A. Introduction

1. Relatively rare autosomal dominant condition
2. Originally called Osler-Weber-Rendu or Rendu-Weber-Osler Syndrome
3. Affects 1/3500 to 1/50,000 persons depending on geographic area
   1. Family members of a case are at risk for HHT with potentially serious AVM's [4]
   2. Pulmonary and cerebral AVM's are most concerning, and occur in >10% of relatives
   3. Screening of all close relatives of a patient is recommended [4]
4. Characteristics of disease are due to abnormalities of vascular structures
5. Telangiectasias are abnormal dilations of venules (end vessels)
   1. Majority of telangiectasias are focal dilations of post-capillary venules
   2. Venules may become markedly dilated and convoluted
   3. Abnormal vessels are lined by a single layer of endothelium attached to continuous basement membrane
6. Arteriovenous malformations (AVM) are also common but not universal

B. Etiology [1,5,6]

1. Two Types of HHT
   1. Type I is due to mutations in endoglin
   2. Type II is due to mutations in activin-receptor-like kinase 1 (ALK-1, chr 12q13)
   3. Both endoglin and ALK-1 bind to transforming growth factor ß (TGFß)
   4. Mutations in these receptors in HHT result in similar phenotypes
2. Endoglin
   1. Integral membrane glycoprotein that binds TGFß (type III TGFß receptor)
   2. Chromsome 9
   3. Endoglin mutations in HHT include abnormal truncation and dominant negative mutations
   4. Thus, abnormal endoglin may block normal responses to TGFß and BMPs
3. ALK-1
   1. Chromosome 12
   2. ALK-1 associates with endoglin and type 2 TGFß receptor on cell surface
   3. Activin binding to this complex leads to phosphorylation and SMAD protein stimulation
   4. Smad-4 translocates to the nucleus and alters gene expression
   5. Pulmonary Hypertension (HTN) in HHT associated with ALK-1 mutations [7]
4. TGFß and BMPs
   1. Bone morphogenic proteins (BMPs) are members of the TGFß growth factor family
   2. Modulates endothelial migration, proliferation, extracellular matrix, adhesion
   3. TGFß and BMPs primarily inhibit vascular and matrix production
5. Juvenile Polyposis with HHT [11,12]
   1. Due to mutations in SMAD4, a tumor suppressor on chromosome 18q21
   2. SMAD4 is a co-SMAD, an integral downstream effector of TGFß signalling
   3. SMAD4 coded by MADH4
   4. Consider genetic testing for these mutations in patients with relevant symptoms
   5. High risk of invasive cancers; upper and lower endoscopy should begin by age 15

C. Symptoms and Signs

1. Telangiectasias in nasal mucosa leading to nosebleeds (epistaxis)
   1. Highly variable severity, usually begins by ages 10-20
   2. Recurrent epistaxis may require transfusions, cauterization, laser therapy
   3. Estrogen therapy may be of some benefit
2. Telangiectasias of the skin
   1. Usually present >30 years
   2. Mucous membranes affected: lips, tongue, palate, conjuctiva (fingers, face also)
   3. Laser ablation may be used
3. Lung
   1. Pulmonary AVMs are the main concern, occuring in ~10% of persons with HHT
   2. Pulmonary HTN occurs in some patients, linked to ALK-1 mutations [7]
   3. Up to 60% of persons with pulmonary AVMs probably have HHT
   4. Direct right to left shunts, possibly producing dyspnea, cyanosis, polycythemia, fatigue
   5. High resolution computed tomographic (CT) scans are usually required
   6. Modern surgical management includes ligation of artery feeding the AVM
4. Brain
   1. AVMs are the main concern
   2. Migraine, brain abcess, stroke, hemorrhage, seizure may all occur
   3. Abscesses and ischemic strokes occur only in patients with pulmonary AVMs
   4. The pulmonary AVMs permit passage of septic and bland emboli from R to L circulation
   5. Neurovascular sugery, embolism implantation, radiosurgery are used
5. Gastrointestinal (GI) Tract [8]
   1. Recurrent GI bleeding usually occurs after 4th decade, <10% of patients
   2. May be very difficult to control bleeding
   3. AVMs and telangiectasias can occur anywhere in the GI tract
   4. Combination estrogen-progesterone therapy reduced short-term need for transfusions
   5. Bipolar Electrocoagulation or Lasar Photocoagulation may be effective in some cases
   6. Liver involvement with AVMs may lead to cardiac failure with high output [9]
   7. May progress with portal hypertension and biliary disease
6. Prevalence of Vascular Lesions [1,3]
   1. Nasal Mucosa - 80%
   2. Oral Mucosa - 70%
   3. Face - 50%
   4. Trunk - ~50%
   5. Extremities - 45%
   6. Ocular - 45%
   7. Pulmonary AVMs - ~20%
   8. Cerebral AVMs - ~8%

D. Diagnosis

1. Requires any two of the following:
2. Recurrent epistaxis
3. Telangiectasias not in nasal mucosa
4. Evidence of autosomal dominant inheritance
5. Visceral involvement

E. Management

1. Directed at symptoms, as described above
   1. Cauterization of recurrent nosebleeds
   2. Iron supplementation for anemia (usually iron deficiency)
2. Screening for pulmonary AVMs is recommended
   1. Arterial blood gas (including response to oxygen)
   2. High resolution CT scanning
   3. Persons with pulmonary AVMs should receive antibiotic prophylaxis for all procedures
3. Gastrointestinal Bleeding
   1. Recurrent bleeding episodes may be reduced with estrogen-protestin therapy
   2. E-aminocaproic acid can reduce GI and nasal bleeding (1gm po bid or 1.5gm po qd) [10]
4. Cerebral AVMs and aneurysms
   1. Family history used as a guide for screening
   2. MRI with angiography should be performed at least once (preferably in childhood)
   3. However, unclear whether asymptomatic lesions should be treated [3]
5. Educational Materials from HHT Foundation International 1-800-448-6389

References

1. Fuchizaki U, Miyamori H, Kitagawa S, et al. 2003. Lancet. 362(9394):1490
2. Guttmacher AE, Marchuk DA, White RI. 1995. NEJM. 333(14):918
3. Haitjema T, Westermann CJJ, Overtoom TTC, et al. 1996. Arch Intern Med. 156(7):715
4. Haitjema T, Disch F, Overtoom TTC, et al. 1995. Am J Med. 99(5):519
5. Blobe GC, Wchiemann WP, Lodish HF. 2000. NEJM. 342(18):1350
6. Loscalzo J. 2001. NEJM. 345(5):368
7. Morse JH. 2003. Lupus. 12(3):209
8. Colletti RB and Compton CC. 1997. NEJM. 336(9):641 (Case Report CPC)
9. Garcia-Tsao G, Korzenik JR, Young L, et al. 2000. NEJM. 343(13):931
10. Saba HI, Morelli GA, Logrono LA. 1994. NEJM. 330(25):1789
11. Gallione CJ, Repetto GM, Legius E, et al. 2004. Lancet. 363(9412):852
12. Korzenik J, Chung DC, Digumarthy S, Badizadegan K. 2005. NEJM. 353(17):1836 (Case Record)