HHT

918 THE NEW ENGLAND JOURNAL OF MEDICINE Oct. 5, 1995

REVIEW ARTICLE

CURRENT CONCEPTS

HEREDITARY HEMORRHAGIC TELANGIECTASIA

A

LAN

E. G

UTTMACHER

, M.D.,D

OUGLAS

A. M

ARCHUK

, P

H

.D.,

AND

R

OBERT

I. W

HITE

, J

R

., M.D.

From the Department of Pediatrics, University of Vermont College of Medi-cine, Burlington (A.E.G.); the Department of Genetics, Duke University MedicalCenter, Durham, N.C. (D.A.M.); and the Department of Diagnostic Radiology,Yale University School of Medicine, New Haven, Conn. (R.I.W.). Address reprintrequests to Dr. Guttmacher at the Vermont Human Genetics Initiative, Box B-10,1 Mill St., Burlington, VT 05401.

Supported by a grant (HL49171) from the National Institutes of Health (to Dr.Marchuk) and by a fellowship from the Baxter Foundation.

I

DENTIFIED nearly a century ago, hereditary hem-orrhagic telangiectasia, or Rendu–Osler–Weber syn-

drome, has long been viewed as a rare condition pro-ducing minor discomfort for affected persons. However,this disorder is now considered to be more commonthan previously thought,

1-5

and the associated brain andpulmonary lesions are sources of substantial morbidityand mortality.

3,6-8

Wider recognition of the conditionand awareness of its sequelae can help avoid the con-siderable risks associated with its mismanagement. Ad-vances in molecular genetics have demonstrated thathereditary hemorrhagic telangiectasia is actually agroup of autosomal dominant disorders.

9-13

The recentidentification of the gene causing one form of the con-dition

14

should lead to a better understanding of these,and perhaps other, vascular disorders.

Although reports as early as Sutton’s

15

in 1864 ap-pear to describe what is now known as hereditary hem-orrhagic telangiectasia, Rendu

16

first recognized thecombination of hereditary epistaxis and telangiectasesin 1896 as a specific entity distinct from hemophilia.The following decade produced a number of case re-ports, including the prominent ones by Osler

17

andWeber,

18

whose names appear in various orders in thecommon eponymous labels for this condition. In 1909,Hanes

19

coined the term “hereditary hemorrhagic tel-angiectasia,” in acknowledgement of the three featuresthat by then defined the disorder.

Hereditary hemorrhagic telangiectasia occurs with awide geographic distribution among many ethnic andracial groups. Studies of prevalence show that, at leastin the populations investigated, it is more frequent thanwas formerly thought. It has been found to occur in atleast the following numbers: 1 in 2351 members of thepopulation in the French department of Ain,

1

1 in 3500

on the Danish island of Funen,

2

1 in 5155 in the Lee-ward Islands,

4

1 in 16,500 in Vermont,

5

and 1 in 39,216in northern England.

3

P

ATHOPHYSIOLOGIC

F

EATURES

The recognized manifestations of hereditary hemor-rhagic telangiectasia are all due to abnormalities ofvascular structure (Fig. 1). The smallest of the hall-mark telangiectases are focal dilatations of postcapil-lary venules, with prominent stress fibers in pericytesalong the luminal border. In fully developed telangiec-tases, the venules are markedly dilated and convoluted,extend through the entire dermis, have excessive layersof smooth muscle without elastic fibers, and often con-nect directly to dilated arterioles. Mononuclear cells,primarily lymphocytes, collect in the perivascular spacethroughout this process.

20

Telangiectases are nearly universal, but the otherprominent lesions of hereditary hemorrhagic telangiec-tasia, arteriovenous malformations, appear to be fre-quent only in certain forms of the condition.

10-12

Thesemalformations, like telangiectases, lack capillaries andconsist of direct connections between arteries and veins,but are much larger.

The recent discovery that a gene causing hereditaryhemorrhagic telangiectasia encodes a protein that bindstransforming growth factor

b

may help elucidate thebasic mechanisms underlying the vascular lesions inthe disorder.

14

C

LINICAL

M

ANIFESTATIONS

The diverse manifestations of hereditary hemorrhag-ic telangiectasia involve vascular abnormalities of thenose, skin, lung, brain, and gastrointestinal tract. Table1 summarizes clinical approaches and treatment op-tions in the care of persons with hereditary hemorrhag-ic telangiectasia.

Nose

Epistaxis caused by spontaneous bleeding from tel-angiectases of the nasal mucosa is the most commonmanifestation of hereditary hemorrhagic telangiectasia,occurring in the vast majority of affected persons, butnot in all.

