Genotype–Phenotype Correlations in Children with HHT

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.

Severe Hypoxemia Caused by High-Output Heart Failure and Pulmonary Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia

“…By contrast, patients who have an ACVRL1 mutation (HHT2) have HAVMs more frequently, and PAVMs are rare. There are many reports concerning genotype-phenotype correlations of HHT in which the gender difference is important ( 2 , 7 ). Letteboer et al ( 2 ) reported that in HHT1, only 1 of 56 male patients had HAVMs, whereas 9 of 88 female patients had HAVMs.…”

“…Letteboer et al ( 2 ) reported that in HHT1, only 1 of 56 male patients had HAVMs, whereas 9 of 88 female patients had HAVMs. Kilian et al ( 7 ) reported that only 1 of 101 male children with HHT1 had HAVMs. Interestingly, Dupuis-Girod et al ( 8 ) published an article that demonstrated the effectiveness of bevacizumab in the treatment of high-output HF due to HAVM.…”

A Rare Case of Upper Gastrointestinal Bleeding: Osler-Weber-Rendu Syndrome

“…In this way, the HHT subtype can be identified and first-degree relatives can be tested for the disease. HHT is estimated to affect approximately 1 in 5000–6000 Europeans [ 7 , 8 ]. More than 76–80% of all cases of HHT are due to mutations in either ENG or ACVRL1 [ 9 , 10 ].…”

The role of nuclear medicine in a case of Rendu–Osler–Weber disease with pulmonary involvement

“…[ 1 ] Its primary pathogenic expression is multiple arteriovenous malformations (AVM), especially in lungs, liver, brain, and rarely the spine. [ 2 ] The incidence is 1:5000–1:10000 worldwide. [ 2 ] Common manifestations are telangiectases, reported in 74% of patients,[ 3 ] in nasal mucosa, gastrointestinal tract, lips, and hands.…”

“…[ 2 ] The incidence is 1:5000–1:10000 worldwide. [ 2 ] Common manifestations are telangiectases, reported in 74% of patients,[ 3 ] in nasal mucosa, gastrointestinal tract, lips, and hands. Over 90% of all HHT patients present chronic epistaxis due to nasal telangiectases by the age of 45 years.…”