Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2)

McDonald, Jamie; Bayrak-Toydemir, Pınar; DeMille, Desiree; Wooderchak-Donahue, Whitney; Whitehead, Kevin J.

doi:10.1038/s41436-020-0775-8

Cited by 52 publications

(47 citation statements)

References 31 publications

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“…Studies suggest that solid organ AVMs in JP/HHT are at least as common as in HHT1 and HHT2, and that pulmonary AVMs may be more frequent [16,21,24,25]. Overall, Curaçao diagnostic criteria for HHT are highly predictive of a pathogenic variant in ENG (HHT1) or ACVRL1 (HHT2) but cannot distinguish between these two genotypes [21]. Furthermore, the genetic heterogeneity does not explain the striking variable expression observed within families.…”

Section: Genetics Of Hht: the Germline Mutationmentioning

confidence: 96%

“…ENG and ACVRL1 are the predominant genes mutated in HHT, each responsible for almost half of cases. A mutation in one of these two genes is detected in over 95% of individuals who meet Curaçao diagnostic criteria, and a mutation in SMAD4 is detected in an additional 1-2% [20,21]. Although the phenotypes generated by mutations in ENG or ACVRL1 are similar enough that they cannot be reliably distinguished in the clinical setting, pulmonary and cerebral AVMs are more frequent in HHT1 patients while GI bleeding and liver AVMs are more common in HHT2 [22,23].…”

Section: Genetics Of Hht: the Germline Mutationmentioning

confidence: 99%

“…Although the phenotypes generated by mutations in ENG or ACVRL1 are similar enough that they cannot be reliably distinguished in the clinical setting, pulmonary and cerebral AVMs are more frequent in HHT1 patients while GI bleeding and liver AVMs are more common in HHT2 [22,23]. Studies suggest that solid organ AVMs in JP/HHT are at least as common as in HHT1 and HHT2, and that pulmonary AVMs may be more frequent [16,21,24,25]. Overall, Curaçao diagnostic criteria for HHT are highly predictive of a pathogenic variant in ENG (HHT1) or ACVRL1 (HHT2) but cannot distinguish between these two genotypes [21].…”

Section: Genetics Of Hht: the Germline Mutationmentioning

confidence: 99%

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Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia

Bernabeu

Bayrak-Toydemir

McDonald

et al. 2020

JCM

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Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that presents with telangiectases in skin and mucosae, and arteriovenous malformations (AVMs) in internal organs such as lungs, liver, and brain. Mutations in ENG (endoglin), ACVRL1 (ALK1), and MADH4 (Smad4) genes account for over 95% of HHT. Localized telangiectases and AVMs are present in different organs, with frequencies which differ among affected individuals. By itself, HHT gene heterozygosity does not account for the focal nature and varying presentation of the vascular lesions leading to the hypothesis of a “second-hit” that triggers the lesions. Accumulating research has identified a variety of triggers that may synergize with HHT gene heterozygosity to generate the vascular lesions. Among the postulated second-hits are: mechanical trauma, light, inflammation, vascular injury, angiogenic stimuli, shear stress, modifier genes, and somatic mutations in the wildtype HHT gene allele. The aim of this review is to summarize these triggers, as well as the functional mechanisms involved.

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Section: Genetics Of Hht: the Germline Mutationmentioning

confidence: 96%

Section: Genetics Of Hht: the Germline Mutationmentioning

confidence: 99%

Section: Genetics Of Hht: the Germline Mutationmentioning

confidence: 99%

See 1 more Smart Citation

Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia

Bernabeu

Bayrak-Toydemir

McDonald

et al. 2020

JCM

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“…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][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…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][8][9]. HHT is characterized by the development of arteriovenous malformations (AVMs) in visceral organs, including the brain, lungs, liver, and rarely the spine.…”

Section: Introductionmentioning

confidence: 99%

Genotype–Phenotype Correlations in Children with HHT

Kilian

Latino

White

et al. 2020

JCM

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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.

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Clinical manifestations of patients with GDF2 mutations associated with hereditary hemorrhagic telangiectasia type 5

Farhan

Yuan

Partan

et al. 2021

American J of Med Genetics Pt A

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Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant fibrovascular dysplasia caused by mutations in ENG, ACVRL1, and SMAD4. Increasingly, there has been an appreciation for vascular conditions with phenotypic overlap to HHT but which have distinct clinical manifestations and arise from novel or uncharacterized gene variants. This study reported on a cohort of four unrelated probands who were diagnosed with a rare form of GDF2‐related HHT5, for which only five prior cases have been described. Two patients harbored heterozygous missense variants not previously annotated as pathogenic (p.Val403Ile; p.Glu355Gln). Clinically, these patients had features resembling HHT1, including cerebrovascular involvement of their disease (first report documenting cerebral involvement of HHT5), but with earlier onset of epistaxis and a unique anatomic distribution of dermal capillary lesions that involved the upper forelimbs, trunk, and head. The other two patients harbored interstitial deletions larger than five megabases between 10q11.22 and 10q11.23 that included GDF2. To our knowledge, this is the first report detailing large genomic deletions leading to HHT5. These patients also demonstrated mucocutaneous capillary dysplasias, including intranasal vascular lesions complicated by childhood‐onset epistasis, with a number of extravascular findings related to their 10q11.21q11.23 deletion. In conclusion, patients with GDF2‐related HHT may present with a number of unique characteristics that differ from classically reported features of HHT.

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Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2)

Cited by 52 publications

References 31 publications

Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia

Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia

Genotype–Phenotype Correlations in Children with HHT

Clinical manifestations of patients with GDF2 mutations associated with hereditary hemorrhagic telangiectasia type 5

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