Hereditary Hemorrhagic Telangiectasia (HHT)/Osler-Weber-Rendu Syndrome: A Review on Contemporary Knowledge, its Accompanying Clinical Manifestations, Diagnostics, and Oro-Dental Management Plan

Abstract

HHT/OWRS is a very rare, hereditary, genetic autosomal-dominant disorder characterized by local angiodysplasias on skin and mucosae, even more rarely reported in the oral and dental health-related literature. It affects blood vessel formation throughout the body and is often accompanied with recurrent and severe episodes of epistaxis and telangiectasia on the skin and mucous membranes, including oral mucosae; and henceforth, perhaps the first sign of OWRS/HHT that can be initially diagnosed is by us, dentists/odontologists, oral and cranio-maxillo-facial surgeons, and specialized oral, dental, head, face and neck health care providers. Such symptoms may be associated with an IgA deficiency and, rarely, with von Willebrand disease. Thus, we are in an optimal position to detect the OWRS/HHT symptoms early, even if symptoms of other conditions may or do mimic OWRS/HHT oral lesions. Herein, this chapter re-visits and reviews, for the interested clinician, surgeon, scientist, researcher, and Innovation in Osteogenesis Research reader, the current knowledge on a very rare yet complex disease. Hence, the aim herein is for it to serve as a reminder as well as a contemporary clinical and surgical guide aiding in detecting, diagnosing, understanding, and efficaciously managing (including Health Care Information Management) patients suffering from OWRS or HHT.

1. Introduction

The Osler-Weber-Rendu syndrome (OWRS) or Osler-Weber-Rendu disease (OWRD) is also known as Morbus-Osler disease and hereditary hemorrhagic telangiectasia (HHT), these 2 (or 3) terms (OWRS, OWRD, and HHT) being inter-changeably used in oral communications, books/atlases, and scientific publications. “Hereditary” tackles the inherited character of the disease, and the term “hemorrhagic” derived from the Greek “haima” (blood) and “rhegnynai” (flow) describes nosebleeds, blood coughing, and gastrointestinal bleeding. “Telangiectasia,” derived from the Greek “telos” (far), “angeion” (vessel), and “ektasis” (expansion), all these together mean or refer to the pathological expansion of the smallest blood vessels (capillaries). In 1864, Henry Gawen Sutton first described HHT, and in 1896, OWRS was readdressed by French physician Henri Jules Louis Marie Rendu [1] who distinguished it from hemophilia. In 1901, it was revisited by Canadian physician Sir William Osler [2], hence the “Osler’s Disease,” and in 1907, English dermatologist Frederick Parkes Weber continued the characterization of this disease [3]. At last, in 1909, Hanes named this syndrome as “hereditary hemorrhagic telangiectasia,” an autosomal dominant trait [3, 4, 5], a disorder in which capillaries throughout the body are weakened (vascular dysplasia) in skin and mucosa. This weakness seemingly is due to defective endothelial interconnections [6] where it affects the blood vessels and is characterized by wide-spread telangiectasias that can involve the skin (face, fingers, and occasionally the palms), mucous membranes (oral, nasal, and gastro-intestinal), lungs, and brain. Characteristically, telangiectasias do not become apparent before the upper 30s or 40s as they rarely manifest during childhood or adolescence, and once they manifest, expansion in number and area covered occurs and may bleed after minor trauma, or even spontaneously [6], a tendency to bleed. Telangiectasia on skin, oral and perioral tissues, nasal, gastro-intestinal, or urogenital mucosae often leads to bleeding resulting in iron-deficiency anemia, or, rarely, even cardiac failure. Telangiectasia may be observed in any part of the oral cavity and may be particularly conspicuous on the lips [7], as is depicted in the clinical case in Figure 1.

Figure 1.

A 55-year-old woman with OWRS presenting with facial telangiactasis (skin of cheeks and base of nasal pyramid).

OWRS, seemingly, is due to defective endothelial interconnections. Herein, the genetic defect involves endothelial cells that are obviously unable to produce overlapping cytoplasmic villi that normally interdigitate with an adjacent endothelial cell, and this results in an ultrastructural gap between the endothelial cells. The capillaries then spread and balloon into telangiectasias after years of systemic vascular pressure [8]. OWRS is specifically characterized by alterations in the growth factor receptors of blood vessels endothelial; the first detectable pathology is the focal dilation of postcapillary veinules [6, 7, 8, 9]. As the lesion begins to enlarge, over time, capillaries have a tendency to completely disappear and produce a complete arteriole and venule connection. The junction between the vein and artery is thin, leading to a dilation in the vessel wall, and this is called or termed “telangiectasia.” In a fully developed telangiectasia, the arteriole and/or venule becomes extremely dilated and manifests superficially on skin or mucosal surfaces as a red or purplish dot. Larger vessel dilations, such as those observed in some internal organs, are named arteriovenous malformations or AVMs. Telangiectasias and AVMs are firstly asymptomatic yet have the tendency to rupture, leading to bleeding episodes that can have serious sequels depending on anatomical location, especially in the case of AVMs, as reported by Sharath Kumar and Shapiro [9]. In about 80% of OWRS patients, a family history is realized [6, 7, 8, 9]. The disease may be present in childhood and is more often to appear during puberty, but usually manifests during the second and/or third decades of life and is usually fully blown after the age of 35 and becomes progressively worse with increasing age [6, 9]. Briefly, HHT is classified into four types, though more types may exist: HHT types I and II (account for approximately 85% of cases); HHT type III; and HHT-juvenile polyposis overlap syndrome (JPS-HHT). The juvenile polyposis syndrome (JPS) is a rare autosomal dominant condition (increases the risk of development of gastro-intestinal malignancy) characterized by five or more gastrointestinal tract hamartomatous polyps or one or more juvenile polyps with a family history of JPS [10, 11]. It is worth noting that a juvenile polyposis-hereditary hemorrhagic telangiectasia overlap syndrome has previously been reported in 22% of patients with JPS due to a SMAD4 gene mutation [10, 11, 12] or BMPR1A gene, which is found in 40–60% of patients with JPS [11]. In 2012, O’Malley and associates studied and determined the prevalence and clinical manifestations of HHT in their juvenile polyposis patients and concluded that nearly all have the overlap syndrome and that healthcare providers must be aware and cognizant of the juvenile polyposis-hemorrhagic hereditary telangiectasia overlap syndrome [10]. In 2021, the first case of JPS-HHT in South Korea was reported (a 15-year-old boy), exhibiting the performed genetic studies of the patient himself and his parents revealing the detection of a de novo variant in the SMAD4 gene, [SMAD4 c.1146_1163del; p.His382_Val387del] [12]. This report recommended that JPS patients should undergo genetic evaluation of associated genes, including SMAD4, and those patients who are genetically confirmed with SMAD4 variants ought to undergo the appropriate evaluation to detect coexisting asymptomatic AVMs and avert life-threatening complication(s) [12].