21

It may be so severe as to require multipletransfusions and oral iron supplementation, or so mildthat hereditary hemorrhagic telangiectasia is never sus-pected. Recurrent epistaxis begins by the age of 10years in many patients and by the age of 21 in most,

21

becoming more severe in later decades in about twothirds of affected persons.

21,22

Multiple treatments for epistaxis have been used, in-cluding cauterization, septal dermatoplasty,

23

laser ab-lation,

24,25

estrogen therapy,

22,26

and transcatheter em-bolotherapy of arteries leading to the nasal mucosa.

27

Few prospective, randomized clinical trials have evalu-

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Vol. 333 No. 14 CURRENT CONCEPTS 919

ated these therapies. One prospective study suggeststhat estrogen supplementation is ineffective,

26

but larg-er, uncontrolled studies support its efficacy.

22

Otolaryn-gologists adept at septal dermoplasty have had goodresults in patients with severe epistaxis,

23

and laser ab-lation has been effective in treating milder forms.

24,25

Skin

Telangiectases of the skin typically present later inlife than epistaxis.

6

By the age of 40, most affected per-sons have multiple telangiectases of the lips, tongue(Fig. 2A), palate, fingers, face, conjunctivas (Fig. 2B),

28

trunk, arms, nail beds, or a combination of these. Theremay be bleeding from cutaneous telangiectases, but itis rarely clinically important. For telangiectases causingcosmetic concern, topical agents may be useful, and la-ser ablation can sometimes be effective.

29

Lung

Pulmonary arteriovenous malformations consist ofdirect connections between a branch of a pulmonaryartery and a pulmonary vein through a thin-walled an-eurysm. They are often multiple and appear in bothlungs, with a predilection for the lower lobes. It is esti-mated that 60 percent of persons with pulmonary arte-riovenous malformations have hereditary hemorrhagictelangiectasia.

30

Conversely, it is estimated that overall,5 to 15 percent of persons with hereditary hemorrhagictelangiectasia have pulmonary arteriovenous malfor-mations,

30

but the incidence of these lesions apparentlyvaries according to the specific gene for the conditionthat is present.

10-12

Pulmonary arteriovenous malformations result in di-rect right-to-left shunts and, particularly when multi-ple, may produce profound dyspnea, fatigue, cyanosis,or polycythemia. Often, however, their initial manifes-tations are the neurologic sequelae of brain abscess andstroke due to shunting.

31

Although standard chest radiographs may demon-

Figure 1. Evolution of a Cutaneous Telangiectasis in HereditaryHemorrhagic Telangiectasia.

In normal skin (top panel), arterioles (A) in the papillary dermisare connected to venules (V) through multiple capillaries (C).These vessels arise from larger arterioles and venules at thejunction of the dermis and fat. The ultrastructure of a normalpostcapillary venule (shown in cross section in the inset) in-cludes the lumen (L), endothelial cells, and two to three layersof surrounding pericytes. In the earliest stage of cutaneous tel-angiectasia (middle panel), a single venule becomes dilated, butit is still connected to an arteriole through one or more capillar-ies. A perivascular lymphocytic infiltrate is apparent (arrow). Ina fully developed cutaneous telangiectasis (bottom panel), thevenule and its branches have become markedly dilated, elon-gated, and convoluted throughout the dermis. The connectingarterioles have also become dilated and communicate directlywith the venules without intervening capillaries. The perivascu-lar infiltrate is still present. The thickened wall of the dilateddescending limb (shown in cross section in the inset) containsas many as 11 layers of smooth-muscle cells. (Adapted from

Braverman et al.

20

)

Epidermis

Epidermis

Epidermis

Fat

Fat

Fat

V

V

V

A

A

A

A

V

V

A

A

V

A

C

C C

L

L

See�inset

See�inset

Dermis

Dermis

Dermis




strate a typical mass with enlarged arteries and veins,many pulmonary arteriovenous malformations are sub-tle and appear below the diaphragm because of theirposterior location in the lung (Fig. 3). High-resolutionhelical computed tomographic scanning without the useof contrast material effectively demonstrates the archi-tecture of vessels in pulmonary arteriovenous malforma-tions and has simplified the diagnosis of these lesions.

32

Chest radiography, arterial-blood gas measurements,and finger oximetry remain important in screening per-sons with suspected pulmonary arteriovenous malfor-mations. Pulmonary angiography is required in order toplan treatments by interventional radiology or sur-gery.

