|Year : 2009 | Volume
| Issue : 2 | Page : 83-88
Rendu-Osler-Weber syndrome: A family investigation and review
VG Mahima, Karthikeya Patil, Madhur Kapoor, Shalini Kalia
Department of Oral Medicine and Radiology, J.S.S. Dental College and Hospital, Mysore, Karnataka-570 015, India
|Date of Web Publication||1-Dec-2009|
V G Mahima
Department of Oral Medicine and Radiology, J.S.S. Dental College and Hospital, S.S. Nagar, Mysore - 570 015
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Rendu-Osler-Weber syndrome is a rare genetic condition characterized by mucocutaneous and visceral fibrovascular dysplasia leading to multiple macular or papular vascular lesions of skin, mucosal surfaces and occasionally viscera that show tendency towards hemorrhage. The orofacial features of the condition in an affected family and in particular a 33-year-old Indian male patient, are illustrated along with summarization of management aspects in a dental setup.
Keywords: Hereditary hemorrhagic telangiectasia, epistaxis, gastrointestinal bleeding, oral petechiae, Rendu-Osler-Weber syndrome
|How to cite this article:|
Mahima V G, Patil K, Kapoor M, Kalia S. Rendu-Osler-Weber syndrome: A family investigation and review. J Indian Acad Oral Med Radiol 2009;21:83-8
|How to cite this URL:|
Mahima V G, Patil K, Kapoor M, Kalia S. Rendu-Osler-Weber syndrome: A family investigation and review. J Indian Acad Oral Med Radiol [serial online] 2009 [cited 2019 Jun 19];21:83-8. Available from: http://www.jiaomr.in/text.asp?2009/21/2/83/57894
| Introduction|| |
Rendu-Osler- Weber syndrome More Details or Hereditary Hemorrhagic Telangiectasia [HHT] is an autosomal dominant mucocutaneous and visceral fibrovascular dysplasia, in which telangiectasia, arteriovenous malformations and aneurysms may be widely distributed throughout the cardiovascular system. Oral and nasal mucosal bleeding may be one of the initial symptoms that should prompt an oral diagnostician to undertake investigations to rule out this rare genetic syndrome. One such instance of a case of an Indian male reporting to a dental setup and subsequent diagnosis of this rare syndrome is presented.
| Case Report|| |
A 33-year-old male patient reported to our department with a complaint of painful lower left back tooth since one month. The patient further reported a six-month history of occasional recurrent episodes of spontaneous epistaxis and bleeding from mouth that lasted for only short periods. There was a negative history of delayed wound healing, melena, hemoptysis or hematemesis. There had been no diagnosis as the patient had never sought medical attention for these episodes, which were self-limiting. Family history was significant as patient's mother and other two siblings, one sister and one brother, had similar episodes of bleeding from nose and mouth.
A comprehensive physical examination revealed satisfactory vital signs and no evidence of anemia, cyanosis or clubbing. Multiple pinpoint erythematous macular lesions were observed on the palmar surface of the hands and fingertips [Figure 1]. The regional lymph nodes were non-palpable.
Intraoral soft tissue examination revealed multiple red to purple-colored macular and papular lesions scattered over the soft and hard palate [Figure 2], dorsum of tongue [Figure 3], and lower labial mucosa. The lesions were non-tender and blanched on diascopic examination. No other abnormalities were observed intraorally.
Considering the symptoms, family history and clinical findings, the mucosal lesions were provisionally diagnosed to be a part of HHT.
The patient was investigated accordingly. His hematological and biochemical parameters were within normal limits. One of the dorsal tongue lesions was subjected to biopsy. The histopathological sections showed stratified squamous epithelium which was keratinized and atrophic. The connective tissue stroma showed lots of endothelium-lined blood vessels dilated and filled with erythrocytes, many of which were in close relation to the epithelium [Figure 4].
The patient was referred to the physician for systemic evaluation. The diagnostic parameters taken into consideration for a general screening were contrast echocardiography to screen for intrapulmonary shunts, auscultation and ultrasound examination for a hepatic assessment. All investigations revealed findings within normal limits. Even so, the patient has been asked to report for bi-annual evaluation.
