Family History Of Hereditary Hemorrhagic Telangiectasia Research Articles

Abstract 17520: Dynamic Intrapulmonary Shunting in the Setting of Amphetamine Use

Description of Case: A 35-year-old female non-smoker with ADHD on amphetamine for the past 3 months and family history of hereditary hemorrhagic telangiectasia (HHT) presented with significant exertional dyspnea for 1 week. She was hypoxic to 82% while walking, with normal oxygen saturation at rest. Transthoracic echocardiogram with agitated saline revealed extracardiac right-to-left shunting with exercise and Valsalva. This was confirmed by dobutamine stress echocardiogram with agitated saline (Figure 1A). Transesophageal echocardiogram with agitated saline (Figure 1B) revealed no shunt through the foramen ovale, but it demonstrated bubbles entering from the left upper pulmonary vein, suggestive of an extracardiac shunt from a pulmonary arteriovenous malformation (AVM). Right heart catheterization and pulmonary angiogram revealed normal pressures, and no pulmonary abnormalities with normal pulmonary venous return. Supine right heart catheterization with exercise revealed normal pressures, although the initial pulmonary artery (PA) saturation was 28%; repeat PA saturation one minute later was 48%. Arterial saturation was 95%. Pulmonary function testing, ventilation perfusion scan, high-resolution CT chest, and coronary CT angiogram were unremarkable. The patient was instructed to avoid all stimulants, and to take a non-hormonal contraceptive. At her 3-month follow-up, she reported significant improvement in her symptoms. She underwent a 6-minute walk test, and her lowest oxygen saturation was 88%. Discussion: This patient presented with exertional hypoxia, normal saturations at rest, evidence of an extracardiac shunt only with exertion and absence of clear sources of the shunt on imaging. With her family history of HHT, this is suggestive of a small pulmonary AVM that opened by elevated PA pressures, likely triggered by amphetamine use, and its discontinuation led to symptom resolution.

Thrombosis in hereditary hemorrhagic telangiectasia

Thrombosis in hereditary hemorrhagic telangiectasia

EP162: Mosaic variant in ENG in infant with pulmonary arteriovenous malformations: Case report and review of hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder with age-related penetrance and an incidence of 1:10,000 in North America. A clinical diagnosis of HHT requires three of the following criteria: recurrent and spontaneous nosebleeds (epistaxis), mucocutaneous telangiectases, visceral arteriovenous malformations (AVMs), and family history of HHT. Epistaxis occurs in almost all individuals with HHT with average age of onset at 12 years of age and telangiectases usually appear later.

S2747 Hereditary Hemorrhagic Telangiectasia: A Rare Disease Diagnosed From Incidental Liver Lesions

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant syndrome characterized by mucocutaneous telangiectasias and AVMs. Epistaxis and GI bleeding are the most common presenting features. HHT-related visceral AVMs have also been well-described and when identified without a prior diagnosis of HHT can present a significant diagnostic challenge. Case Description/Methods: A 60-year-old male with prior history of prior tobacco and alcohol use was referred to GI clinic for two years of chronic diarrhea and dyspepsia. No unintentional weight loss although he reported intermittent episodes of epistaxis every 2-3 months for past 40 years. Physical examination and family history was unremarkable. CT A/P showed a heterogeneous liver with innumerable liver lesions. (Figure 1) An EGD was performed for dyspepsia which revealed an 8mm gastric body ulcer and biopsy negative for H.pylori. The patient’s diarrhea resolved with probiotics and changes to diet. Hepatology recommended a liver biopsy which was suggestive of an arteriovenous or vascular malformation with scarring. Follow up EGD revealed a healed stomach ulcer and a 5mm gastric AVM. Chart review revealed a prior CT chest with a small pulmonary vascular malformation. The patient was referred to genetics for evaluation of HHT. A HHT genetic panel was positive for a pathogenic heterozygous variant in the ACVRL1 gene and the diagnosis of HHT was confirmed. Discussion: HHT is a clinically heterogenous disorder and diagnosis requires at least three of the following Curaçao criteria: epistaxis, mucocutaneous telangiectasias, visceral AVMs and family history of HHT. HHT-related AVMs can involve the brain, lung or liver. Hepatic involvement is common ranging from 32% up to 95%. Hepatic AVMs, are rarely symptomatic and routine screening is not recommended. Symptomatic hepatic AVMs can present with three distinct clinical presentations – high output heart failure from AV shunting, portal hypertension from arterioportal shunting and biliary disease from chronic ischemia. In the absence of routine screening, follow-up of these patients requires close attention to the development of these complications. In these cases, multi-phasic CT may be the preferred imaging modality. In conclusion, hepatic AVMs should be included in the differential for hepatic lesions and genetic evaluation should be considered with concomitant history of epistaxis, GI bleeding and/or evidence of other visceral AVMs.Figure 1.: CT abdomen and pelvis without contrast revealed several liver lesions, largest lesion 3.3cm in diameter.