2. Epidemiology, etiology, and genetics (+ involved mutations) for HHT type I and II

Given its rarity and scarcity in clinical case reports, no reliable data about the incidence of ORWS exists; the overall prevalence is 1–2 cases per 100,000 in the general North American population according to Marx and Stern [6] and 1 in 5000 to 8000, according to and Begbie et al. [13] and Bailly et al. [14], an underestimation because many cases are asymptomatic (and variable penetrance because main symptoms do not present/appear until later in adult life, in general). Sekarski and Spangenberg [15] and the HHT Foundation International (established in June of 1991 and renamed cure HHT in 2014), reports that more than 1 million cases worldwide are affected by this disorder. OWRS affects men and women in almost equal numbers and manifestations (epistaxis and skin telangiectasias being the most common). Whites are much more frequently affected with HHT than blacks and skin lesions are more common on the face and fingers and are usually well apparent [6]. Children and adults share the same manifestations and parents, once diagnosed, often seek medical attention for their children, with potentially life-threatening manifestations and complications of HHT/OWRS identified in asymptomatic children under 12 years of age [15], rendering screening to recognize this disease (appropriate diagnostic screening), and becoming familiar with evaluation, its manifestations, and treatment options (including prevention of internal bleeding or even death), critical, for the healthcare provider. According to Macri et al. [16] two main types of HHT, HHT1 and HHT2 caused by heterozygous/heterogenic mutations, have been identified, thus far (as of 2022). Briefly, HHT1 involves a mutation (61%) in the ENG gene (endoglin, in chromosome 9, 9q33–34), wherein patients, especially women, are at a higher risk of developing pulmonary and cerebral AVMs. On the other hand, the HHT2 type involves a mutation (37%) in ACVRL1 (activin A receptor-like type 1, in chromosome 12, 12q13) also known as ALK1. Herein, patients tend to have a higher risk of developing AVMs in the liver. Furthermore, mutations in GDF2 (growth differentiation factor 2) that encode the protein that binds to ENG and ACVRL1 have been detected. Both ALK-1 and ENG encode putative receptors for the transforming growth factor-ß (TGF-ß) super-family that plays a crucial role in blood vessels proper development. OWRs, therefore, it has been stated, for decades, to be caused by genetic mutations involving the signaling of TGF-ß, with defects in at least four genes implicated (ENG, ALK1, mutations of chromosome 5, and mutations of SMAD4/MADH4). Mutations in SMAD4/MADH4 (encoding SMAD4 also involves chromosome 18). Today, OWRS/HHT is considered as a disease of the BMP9/10 pathway rather than a disease of the TGF-ß pathway. Furthermore, in dystonia (involuntary muscle contractions) and posture research, genetic studies explained which deletions in 9q34.11 [17] involve the genes ENG, TOR1A (early-onset primary dystonia), STXBP1 (syntaxin binding protein 1 - encephalopathy) and SPTAN 1 (spectrin alpha) are responsible for the multisystemic vascular dysplasia, early-onset dystonia, epilepsy and the intellectual impairment or disability (neuro-developmental disorders/developmental delay), which shows the potential association between dystonia, ±muscle tone, movement disorders, and OWRS.

3. Clinical presentation of OWRS/HHT and its ORO-facial manifestations

OWRS is characterized by spontaneous and recurrent epistaxis, telangiectasia in pre-determined areas (oral cavity, nose, fingers, and lips; Figure 2), visceral injuries (gastrointestinal, hepatic, pulmonary, cerebral, and spinal), and a family history of HHT. OWRS is an under-diagnosed condition, and without accurate diagnosis, it may lead to serious morbidity and mortality. Clinically, patients develop telangiectatic capillary dilations within the superficial layers of skin and mucous membrane, which always blanch on compression [6, 18, 19]. Below, the most common symptoms and clinical presentation of OWRS/HHT manifestations are summarized to the healthcare attendant:

1. The earliest and most common symptom of OWRS is persistent and recurrent epistaxis (nosebleeds), from childhood. Epistaxis is the most troublesome and most frequently presenting symptom of this multisystem disorder; it is present in more than 90% of affected individuals [20]. It is frequently severe, leading to severe anemia that often necessitates repetitive blood transfusions. On clinical examination, mucosa of the nasal septum displays small vascular dilations, and epistaxis results from lesions in the anterior septal mucosa within the Kiesselbach’s plexus or area (i.e., the wall separating the right and left sides of the nose; a vascular network formed by the five arteries—anastomose—that supply oxygenated blood to the nasal septum, named after the German otolaryngologist Wilhelm Kiesselbach ~ year 1884). It is noteworthy, nonetheless, that while epistaxis in OWRS/HHT can be present all over the nasal surface (medial, lateral, and first 2/3 of the nose), it should not be confused with other unrelated bleedings that can also occur in the K area. Such bleedings are often referred to as “idiopathic hemorrhages” or “idiopathic epistaxis.”