In addition, a positive family history of mucosal bleeding prompted examination of the patient's family members. Lesions similar to the ones detected in our patient were noted in some of them [Figure 5],[Figure 6],[Figure 7],[Figure 8],[Figure 9],[Figure 10]. The pattern of inheritance of the disease was charted out with the help of the information acquired [Figure 11]. Pedigree analysis revealed autosomal dominant pattern of inheritance where there is only 50% probability of transmission of altered genes. In our case the affected mother had transmitted the altered genes to three of the five offspring.
| Discussion|| |
Rendu-Osler-Weber syndrome, also known as Hereditary Hemorrhagic Telangiectasia (HHT), is an autosomal dominant mucocutaneous and visceral fibrovascular dysplasia that is usually recognized as a "classic triad" of telangiectasia, recurrent epistaxis and a family history of the disorder. ,
The syndrome was first mentioned by Sutton in 1864 , and Babinton in 1865. Both authors described patients and members of their families who suffered from epistaxis. Legg in 1876 demonstrated a patient with hemophilia complicated with multiple nevi. Epistaxis had occurred in three generations.  Rendu in 1896 reported a man suffering from recurrent epistaxis and numerous dilated vessels on the face and oral mucosa.  Osler in 1901 gave a full account of the syndrome, while Weber in 1906 pointed out that the condition became worse with age. , However, it was Hanes who in 1909 suggested the term 'hereditary hemorrhagic telangiectasia'. ,,
Although various eponyms have been used for this genetic disorder like Osler's disease, Rendu-Osler disease, familial hemorrhagic telangiectasia, Sutton-Babinton-Rendu-Osler -Weber syndrome, Osler-Rendu-Weber syndrome, multiple hereditary telangiectasis with recurrent hemorrhages, Goldstein's heredofamilial angiomatosis, Angiomatose Hemorrhagique Héréditaire, Generalized angiomatosis (telangiectasia), ,,, the term proposed by Hanes is widely used now. ,
It is a disorder of capillaries and small blood vessels and is transmitted by simple autosomal dominant inheritance. ,,,,,, The presented case had similar mode of inheritance with three affected (two males and one female) family members in one generation. Although the mother of the patient was affected with HHT and the father was normal, consanguineous marriage involving the two carried a risk of one in two as there was 50% segregation of the trait in their offspring.
Most patients with HHT report similarly affected relatives.  There are now at least two types of HHT, one linked to Chromosome 9 and the other linked to Chromosome 12.  However, in 20% of cases, there is no family history of either telangiectasia or recurrent bleeding. , Such cases could possibly be due to sporadic spontaneous mutation, incomplete pedigree, relatives without symptoms, or atavism. ,
A deficiency in elastic fibers was thought to produce abnormally thin vascular walls, resulting in vascular dilation and spontaneous rupture.  However, following an electron microscope study, the actual cause of hemorrhage was attributed to either a primary intrinsic defect of the endothelial cells permitting their detachment, or a defect in the perivascular supportive tissue bed which weakens the vessels, rather than a lack of elastic fibers.  Thus oral lesions represent multiple micro-aneurysms resulting from a weakening defect in the adventitial coat of venules.  Other explanations for bleeding lesions in HHT include mechanical fragility and rupture of telangiactic vessel walls, impaired aggregation and adhesion of platelets and abnormal synthesis of von Willebrand factor from defective endothelial cells. 
The estimated prevalence of HHT is 2-20 per 100,000 population.  Males and females are equally affected. , HHT occurs in all races but has a particular predilection for white persons.  In addition a high prevalence has been reported for Anglo-Germanic, Latin, Scandinavian and Jewish population. ,
The characteristic lesions of the syndrome, telangiectases, may occur at or shortly after birth , but become conspicuous after puberty ,,, or menopause or the male climacteric. 