A Suspected Case of Hemorrhagic Hereditary Telangiectasia Presented with Cerebral Hemorrhage in Infancy

Hereditary hemorrhagic telangiectasia (HHT) is characterized by telangiectasias in multiple organs. We experienced an infant with cerebral hemorrhaging and suspected HHT based on his family history of HHT. Computed tomography angiography confirmed a cerebral arteriovenous fistula. The onset of cerebral arteriovenous fistulas associated with HHT is relatively early, and the incidence of bleeding is relatively common. When HHT is suspected based on a family history, early imaging screening is recommended to improve the neurological prognosis, even in asymptomatic cases. (Received April 7, 2020; Accepted May 7, 2020; Published August 1, 2020).

HEREDITARY HEMORRHAGIC TELANGIECTASIA: A CASE REPORT

Hereditary hemorrhagic telangiectasia (HHT) is a rare mucocutaneous disease, inherited by autosomal dominant trait. Its diagnosis can be established by the identification of 3 of the following criteria: (1) frequent episodes of epistaxis; (2) telangiectasias of the skin and mucosa; (3) arteriovenous malformations involving lungs, liver, or central nervous system; and (4) family history of HHT. The purpose of this study is to perform a case report of HHT, attended at a stomatology service. The patient was a 70-year-old female, with numerous vascular lesions affecting the oral mucosa, hands, and feet. Endoscopic analysis also showed telangiectasias in the gastric mucosa. The patient had anemia and frequent episodes of epistaxis, and also reported a family history of these manifestations, involving her father, sister, and children. The diagnosis was defined as HHT. The dentist should be aware of the different manifestations of HHT and consider it as a possible diagnosis for patients with various vascular lesions.

SMAD4 Mutation and the Combined Juvenile Polyposis and Hereditary Hemorrhage Telangiectasia Syndrome: A Single Center Experience

