A 58-year-old woman had sudden right-sided numbness without apparent trigger, mainly in the right lower limb. He had a history of ischemic stroke 2 years ago, multiple episodes of epistaxis, and iron-deficiency anemia for years.
On examination, sensation to vibration was slightly impaired in the right extremities, and multiple small-haemangioma-like telangiectatic lesions were found on the tongue and several parts of the skin. The patient’s father, grandfather, siblings, and kids also had a history of epistaxis.
Laboratory investigation showed mild iron-deficiency anemia with a positive fecal occult blood test and slightly elevated D-dimer. Renal function, liver function, C-reactive protein level, and hemoglobin A1c level were all in normal ranges.
MRI of the head revealed a recent infarct in the left fronto-parietal lobe and insula, and bilateral globus pallidus showed patchy high signal intensity on T1-weighted images, indicating manganese deposition(Fig. 1a). No cerebral arterial abnormality was found by the assessment of magnetic resonance angiography. Aortic and carotid ultrasonography were negative for atherosclerotic plaques. Deep veins of both lower limbs and bilateral iliac veins were normal via ultrasonography. Chest computed tomography (CT) image demonstrated a mass shadow in the right lower lung field, suggesting a vascular malformation. Also, a bubble contrast study disclosed a right-to-left shunt with transcranial Doppler, which suggested the existence of a right-to-left shunt. Thus, we performed a chest CT with contrast revealed a PAVM in the right lower lung(Fig. 1b), while transthoracic echocardiography showed an atrial septal aneurysm.
Subsequently, transesophageal echocardiography was performed and found an atrial septal aneurysm, yet no PFO or thrombus. In addition, a dynamic electrocardiogram (ECG) examination found occasional atrial premature beats and ventricular premature beats. For the presence of high signal intensity on the T1-weighted image, we deduced the patient might have hepatic AVM. Subsequent hepatic enhanced contrast CT demonstrated portal vein to hepatic vein shunt and obvious dilation of hepatic arteries(Fig. 1c and 1d).
This patient had a recurrent ischemic stroke, with a nose bleeds history as well as her family members, tongue and skin telangiectasia, gastrointestinal bleeding may be caused by telangiectasia, hepatic AVM and PAVM, all of which matched well with the four consensus diagnostic criteria of HHT, described as epistaxes, telangiectasia, visceral lesions and a family history of a first degree relative in Curaçao criteria [15].
This patient received antithrombotic therapy with aspirin and embolization of PAVM. Pulmonary angiography showed the disappeared pulmonary arteriovenous fistula. In addition, iron supplement therapy was prescribed to the patient. She was discharged on the third day after the gradual recovery from the surgery.
For the further evaluation of this patient as well as the assessment of the risk for other family members [16], high-throughput sequencing was recommended and tested positive for a variant, ENG_ex7 c.861dup(p.Arg288SerfsTer46), resulting in the premature termination of the protein coding sequence(Fig. 2). According to the ACMG guideline, the variant was judged to be pathogenic, and it was not included in the ClinVar database. ENG gene encodes a major glycoprotein of the vascular endothelium, endoglin [14], while the mutation detected in our patient may cause the malfunction of the protein coded and eventually result in vascular dysplasia. A former study found that PAVM was more frequent in patients with the ENG variant [17].
Considering that several family members of this patient also had a history of epistaxis, genetic counseling for HHT was recommended, but they refused.