutis marmorata telangiectatica

congenita. Pediatrics 1982;70:52-3.

73. Danarti R, Happle R, Konig A. Paradominant inheritance may

explain familial occurrence of cutis marmorata telangiecta-

tica congenita. Dermatology 2001;203:208-11.

74. Amitai DB, Fichman S, Merlob P, Morad Y, Lapidoth M,

Metzker A. Cutis marmorata telangiectatica congenita:

clinical findings in 85 patients. Pediatr Dermatol 2000;17:

100-4.

75. Adams FH, Oliver CP. Hereditary deformities in man due to

arrested development. J Hered 1945;36:3-7.

76. Scribanu N, Temtamy SA. Syndrome of aplasia cutis con-

genita with terminal transverse defects of the limbs. J Pediatr

1975;87:79-82.

77. Zapata HH, Sletten LJ, Pierpont MEM. Congenital cardiac

malformations in Adams-Oliver syndrome. Clin Genet 1995;

47:80-4.

78. Toriello HV, Graff RG, Florentine MF, Lacina S, Moore WD.

Scalp and limb defects with cutis marmorata telangiectatica

congenita: Adams-Oliver syndrome? Am J Med Genet 1988;

29:269-76.

79. Swartz EN, Santani S, Sandor GGS, Schreiber RA. Vascular

abnormalities in Adams-Oliver syndrome: cause or effect?

Am J Med Genet 1999;82:49-52.

80. Klinger G, Merlob P. Adams-Oliver syndrome: autosomal

recessive inheritance and new phenotypic-anthropometric

findings. Am J Med Genet 1998;79:197-9.

J AM ACAD DERMATOL

VOLUME 56, NUMBER 4

Garzon et al 561

81. Unay B, Sarici SU, Gul D, Akin R, Gokcay E. Adams-Oliver

syndrome: further evidence for autosomal recessive inheri-

tance. Clin Dysmorphol 2001;10:223-5.

82. Verdyck P, Holder-Espinasse M, Hul WV, Wuyts W. Clinical

and molecular analysis of nine families with Adams-Oliver

syndrome. Eur J Hum Genet 2003;11:457-63.

83. Harrison MS. The Treacher Collins-Franceschetti syndrome.

J Laryngol Otol 1957;71:597-603.

84. Hall BD, deLorimier A, Foster LH. A new syndrome of

hemangiomatous branchial clefts, lip pseudoclefts, and

unusual facial appearance. Am J Med Genet 1983;14:135-8.

85. DaSilva EO, Bezerra LH. The Roberts syndrome. Hum Genet

1982;61:372-4.

86. Zergollern L, Hitrec V. Four siblings with Roberts syndrome.

Clin Genet 1982;21:1-6.

87. Urban M, Rogalla P, Tinschert S, Krietsch P. Tetraphocomelia

and bilateral cleft lip in a historical case of Roberts syndrome.

Am J Med Genet 1997;72:307-14.

88. Tomkins D, Hunter A, Roberts M. Cytogenetic findings in

Roberts-SC phocomelia syndrome(s). Am J Med Genet 1979;

4:17-26.

89. Sinha AK, Verma RS, Mani VJ. Clinical heterogeneity of

skeletal dysplasia in Roberts syndrome: a review. Hum Hered

1994;44:121-6.

90. Rubinstein JH, Taybi H. Broad thumbs and toes and facial

abnormalities. A possible mental retardation syndrome.

Am J Dis Child 1963;105:88-108.

91. Hennekam RCM, Van Den Boogaard MJ, Sibbles BJ, Van

Spijker HG. Rubinstein-Taybi syndrome in The Netherlands.

Am J Med Genet Suppl 1990;6:17-29.

92. Wallerstein R, Anderson CE, Hay B, Gupta P, Gibas L,

Ansari K, et al. Submicroscopic deletions at 16p13.3 in

Rubinstein-Taybi syndrome: frequency and clinical mani-

festations in a North American population. J Med Genet

1997;34:203-6.

93. Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RC,

Masuno M, et al. Rubinstein-Taybi syndrome cause by

mutations in the transcriptional co-activator CBP. Nature

1995;376:348-51.

94. Alarcon JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel

ER, et al. Chromatin acetylation, memory, and LTP are

impaired in CBP1/� mice: a model for the cognitive deficit

in Rubinstein-Taybi syndrome and its amelioration. Neuron

2004;42:947-59.

95. Bourtchouladze R, Lidge R, Catapano R, Stanley J, Gossweiler

S, Romashko D, et al. A mouse model of Rubinstein-Taybi

syndrome: defective long-term memory is ameliorated by

inhibitors of phosphodiesterase 4. Proc Natl Acad Sci U S A

2003;100:10518-22.

96. Hall JG, Levin J, Kuhn JP, Ottenheimer EJ, van Berkum KA,

McKusick VA. Thrombocytopenia with absent radius (TAR).

Medicine 1969;48:411-39.

97. Anayane-Yeboa K, Jaramillo S, Nagel C, Grebin B. Tetrapho-

comelia in the syndrome of thrombocytopenia with absent

radii (TAR syndrome). Am J Med Genet 1985;20:571-6.

98. Ashinoff R, Geronemus RG. Thrombocytopenia-absent radii

syndrome and lack of response to the pulsed dye laser

[letter]. Arch Dermatol 1990;126:1520-1.

99. Ballmaier M, Schulze H, Cremer M, Folman CC, Strauss G,

Weite K. Defective c-Mpl signaling in the syndrome of

thrombocytopenia with absent radii. Stem Cells 1998;

16 Suppl 2:177-84.

100. Wu NF, Kushnick T. The Beckwith-Wiedemann syndrome.

The exophalos-macroglossia-gigantism syndrome. Clin Pediatr

1974;13:452-7.

101. Niemitz EL, DeBaun MR, Fallon J, Murakami K, Kugoh H,

Oshimura M, et al. Microdeletion of LIT1 in familial

Beckwith-Wiedemann syndrome. Am J Hum Genet 2004;75:

844-9.

102. Weksberg R, Smith AC, Squire J, Sadowski P. Beckwith-

Wiedemann syndrome demonstrates a role for epigenetic

control of normal development. Hum Mol Genet 2003;

12Spec No 1:R61-8.

103. Nova HR. Familial communicating hydrocephalus, posterior

cerebellar agenesis, mega cisterna magna and port-wine nevi.

Report on five members of one family. J Neurosurg 1979;

51:862-5.

104. Torrelo A, Zambrano A, Happle R. Cutis marmorata telan-

giectatica congenita and extensive mongolian spots: type 5

phacomatosis pigmentovascularis. Br J Dermatol 2003;148:

342-5.

105. Hasegawa Y, Yashura M. Phakomatosis pigmentovascularis

type IV a. Arch Dermatol 1985;121:651-5.

106. Happle R. Phacomatosis pigmentovascularis revisited and

reclassified. Arch Dermatol 2005;141:385-8.

107. Sawada Y, Iwata M, Mitsuhashi Y. Nevus pigmentovascularis.

Ann Plast Surg 1990;25:142-5.

108. Ruiz-Maldonado R, Tamayo L, Laterza AM, Brawn G, Lopez A.

Phacomatosis pigmentovascularis: a new syndrome? Report

of four cases. Pediatr Dermatol 1987;4:189-96.

109. Libow L. Phakomatosis pigmentovascularis type IIIb. J Am

Acad Dermatol 1993;29:305-7.

110. Guiglia MC, Prendiville JS. Multiple granular cell tumors

associated with giant speckled lentiginous nevus and

nevus flammeus in a child. J Am Acad Dermatol 1991;

24:359-63.