2. Mucocutaneous telangiectasias and angiomas are not generally observed until young adulthood, as tiny red, pulsating, usually punctate, macules and papules (1–3 mm in size) characteristically observed on mucosae and skin, and as skin lesions on trunk and arms, yet more common on the face (base of the nasal pyramid, cheeks, conjunctivae, and ears), and acrally (on peripheral portions of limbs, fingers and toes and nail beds, and head, ears, and nose). These lesions are often red or brown, rather than purple, then readily blanch on diascopy (blanch upon pressure and regain their color when pressure is released). They easily bleed, even after a mild trauma; bleeding is not the result of a deficiency in clotting factor(s), but rather occurs as a result of the rupture of weak capillaries. As the affected patient grows, bleeding episodes increase in intensity and frequency. These diagnostic lesions are also observed within the nasopharynx, gastrointestinal and genitourinary tracts. Note that telangiectasias are permanent small dilations of blood vessels [6] and not angiomas or areas of bleeding; they do not appear characteristically apparent until upper 30s or 40s of age, with rare exceptions manifesting earlier in life. Telangiectasias of the skin and oral mucosae are observed in approximately 75% of patients with OWRS; they are usually visible by age 30,and increase in number and size with age [13]. As mentioned earlier above, the skin lesions occur primarily on the hands, face, and feet [9].

3. GI severe bleeding is also prevalent because of GI telangiectasis. GI bleeding usually recurs in older patients [21]. Gastric, visceral, and lung mucosae may all be involved in OWRS, and because of that, hematemesis (vomiting of blood—indicating upper GI tract bleeding), melena (dark black and tarry feces), or hemoptysis (spitting and coughing of blood originating in the lungs) may be part of the existing symptoms.

4. Visceral arteriovenous malformations or AVMs are also an important manifestation of OWRS, as described earlier. AVMs are observed in different anatomic locations of the body (nasopharynx, central nervous system, lungs, liver, spleen, and, sometimes, on the fingers and tips). Pulmonary, brain, and hepatic AVMs can cause serious complications. Liver lesions occur very frequently in women but the greatest documented risk results from pulmonary areteriovenous fistulae that often predispose patients to septic brain emboli (often lethal), and other central nervous system signs (such as strokes, migraines, and epilepsy) may occur. Cerebral AVMs may lead to headaches, ischemia, seizures, or devastating hemorrhages. Mucocutaneous telangiectasias (occur in about 75% of patients with the condition and are most common to be present on the lips, tongue, buccal mucosa, and fingertips) and AVMs (+ brain/cerebral) are a potential source of serious morbidity and mortality.

5. As consequence of chronic low-level blood loss, iron-deficiency anemia may develop—a condition in which the blood lacks sufficient healthy red blood cells. Without enough iron, the body cannot produce enough hemoglobin in the red blood cells that enable them to carry oxygen. As a result, iron-deficiency anemia may leave the patient feeling tired/fatigued, chest pains, and shortness of breath. Other signs and symptoms may include weakness, headache, dizziness, cold hands and feet, pale skin, brittle nails, poor appetite, and sometimes unusual cravings for nonnutritive substances (starch, ice, or dirt) and inflammation and soreness of the tongue.

6. Spleen and liver vascular anomalies may also occur and are usually associated with liver cirrhosis (scar tissue replaces the healthy tissue) and parenchymal proliferations.

7. In rare cases, some blood coagulation and clotting abnormalities (such as von Willebrand disease or vWD, low level of vWD factor) may be associated with OWRS.

8. For the oral and cranio-maxillo-facial surgeon, OWRS has also been associated with FCOD [22] or florid cemento-osseous dysplasia (a benign fibro-osseous lesion, characterized by the replacement of normal bone with fibrous tissue and metaplastic/nonneoplastic bone in the periapical region of the tooth-bearing jaw areas, predominantly in the mandible, suggested to originate from the periodontal ligament).

Figure 2.

Same patient in Figure 1 with telangiectasias of right external ear, right and left fingertips, and lower lip.

Technical note: Given the wide variability in disease expression and severity, in addition to OWRS/HHT established to affect multiple organ systems, several scaling and grading tools have been developed and validated over the years. Indeed, ESS or the epistaxis severity score, the HHT-score, and the Bergler-Sadick scale, among other instruments and PROM or patient-reported outcome measures (such as daily diaries), are available (classification criteria can vary though Food and Drug Administration or FDA guidance criteria for weighing PROM instruments exist) to aid in (a) measuring the frequency and intensity of epistaxis and (b) rank disease severity, to properly assess the specific or individual case of OWRS/HHT and OWRS/HHT-related epistaxis. For example, the Bergler-Sadick criteria to scale the severity of epistaxis or nose-bleeds in OWRS/HHT patients go as follows: GRADE I (Frequency: ≤ Once a Week; Quantity: Stains on Napkin); GRADE II (Frequency: Several per Week; Quantity: Soaked Napkin); and GRADE III (Frequency: Daily or Several per Week; Quantity: Bowl or similar utensil deemed necessary). Henceforth, several scales do take into consideration the impact of the disease and its symptoms on quality of life. For instance, besides frequency and quantity of epistaxis, the ESS considers the characteristics of bleeding, presence of anemia, and hospital requirements in addition to the general QoL impact secondary to associated symptoms.