Introduction: Juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT) are autosomal dominant disorders with characteristic clinical phenotypes. Mutations of the SMAD4 gene can result in a distinct syndrome with combined clinical features of both HHT and JPS. We aimed to describe the clinical phenotype of patients with the SMAD4 mutations seen at Mayo Clinic Rochester. Methods: Retrospective review of patients with genetically confirmed diagnosis of combined JP-HHT syndrome between January 1998 and January 2018. HHT phenotype was assessed using the Curacao criteria. JPS features were determined by review of endoscopy and pathology reports. Additional outcomes included: incidence of gastrointestinal (GI) malignancies, vascular events, hospitalization for gastrointestinal bleeding (GIB) and overall mortality. Results: A total of 22 patients were identified. Median age was 34 years (1-67) and 41% were males. Median age diagnosis and time of follow-up were 24 (1-66) and 6.5 (0-58) years, respectively. Median Curacao score was 3 (1-4). Seventy-seven percent of patients had a prior episode of epistaxis, 56% skin telangiectasias and 60% visceral arteriovenous malformations (AVM). Common sites for visceral AMV were lower respiratory (45%), liver (27%), GI (10%) and central nervous system (10%). Eighty two percent of patients had family history of HHT. Lower GI polyps (LGP) were found in 86% of patients, most commonly located in the right side of the colon. Upper GI polyps (UGP) were seen in 68% of patients, mainly in the stomach (10/15) and duodenum (5/15). Forty percent of LGP were found to be tubular adenomas compared to 20% of UGP. Family history of polyps and colorectal cancer were present in 91% and 54% of patients, respectively. Two patients had GI malignancies, one rectal and one small bowel adenocarcinoma. One patient had an ischemic cerebellar stroke at age 24 years. A third of the cohort (6/16) had a history of hospitalization for GIB. Overall mortality was 14% with average age of death at 66 years. Conclusion: In our cohort, patients with the combined JP-HHT syndrome had epistaxis and pulmonary AVMs as common manifestations of HHT. Hospitalization for GIB and cerebrovascular events occurred at a rate of 28% and 4%, respectively. Polyps were more commonly seen in the lower GI tract and tubular adenomas were seen in 50%. GI adenocarcinoma occurred at a rate of 10% and overall mortality was 14% within the observed follow-up period.

Applicability of the Curaçao Criteria for the Diagnosis of Hereditary Hemorrhagic Telangiectasia in the Pediatric Population

To evaluate the accuracy of the clinical Curaçao criteria in the diagnosis of hereditary hemorrhagic telangiectasia (HHT) in children and adolescents. This was a retrospective, multicenter chart review of 673 patients evaluated between 2002 and 2016; 290 were eligible for the study. Genetic testing for a pathogenic mutation was considered the gold standard against which the clinical Curaçao criteria were compared. Patients were divided into 4 age categories: 0-5, 6-10, 11-15, and 16-21-years. Sensitivity and specificity were calculated for each age group, and for the overall population. Overall the Curaçao criteria had a sensitivity of 68% (95% CI 60%-76%) and a specificity of 98% (95% CI 91%-100%). Sensitivity was lowest in the 0- to 5-year group, and increased with advancing age. The Curaçao criteria had the highest sensitivity in the 16- to 21-year-olds. Specificity was 100% in all age groups except for the 11- to 15-year-olds. This study evaluated the use of the Curaçao criteria for the diagnosis of HHT in the pediatric population with a family history of HHT. In those between the age of 0 and 21 years who meet 1 criterion (unlikely HHT) or 2 criteria (possible HHT), genetic testing is preferred for diagnosis. The Curaçao criteria appear to reliably diagnose HHT in children and adolescents who meet 3 or 4 criteria (definite HHT).

Epistaxis in children and adolescents with hereditary hemorrhagic telangiectasia.

Our objective was to describe epistaxis onset and severity in pediatric hereditary hemorrhagic telangiectasia (HHT) patients and study the cumulative incidence of epistaxis by age of onset within each genetic subtype. Retrospective cohort chart review. Charts were reviewed of patients age 0 to 18 years with a clinical or genetic diagnosis of HHT who were evaluated at a tertiary multidisciplinary HHT clinic from January 2010 to June 2016. The epistaxis severity score (ESS), a validated tool for assessing epistaxis severity, was used to assess epistaxis. Statistical analyses were conducted on the full HHT cohort as well as subgroups stratified by the HHT causative gene (HHT1 = ENG and HHT2 = ACVRL1). Sixty-nine pediatric subjects were identified; 60 had HHT confirmed by genetic testing, and nine (from families with known mutations) met published clinical diagnostic criteria alone. Fifty-nine (85%) had onset of epistaxis. The median age of onset of epistaxis was 5 years (interquartile range [IQR]: 2-9 years). The median ESS for the entire cohort was 1.6 (IQR: 0-2.6). The median ESS was higher in HHT1 versus HHT2 (2.3 vs. 1.1, P = .002), and age of epistaxis onset was earlier in HHT1 (3 vs. 5 years, P = .03). Sex and age were not associated with ESS. Epistaxis may present early in HHT, but is typically mild in the pediatric period. Severity in the pediatric population is worse in patients with HHT1. By recognizing the significance of even mild, infrequent epistaxis in a child with a family history of HHT, and understanding that not all HHT patients have epistaxis during childhood, community providers and otolaryngologist can assist in the early detection of HHT. 4 Laryngoscope, 128:1714-1719, 2018.