111. Gilliam AC, Ragge NK, Perez MI, Bolognia JL. Phakomatosis

pigmentovascularis IIb with iris mammillations. Arch Derma-

tol 1993;129:340-2.

112. Luna ML, Barquin MA, Casas JG, Sidelsky S. Phacomatosis

pigmentovascularis with selective IgA deficiency. Pediatr

Dermatol 1995;12:159-63.

113. Suzuki K, Ishizaki H, Takahashi H. [Phacomatosis pigmento-

vascularis IIIb associated with porokeratosis, acanthosis

nigricans and endocrinopathy in brother and sister.] Skin

Res (Hifu) 1990;32:65-70. Japanese, with an English summary.

114. Danarti R, Happle R. Paradominant inheritance of twin

spotting: phacomatosis pigmentovascularis as a further pos-

sible example. Eur J Dermatol 2003;13:612.

115. Happle R. Allelic somatic mutations may explain vascular

twin nevi. Hum Genet 1991;86:321-2.

116. Happle R. Mosaicism in human skin. Arch Dermatol 1993;

129:1460-70.

117. Teekhasaenee C, Ritch R. Glaucoma in phakomatosis pig-

mentovascularis. Ophthalmology 1997;104:150-7.

118. Bonnet P, Dechaume J, Blanc E. L’aneurysme cirsoide de

la retine (aneurysme vasemeaux). J Med Lyon 1937;18:

165-78.

119. Wyburn-Mason R. Arteriovenous aneurysm of midbrain and

retina, facial naevi and mental changes. Brain 1943;66:

163-203.

120. Theron J, Newton TH, Hoyt WF. Unilateral retinocephalic

vascular malformations. Neuroradiology 1974;7:185-96.

121. Patel U, Gupta SC. Wyburn-Mason syndrome. A case

report and review of the literature. Neuroradiology 1990;

31:544-6.

122. Willinsky RA, Lasjaunias P, Terbrugge K, Burrows P. Multiple

cerebral arteriovenous malformations (AVMs). Review of our

experience from 203 patients with cerebral vascular lesions.

Neuroradiology 1990;32:207-10.

J AM ACAD DERMATOL

APRIL 2007

562 Garzon et al

123. Lin AE, Gorlin RJ, Lurie IW, Brunner HG, van der Burgt I,

Naumchik IV, et al. Further delineation of the branchio-oculo-

facial syndrome. Am J Med Genet 1995;56:42-59.

124. Gabriel KR, Crawford AH, Roy DR, True MS, Sauntry S. Percu-

taneous epiphyseodesis. J Pediatr Orthop 1994;14:358-62.

125. Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A,

Watanabe S, et al. Capillary malformation-arteriovenous mal-

formation, a new clinical and genetic disorder caused by

RASA1 mutations. Am J Hum Genet 2003;73:1240-9.

126. Boon LM, Mulliken JB, Vikkula M. RASA1: variable phenotype

with capillary and arteriovenous malformations. Curr Opin

Genet Dev 2005;15:265-9.

127. Bean WB. Blue rubber bleb nevi of the skin and gastrointes-

tinal tract. In: Vascular spiders and related lesions of the skin.

Springfield (IL): Charles Thomas; 1958. pp. 178-85.

128. Oranje AP. Blue rubber bleb nevus syndrome. Pediatr

Dermatol 1986;3:304-10.

129. Morris SJ, Kaplan SR, Ballan K, Tedesco FJ. Blue rubber-bleb

nevus syndrome. JAMA 1978;239:1887.

130. McCarthy JC, Goldberg MJ, Zimbler S. Orthopaedic dysfunc-

tion in the blue rubber-bleb nevus syndrome. J Bone Joint

Surg [Am] 1982;64:280-3.

131. Wong YC, Li YW, Chang MH. Gastrointestinal bleeding and

paraparesis in blue rubber bleb nevus syndrome. Pediatr

Radiol 1994;24:600-1.