3.1 Orofacial manifestations

In OWRS/HHT, lesions in the oral cavity (Figure 3) are most remarkable and noteworthy on the mucosae of dorsal tongue, palate, lips, and buccal mucosa; however, remember, any type of oral mucosa can be affected [23, 24]. Herein, the intraoral lesions are either macular (flat) or papular (elevated), and they usually present as “pinpoint-sized” or “pea-sized,” and less commonly, may be linear in appearance. With their red/purple appearance, they may resemble mucocutaneous petechiae, yet, unlike petechiae, OWRS telangiectasias blanch upon applying pressure (diascopy test). They are asymptomatic but have a tendency to rupture, leading to oral bleedings. Tens (sometimes hundreds) of round or oval macules/papules are observed on the perioral soft tissues (mucosal base of the nasal pyramid) and inside the oral cavity, particularly on the dorsal tongue and mucosal surface of the lips (vermilion zone), and less often, on the gingiva, palatal mucosa, and buccal mucosa [14, 18, 23, 24]. Lips and tongue are characteristically the prime areas for small pinpoint-sized telangiectasias. Mucocutaneous telangiectasias are observed in about 90% of OWRS cases [25, 26]. and histopathologically are displayed as a superficial collection of dilated blood vessels with a lamina propria characterized by a layer of endothelial cells. The most frequent and worrisome clinical symptom is epistaxis (nosebleed recurrent epistaxis in both children and adults.), as mentioned earlier, from lesions located in the Kiesselbach’s plexus (Figure 4), which lies within the Kiesselbach’s triangle (also known as Little’s area in some resources), an anatomical region located in the anteroinferior part of the nasal septum where four (or five) arteries anastomose to form a very rich vascular plexus; these arteries are the anterior ethmoidal artery (branch of ophthalmic artery), the greater palatine artery (branch of maxillary artery), the septal branch of superior labial artery (branch of facial artery), and the sphenopalatine artery (terminal branch of maxillary artery). It is important to notice that 90% of nosebleeds occur in Little’s area as this area is constantly exposed to fingernail trauma and to the drying effect of inspiratory currents. Blood in this area is then drained by the facial vein, ophthalmic veins, and the pterygoid plexus. It is noteworthy to mention herein that it is exceptionally rare for a single patient to present with all the “outlined” clinical manifestations of OWRS. It is also noteworthy, as previously mentioned, that while epistaxis in OWRS/HHT can be present over the oral and nasal mucosal surfaces, it should not be clinically confused with other unrelated or idiopathic hemorrhages/epistaxis that can ensue in the K-area.

Figure 3.

Telangiectasias on palate and dorsal tongue in the same patient as in the previous figures.

Figure 4.

Epistaxis and the Kiesselbach plexus (triangle or area) supplying blood to the anterioro-inferior quadrant of the nasal septum.

3.2 Diagnosis (D_x)

D_x— Today, OWRS/HHT clinical diagnosis [20] remains based on the “Curaçao Criteria,” established in 1999 by the Scientific Advisory Board of the HHT Foundation International (Cure HHT in 2014). The four diagnostic criteria of Cure HHT are as follows:

1. Spontaneous and recurrent epistaxis (up to 30 episodes per week). No consensus on number of bleeding episodes or degree of epistaxis necessary for diagnosis; however, nighttime nosebleeds should be considered as especially suspicious;

2. Multiple cutaneous and mucosal telangiectasias in the typical and characteristic locations (tongue, lips, face, extremities of fingers, etc…) that blanch on diascopy (use a clear glass to press against skin to empty blood from lesion, under pressure);

3. Clinically-proven visceral AVMs (lungs, liver, brain, spine); and Family history in a first-degree relative with OWRS/HHT.

Briefly, if three out of the four criteria are met, the diagnosis of OWRS/HHT is definitive. If only two criteria are present, the diagnosis is considered possible or suspected, and if the patient presents only one criterion, the diagnosis of OWRS/HHT is deemed unlikely. Remember, this is a genetically transmitted disease/condition, and it is inherited as an autosomal dominant trait. As described earlier, genetic testing of patients and their family members can confirm the presence of specific mutations with implicated genes. Herein, it is important to note that some families do not or cannot show a link to any of the known loci. Consequently, children have a 50% chance of contracting this disorder. Screening of family members for signs of OWRS/HHT should include a complete history, physical examination, chest radiography, and arterial blood gas testing (with measurement of the shunt fraction). Recent breakthroughs in molecular genetics have provided the medical community with a deeper understanding of this genetic disorder, but, variability–even among members of the same family renders the D_x tricky. Also, remember that the severity of this genetic disorder largely varies, even between close relatives. Precise testing is advised.

3.3 Differential diagnosis (DDx)

DD_x— Reference to laboratory testing (blood work, Figure 5) and an internal medicine specialist is critical, for confirming the D_x agreeing to the Curaçao Criteria. In DD_x, note:

1. In some cases, multiple telangiectasis can be associated with connective tissue disorders, such as the CREST syndrome [26, 27], hence may cause confusion, because of telangiectasia. CREST (Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia) is the predominantly acral form of PSS or progressive systemic sclerosis (known as scleroderma) in which narrowed lips turn to microstomia and opening the mouth becomes a real problem. CREST syndrome features finger, facial, and oral telangiectasias somehow similar to those of/in OWRS; yet, PSS patients have anti-centromere antibodies, a finding not seen in OWRS/HHT.