31,33

Surgical management of pulmonary arteriovenousmalformations has evolved from lobectomy to wedgeresection to ligation of the arterial supply of the malfor-mation.

34

Transcatheter embolotherapy with detachableballoons or stainless-steel coils has also been used toclose such malformations.

31,33,35,36

Although no prospec-tive studies have compared these approaches, embolo-therapy is less invasive than surgery and does notrequire bilateral thoracotomy to treat multiple malfor-mations. Small remaining malformations may becomeenlarged after either embolotherapy or surgery. Long-term follow-up of treated patients is important, becausethe growth of malformations in the interval may re-quire further therapy.

Brain

Neurologic symptoms, including migraine headache,brain abscess, transient ischemic attack, stroke, seizure,and intracerebral and subarachnoid hemorrhage, arecommon in patients with hereditary hemorrhagic telan-giectasia,

8,37

particularly those with a personal or familyhistory of pulmonary arteriovenous malformations.

3,31,38-40

For two thirds of those in whom neurologic symptomsdevelop, pulmonary arteriovenous malformations arethe source of the symptoms.

31

In the remaining third,cerebral or spinal arteriovenous malformations causesubarachnoid hemorrhage, seizure, or less commonly,paraparesis.

4,8,37

Brain abscess, transient ischemic attack, and ischemicstroke occur exclusively in patients with pulmonary ar-teriovenous malformations who have right-to-left shunt-ing that facilitates the passage of septic and bland em-boli into the cerebral circulation.

31

These symptoms areoften the first manifestations of a pulmonary arteriove-nous malformation and even of hereditary hemorrhagictelangiectasia itself.

38,40

The frequency and architecture of cerebral arteriove-nous malformations have not been characterized in anylarge cohort with hereditary hemorrhagic telangiecta-sia. In one series, 5 percent of patients with hereditaryhemorrhagic telangiectasia who underwent computedtomography had cerebral arteriovenous malforma-tions,

31

but the application of more sensitive techniquesof magnetic resonance imaging and angiography willapparently demonstrate a higher prevalence.

41

Neurovascular surgery, embolotherapy, and stereo-tactic radiosurgery have all been used to treat cerebralarteriovenous malformations. Further experience isneeded for any single treatment to be recommended asoptimal for vascular malformations of the brain or spi-nal cord in persons with hereditary hemorrhagic telan-giectasia.

Gastrointestinal Tract

Recurrent hemorrhage of the upper or lower gas-trointestinal tract occurs in a substantial minority ofpersons with hereditary hemorrhagic telangiectasia

2,42

and is one of the manifestations of the condition that is

Table 1. Summary of Clinical Approaches and Therapeutic Options in Patients with Hereditary Hemorrhagic Telangiectasia.

A

FFECTED

O

RGAN

OR

S

YSTEM

T

YPE

OF

L

ESION

S

ITES

S

YMPTOMS

AND

S

IGNS

S

CREENING

T

OOLS

D

IAGNOSTIC

M

ETHODS

A

PPROPRIATE

T

REATMENT

Nose Telangiectases Nasal mucosa Epistaxis Medical history Visual inspection Humidification, packing, transfusion, estrogen therapy, septal der-moplasty, laser, cautery, embo-lotherapy

Skin Telangiectases Lips, tongue, palate, face, conjunctivas, trunk, nail beds, finger pads

Bleeding (usually minor)

Visual inspection Visual inspection Topical agents, laser ab-lation

Lung Arteriovenous malformations

Often multiple; predilec-tion for lower lobes

Cyanosis, clubbing, bruit, migraine, cerebral abscess, embolic stroke

Medical and family history, linkage to 9q3, blood gas meas-urement, oximetry, chest radiography

High-resolution helical computed tomog-raphy, angiography

Embolotherapy, surgical resection, ligation of arterial supply

Central nervous system

Arteriovenous malformations

Brain, spinal cord Headache, sub-arachnoid hem-orrhage

Medical and family history

Magnetic resonance im-aging, magnetic reso-nance angiography

Neurovascular surgery, embolotherapy, ster-eotactic radiosurgery

Gastrointestinal tract

Arteriovenous mal-formations, tel-angiectases, an-giodysplasias

Stomach, duodenum, small bowel, colon, liver

Bleeding; if hepatic lesion, heart fail-ure with bruit

Medical and family history

Endoscopy, angiography; for liver lesions, com-puted tomography

Transfusion, photocoag-ulation, estrogen–pro-gesterone therapy




most difficult to manage. Gastrointestinal bleeding doesnot usually start until the fifth or sixth decade. Endos-copy may reveal telangiectases in the stomach, duode-num, small bowel, or colon that are similar in size andappearance to those of the nasal and oral mucosa. Lesscommonly, gastrointestinal angiography demonstrateslarger telangiectases, arteriovenous malformations, orangiodysplasias.

