Current HHT genetic overview in Spain and its phenotypic correlation: data from RiHHTa registry

Abstract

Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease with autosomal dominant inheritance. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in more than 90% of cases submitted to molecular diagnosis. Methods: We used data from the RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry to describe genetic variants and to assess their genotype-phenotype correlation among HHT patients in Spain. Results: By May 2019, 215 patients were included in the RiHHTa registry with a mean age of 52.5 ± 16.5 years and 136 (63.3%) were women. Definitive HHT diagnosis defined by the Curaçao criteria were met by 172 (80%) patients. Among 113 patients with genetic test, 77 (68.1%) showed a genetic variant in ACVRL1 and 36 (31.8%) in ENG gene. The identified genetic variants in ACVRL1 and ENG genes and their clinical significance are provided. ACVRL1 mutations were more frequently nonsense (50%) while ENG mutations were more frequently, frameshift (39.1%). ENG patients were significantly younger at diagnosis (36.9 vs 45.7 years) and had pulmonary arteriovenous malformations (AVMs) (71.4% vs 24.4%) and cerebral AVMs (17.6% vs 2%) more often than patients with ACVRL1 variants. Patients with ACVRL1 variants had a higher cardiac index (2.62 vs 3.46), higher levels of hepatic functional blood tests, and anemia (28.5% vs 56.7%) more often than ENG patients. Conclusions: ACVRL1 variants are more frequent than ENG in Spain. ACVRL1 patients developed symptomatic liver disease and anemia more often than ENG patients. Compared to ACVRL1, those with ENG variants are younger at diagnosis and show pulmonary and cerebral AVMs more frequently.

Genotype–Phenotype Correlations in Children with HHT

“…In our cohort, ENG mutation was associated with increased prevalence of brain VMs and pulmonary AVMs. This is consistent with previous literature describing genotype-phenotype correlations in adults, in which the ENG genotype was associated with the presence of pulmonary AVMs [10,[13][14][15]17,[19][20][21] and with the presence of brain VMs [10,[13][14][15][16]21]. Our results also confirm those of previous smaller pediatric series reported by Giordano et al [23] and A-Saleh et al [24], comprised of 44 and 61 patients, respectively.…”

“…There is, therefore, no evidence to support genotype based pulmonary screening recommendations. Similarly, while the literature suggests increased prevalence of brain VMs in adult patients with an ENG mutation [10,[13][14][15][16]21], brain VMs have been described across all genotypes in adult patients [16]. Our observations are consistent with this; while an ENG mutation is associated with brain VM in children, brain VMs are also reported in children with an ACVRL1 mutation.…”

“…Here, we report data from a large pediatric cohort of patients with HHT and describe genotype-phenotype correlations. Most significantly, our data demonstrate that in pediatric patients, pulmonary AVMs and brain VMs are more frequent in patients with an ENG mutation, as reported in adult studies [10,[13][14][15]17,[19][20][21]. Moreover, the ENG genotype is associated with a combined phenotype, characterized by the presence of both pulmonary AVM(s) and brain VM(s), in pediatric patients.…”

“…Genotype-phenotype correlations have been well described in adult cohorts [10,[13][14][15][16][17][18][19]. Most conclusively, the ENG genotype (HHT1: OMIM# 18730) has been associated with the presence of pulmonary AVMs [10,[13][14][15]17,[19][20][21] and brain VMs [10,[13][14][15][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].…”

“…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.…”