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. 2022 Jun;77(6):628-630.
doi: 10.1136/thoraxjnl-2021-218332. Epub 2022 Feb 14.

Pulmonary arteriovenous malformations may be the only clinical criterion present in genetically confirmed hereditary haemorrhagic telangiectasia

Emily Anderson  1   2 , Lakshya Sharma  3 , Ali Alsafi  4 , Claire L Shovlin  5   3
Affiliations

Pulmonary arteriovenous malformations may be the only clinical criterion present in genetically confirmed hereditary haemorrhagic telangiectasia

Emily Anderson et al. Thorax. 2022 Jun.

Abstract

Pulmonary arteriovenous malformations (PAVMs) result in preventable complications demanding specialty care. Underlying hereditary haemorrhagic telangiectasia (HHT) can be identified by genetic testing, if the diagnosis is considered. Retrospectively reviewing 152 unrelated adults with genetically confirmed HHT due to ACVRL1, ENG or SMAD4, we found that only 104/152 (68%) met a clinical diagnosis of HHT with three Curaçao criteria. The genetic diagnostic rate was similar for patients with three (104/137, 76%) or one to two (48/71, 68%; p=0.25) criteria. Of 83 unrelated probands with PAVM(s) and genetically-confirmed HHT, 20/83 (24%) had few, if any, features of HHT. Enhanced clinical suspicion, as well as HHT genetic testing, is recommended if one or more PAVMs are present.

Keywords: pulmonary vasculitis; rare lung diseases.

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Conflict of interest statement

Competing interests: The authors have no financial competing interests to declare. CLS chairs the Genomics England Respiratory GeCIP, the North Thames Genomic Medicine Service Alliance R&D Committee, the NHS Hereditary Haemorhagic Telangiectasia Rare Disease Collaborative Network and the British Thoracic Society Pulmonary AVM Clinical Statement Group; sits on the Cure HHT Global Research and Medical Advisory Board, the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel; and chaired the European Reference Network for Rare Multisystemic Vascular Diseases HHT Working Group 2016–2020.

Figures

Figure 1
Figure 1
Genotype–phenotype analyses in 208 genotyped patients with HHT. Proportion of genotyped patients with (black) and without (pale yellow) causal HHT variant identification, if (A) meeting three Curaçao criteria for ‘definite HHT’, (B) meeting one to two Curaçao criteria. The Curaçao criteria are spontaneous, recurrent nosebleeds; multiple telangiectasia at characteristic sites (lips, oral cavity, fingers and nose); visceral lesions such as gastrointestinal telangiectasia (with or without bleeding), pulmonary AVM, hepatic AVM, cerebral AVM, spinal AVM and a first-degree relative with HHT according to these criteria. AVM, arteriovenous malformation; HHT, hereditary haemorrhagic telangiectasia.
Figure 2
Figure 2
Genotype–phenotype analyses in subgroups of genotyped patients with HHT who did not meet the threshold for a clinical diagnosis of HHT. Proportion of genotyped patients with (black) and without (pale yellow) causal HHT variant identification, if meeting the stated patterns. 1CC from spontaneous, recurrent nosebleeds; multiple telangiectasia at characteristic sites (lips, oral cavity, fingers and nose); visceral lesions such as gastrointestinal telangiectasia (with or without bleeding) or HHT-site AVMs (pulmonary AVM, hepatic AVM, cerebral AVM and spinal AVM); and a first-degree relative with HHT according to these criteria. 1CCT: severe nosebleeds requiring blood transfusions. 1CC, 1 Curaçao criteria; AVM, arteriovenous malformation; HHT, hereditary haemorrhagic telangiectasia.
Figure 3
Figure 3
Causal HHT variants on ClinVar. The distribution of 814 unique likely pathogenic and pathogenic variants in ENG, ACVRL1 and SMAD4 listed in ClinVar. Loss-of-function variants meeting very strong evidence of pathogenicity include frameshifts (green) due to an out-of-frame insertion or deletion (indels), nonsense (stop gain) substitutions generating a premature stop codon and splice site variants affecting the exon-flanking consensus (±1 and ±2) splice sites. Missense variants (purple) where a single amino acid is substituted represent a higher proportion of pathogenic and likely pathogenic variants in ACVRL1 than ENG or SMAD4 (109/264 (41%) compared with 85/550 15.5%) for ENG/SMAD4 (p<0.0001, Fisher’s exact test). HHT, hereditary haemorrhagic telangiectasia.
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References

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