**1. Introduction**

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease affecting approximately 1 in 5000 people [1–4]. HHT can be diagnosed clinically using the Curaçao clinical diagnostic criteria [5] or by genetic testing [6]. Mutations in the endoglin (*ENG*) and activin A receptor-like kinase 1 (*ACVRL1*) genes account for approximately 96% of cases, when the Curaçao clinical diagnostic criteria are strictly applied [7]. In addition, less than 2% of patients present with an HHT–Juvenile Polyposis (JP) overlap syndrome, caused by mutations in the *SMAD4* gene [7–9]. HHT is characterized by the development of arteriovenous malformations (AVMs) in visceral organs, including the brain, lungs, liver, and rarely the spine. AVMs carry risks of life-threatening complications, including hemorrhage and paradoxical embolisms [6,10,11]. Additionally, smaller vascular malformations—called telangiectases—occur on mucocutaneous surfaces [11]. Bleeding from telangiectases in the nasal mucosa results in spontaneous recurrent epistaxis. Additionally, patients can have chronic bleeding from telangiectases in the gastrointestinal (GI) mucosa, often complicated by secondary iron-deficiency anemia [12].

Genotype–phenotype correlations have been well described in adult cohorts [10,13–19]. Most conclusively, the *ENG* genotype (HHT1: OMIM# 18730) has been associated with the presence of pulmonary AVMs [10,13–15,17,19–21] and brain VMs [10,13–16,21] in adults. While there are multiple brain VM subtypes seen in HHT, including arteriovenous fistulas (AVFs), nidus-type AVMs, and capillary vascular malformations, no correlations between brain VM subtype and genotype have been described [22]. The *ACVRL1* mutation (HHT2: OMIM# 600376) has been associated with the presence of liver VMs [10,13,14,20,21]. However, there is a relative paucity of literature regarding genotype–phenotype correlations, as well as HHT manifestations and complications in pediatric patients. Smaller pediatric cohorts have demonstrated that the *ENG* genotype is correlated with pulmonary AVMs and brain VMs [23–25]. The visible features of HHT—mucocutaneous telangiectases and spontaneous recurrent epistaxis—increase with age [26–28]. This, combined with the rarity of the disease, can result in delayed presentation and diagnosis in children [5,6,29,30]. Thus, a more robust understanding of genotype–phenotype correlations will have implications for diagnosis of HHT and organ screening in children. Accordingly, we aimed to report data from a large pediatric cohort of patients with HHT and describe the genotype-phenotype correlations.

#### **2. Materials and Methods**

## *2.1. Cohort*

Demographic, clinical, and genetic data were collected from 205 pediatric patients (age at recruitment ≤18) enrolled in the Brain Vascular Malformation Consortium (BVMC) HHT Project. The BVMC HHT Project includes 1679 HHT patients with a definite clinical or genetic diagnosis of HHT, enrolled at multiple recruiting centers in the US, Canada, and the Netherlands between 2010 and 2019. Cohort recruitment has been previously described [18,31]. The 205 pediatric patients in this study were recruited from nine of the BVMC recruiting centers. Informed written consent was obtained from all patients to be included in all BVMC related projects. The study protocol was approved by the institutional review board at each recruiting center (SMH REB#09-212 for lead site at St. Michael's Hospital). Patients were screened for organ VMs and other clinical features according to standard clinical practice (not as study procedure) and International HHT Guidelines [6]. Organ VM screening typically included: comprehensive history, physical exam, and routine investigations; pulmonary AVMs screening with contrast echocardiography or positional oximetry (protocols varied by center); brain VM screening by magnetic resonance imaging (MRI); clinical screening for liver VMs (chronic right upper quadrant pain, portal hypertension, high-output heart failure, liver bruit on examination); clinical screening for recurrent spontaneous epistaxis (>1 episode per month for >1 year); and screening for HHT-related GI bleeding (history of anemia, iron deficiency, known GI telangiectases on endoscopy, melena, rectal bleeding). If screening was positive for pulmonary AVM or brain VM, patients underwent confirmatory diagnostic imaging and treatment where appropriate. If clinical assessment was suggestive of symptomatic liver VM, diagnostic imaging was recommended and therapy was initiated where appropriate. Finally, if the initial clinical assessment was suggestive of GI bleeding, diagnostic endoscopy was recommended and endoscopic, medical, and supportive therapies were undertaken on a case-by-case basis. The BVMC HHT cohort targets 25% of brain VM-positive patients, while other characteristics are similar to other cohorts [13,16].