132. Hofhuis WJ, Oranje AP, Bouquet J, Sinaasappel M. Blue

rubber bleb nevus syndrome: report of a case with con-

sumption coagulopathy complicated by manifest thrombo-

sis. Eur J Pediatr 1990;149:526-8.

133. Waybright EA, Selhorst JB, Rosenblum WI, Suter CG. Blue

rubber bleb nevus syndrome with CNS involvement and

thrombosis of a vein of Galen malformation. Ann Neurol

1978;3:464-7.

134. Moodley M, Ramdial P. Blue rubber bleb nevus syndrome:

case report and review of the literature. Pediatrics 1993;

92:160-2.

135. McCannel CA, Hoenig J, Umlas J, Woog JJ, Newman AN,

Bateman JB. Orbital lesions in the blue rubber bleb nevus

syndrome. Ophthalmology 1996;103:933-6.

136. Radke M, Waldschmidt J, Stolpe HJ, Mix M, Richter I.

Blue rubber-bleb-nevus syndrome with predominant uri-

nary bladder hemangiomatosis. Eur J Pediatr Surg 1993;

3:313-6.

137. Busund B, Stray-Pedersen S, Iversen O, Austad J. Blue rubber

bleb nevus syndrome with manifestations in the vulva.

Acta Obstet Gynecol Scand 1993;72:310-3.

138. Jorizzo JR, Amparo EG. MR imaging of blue rubber

bleb nevus syndrome. J Comput Assist Tomogr 1986;10:

686-8.

139. Olsen TG, Milroy SK, Goldman L, Fidler JP. Laser surgery for

blue rubber bleb nevus. Arch Dermatol 1979;155:81-2.

140. Buchi KN. Vascular malformations of the gastrointestinal

tract. Surg Clin North Am 1992;72:559-70.

141. Morris L, Lynch PM, Gleason WA Jr, Schauder C, Pinkel D,

Duvic M. Blue rubber bleb nevus syndrome: laser photoco-

agulation of colonic hemangiomas in a child with microcytic

anemia. Pediatr Dermatol 1992;9:91-4.

142. Boente MD, Cordisco MR, Frontini MD, Asial RA. Blue rubber

bleb nevus (Bean syndrome): evolution of four cases and

clinical response to pharmacologic agents. Pediatr Dermatol

1999;16:222-7.

143. Apak H, Celkan T, Ozkan A, Yildiz I, Aydemir EH, Ozdil S, et al.

Blue rubber bleb nevus syndrome associated with consump-

tion coagulopathy: treatment with interferon. Dermatology

2004;208:345-8.

144. Gonzalez D, Elizondo BJ, Haslag S, Buchanan G, Burdick JS,

Guzzetta PC, et al. Chronic subcutaneous octreotide de-

creases gastrointestinal blood loss in blue rubber-bleb

nevus syndrome. J Pediatr Gastroenterol Nutr 2001;33:

183-8.

145. Weidemann HR, Burgio GR Aidenhoff P. The Proteus syn-

drome. Eur J Pediatr 1983;140:5-12.

146. Delaporte E, Wendehenne R, Descamps S, Bitbol-Duneton V,

Hatron PY, Piette F, et al. Dysplasias hamartomateux avec

hemihypertrophie: deux observations dont il syndrome

Protee. Arch Pediatr 1995;2:52-6.

147. Havard S, Enjolras O, Lessana-Leibowitch M, Escande JP.

Protee: huit cas. Ann Dermatol Venereol 1994;121:303-8.

148. Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM

Jr, Viljoen DL, et al. Proteus syndrome: diagnostic criteria,

differential diagnosis, and patient evaluation. Am J Med

Genet 1999;84:389-95.

149. Turner JT, Cohen MM Jr, Biesecker LG. Reassessment of

the Proteus syndrome literature: application of diagnostic

criteria to published cases. Am J Med Genet A 2004;130:

111-22.