43

Requirements for the transfusion ofmore than 100 units of blood are well documented.

44

Photocoagulation using bipolar electrocoagulation orlaser techniques may control bleeding gastrointestinaltelangiectases in the short term, but less commonly inthe long term.

45,46

A prospective, double-blind, cross-over study showed that, as compared with placebo, amixture of estrogen and progesterone significantly de-creased the short-term requirement for transfusion insubjects with hereditary hemorrhagic telangiectasia andgastrointestinal bleeding.

44

The mechanism responsiblefor the decrease was not determined.

Liver involvement due to the presence of multiple ar-teriovenous malformations or atypical cirrhosis is a rarebut important manifestation of hereditary hemorrhagic

telangiectasia.

47,48

High cardiac output caused by left-to-right shunting within the liver can lead to heart fail-ure.

48

Treatment that includes segmental embolothera-py of branch hepatic arteries may be helpful but canproduce severe complications.

48

M

OLECULAR

G

ENETICS

Genetic linkages to hereditary hemorrhagic telangi-ectasia have been established to chromosome 9q33-q34in some families

9,49

and to chromosome 12q in oth-ers.

13,50

It is possible that genes on other chromosomesmay also create the condition.

The gene for hereditary hemorrhagic telangiectasiaat chromosome 9q3 has been identified as endoglin,

14

which encodes an integral membrane glycoprotein thatis the most abundant protein on endothelial cells tobind transforming growth factor

b

. This locus appearsto initiate a response to the growth factor.

51,52

The mu-tations of the endoglin gene identified thus far in he-reditary hemorrhagic telangiectasia

14

(and unpublisheddata), including numerous protein truncations, suggestthat the altered gene either may produce less of thenormal protein (“loss of function” mutations) or mayproduce a dysfunctional protein that interferes with theremaining normal protein (“dominant negative” muta-tions). Transforming growth factor

b

modulates severalprocesses of endothelial cells, including migration, pro-liferation, and adhesion and the composition and or-ganization of the extracellular matrix. Perturbation ofone or more of these processes may cause the vasculardysplasia. The restriction of vascular disease to discretelesions suggests that an initiation event, mechanical,physiologic, or genetic, is required for the developmentof each lesion.

D

IAGNOSIS

The clinical criterion for the diagnosis of hereditaryhemorrhagic telangiectasia is the presence of any twoof the following: recurrent epistaxis, telangiectases else-where than in the nasal mucosa, evidence of autosomaldominant inheritance, and visceral involvement.

6

By definition, autosomal dominant diseases are thosein which the disease is found in heterozygotes. Howev-er, hereditary hemorrhagic telangiectasia shares withmany autosomal dominant disorders the property of in-complete penetrance; occasionally, persons who inheritthe gene for the disease do not demonstrate it pheno-typically. Also, epistaxis, the most common manifesta-tion of hereditary hemorrhagic telangiectasia, is com-mon in the general population. Thus, clinical criteriaare not entirely reliable for making the diagnosis, es-pecially in children. The fact that mutations causinghereditary hemorrhagic telangiectasia have been iden-tified raises the possibility of molecular diagnosis. How-ever, preliminary results suggest that many familieswith disease linked to chromosome 9q3 have uniquemutations of the endoglin gene (unpublished data). Inother families the gene or genes have yet to be identi-fied. Therefore, DNA-based diagnostics may prove dif-

Figure 2. Telangiectases in Patients with Hereditary Hemorrhag-

A

B

ic Telangiectasia.Panel A shows telangiectases of the tongue and lower lip, and

Panel B shows conjunctival telangiectases.




Figure 3. Treatment of a Pulmonary Arteriovenous Malformation

A

by Embolotherapy.In Panel A, a chest radiograph shows a pulmonary arteriove-nous malformation in the right lower lobe (arrow). Panel B showsa pulmonary angiogram of the same lesion before occlusion.There is an aneurysm with an enlarged artery and vein. PanelC shows the lesion immediately after embolotherapy with a de-tachable balloon. Panel D shows a chest radiograph of the le-sion 30 months after occlusion, with the balloon in place. The

aneurysm has disappeared.

B

C

D




ficult, except in research settings or when genetic link-age can be established in a multigenerational pedigree.

