Genotype-Phenotype Correlations in Children with HHT.

Alexandra Kilian,Helen Kim,Felix Ratjen,Marie Faughnan,Andrew White,Kevin Whitehead,James Gossage,Katharine Henderson,Justin Mcwilliams,Doris Lin,Michael Lawton,Jeffrey Pollak,Murali Chakinala,Giuseppe Latino,Jamie Mcdonald,Dewi Clark

doi:10.3390/jcm9092714

Abstract

Hereditary hemorrhagic telangiectasia (HHT), a rare autosomal dominant disease mostly caused by mutations in three known genes (ENG, ACVRL1, and SMAD4), is characterized by the development of vascular malformations (VMs). Patients with HHT may present with mucocutaneous telangiectasia, as well as organ arteriovenous malformations (AVMs) of the central nervous system, lungs, and liver. Genotype–phenotype correlations have been well described in adults with HHT. We aimed to investigate genotype–phenotype correlations among pediatric HHT patients. Demographic, clinical, and genetic data were collected and analyzed in 205 children enrolled in the multicenter Brain Vascular Malformation Consortium HHT Project. A chi-square test was used to determine the association between phenotypic presentations and genotype. Among 205 patients (age range: 0–18 years; mean: 11 years), ENG mutation was associated with the presence of pulmonary AVMs (p < 0.001) and brain VM (p < 0.001). The presence of a combined phenotype—defined as both pulmonary AVMs and brain VMs—was also associated with ENG mutation. Gastrointestinal bleeding was rare (4.4%), but was associated with SMAD4 genotype (p < 0.001). We conclude that genotype–phenotype correlations among pediatric HHT patients are similar to those described among adults. Specifically, pediatric patients with ENG mutation have a greater prevalence of pulmonary AVMs, brain VMs, and a combined phenotype.

Highlights

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease affecting approximately 1 in 5000 people [1,2,3,4]
This is consistent with previous literature describing genotype–phenotype correlations in adults, in which the ENG genotype was associated with the presence of pulmonary arteriovenous malformations (AVMs) [10,13,14,15,17,19,20,21] and with the presence of brain vascular malformations (VMs) [10,13,14,15,16,21]
From the largest genotype–phenotype cohort of pediatric patients with HHT to date, we demonstrate that organ involvement and associated genotype-phenotype correlations in children with HHT are similar to those previously described in the adult population

Summary

Introduction

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease affecting approximately 1 in 5000 people [1,2,3,4]. 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]. HHT is characterized by the development of arteriovenous malformations (AVMs) in visceral organs, including the brain, lungs, liver, and rarely the spine. Patients can have chronic bleeding from telangiectases in the gastrointestinal (GI) mucosa, often complicated by secondary iron-deficiency anemia [12]

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