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Abstract
Background We report two cases of RASA1-related capillary malformation-arteriovenous malformation (CM-AVM1) syndrome mimicking hereditary haemorrhagic telangiectasia (HHT).
Methods and results A 28-year-old man, previously embolised for cerebral arteriovenous malformations (AVMs), presented with epistaxis and typical nasal telangiectasias of HHT. CT scan revealed a large portocaval shunt. The second patient was a 9-year-old girl presenting with cyanosis and several mucocutaneous telangiectasias, similar to those observed in typical cases of HHT. CT scan revealed a huge and complex pulmonary AVM of the right lower lobe and a hepatic AVM within the left lobe. HHT diagnosis was considered possible according to the Curaçao criteria for the two patients, with at least two criteria for each. Genetic tests did not find any mutation in the three classic genes (Endoglin, Activin receptor-like kinase 1 or Mothers against decapentaplegic homolog 4), but identified in both cases an RASA1 mutation, known to cause CM-AVM1 syndrome.
Conclusions Pulmonary AVM and portocaval shunt, usually encountered in HHT, have not yet been described in the CM-AVM1 syndrome. RASA1 screening may be considered in case of HHT suspicion, particularly when mutations are not found in the usually affected genes.
- cardiovascular medicine
- clinical genetics
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Introduction
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterised by the presence of mucocutaneous telangiectasias and arteriovenous malformations (AVMs). HHT can be diagnosed on the basis of the clinical Curaçao criteria.1 In adults, three criteria are needed among the following four: mucocutaneous telangiectasias, recurrent epistaxis, visceral involvement and a first-degree family history of HHT. In children, the clinical diagnosis may be challenging since all the criteria may not be present yet.
This genetic disorder is primarily caused by mutations in the Endoglin (ENG), Activin receptor like-kinase (ACVRL1) and Mothers against decapentaplegic homolog (SMAD4) genes. All these genes encode proteins that transmit bone morphogenetic proteins signal particularly in the vascular endothelial cells.
Other vascular genetic disorders may mimic HHT and constitute a real challenge for clinicians. The capillary malformation-arteriovenous malformation type 1 (CM-AVM1) syndrome is associated with mutations in the RAS P21 protein activator 1 gene (RASA1).2 3 Most patients with RASA1 mutation present with cutaneous capillary malformations. AVMs and arteriovenous fistulas (AVFs) are present in 25%–30% of patients particularly in the brain. Extracranial AVMs and AVFs are often described in the skin, muscles and spine. Parkes-Weber syndrome (AVFs associated with excessive soft tissue, skeletal growth and cutaneous capillary stain) is also part of the clinical spectrum of RASA1-related diseases.4 Recently mutations in EphB4 have been described in CM-AVM2 having similarities and differences with CM-AVM1 and HHT.5
We report herein two patients with vascular malformations associated with RASA1 mutation and in whom the clinical presentation mimicked HHT.
Cases
Patients
The two patients were referred to our HHT centre due to a clinical presentation suggestive of this disease. They underwent a routine evaluation protocol which included clinical examination by expert dermatologist, gastroenterologist, ear, nose and throat (ENT) specialist, pulmonologist, paediatrician, genetic testing, transthoracic contrast echocardiography, and CT scan of the chest and abdomen.
Genetic testing
Patient 1 was analysed by Sanger sequencing and Multiplex Ligation-dependent Probe Amplification analysis for ENG, ACVRL1 and RASA1 genes,4 while patient 2 was analysed for ENG, ACVRL1 and SMAD4 genes using the same techniques. The reference sequences used are ACVRL1 (NM_000020.2), ENG (NM_001114753.1) and RASA1 (NM_002890.1). Since no mutation was identified in patient 2, further analysis by targeted capture Next Generation Sequencing approach using a custom gene panel that includes RASA1 and other genes related to hereditary vascular diseases was done. For both patients, the results were controlled by Sanger sequencing of DNA obtained from an independent blood sample.
Patient 1
A 28-year-old man was admitted to our HHT centre due to cerebral AVM and epistaxis. The cerebral AVM was treated with five sessions of embolisation (figure 1A). Nosebleeds started at the age of 6, occurred usually twice a month and needed several sessions of laser therapy until the age of 12. Then, the frequency and abundance of bleeding decreased to approximately 5–10 mild episodes per year where the patient bled continuously for 2–10 days. Sometimes the bleeding was gushing and required nasal laser therapy. ENT examination revealed 40–50 nasal telangiectasias considered as typical of HHT. Skin examination found 50 telangiectasias typical for HHT (1–3 mm, pink to bright red, blanchable macules or thin papules, disappearing after diascopy). The patient had also 14 non-typical cutaneous telangiectasias (figure 1B). These lesions, observed on the forehead (1), right ear (1), lips (8), hand (3) and forearm (1), were pale pink capillary malformations with a diameter of 5 mm (like plan angiomas) and were not in favour of HHT. Interestingly numerous other lesions were observed on the trunk and upper limbs and had an aspect of cutaneous vascular steal with white halos giving the skin a mottled effect (figure 1C). CT scan revealed a typical liver involvement of HHT with diffuse telangiectasias, multiple pseudonodular hyperplasia and enlargement of the hepatic artery (figure 1D). An atypical feature was observed consisting of a large portocaval shunt between the right portal vein branch and the inferior vena cava (figure 1E). Thus, the patient had three Curaçao criteria (epistaxis, mucocutaneous and hepatic vascular lesions) suggesting the diagnosis of HHT. However, the genetic tests did not find mutations in the ENG and ACVRL1 genes but a loss of function mutation c.556_562del, p.Leu186Glufs*3 in exon 2 of the RASA1 gene. DNA samples from the parents were available and genetic testing revealed the absence of the identified mutation in both, leading to conclude (after paternity testing) that the RASA1 mutation occurred de novo (figure 1).