Recurrent epistaxis is the most common and presenting symptom and may appear in childhood or adolescence. ,,,,,[ 15] Ninety-five per cent of the affected present with recurrent epistaxis, with a mean age at first event of about 12 years and mean frequency of 18 episodes per month.  Cutaneous telangiectasia usually manifest in the second and third decades. ,, The lesions characteristically increase in size and number with age. ,
The telangiectasia observed in the syndrome may vary in appearance. Osler in 1907 distinguished three types - pinpoint, nodular and spider-like. The color of these lesions depends on the type of blood within the dilated vessels and may be bright red, violaceous or purple. The lesions blanch upon pressure and regain their original color upon release. , HHT may affect any part of the vascular tree.  Mucocutaneous lesions are generally well-defined, superficial, angiomatous nodules or telangiectases less than 5 mm, but systemic arteriovenous malformation or fistulae and aneurysms are important manifestations. ,
Telangiectasis in nasal mucosa commonly results in frequent episodes of epistaxis. There may be oozing, sometimes persisting continuously for several days. Profuse hemorrhage may be initiated by sneezing or coughing.  Nasal lesions are present in as many as 90% of cases. ,
The skin lesions are most common on the face, neck and chest.  Lesions on the face are evident mostly on the cheeks and nasal orifices and may occur on the ears, scalp, fingers, toes and nail beds. Dermal lesions may be purpuric and frequently spider-like in elderly patients. Onset of these lesions is in the second to third decades or even later. 
The involvement of gastric mucosa, bladder, vagina or uterus may manifest as melena, hematemesis and genitourinary bleeding.  Organs affected by the syndrome are liver, brain, spinal cord and lungs. ,,
The site predilection for oral lesions of HHT has been reported to be varied. Although lesions may be seen most frequently on mucosal surfaces of the lips, perioral skin, tip and dorsum of the tongue, the palate, gingiva, floor of the mouth and buccal mucosa may also be affected. ,,,, The early oral lesion is a cherry-red macule ranging from 1 to 3 mm in diameter. , There may be hundreds of such red to purple papules on the vermilion border and other oral mucosal areas.  Cutaneous circumoral lesions are said to be pathognomonic. 
A possibility of association of external root resorption with multiple gingival tissue telangiectases in HHT has been reported. 
Similar telangiectases of the skin and oral mucosa may occur in progressive systemic sclerosis, the calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly and telangiectasia (CREST) syndrome, lupus erythematosus, angiokeratoma corporis diffusum (Fabry's disease), ataxia telangiectasia and sarcoid. ,, Although the differential diagnosis should also include platelet disorder, the petechiae in HHT are macular rather than papular foci of erythrocyte extravasation with breakdown to hemosiderin. As a consequence, they are red to brown rather than purple. 
Often, patients are pale and have a history of fatigue and weakness caused by bleeding from the lesions with resultant anemia. , The hemorrhages are often non-traumatic and the most severe complication that becomes more frequent with advancing age. Hemorrhages aggravated by anemia produce a vicious cycle.  Spontaneous bleeding is more common from the mucosal telangiectases than skin lesions. , Bleeding from oral lesions is second in frequency to epistaxis, ,,,, followed by gastrointestinal, genitourinary and hemoptysis in that order. 
A mortality of 4% due to epistaxis in affected families has been reported. There are rare reports of fatal outcome after gingival hemorrhage.  In spite of the reported deaths from severe hemorrhage in HHT, ,, the disease is seldom life-threatening 5 and fortunately preventable. 
The diagnosis of HHT is based on the presence of arteriovenous malformations (AVMs), which may be cutaneous or mucocutaneous telangiectases or large visceral AVMs.  The clinical diagnosis of HHT is considered: 
- Definite when three or more findings are present,
- Possible or suspected when two findings are present, and
- Unlikely when fewer than two findings are present.
The findings are as follows:
- Nosebleeds (epistaxis): spontaneous and recurrent (night-time nosebleeds heighten the concern for HHT).
- Mucocutaneous telangiectases (small blanchable red spots that are focal dilatations of post-capillary venules or delicate, lacy red vessels composed of markedly dilated and convoluted venules): multiple, at characteristic sites, including lips, oral cavity, fingers, and nose.