Mucocutaneous Telangiectasia as a Diagnostic Clue of Hereditary Hemorrhagic Telangiectasia: An Activin Receptor-Like Kinase-1 Mutation in a Korean Patient.

Dear Editor: Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant vascular disorder manifested by variable-sized arteriovenous malformations (AVMs) of the skin, central nervous system, and respiratory, gastrointestinal, and urogenital tracts1,2. A 43-year-old woman visited our dermatology clinic with a 3-year history of increasing numbers of purpuric, punctate, and tiny macules of the lip, oral cavity, and fingers (Fig. 1A~C). The patient had no history of recurrent epistaxis; however, her mother had recurrent epistaxis and brain AVMs. No other abnormalities were detected in laboratory workups, particularly to detect visceral AVMs, including computed tomography scans of the chest and abdomen, brain magnetic resonance imaging, and gastrointestinal endoscopy. Under clinical suspicion, we performed a mutation analysis for HHT in the patient and her mother. The mutation c.940C>T (p.His314Tyr) in activin receptor-like kinase-1 (ACVRL1) was confirmed in both the patient and her mother, confirming the diagnosis of HHT (Fig. 1D). Interestingly, this genetic alteration, previously reported in a Western pedigree3, is a novel point mutation in a Korean family. The cutaneous lesions were well improved by pulsed dye laser (Fig. 2). Fig. 1 (A~C) Typical cutaneous telangiectasias at characteristic sites: lip, oral cavity, and fingers. (D) Presence of the mutation c.940C>T (p.His314Tyr) in activin receptor-like kinase-1. Fig. 2 Skin lesions on the tongue showed excellent response after a single treatment using pulsed dye laser (Vbeam Perfecta; Candela Laser Corporation, Wayland, MA, USA): (A) before treatment and (B) after treatment. Clinically, HHT is diagnosed by the Curacao criteria, which include spontaneous and recurrent epistaxis, mucocutaneous telangiectasias, visceral AVMs, and family history of HHT in a first-degree relative1,3. HHT is definitively diagnosed when three of the criteria are satisfied, whereas a suspected diagnosis is given when two of the criteria are met. In molecular diagnosis, mutations are found in approximately 85% of HHT families; most of these cases involve mutations in the endoglin (HHT1) or ACVRL1 (HHT2) genes4. Mutations of the endoglin gene on chromosome 9, which cause HHT1, were not detected in this family. The prevalence of specific vascular abnormalities varies according to genotype; patients with HHT1 have a higher prevalence of pulmonary and cerebral AVMs, while hepatic AVMs occur more commonly in HHT2 patients4. In our case, although the patient and her mother did not fulfill the criteria for a definitive diagnosis, HHT was strongly suspected because of the patient's typical mucocutaneous lesions. Therefore, targeted genetic testing for the endoglin and ACVRL1 genes should be performed to establish an early diagnosis if there are characteristic cutaneous features and/or a family history of HHT. The cutaneous stigmata, which are characterized by an accumulation of small-caliber and superficial vessels, can cause cosmetic concerns and a risk for bleeding1,2,5. In our case, treatment with pulsed dye laser resulted in dramatic improvement of the skin lesions, similar to results reported by Halachmi et al.2. Multiple treatments and follow-up visits can be necessary because of the lower response of HHT than non-HHT telangiectasia and the possible accumulation of new vascular lesions2. In conclusion, to initially rule out an HHT diagnosis, genetic study is an available option. Because of the superficial nature of vascular lesions, shorter wavelength vascular lasers such as the pulsed dye laser can be considered an effective and safe treatment option for HHT.