Patient 1. (A) Left internal carotid angiography in sagittal and frontal view showing left anterior cerebral arteriovenous malformation (arrows). (B) Typical telangiectasia of HHT (A) and atypical lesion like a plan angioma (B). (C) Cutaneous vascular steals with white halos giving the skin a mottled effect (forearm and trunk). (D) CT in axial and frontal view showing typical liver involvement in HHT: numerous telangiectasias, pseudofocal nodular hyperplasia, and enlargement of the three hepatic arteries, phrenic artery and inferior vena cava. (E) CT in axial and frontal view showing large fistula between the right portal vein and inferior vena cava (arrow). HHT, haemorrhagic telangiectasia.
Patient 2
A 9-year-old girl presented with nail and lips cyanosis and clubbing due to a huge and complex pulmonary AVM located in the right lower lobe (figure 2A). Typical telangiectasias such as observed in HHT were present on the fingers (4), on the lips (4), on the sole of the right foot (1) and on the lateral side of the neck (1) (figure 2B). Otherwise, she had a frontal cutaneous angioma not in favour of CM-AVM1. The patient reported occasional episodes of nosebleeds, usually mild, and nasal endoscopy revealed few mucosal telangiectasias. The CT scan revealed a hepatic AVM within the left lobe (figure 2C). The pulmonary AVM was successfully embolised with coils. Three years later, it was surgically resected to prevent high risk of severe haemoptysis due to its reperfusion and the enlargement of the bronchial and systemic arterial supply (figure 2D). As the patient had only punctate telangiectasias and no capillary malformations that typify CM-AVM1, she was considered as having HHT in front of two Curaçao criteria. Despite high clinical suspicion for HHT, the genetic analysis found no mutation in the ENG, ACVRL1 and SMAD4 genes but a loss of function mutation c.2698_2701del p.Val900Phefs*10 ex21 in the RASA1 gene. This mutation was identified in three non-symptomatic relatives to targeted history and examination: the mother, maternal grandmother and maternal aunt (figure 2).
Patient 2. (A) Axial, frontal and volume rendering CT demonstrating a right lower lobe complex pulmonary arteriovenous malformation (B) Typical finger telangiectasias (arrows). (C) Axial CT with typical HHT liver involvement: two arteries feeding the liver and an AVM of the left lobe (arrow). (D) CT and angiographic control: reperfusion of the previously embolised PAVM leading to surgery. AVM, arteriovenous malformation; HHT, haemorrhagic telangiectasia.
Discussion
The two cases illustrate a phenotype presentation of CM-AVM1 overlapping with the classic description of HHT. Indeed, visceral involvement and nasal telangiectasias in patient 1 and pulmonary AVM, nasal telangiectasias and typical cutaneous telangiectasias in patient 2 were suggestive of HHT.
Liver and lung AVM are not classic organs affected in the course of RASA1 mutations.2 Curaçao criteria were met in both patients. These two cases show that clinical and radiological features of HHT may be encountered with RASA1 mutation.6 As a matter of fact, thoracoabdominal visceral AVMs described here have not been reported in the CM-AVM1 syndrome.
Before RASA1 and EPHB4 genes were identified, these cases would have been considered as HHT without identified mutations in the three known genes of HHT, suggesting either the possibility of deep intronic mutations in the known genes or of mutations in a putative new HHT gene, yet to be identified.2 5 These data suggest that families presenting with an HHT-like phenotype in which no variant is detected in an HHT gene may indeed have a mutation in a CM-AVM1 gene.
These cases justify the simultaneous testing of HHT genes and CM-AVM with NGS-based gene panels in order to accelerate the diagnosis of these syndromic hereditary vascular disorders.3 7 8
In conclusion, RASA1 screening may be considered in case of HHT suspicion, particularly when mutations are not found in the usually affected genes.
Ethics statements
Footnotes
MEH and AM are joint first authors.
MEH, AM, RYC and TC contributed equally.
Contributors MEH and AM designed and supervised the study and wrote the first draft. MEH, AM, AP, ME, FS, IB, AO, RYC and TC participated in the diagnosis. MEH, AM, RYC and TC analysed the imaging data. AP, ME and FS were involved in genetic data analysis. IB was responsible for the analysis of skin anomalies. All authors read and approved the final manuscript. The authors wish it to be known that, in their opinion, RYC and TC are joint last authors.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.