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Life-Threatening OralBleed—A Rare Presentation of Hereditary

Hemorrhagic Telangiectasia

*Assista

dullah M

ySwedi

dullah M

nsultan

ntistry,

Addres

partme

kkah, S

Syed Kowsar Ahamed, MDS,* and Yasser Al-Thobaiti, MDSy

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder of fibrovascular tissues.Patients with HHToften develop life-threatening bleeds from telangiectasias in the nasal or gastrointestinal

mucosa or from visceral arteriovenousmalformations. Recurrent oral bleeds are rare presentations in these

patients and are seldom reported. This report describes a rare case of 72-year-old man with a known his-

tory of HHT who presented with a recurrent life-threatening oral bleed from telangiectasia of the palate

and reviews the literature for current trends of medical and dental management. This study is an effort

to draw the attention of oral physicians and surgeons to such drastic complications of the disease and

various current treatment modalities.

� 2015 American Association of Oral and Maxillofacial Surgeons

J Oral Maxillofac Surg 73:1465.e1-1465.e5, 2015

Pathologic life-threatening oral bleeds are rare; themost

common oral bleeds result from arteriovenous malfor-

mations (AVMs) of the jaws and facial trauma in hemo-

philiac patients. Hereditary hemorrhagic telangiectasia

(HHT) also can cause postoperative bleeding complica-

tions. Osler-Weber-Rendu syndrome (or HHT) is a rare,autosomal dominant, inherited, fibrovascular disorder;

it is characterizedbyvascularmalformations inmucocu-

taneous tissues, internal organs, and the central nervous

system. The disease has an incidence rate of 1:5,000.1-5

Although Benjamin Green Babington was the first to

describe the symptoms of HHT in 1865, it is named

after 3 physicians, Marie Rendu, Bert Osler, and

Fredrick ParksWeber, who extensively reported similarcases.1 In 2000, diagnostic criteria were developed and

named the Curacao criteria: 1) epistaxis, 2) cutaneous

and mucosal telangiectasias, 3) visceral AVMs, and 4) a

positive family history. A minimum of 2 of the 4 criteria

should be present for the diagnosis.5

Report of Case

A 72-year-old male patient was admitted to the inten-sive care unit (ICU) with acute respiratory distress

nt Consultant, Department of Maxillofacial Surgery, King

edical City, Makkah, Saudi Arabia.

sh Board, Consultant, Department of Maxillofacial Surgery,

edical Center, Makkah, Saudi Arabia; Assistant Professor,

t, Department of Oral & Maxillofacial Surgery, Faculty of

Taif University, Taif, Saudi Arabia.

s correspondence and reprint requests to Dr Ahamed:

nt of Maxillofacial Surgery, King Abdullah Medical City,

audi Arabia; e-mail: dr_syed03@yahoo.co.in

1465.e

syndrome, acquired pneumonia, and septic shock. He

was intubated andputonventilator support.Thedepart-

ment of oral andmaxillofacial surgery was consulted for

a severe recurrent oral bleed and hemoptysis. The pa-

tient was known to have HHT with a 2-year history of

chronic epistaxis andminororal bleeds; hewas admittedto the ICU for acute respiratory distress resulting from

aspiration pneumonia.Onemonth previously, he under-

went intranasal laser cauterization andwas administered

bevacizumab (Avastin; Genentech, South San Francisco,

CA). His hemoglobin level was 4.3 mg/dL. The patient

had a strong positive family history, with an affected

aunt, 2 sons, 1 daughter, and 1 grandson (Fig 1). There

were telangiectatic lesions over his lips, face, and fin-gers, and hehad profuse bleeding frompalatal telangiec-

tasias (Fig 2). The telangiectatic spots were spread

widely over the palatal, gingival, and lingual mucosa. A

chest computed tomogram showed bilateral multiple

small AVMs in the lungs (Figs 3, 4). Genetic analysis for

the endoglin (ENG) and ACVLR1 genes showed a

mutation in the ENG gene (exon 3, nucleotide

c.277 C>T, amino acid p.Arg93X [p.R93X]). Amutation in the ACVRL1 gene was not detected. Thus,

he was diagnosed with HHT type 1 disease.