2. Fabry syndrome or disease [28] may also manifest with multiple vascular lesions, particularly diffuse full-body telangiectasias that do not blanch upon pressure, as in OWRS/HHT; these telangiectasias and skin lesions begin in childhood and increase (in number and anatomical locations) with age. Fabry syndrome or Anderson-Fabry disease or angiokeratoma corporis diffusum is a rare genetic (X-linked, passed from parent to child) lysosomal storage disease (typically associated with an enzyme deficiency in the metabolism of glycoprotein, lipids, and fat) that can cause a range of systemic symptoms. This disorder leads to excessive deposition of neutral glycosphingolipids in the vascular endothelium of several organs, and progressive endothelial accumulation of glycosphingolipids will account for associated anomalies of skin, eye (corneal whorls), the peripheral nervous system, kidney, heart, and brain.

3. Mafucci syndrome [29] is a sporadic congenital disease featuring multiple enchondromas (benign enlargements of cartilage) and deformities of metacarpal bones and hand phalanges, multiple cutaneous spindle cell hemangiomas (notably, small tongue hemangiomas) and lymphangiomas, and phleboliths. Enchondromas of the digits are observed in childhood with hands and feet becoming distorted. Etio-pathogenic cause remains unknown, and the risk of sarcomatous (malignant) transformation of enchondromas, hemangiomas, or lymphangiomas is about 15–30%.

4. OWRS should be differentiated from benign hereditary telangiectasis (genetic tests).

5. Cherry angiomas (Campbell de Morgan spots) develop in more than 85–90% of adults over 30–40 years old; these lesions may look similar but are less clustered and more diffuse than of/in OWRS/HHT. Furthermore, those spots or moles [30] do not increase in number with age. Briefly, cherry angiomas are round skin growths that appear bright red in color (hence, “cherry”), and mostly develop on the trunk or torso.

6. Spider nevi (also known as spider telangiectasias, spider angiomas, vascular spider, or nevus araneus) may also mimic OWRS/HHT lesions [31]; they present as a developmental malformation in children and adolescents, as multiple or solitary lesions, and do not change during adult life. These vascular lesions (characterized by anomalous dilatation of end vasculature) are a type of telangiectasis found beneath the skin surface. These lesions, typically painless, can be observed anywhere on the body, most common on the face, neck, and legs (sun-exposed areas). However, having more than three spider angiomas is likely to be an abnormality and is a physically- diagnostic sign of liver disease in adults (seen in many alcoholics with liver cirrhosis).

Figure 5.

Blood work (CBC: Complete Blood Count) laboratory testing conducted for D_x/DD_x.

3.4 Diagnostic workup and progrnosis

Diagnostic work-up— Recurrent and persistent severe bleeding episodes may lead to an iron-deficiency anemia [26], as mentioned earlier, requiring regular blood work (CBC: Complete blood count) with an assessment of Wintrobe indices (hematocrit, MCV, MCH, MCHC) in order to measure quantitatively the red blood cell population, serum iron, and the total iron binding capacity. In the case of a gastrointestinal bleeding, a gastroscopy and a colonoscopy may be indicated by the attending physician. AVMs are obviously the most dangerous complication of OWRS/HHT; approximately, 30% of patients will develop pulmonary AVMs, which usually develop during puberty, and 10% will develop cerebral AVMs (which may be lethal). Screening for OWRS should also include a contrast echocardiography of the lungs and magnetic resonance imaging/MRI of the brain. After confirming the diagnosis, angiography and magnetic resonance angiogram/MRA scans are to be done in order to assess the AVMs. Genetic counseling is strongly advised, and genetic testing is favored in families with history of OWRS/HHT.

Prognosis of OWRS/HHT— relatively good although morbidity is significant. Life expectancy may be shortened; however, this depends on the severity of symptoms and the manifestations/complications of the disease, and the degree of systemic involvement (especially hepatic, pulmonary, and central nervous system involvement). Briefly, mortality shows an early peak at the age of 50 years and a later peak at 60–80 years, this being related to acute complications [19, 20, 27]. Only, 10% of patients die of complications. Patients with AVMs may experience early-onset stroke and brain abscesses, and it is estimated that a mortality rate of 1–2% is due to complications related to epistaxis, and it rises to 10% in patients with cerebral abscesses [32]. In general, the disease prognosis remains good and acceptable as long as the bleeding episodes are promptly identified and adequately controlled. OWRS/HHT is often unrecognized by physicians and other health care providers, as emphasized earlier. In 2012, the HHT Foundation estimated that 9 out of 10 people with OWRS go undiagnosed, and among individuals with un-diagnosed OWRS, 20% are either disabled or die because healthcare providers failed to recognize and subsequently treat or manage the disease. If properly diagnosed, AVMs and complications can be prevented.

3.5 Management and Rx

Management and R_x— OWRS/HHT are obviously not curable, yet, are manageable. Nowadays, it is worldwide accepted that no treatment is indicated other than local hemostatic measures during the bleeding episodes. Currently-used “therapeutic” protocols are essentially symptomatic, dealing with symptoms and signs rather than the disease itself and knowing that no therapy is able to stop the development of AVMs and telangiectasias. The following “therapeutic” modalities, deduced from various resources, clinical case studies, and series, might be perhaps useful in the management of OWRS:

1. Spontaneous bleedings are controlled by pressure packs (Ethicon surgical dressing, for example), and particularly nasal bleedings. Packing of the nasal cavity with absorbent swabs or gels is a very popular method and LASER coagulation therapy [33] also works relatively well for nasal telangiectasias that cause the nosebleeds.