150. Viljoen DL, Saxe N, Temple-Camp C. Cutaneous manifes-

tations of Proteus syndrome. Pediatr Dermatol 1988;5:

14-21.

151. Cohen MM Jr. Proteus syndrome: clinical evidence for

somatic mosaicism and selective review. Am J Med Genet

1993;47:645-52.

152. Samlaska CP, Levin SW, James WD, Benson PM, Walker JC,

Perlik PC. Proteus syndrome. Arch Dermatol 1989;125:

1109-14.

153. Nazzaro V, Cambiaghi S, Montagnani A, Brusasco A, Cerri A,

Caputo R. Proteus syndrome. Ultrastructural study of linear

verrucous and depigmented nevi. J Am Acad Dermatol

1991;25:377-83.

154. Happle R. Lethal genes surviving by mosaicism: a possible

explanation for sporadic birth defects involving the skin.

J Am Acad Dermatol 1987;16:899-906.

155. Cohen MM Jr, Turner JT, Biesecker LG. Proteus syndrome:

misdiagnosis with PTEN mutations. Am J Med Genet A 2003;

122:323-4.

156. Lacombe D, Taieb A, Vergnes P, Sarlangue J, Chateil JF, Bucco

P, et al. Proteus syndrome in seven patients. Genet Couns

1990;2:93-101.

157. Zhou X, Hampel H, Thiele H, Gorlin RJ, Hennekam RC,

Parisi M, et al. Association of germline mutation in the

PTEN tumour suppressor gene and Proteus and Proteus-like

syndromes. Lancet 2001;358:210-1.

158. Nguyen D, Turner JT, Olsen C, Biesecker LG, Darling TN.

Cutaneous manifestations of proteus syndrome: correla-

tions with general clinical severity. Arch Dermatol 2004;140:

947-53.

159. Biesecker LG, Peters KF, Darling TN, Choyke P, Hill S,

Schimke N, et al. Clinical differentiation between Proteus

syndrome and hemihyperplasia: description of a distinct

form of hemihyperplasia. Am J Med Genet 1998;79:

311-8.

160. Cohen MM. Bannayan-Riley-Ruvalcaba syndrome: renaming

three formerly recognized syndromes as one etiologic entity.

Am J Med Genet 1990;35:291.

161. Gorlin RJ, Cohen MM Jr, Condon LM, Burke BA. Bannayan-

Riley-Ruvalcaba syndrome. Am J Med Genet 1992;44:

307-14.

162. Fargnoli MC, Orlow SJ, Semel-Concepcion J, Bolognia JL.

Clinicopathologic findings in the Bannayan-Riley-Ruvalcaba

syndrome. Arch Dermatol 1996;132:1214-8.

J AM ACAD DERMATOL

VOLUME 56, NUMBER 4

Garzon et al 563

163. Arch EM, Goodman BK, Van Wesep RA, Liaw D, Clarke K,

Parsons R, et al. Deletion of PTEN in a patient with Bannayan-

Riley-Ruvalcaba syndrome suggests allelism with Cowden

disease. Am J Med Genet 1997;71:489-93.

164. Zori RT, Marsh DJ, Graham GE, Marliss EB, Eng C. Germline

PTEN mutation in a family with Cowden syndrome and

Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet 1998;

80:399-402.

165. Marsh DJ, Kum JB, Lunetta KL, Bennett MJ, Gorlin RJ, Ahmed

SF, et al. PTEN mutation spectrum and genotype-phenotype

correlations in Bannayan-Riley-Ruvalcaba syndrome suggest

a single entity with Cowden syndrome. Hum Mol Genet

1999;8:1461-72.

166. Blum RR, Rahimizadeh A, Kardon N, Lebwohl M, Wei H.

Genital lentigines in a 6-year-old boy with a family history

of Cowden’s disease: clinical and genetic evidence of the

linkage between Bannayan-Riley-Ruvacalba syndrome and

Cowden’s disease. J Cutan Med Surg 2001;5:228-30.

