Hereditary Hemorrhagic Telangiectasia in Pediatric Age: Focus on Genetics and Diagnosis

Abstract

Hereditary Hemorrhagic Telangiectasia (HHT) or Rendu–Osler–Weber Syndrome (ROW) is an autosomal dominant vascular disease, with an estimated prevalence of 1:5000. Genes associated with HHT are ACVRL1, ENG, SMAD4, and GDF2, all encoding for proteins involved in the TGFβ/BMPs signaling pathway. The clinical diagnosis of HHT is made according to the “Curaçao Criteria,” based on the main features of the disease: recurrent and spontaneous epistaxis, muco-cutaneous telangiectases, arteriovenous malformations in the lungs, liver, and brain, and familiarity. Since the clinical signs of HHT can be misinterpreted, and the primary symptom of HHT, epistaxis, is common in the general population, the disease is underdiagnosed. Although HHT exhibits a complete penetrance after the age of 40, young subjects may also present symptoms of the disease and are at risk of severe complications. Here we review the literature reporting data from clinical, diagnostic, and molecular studies on the HHT pediatric population.

Endothelial-to-Mesenchymal Transition in an Hereditary Hemorrhagic Telangiectasia-like Pediatric Case of Multiple Pulmonary Arteriovenous Malformations

“…Clinical diagnosis of HHT is possible following the Curaçao criteria, which are epistaxis, telangiectasia, arteriovenous malformation in internal organs and a familiar pattern of autosomal dominant inheritance [ 8 ]. Nevertheless, the Curaçao criteria are not accurate for infants, due to the late development of certain symptoms and to the intra-familial phenotypic variability [ 9 ].…”

“…Furthermore, we can add the difficult diagnosis in pediatric cases and the existence of sporadic (non-inherited) cases of HHT. In this context, we have studied a clinical case with multiple diffuse pulmonary fistulas of pediatric age who underwent a bilateral lung transplantation [ 9 ]. Previous genetic analysis such as Sanger sequencing analysis and Optical genome did not show any genetic alterations associated with HHT or any of the other related syndromes mentioned above.…”

Oral manifestations and dental considerations of hereditary haemorrhagic telangiectasia in paediatric population — a systematic review

“…Минимальная травма может приводить к разрыву сосудистых сплетений, которые обычно располагаются на поверхности слизистой оболочки. Повторяющиеся кровотечения в носовой области являются наиболее частым клиническим проявлением НГТ [1,2,3,4,5]. Артериовенозные мальформации могут возникать в легких (легочная артериовенозная мальформация -ЛАВМ), в гепатобиллиарной системе (печеночная артериовенозная мальформация) и мозге (ЦАВМ -церебральная артериовенозная мальформация).…”

Pharmacogenomic Considerations for Anticoagulant Prescription in Patients with Hereditary Haemorrhagic Telangiectasia

“…Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant multisystem vascular dysplasia arising from a single heterozygous loss-of-function variant ("mutation"), usually in ENG, ACVRL1, or SMAD4 [1][2][3][4][5]. As recently reviewed [6][7][8][9], patients develop internal, visceral arteriovenous malformations (AVMs) and smaller telangiectasia that bleed recurrently. International consensus is available to guide clinical management [7,8,10,11].…”

“…Initial guidance was through the generation of consensus clinical diagnostic criteria (the Curaçao Criteria) where the presence of three criteria from spontaneous recurrent nosebleeds, mucocutaneous telangiectasia, visceral involvement, and family history can be used to define definite clinical HHT [10][11][12]. These criteria are less helpful in children where there are fewer clinical features [9,[13][14][15], and conversely, it is possible to overdiagnose HHT if based on nosebleeds, telangiectasia, and family history alone [16,17]. The 2020 Second International Guidelines [7] recommended obtaining a genetic diagnosis of the HHT-causative mutation to facilitate targeted screening for internal AVMs.…”