2. Silver-nitrate (chemical cautery), electric cautery (hotwire or bipolar cautery), and Nd: YAG laser pulse dye laser [34], or combinations of those techniques, are prophylactically used by some clinicians in lesions that are more likely to bleed and for the destruction of cutaneous and accessible mucosal lesions. Nasal coagulation and cauterization may reduce bleeding (once the bleeding point is identified) resulting from telangiectasias and is currently recommended before surgery is indicated (often, several cauterization/coagulation sessions are needed).

3. If all interventions to stop epistaxis have failed, special procedures have to be considered, such as septal dermoplasty, also known as Saunder’s procedure [35], in which skin is transplanted into the nostrils in order to replace the involved mucosae and Young’s procedure [36] in which nostrils are completely sealed off.

4. Corticosteroid nasal sprays, such as beclomethasone dipropionate (inhaled form is used in the management of asthma), often reduce minor recurrent nasal bleeds.

5. Sclerosing agents (such as sodium morrhuate and sodium tetradecyl sulfate) can be injected into OWRS/HHT lesions.

6. Lung lesions are currently managed by transcatheter embolization (blocking off the feeding artery). Brain AVMs are managed with more than one modality (surgical removal, embolization, or treating the affected area with radiation), depending on location, size, and structure of the abnormal vessels.

7. Chronic and repeated epistaxis and GI bleedings often lead to severe anemia, requiring iron supplements. Patients who cannot tolerate iron solutions or tablets usually require administration of IV iron sucrose and blood transfusions if the anemia causes severe symptoms that urgently warrant rapid recovery of the CBC.

8. Other therapies, such as estrogen-containing creams, progesterone, and oral tranexamic acid, were also suggested in the medical literature.

4. Dental aspects and implications of HHT

After epistaxis, oral bleeding is the second most frequent and annoying complaint of ORWS/HHT patients. Though relatively uncommon, oral bleeding may be the result of traumatic tooth brushing or after an inadvertent bite of the oral soft tissues or following an oral surgical procedure [37, 38, 39, 40, 41]. In everyday general dental practice, gingival bleeding upon oral debridement (scaling/root planning) and post-extraction hemorrhage are a prime concern for dentists. Herein, drugs, such as aspirin and non-steroidal anti-inflammatory drugs (diclofenac, ibuprofen, naproxen, etc…) should be strictly avoided due to the elevated risk of bleeding [15]. In very rare cases, a fatal hemorrhage can happen after a dental or oral surgical procedure [37, 38, 39, 40, 41, 42, 43, 44]. Regarding the need for antibiotic prophylaxis before routine dental and oral surgeries (implant placement, surgical extractions, biopsies, cysts, and tumors excision among others,) there is no consensus yet, and to the best of our knowledge and expertise, some patients with OWRS/HHT can develop brain and pulmonary abscesses following teeth extractions in the absence of antibiotic prophylaxis [42, 43, 44, 45]. These specific cases confirm the importance of prevention of cerebral and pulmonary abscess with antibiotics in this specific group of patients, despite the absence of evidence of the indication to use antibiotic prophylaxis for OWRS/HHT in the scientific and clinical literature [46]. According to several studies [9, 20], many patients with OWRS/HHT need/require antibiotic prophylaxis before undergoing any dental/oral invasive procedure that may produce a bacteremia (oral debridement, extractions, biopsies, cyst enucleation, implant placement, etc…), and this issue is primarily due to problems resulting from pulmonary AVMs, which obviously lack the capillaries to filter the blood when passing through the lungs, thereby, allowing bacteria to travel to the brain. Indeed, vascular malformations and arteriovenous fistulae in the lungs play an important role in the pathogenesis of a cerebral abscess, and it is known that a peripheral septic microembolism is able to reach the brain and cause a brain abscess [42]. Nowadays, the use of antibiotic prophylaxis preventively remains empirical for OWRS/HHT dental patients; nonetheless, most dental clinicians prefer to implement protocols before dental/oral invasive procedures in order to avoid the development of a cerebral abscess. If a patient with OWRS/HHT was not tested properly to have the diagnostics for AVMs, dental treatment should be mandatorily delayed until appropriate testing is done and completed [23, 42, 47]. Medication before dental/oral invasive procedures is not necessary for OWRS patients who present with AVMs in other organs but is mandatory for those with pulmonary AVMs that occur in approximately a third of OWRS patients and may lead to many complications. Among those, pulmonary hemorrhage, cerebral embolism, and hypoxia have been reported [48, 49]. Consequently, dentists must keep the dental chair in a vertical position during the treatment sessions and be prepared, at any time, to administer oxygen [42]. OWRS/HHT patients with severe anemia (hemoglobin level less than 10 mg/dL) better avoid such invasive procedures as well as might exacerbate anemia, depending on the lost amount of blood [50]. Regional analgesia of nerve trunks (such as the inferior alveolar nerve) also should be better avoided due to the risk of bleeding (nerve accidental trauma with the anesthetic needle), and, for the general anesthesia of dental patients, nasal intubation is better be avoided.