167. Hendriks YM, Verhallen JT, van der Smagt JJ, Kant SG,

Hilhorst Y, Hoefsloot L, et al. Bannayan-Riley-Ruvalcaba

syndrome: further delineation of the phenotype and man-

agement of PTEN mutation-positive cases. Fam Cancer

2003;2:79-85.

168. McDermott AL, Dutt SN, Chavda SV, Morgan DW. Maffucci’s

syndrome: clinical and radiological features of a rare condi-

tion. J Laryngol Otol 2001;115:845-7.

169. Lee NH, Choi EH, Choi WK, Lee SH, Ahn SK. Maffucci’s

syndrome with oral and intestinal haemangioma. Br J

Dermatol 1999;140:968-9.

170. Auyeung J, Mohanty K, Tayton K. Maffucci lymphangioma

syndrome: an unusual variant of Ollier’s disease, a report and

a review of the literature. J Pediatr Orthop B 2003;12:147-50.

171. Yanez S, Val-Bernal JF, Mira C, Echevarria MA, Gonzalez-Vela

MC, Arce F. Spindle cell hemangioendotheliomas associated

with multiple skeletal enchondromas: a variant of Maffucci’s

syndrome. Gen Diagn Pathol 1998;143:331-5.

172. Hisaoka M, Aoki T, Kouho H, Chosa H, Hashimoto H.

Maffucci’s syndrome associated with spindle cell hemangio-

endotheliomas. Skeletal Radiol 1997;26:191-4.

173. Hopyan S, Gokgoz N, Poon R, Gensure RC, Yu C, Cole WG,

et al. A mutant PTH/PTHrP type I receptor in enchondroma-

tosis. Nat Genet 2002;30:306-10.

174. Roseman LB, Sangiorgi L, Bruijn IH, Mainil-Varlet P, Bertoni F,

Cleton-Jansen AM, et al. Enchondromatosis (Ollier disease,

Maffucci syndrome) is not caused by the PTHR1mutation

p.R150C. Hum Mutat 2004;24:466-73.

175. Gorham LW, Stout AP. Massive osteolysis (acute spontaneous

absorption of bone, phantom bone, disappearing bone);

its relation to hemangiomatosis. J Bone Joint Surg Am 1955;

37:985-1004.

176. Bruch-Gerharz D, Gerharz CD, Stege H, Krutmann J, Pohl M,

Koester R, et al. Cutaneous vascular malformations in

disappearing bone (Gorham-Stout) disease. JAMA 2003;289:

1479-80.

177. Dickson GR, Mollan RA, Carr KE. Cytochemical localization

of alkaline and acid phosphatase in human vanishing bone

disease. Histochemistry 1987;87:569-72.

178. Hirayama T, Sabokbar A, Itonaga I, Watt-Smith S, Athanasou

NA. Cellular and humoral mechanisms of osteoclast forma-

tion and bone resorption in Gorham-Stout disease. J Pathol

2001;195:624-30.

179. van Geest AJ, Veraart JC, de Haan M, Neumann HA.

Bockenheimer’s syndrome. J Eur Acad Dermatol Venereol

1999;12:165-8.

180. Eerola I, Plate KH, Spiegel R, Boon LM, Mulliken JB, Vikkula M.

KRIT1 is mutated in hyperkeratotic cutaneous capillary-

venous malformation associated with cerebral capillary

malformation. Hum Mol Genet 2000;9:1351-5.

181. Porteous ME, Burn J, Proctor SJ. Hereditary haemorrhagic

telangiectasia: a clinical analysis. J Med Genet 1992;29:

527-30.

182. Folz BJ, Lippert BM, Wollstein AC, Tennie J, Happle R, Werner

JA. Mucocutaneous telangiectases of the head and neck

in individuals with hereditary hemorrhagic telangiectasia—

analysis of distribution and symptoms. Eur J Dermatol

2004;14:407-11.