M

ANAGEMENT

Until appropriate studies validate treatment proto-cols, the care of patients with hereditary hemorrhagictelangiectasia must be based on clinical experience andan understanding of the pathophysiologic features ofthe disorder. In the follow-up of affected persons, thelung and brain are of particular concern, because eachmay contain clinically silent lesions that can result insudden morbidity or death. Presymptomatic interven-tion in such cases may substantially affect the outcome.

Pulmonary screening attempts to identify personswhose risk of pulmonary arteriovenous malformations issufficient for diagnostic imaging to be warranted. Meas-urement of blood oxygen and the family history mayboth help determine this risk. Because most pulmonaryarteriovenous malformations occur near the bases of thelungs, the greatest deoxygenation often occurs when aperson is standing (i.e., orthodeoxia), since the gravita-tional redistribution of pulmonary blood flow increasesthe flow through basilar malformations. Thus, arterial-blood gas measurements and finger oximetry may bemost sensitive when the patient is in the upright posi-tion.

31,36

Family history is also important, because mo-lecular evidence of genetic heterogeneity appears toconfirm the clinical impression that the incidence ofpulmonary arteriovenous malformations varies amongfamilies, being particularly high in those with geneticlinkage of the condition to chromosome 9q3.

7,10-12

Persons affected by, or at risk for, hereditary hemor-rhagic telangiectasia who have a family history of pul-monary or cerebral arteriovenous malformations shouldundergo pulmonary screening at puberty, or sooner ifthe family history includes prepubertal arteriovenousmalformations, and again at the end of adolescence.For persons from families without such a history, pul-monary screening should be considered but is lessclearly indicated. Because there have been cases of life-threatening pulmonary hemorrhage in the third trimes-ter of pregnancy, affected women should have pulmo-nary screening before conception.

7

Anyone in whom apulmonary arteriovenous malformation is found shouldundergo helical computed tomography every five yearsto rule out the possible growth of residual malforma-tions in the intervening period.

Family history may also serve as a guide to screeningfor cerebral arteriovenous malformations and aneu-rysms, because at least the malformations appear to besignificantly more common in certain families. Cerebralscreening by magnetic resonance imaging should beperformed at least once, preferably in childhood, ifthere is a family history of cerebral arteriovenous mal-formations. Even persons at low risk for such malfor-mations are at high risk for cerebral abscess and strokeif they have a pulmonary arteriovenous malformation.

Anyone who has had a pulmonary arteriovenousmalformation should receive antibacterial prophylaxisat the time of a dental or surgical procedure. Otherswho are affected or at risk and who have a family his-

tory of pulmonary arteriovenous malformations shoulduse prophylaxis until the possibility that they may havesuch a malformation is ruled out.

It is important that persons with hereditary hemor-rhagic telangiectasia be aware of their diagnosis and itsimplications and that they inform health care providersthat they are affected. Educational materials for pa-tients and providers are available from the HHT Foun-dation International (P.O. Box 8087, New Haven, CT06530; 800-448-6389).

F

UTURE

D

EVELOPMENTS

The understanding of hereditary hemorrhagic telan-giectasia is expanding rapidly. Recently, the conditionhas been shown to be a family of disorders caused bymutations in various genes, and the gene responsiblefor one form has been identified. This discovery of ge-netic heterogeneity should bring a reevaluation of thenatural history of these disorders, because the inci-dence of many clinical manifestations may vary widelyamong the various forms. A current multicenter effortis attempting to produce the needed correlations be-tween genotype and phenotype. Multicenter coopera-tion may also lead to randomized, prospective trials todetermine the efficacy of various therapies. The devel-opment of a functional assay to provide presymptomat-ic diagnosis appears possible. The finding that a pro-tein binding transforming growth factor

b

has a keyrole in the disease should help elucidate the pathophys-iologic features. Therapeutic advances, including genereplacement, may now be a realistic possibility giventhe ease of access through the bloodstream to endothe-lial cells, the target tissue.

Better understanding of hereditary hemorrhagic tel-angiectasia may also bring critical insights into otherdiseases involving vascular damage and repair. PerhapsOsler’s hope will be fulfilled: “To wrest from nature thesecrets which have perplexed philosophers in all ages,to track to their sources the causes of disease, to corre-late the vast stores of knowledge, that they may bequickly available for the prevention and cure of disease— these are our ambitions.”

53

We are indebted to Wendolyn Hill, Dr. Irwin Braverman, andAgnes Keh for the artwork and concepts used in Figure 1.

R

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