Received November 21 2014

Accepted March 13 2015

� 2015 American Association of Oral and Maxillofacial Surgeons

0278-2391/15/00335-3

http://dx.doi.org/10.1016/j.joms.2015.03.043

1

FIGURE 1. Pedigree of patient (purple square) and affected family members.

Ahamed and Al-Thobaiti. Hereditary Hemorrhagic Telangiectasia. J Oral Maxillofac Surg 2015.

1465.e2 HEREDITARY HEMORRHAGIC TELANGIECTASIA

The bleeding did not respond to conservative topical

hemostatic measures; therefore, he underwent diode

laser application over the oral telangiectatic spots and

an intralesional injection of Avastin, after which thebleeding stopped. A blood transfusion was adminis-

tered, his hemoglobin level increased to 13 mg/dL,

and his condition improved. After his discharge, he

was followed in the outpatient department. Informed

surgical consent was taken from the patient after he

was provided with detailed information regarding

the procedure. This study was approved by the

ethics committee.

FIGURE 2. Telangiectasias with engorged vessels in the hard pal-ate.

Ahamed and Al-Thobaiti. Hereditary Hemorrhagic Telangiectasia.

J Oral Maxillofac Surg 2015.

Discussion

HHT is an autosomal dominant disorder of the

vascular endothelium resulting from AVMs and causing

recurrent epistaxis. Based on the mutated gene, it isclassified as HHT1 or HHT2. HHT1 is more aggressive

and caused by a mutant ENG gene on chromosome

9q33-34.6-8 The patient showed an ENG mutation in

the 93p arm; no activin receptor-like kinase-1 (ALK1)

mutations were detected. HHT2 is a relatively mild

variant with a mutant ALK1 gene on chromosome

12q-13. Sabba9 and Abdalla and Letarte10 reported

that the SMAD4 gene is associated with juvenile polyp-osis HHT or HHT3.9,10 These genes are responsible for

endothelial cells signaling for proteins that act as

surface receptors for transforming growth factor-b

and vascular endothelial growth factor (VEGF).

Therefore, increased levels of VEGF are observed

in patients with HHT, which forms a basis for using

bevacizumab, an anti-VEGF monoclonal antibody.11,12

Recurrent epistaxis is the most common clinicalpresentation of HHT and is a presenting symptom

in 90% of patients.5,9 Eighty percent show

mucocutaneous telangiectatic spots in the face,

fingers, and oral mucosa. According to the literature

review, despite the commonness of oral mucosal

telangiectasias, only 2 cases with minor oral bleeds

have been reported.13 Pulmonary and cerebral AVMs

have been observed in 13 to 15% and 9 to 10% of pa-tients, respectively.14 Gastrointestinal telangiectasias

have been reported in 13 to 45% of patients.15 Hepatic

involvement is rare and is present in approximately 8%

of patients with HHT.1 AVMs in the liver can produce a

left-to-right shunt leading to heart failure or portal

FIGURE 3. Chest computed tomogram in axial view shows pulmonary arteriovenous malformations (red circles).

Ahamed and Al-Thobaiti. Hereditary Hemorrhagic Telangiectasia. J Oral Maxillofac Surg 2015.

AHAMED AND AL-THOBAITI 1465.e3

hypertension; occasionally, patients present with

cirrhosis of the liver, causing coagulopathies.

HHT treatment options are mainly therapeutic and

should be tailored for each patient. Epistaxis and itsmanagement in patients with HHT is thoroughly

FIGURE 4. Chest computed tomogram in sagittal view show

Ahamed and Al-Thobaiti. Hereditary Hemorrhagic Telangiectasia. J Ora

discussed and documented in the literature. Treatment

ranges from medical, surgical, to medical and surgical,

based on the location and severity of the bleed. An

estrogen and progesterone combination helps tomodulate nasal mucosa by metaplasia and increase

s pulmonary arteriovenous malformations (red circles).

l Maxillofac Surg 2015.