183. Porteous ME, Burn J, Proctor SJ. Hereditary haemorrhagic

telangiectasia: a clinical analysis. J Med Genet 1992;29:

527-30.

184. Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemor-

rhagic telangiectasia. N Engl J Med 1995;333:918-24.

185. McAllister KA, Grogg KM, Johnson DW, Gallione CJ,

Baldwin MA, Jackson CE, et al. Endoglin, a TGF-beta

binding protein of endothelial cells, is the gene for

hereditary haemorrhagic telangiectasia type 1. Nat Genet

1994;8:345-51.

186. Berg JN, Gallione CJ, Stenzel TT, Johnson DW, Allen WP,

Schwartz CE, et al. The activin receptor-like kinase 1 gene:

genomic structure and mutations in hereditary hemor-

rhagic telangiectasia type 2. Am J Hum Genet 1997;61:

60-7.

187. Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I,

Yoon SJ, et al. Mutations in the activin receptor-like kinase 1

gene in hereditary haemorrhagic telangiectasia type 2. Nat

Genet 1996;13:189-95.

188. Fuchizaki U, Miyamori H, Kitagawa S, Kaneko S, Kobayashi K.

Hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber

disease). Lancet 2003;362:1490-4.

189. Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor

DG, et al. Defective angiogenesis in mice lacking endoglin.

Science 1999;284:1534-7.

190. Urness LD, Sorensen LK, Li DY. Arteriovenous malformations

in mice lacking activin receptor-like kinase-1. Nat Genet 2000;

26:328-31.

191. Sorensen LK, Brooke BS, Li DY, Urness LD. Loss of distinct

arterial and venous boundaries in mice lacking endoglin,

a vascular-specific TGFbeta coreceptor. Dev Biol 2003;261:

235-50.

192. Piantanida M, Buscarini E, Dellavecchia C, Minelli A, Rossi A,

Buscarini L, et al. Hereditary haemorrhagic telangiectasia

with extensive liver involvement is not caused by either

HHT1 or HHT2. J Med Genet 1996;33:441-3.

193. Bourdeau A, Dumont DJ, Letarte M. A murine model of

hereditary hemorrhagic telangiectasia. J Clin Invest 1999;104:

1343-51.

194. Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME,

Hyland RH, Westermann CJ, et al. Diagnostic criteria for

hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber

syndrome). Am J Med Genet 2000;91:66-7.

195. Gatti RA. Ataxia telangiectasia. In: Scriver CR, Beaudet AL,

Sly WS, Valle D, editors. The molecular and metabolic basis

of inherited disease. New York: McGraw-Hill; 1996.

196. Swift M, Morrell D, Massey RB, Chase CL. Incidence of cancer

in 161 families affected by ataxia-telangiectasia. N Engl J Med

1991;325:1831-6.

197. Swift M, Reitnauer PJ, Morrell D, Chase CL. Breast and other

cancers in families with ataxia-telangiectasia. N Engl J Med

1987;316:1289-94.

J AM ACAD DERMATOL

APRIL 2007

564 Garzon et al

198. Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y,

Vanagaite L, et al. A single ataxia telangiectasia gene

with a product similar to PI-3 kinase. Science 1995;268:

1749-53.

199. Lee Y, Chong MJ, McKinnon PJ. Ataxia telangiectasia

mutated-dependent apoptosis after genotoxic stress in the

developing nervous system is determined by cellular differ-

entiation status. J Neurosci 2001;21:6687-93.

200. Qi L, Strong MA, Karim BO, Armanios M, Huso DL, Greider

CW. Short telomeres and ataxia-telangiectasia mutated

deficiency cooperatively increase telomere dysfunction and

suppress tumorigenesis. Cancer Res 2003;63:8188-96.