Pharmaceutical note: As described earlier, epistaxis due to rupture of telangiectases of the nasal mucosa is the most frequent clinical manifestation in OWRS/HHT patients. Epistaxis leads, in many cases, to severe impairment of QoL, which is also known to worsen with age, among other physiological, psycho-socio-economic factors and lifestyle parameters. Daiana de Morais and group [51, 52, 53, 54] investigated and reported on more than 15 years of using several sub-mucosal or sub-pericondrial treatments aimed at reducing epistaxis in OWRS/HHT patients. They have concluded that sub-mucosal 1–2 mL injections of 0.5% polidocanol, also known as lauromacrogol 400 (Aethoxysklerol^®, Kreussler Pharma, Ferrer Farma S.A, Spain), improved nose-bleeds (in frequency and quantity) in 95% of all the cases studied (N=45 patients diagnosed with OWRS/HHT based on the clinical Curaçao criteria; ~245–300 infiltrations administered using 25-gauge needles in the septum or in the telangiectasia area, at the ENT/Otorhinolaryngology unit of the Valladolid University Hospital in Valladolid, Spain), without any significant side effects. The authors reported that the average number of sclerosing infiltrations per patient was 5–6 in each nasal cavity. They only administered the polidocanol injections in one nasal cavity and never bi-laterally at the same time. Aethoxysklerol^® as a sclerosant / anti-angiogenic has a concentration-dependent effect on the endothelium of blood vessels, often used for the treatment of treatment of varicose/spider veins and hemorrhoids. The active sclerosan polidocanol, a solvent and non-ionic emulsifier that contains 95% hydroxypolyethoxydodecane and 5% ethyl alcohol, has been described to form aggregations of molecules (in micellar form), to act as a detergent and has been used as an anaesthetic or an anti-pruritic in medicaments.

In a recent systematic review [55] of a total of 21 randomized controlled clinical trials, the obtained data were pooled for qualitative- and meta-analysis. Treatments included timolol, propranolol, bevacizumab, doxycycline, tacrolimus, estriol/estradiol, tranexamic acid, tamoxifen, sclerosing agent, electrosurgical plasma coagulation, KTP laser, and post-operative packing. Interestingly, propranolol was concluded to offer the most improved epistaxis severity score, when compared to placebo, followed by timolol. The analysis also showed that tranexamic acid significantly reduced the frequency of epistaxis. Briefly, the authors concluded that propranolol, timolol, tranexamic acid, tamoxifen, and estriol were effective for epistaxis management in OWRS/HHT patients. The study also noted the potential post-therapeutic adverse events and impact on QoL Herein, remember that lifestyle and dietary factors do influence the severity of epistaxis. Indeed, while alcohol and salicylates such as red wine, coffee, spices, and chocolate are reported in the literature to exacerbate epistaxis, room humidification and nasal lubrication can help improve the nose-bleeds and the QoL of our OWRS/HHT patients.

5. Key points to note: Contemporary clinical and innovation summary

5.1 Bone-related manifestations

While the primary symptoms of OWRS/HHT typically involve the skin and mucous membranes (nosebleeds, telangiectasias, and arteriovenous malformations), the disorder can also affect other parts of the body, including the bones. Some of the rare (or not so well-documented) and possible bone-related symptoms and manifestations of OWRS/HHT may include Osteoporosis: Osteoporosis is a condition characterized by reduced bone density and increased susceptibility to fractures due to the weakening of bone tissue. OWRS/HHT can cause a decrease in bone mineral density, leading to osteoporosis, which is characterized by weakened bones and an increased risk of fractures. Avascular necrosis: Avascular necrosis is a condition in which bone tissue dies due to a lack of blood supply, leading to bone collapse and joint damage. The abnormal blood vessels in OWRS/HHT can affect blood flow to the bones, potentially leading to avascular necrosis, a condition in which bone tissue dies due to a lack of blood supply. Osteoarthritis: Osteoarthritis is a degenerative joint disease characterized by the breakdown of cartilage and bones in the joints, resulting in pain, stiffness, and loss of function. The abnormal blood vessels and inflammation associated with OWRS/HHT can contribute to the development of osteoarthritis, a degenerative joint disease that affects the cartilage and bones in the joints. Bone abscesses: Bone abscesses are collections of pus within bone tissue, typically caused by bacterial infection and characterized by pain, swelling, and localized inflammation. OWRS/HHT can increase the risk of infections in the bone, leading to the formation of bone abscesses. Pathological fractures: Pathological fractures are fractures that occur in weakened or diseased bone, typically due to underlying conditions, such as osteoporosis or bone cancer. Weakened bones and bone infections associated with OWRS/HHT can increase the risk of pathological fractures, which occur when a bone breaks due to an underlying disease or condition(s).