1465.e4 HEREDITARY HEMORRHAGIC TELANGIECTASIA

the mucosa’s thickness. However, its use is restricted

because of the side effects of hormonal therapy.

Antifibrinolytic agents, such as tranexamic acid and

aminocaproic acid, can be used as a supportive and

local measure in controlling mild recurrent bleeds,

but their efficiency is questionable.16 Topical or intra-

venous (IV) bevacizumab (Avastin) is a well-proven

promising option. Bevacizumab binds to circulatingVEGF and decreases the stimulation of VEGF, thereby

decreasing angiogenesis.3

Surgical options include the Young procedure (sur-

gically closing the nostrils, making the nose nonfunc-

tional), thermo- or laser coagulation or dermoplasty

of the nasal mucosa. Symptomatic large pulmonary

and cerebral AVMs are treated with a balloon, coil em-

bolotherapy, or sclerosing agents and can be followedwith surgery. However, this treatment poses the risk

of a distant thrombosis leading to cerebrovascular

accidents or ischemia.3 It is well understood that

multimodal therapies yield better results than a single

therapy.2,11,17 A combination of laser application and

Avastin is a well-documented therapeutic modality

for controlling nasal bleeds. Lasers act specifically on

vascular telangiectatic spots, causing minimal damageto adjacent mucosa. The efficacy of a diode laser is

comparable to that of a KTP laser or an Nd:YAG laser.2

These IVand local (topical) bevacizumab preparations

have been tried and resulted in successful improve-

ment in quality of life by decreasing the severity and

frequency of nasal bleeds. IV bevacizumab (10 mg/

kg once every 2 weeks) is associated with a consider-

able number of serious side-effects, such as anaphy-laxis, hypertension, and pulmonary hemorrhage.11,18

Hence, submucosal injection of Avastin at a dose of

100 mg followed by a topical spray at a dose of

100 mg/4 mL is a better option for long-term control

of epistaxis.11 Treatment options for oral bleeds have

not been reported to date. The authors’ experience

with such a severe bleed was the first of its kind, and

they used photocoagulation with a diode laser and asubmucosal injection of Avastin in the palate under

general anesthesia. This resulted in prolonged relief

from severe oral bleeds and decreased the frequency

of minor oral bleeds to once every 10 to 12 weeks.

The authors believe a long-term IV or topical spray

or mouthwash of bevacizumab would have been

better, but this was not possible because there was

no clinical evidence or internationally approved trialsfor such use in HHT. In addition, there were no

available topical oral preparations of the drug; hence,

they could not obtain the benefit of the drug. Because

oral telangiectasias are common presentations, oral

and maxillofacial surgeons can play a key role in the

recognition of this disease. Patients with HHT and

pulmonary AVMs have higher chances of septic

embolization through a right-to-left shunt and thus

are predisposed to develop brain abscesses. Invasive

dental procedures in such patients should be

performed with endocarditis prophylaxis because

there is a risk of developing brain abscesses.1,19,20

The American Heart Association states that the

risks from antibiotics exceed the benefits from

prophylaxis, and prophylaxis should be reserved for

high-risk conditions. One high-risk condition is cardiacmalformation with a right-to-left shunt similar to situa-

tions observed in patients with HHT and pulmonary

AVMs.18 Despite the controversy, certain HHT centers,

such as the Irish HHT center, advocate the use of

antibiotic prophylaxis for dental and surgical proce-

dures in patients in whom pulmonary AVMs are not

excluded by negative echo findings.14

Oral and maxillofacial surgeons can help in the earlydiagnosis of such patients. There are notably few

reported HHT cases with oral bleeds. The treatment

options for oral complications are limited because

there are no reports of such cases. Hence, it is essential

to report such encounters to accumulate well-

accepted evidence-based treatment protocols for oral

complications of this disorder. Oral mouth rinses of

Avastin for chronic oral bleeds in patients with HHTcould be a novel treatment. Long-term preventive

efforts for nasal and oral bleeds can improve the qual-

ity of life and life expectancy of such patients.

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