- Visceral arteriovenous malformation (AVM): an AVM lacks capillaries and consists of direct connections between arteries and veins. AVMs may be pulmonary, cerebral, hepatic, spinal and/or gastrointestinal.
- Family history: a first-degree relative in whom HHT has been diagnosed.
The diagnosis of HHT in our case was a definite one owing to the existence of three of the criteria.
Both bleeding and clotting times are normal, as are the blood elements, although with severe bleeding mild anemia and thrombocytopenia may result.  Biopsy is occasionally indicated, since the syndrome is easily diagnosed from the pathognomonic skin and oral lesions and from family history.  In and around the mouth, the nodules and angiomas develop from venules, whereas telangiectases appear to be dilated capillaries lined with a single layer of endothelium. ,,, The intrinsic lesion has been shown to be endothelial discontinuity caused by degeneration or defective overlapping at endothelial junctions. Thrombi may seal the endothelial gaps. ,
Treatment of the disease is varied and depends on the severity.  Persistent troublesome lesions may be treated with laser therapy, irradiation, cauterization, cryosurgery and surgical excision. ,,, Aminocaproic acid has been tried topically or systemically for severe epistaxis. Estrogens have been administered systemically to reduce the frequency and severity of bleeding, with varying degrees of success. ,, This drug has been thought to induce improved continuity of the vascular endothelium and squamous metaplasia of nasal mucosa. 
For good preventive treatment, a low-roughage diet and avoidance of drugs such as aspirin with erosive and anticoagulant properties are recommended. ,, Further, living quarters may be well humidified to reduce irritation of oral and nasal mucosa.  Iron and foliate supplements may be required if there is chronic anemia. Severe anemia and bleeding may necessitate blood transfusion which carries risk of viral infections. Thus Hepatitis B vaccination is recommended for such cases. 
An awareness of episodes of bleeding from oral lesions with or without traumatic insult following scaling and polishing, rubber dam placement or flossing is essential. The patient with gingival telangiectases should be advised to brush the teeth gently. ,,, Prosthesis should be kept away from the lesions. In case of occurrence, hemorrhages can be controlled by applying direct pressure or by cauterizing the lesions. Prophylaxis of bleeding has been tried using sclerosing agents such as Morrhuate Sodium or Sodium Tetradecyl Sulphate injected into the lesion.  Dental practitioners should be aware that patients with chronic nose bleeds reported during detailed history recording could have HHT. 
Dental surgical procedures should be performed after obtaining a hemoglobin, hematocrit, platelet count and medical consultation. , This is done to exclude the possibility of the occasional association of HHT with detectable bleeding diathesis and hepatic dysfunction. ,,, General anesthesia for oral surgical procedures may be complicated by nasal mucosal telangiectases, anemia, high-dose estrogen therapy predisposing to thromboembolic disease, congestive high-output heart failure, symptomatic pulmonary arteriovenous shunts inducing pulmonary hypertension. 
Bacteremias may be caused during dental procedures causing gingival bleeding. Potentially life-threatening brain abscesses may result in a patient with pulmonary AVMs. Recently revised American Heart Association guidelines recommend prophylactic antibiotics in a patient with suspected HHT until the presence of pulmonary AVMs can be ruled out. , Septic pulmonary emboli in a patient with multiple and periodontal abscesses has also been reported. 
Genetic screening, counseling and monitoring is recommended for cases of HHT for early detection of systemic complications. , Prenatal testing is also available but is not widely employed. 
| Conclusion|| |
Despite frequent oral involvement, reports of HHT in the dental literature are limited. ,,,,,,,, Oral lesions as presenting manifestation are even rarer and their recognition may lead to the correct diagnosis  as demonstrated by our case. The case reinforces the necessity for a thorough history, examination and adjuvant laboratory tests for better patient care. Our case had oral and nail telangiectasia, epistaxis, a strong family history with immediate affected relatives and thus represents a classic example of the rare Rendu-Osler-Weber syndrome.
| Acknowledgments|| |
The authors are thankful to Dr. Sharada B. Menasinkai, MD, Asst Professor, Dept of Anatomy and Cytogenetics, JSS Medical College and Hospital, Mysore
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]