5.2 Innovations in OWRS/HHT research

There are several innovative approaches being explored to address OWRS/HHT and its bone-related manifestations. While there is currently no cure for OWRS/HHT, advancements in research and treatment options are helping to improve outcomes and quality of life for individuals with the condition. Some of the key innovations in this field include Targeted therapies: Researchers are investigating targeted therapies that aim to block specific molecular pathways involved in OWRS/HHT, such as the vascular endothelial growth factor (VEGF) pathway. Drugs, such as bevacizumab (Avastin) and thalidomide (Thalomid) have shown promise in reducing bleeding and stabilizing telangiectasias in some patients. Gene therapy: Gene therapy is a cutting-edge approach that involves modifying a patient’s genetic material to correct a faulty gene or introduce a functional gene. In the case of OWRS/HHT, researchers are exploring the use of gene therapy to target the underlying genetic mutations responsible for the disorder. Angiogenesis inhibitors: Angiogenesis inhibitors are drugs that prevent the formation of new blood vessels. These drugs are being studied for their potential to reduce bleeding and stabilize telangiectasias in patients with OWRS/HHT. Surgical interventions: Surgical interventions, such as embolization or laser therapy, are used to treat severe bleeding or arteriovenous malformations (AVMs) in patients with OWRS/HHT. These procedures aim to block abnormal blood vessels or reduce blood flow to affected areas. Stem cell therapy: Stem cell therapy is an emerging field that holds promise for regenerating damaged tissues and organs. While still in the early stages of research, stem cell therapy may offer potential benefits for individuals with OWRS/HHT and bone-related manifestations by promoting bone repair and regeneration. Biologics: Biologics are a class of drugs derived from living organisms, such as proteins or antibodies. Some biologics have shown promise in reducing inflammation and tissue damage associated with OWRS/HHT and its bone-related manifestations. Patient education and support: In addition to medical treatments, patient education, and support play a crucial role in managing OWRS/HHT and its complications. Support groups and online resources can provide valuable information and support for individuals with OWRS/HHT and their families. Furthermore, it is perhaps noteworthy herein that many of these innovations are still in the early stages of research and may not be widely available. Additionally, the effectiveness of aforementioned treatments can vary from person to person, and more research is needed to fully understand their long-term effects and safety. However, these advancements offer hope for improved outcomes and quality of life for individuals living with OWRS/HHT and its bone-related manifestations. It is also perhaps mentioning that nanotechnology as well can and will contribute to develop novel therapeutic strategies for such bone-related manifestations of OWRS/HHT, offering several potential benefits, not limited to. Drug delivery: Nanoparticles can be engineered to carry drugs or therapeutic agents directly to bone tissue, enabling targeted treatment of bone-related complications, such as osteoporosis or avascular necrosis. Bone regeneration: Nanomaterials can be used to develop scaffolds or matrixes that promote bone growth and repair, addressing bone defects or fractures caused by OWRS/HHT. Imaging: Nanoparticles can be designed to enhance the detection and imaging of bone lesions, allowing for more accurate diagnosis and monitoring of bone-related complications in patients with OWRS/HHT. Theranostics: Nanotechnology can enable the development of theranostic agents that combine therapeutic and diagnostic capabilities, offering a personalized approach to the treatment of bone-related manifestations in OWRS/HHT. Antiangiogenic Therapy: Nanoparticles can be engineered to deliver antiangiogenic agents directly to abnormal blood vessels associated with OWRS/HHT, potentially reducing the risk of bleeding and stabilizing telangiectasias. While nanotechnology holds great promise for addressing various medical conditions, extending to tackling the complex bone-related manifestations of OWRS/HHT by providing targeted and personalized therapeutic options, it is nonetheless important to note that many of these applications are still in the early stages of research, development, and innovation and more studies are needed to fully understand their effectiveness and safety in clinical settings, topics of ongoing investigation at our BioMAT’X I + D + i (HAiDAR R&D&I) Lab at Universidad de los Andes in Santiago de Chile.

6. Conclusions and perspective

OWRS is a multisystem disorder. It is manageable but obviously not curable. The symptoms of OWRS/HHT are often unrecognized; hence, many patients, even those with affected and diagnosed family members, may go un-diagnosed. Clinical diagnosis, typically, is based on the presence of three of four criteria: epistaxis, telangiectasias, visceral arteriovenous malformations, and/or a family history of the disease. Many patients do not need any treatment, and those who need intervention, typically, are those who suffer from regular and severe epistaxis. Most importantly, to limit the morbidity and mortality associated with OWRS/HHT, its manifestations, and complications, some of which can be lethal recommendations for diagnostic screening, monitoring, and proper management of signs and symptoms have been created. Such, if implemented, have contributed to the prognosis (and survival) of OWRS/HHT. This article attempted to provide the health care personnel, attendants, and professionals, particularly those involved in the dental and cranio-maxillo-facial field (as potentially the front liner or first to detect the present vascular changes/malformations intra-orally and facially and aid in diagnosis) with a concise yet comprehensive review (and guide) of the condition, its clinical presentation, and management strategies, most of which are palliative. Indeed, medical intervention in OWRS/HHT depends on the severity of its manifestations and stage of the condition and its accompanying complications. Remember, oral lesions, which later become obvious through hemorrhagic telangiectasia, are often the first sign of this disease. Further, TMJ (temporomandibular joint) dislocation has been associated with OWRS/HHT. Also and generally, the disease/condition depends on the age of the patient. To control epistaxis, surgical intervention is becoming routine. Hemostatic cautery (and skin grafting) procedures have been reported as well with good results; specifically, to reduce long-term oral bleeding. The dentist (and dental hygienist) is to be cautious when attending patients with pulmonary and cerebral AVMS given their high risk of developing abscesses from dental bacteremia, post-routine, and/or invasive oral, dental, and periodontal procedures. On the other hand, despite the constantly accruing advances in understanding the underlying signaling and genetic mutation mechanisms (evident by the recent discovery that OWRS/HHT is a disease of the BMP9/10 pathway rather than a disease of the TGF-ß pathway, as was initially thought for decades), the rare OWRS/HHT continues to pose a perplexing challenge to medicine, pathologists, and biologists, rendering the need for more studies and analysis. Yet, on an optimistic closing note, innovative mechanism-driven pharmaceuticals can be someday anticipated to be designed, formulated, characterized, evaluated, optimized, and translated to the clinic.

Acknowledgments

This work was supported by operating grants provided to the HAiDAR I + D + i/R&D&I LAB/BioMAT’X (Laboratorio de Biomateriales, Farmacéuticos y Bioingeniería de Tejidos Cráneo Máxilo-Facial), member of CiiB (Centro de Investigación e Innovación Biomédica), Faculties of Medicine and Dentistry, Universidad de los Andes, Santiago de Chile, through the ANID-NAM (Agencia Nacional de Investigación y Desarrollo, Chile and National Academy of Medicine, NIH, USA) Grant código # NAM21I0022 (2020-2022), CORFO Crea y Valida I + D + i Grant código # 21CVC2-183649 (2021-2023), CORFO Crea y Valida — Proyecto de I + D + i Colaborativo - Reactívate” Grant código # 22CVC2-218196 (2022-2024), and FONDEF Concurso IDEA de I + D, ANID, Grant código # ID22I10215 (2022-2024). The author acknowledges orofacial pathology clinical insights from Dr. Ziad E. F. Noujeim.

Conflict of interest

None.