The effects of epistaxis on health‐related quality of life in patients with hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease mainly characterized by epistaxis in more than 96% of patients. Recently, a validated questionnaire known as the HHT Epistaxis Severity Score (ESS) was developed. However, little is known about the relationship between epistaxis and quality of life. We hypothesize that epistaxis severity is a major factor predicting health-related quality of life (HR-QoL) in HHT patients. This is a cross-sectional study. The ESS questionnaire and Medical Outcomes Study 36-item short form (SF-36) were administered to subjects through an Internet survey. All participants had a definitive diagnosis of HHT through Curaçao criteria or genetic testing. Demographic information, genetics, and extensive histories were also collected. Descriptive analyses were performed with calculations of means and standard deviations (SDs) for continuous variables and proportions for categorical variables. Linear regressions were then performed to assess the association between HR-QoL and ESS. A total of 604 subjects participated between April and August 2008. All patients reported epistaxis, 285 (47.2%) had telangiectasias, and 545 (90.2%) had a family history of HHT; 167 (27.6%) patients had mild epistaxis (ESS <4), 285 (47.2%) reported moderate epistaxis (≥4 ESS <7), and 152 (25.2%) reported severe epistaxis (ESS ≥7). Patients with severe epistaxis had lower scores for both the Physical Component Summary (PCS) and the Mental Component Summary (MCS) of HR-QoL when compared to those with mild epistaxis (p < 0.001, p < 0.001). The ESS is a major determinant of HR-QoL and should be considered as a measurement of treatment efficacy in HHT-related epistaxis.

Early neonatal complications from pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: case report and review of the literature

Hereditary hemorrhagic telangiectasia (HHT) is a rare but life-threatening disease characterized by multi system telangiectasias and arteriovenous malformations (AVM). Complications in adults have been reported extensively, but neonatal (NN) complications have only been published in incidental case reports. In this paper, we present a literature review on NN pulmonary AVM related to HHT, following our own experience with a NN death due to this disease. As prenatal diagnosis of pulmonary AVM is feasible, we recommend that a family history of HHT should be an indication for expertise prenatal anomaly scanning, in order to organise optimal NN support at birth.

Mosaic ACVRL1 and ENG mutations in hereditary haemorrhagic telangiectasia patients

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder caused by mutations in the ACVRL1, ENG, and SMAD4 genes. HHT is commonly characterised by small arteriovenous malformations (AVMs) known as...

Clinical features of pulmonary arterial hypertension in young people with an ALK1 mutation and hereditary haemorrhagic telangiectasia

Background:Pulmonary arterial hypertension (PAH) has been linked to mutations in genes encoding two members of the transforming growth factor-β family, BMPR2 and ALK1, the latter of which is also associated...

Acute paraplegia due to spinal arteriovenous fistula in two patients with hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by recurrent epistaxis, cutaneous telangiectasia, and visceral arteriovenous malformations (AVM). Of these, spinal AVM is a rare manifestation that concerns mainly children. In this report, we describe two cases of spinal AVM revealed by acute paraparesis due to subarachnoid hemorrhage in children with HHT and reviewed the literature on spinal arteriovenous malformations in HHT. In most of the cases reported, the clinical presentation was acute in the pediatric population and insidious during adulthood. The prognosis of spinal AVM mainly depends on the presence or not of medullar signs and symptoms and on the delay before treatment. In conclusion, any child with a family history of HHT should be considered at risk for spinal AVM in order to improve management of such complications and to decrease the risk of neurological sequellae.