A Novel GDF2 Mutation in a Patient With Hereditary Hemorrhagic Telangiectasia Complicated by Acute Cerebral Infarction

ABSTRACT

Introduction

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease and the growth differentiation factor 2 (GDF2) variants have been identified as an infrequent cause of HHT.

Case Report

We report a 64‐year‐old female patient with an onset of ischemic stroke suspected related with microscopic pulmonary arteriovenous malformations. She had cutaneous vascular lesions, a history of spontaneous recurrent epistaxis, and a family history with her mother exhibiting similar clinical manifestations. The patient was diagnosed with HHT and subsequently found to have a novel heterozygous frameshift mutation of GDF2.

Conclusion

This case broadens the known clinical spectrum of HHT associated with GDF2 variants.

1. Introduction

Hereditary hemorrhagic telangiectasia (HHT), or Rendu–Osler–Weber syndrome, is an autosomal dominant vascular disorder with a global prevalence estimated to affect 1 in 5000 people, and its pathology is characterized by multisystemic vascular dysplasia [1]. Common clinical features include recurrent epistaxis, mucocutaneous telangiectasias, and visceral arteriovenous malformations (AVMs), particularly in the lungs, liver, and brain.

To date, it is recognized that HHT pathogenesis relies heavily on genetic variants and HHT is driven by genetic defects in the transforming growth factor‐beta (TGF‐β) signaling pathway, affected by three primary genes: endoglin (ENG), activin A receptor‐like type 1 (ACVRL1), and mothers against decapentaplegic homolog 4 (SMAD4) [2]. More recently, growth differentiation factor 2 (GDF2) variants, encoding recombinant bone morphogenetic protein 9 (BMP9), also implicate in the aberrant angiogenesis and have been identified as a rare cause of HHT [3]. Here we report a case of HHT presented as acute cerebral infarction and with a novel GDF2 heterozygous frameshift mutation.

2. Case Report

A 64‐year‐old female patient attended the emergency department with 4‐h slurred speech and right‐sided limb weakness. She reported a history of hypertension and a prior cesarean section. Neurological examination revealed dysarthria, flattening of the right nasolabial fold, and rightward tongue deviation. The muscle strength in the left limbs was Grade 5 and it was Grade 2 in the right limbs with a positive Babinski sign on the right. A head computed tomography (CT) performed immediately showed no hemorrhage. Therefore, she was highly suspected of having an acute cerebral infarction. Since the onset was within the time window for intravenous thrombolysis, the patient immediately received intravenous thrombolysis with 42 mg of alteplase. In addition, she was treated with aspirin for antiplatelet therapy. Gradually, her muscle strength recovered to grade 5⁻ later. Subsequent brain magnetic resonance imaging (MRI) clearly revealed an acute infarct in the left corona radiata‐basal ganglia region (Figure 1A,B), while magnetic resonance angiography (MRA) of the head demonstrated no evidence of stenosis, occlusion, or malformations. A comprehensive evaluation for the stroke etiology, including head, cervical and limb vascular ultrasonography, dynamic electrocardiography, and echocardiography, indicated unremarkable results. In addition, blood tests, including compete blood count, coagulation profile, blood glucose, lipid panel, and tumor markers, were also within normal limits.

FIGURE 1.

(A and B) Brain MRI showing acute infarction with a red arrowhead in the left corona radiata and basal ganglia region. (C and D) Nasal endoscopy revealing slightly increased small blood vessels and mucosal hemorrhage indicated by black arrows.

Upon further history‐taking, she reported spontaneous recurrent epistaxis since childhood and had previously undergone endoscopic hemostasis (Figure 1C,D). The patient had no history of gastrointestinal bleeding, and had experienced no significant epistaxis since undergoing endoscopic nasal treatment in 2020. A careful re‐examination revealed scattered vascular lesions on her trunk and upper limbs (Figure 2A). She mentioned that her mother, who was deceased with an unknown cause, also had frequent epistaxis and many cutaneous vascular lesions. The test of transthoracic contrast echocardiography (TTCE) with bubbles was subsequently performed. No obvious abnormal echoes were detected in the left atrial body or left atrial appendage, and the interatrial septum was intact. After injecting 10 mL of agitated saline into a left upper extremity superficial vein and six cardiac cycles later, a significant number of microbubbles were detected in the left atrium and left ventricle, originating from the left upper pulmonary vein, suggesting possible pulmonary arteriovenous fistula (Figure 2B). However, subsequent pulmonary angiography showed no abnormalities in the left and right pulmonary artery trunks and their branches (Figure 2C,D), leading to the consideration of microscopic arteriovenous fistulae. Based on the patient's history, HHT was suspected. Genetic testing for ENG, ACVRL1, SMAD4, and GDF2 was performed, revealing a mutation in GDF2. Sanger sequencing further confirmed a heterozygous c.639_652delCGCTGGGTCCGGTC (p.W214Lfs*7) on Exon‐2 of the GDF2 gene, causing a frameshift mutation (Figure 2E). Regretfully, her offspring refused to receive the associated genetic testing. The patient was ultimately diagnosed with HHT. At the 6‐month telephone follow‐up after discharge, she had self‐discontinued aspirin but with no recurrent stroke.

FIGURE 2.

(A) Vascular lesions on the back skin as black arrows indicate. (B) Transthoracic contrast echocardiography (TTCE) demonstrating numerous bubbles as indicated by the red arrow in the left atrium and left ventricle after six cardiac cycles. (C and D) Pulmonary angiography showing unremarkable main left and right pulmonary arteries and their branching vessels. (E) Sanger sequencing identifying the deletion of nucleotides c.639_652 in GDF2 exon2 as the red arrow indicates, resulting in a heterozygous frameshift mutation.

3. Discussion

HHT typically presents with mucocutaneous telangiectasia and visceral vascular malformations and is usually diagnosed according to the Curaçao criteria, including (1) recurrent and spontaneous epistaxis; (2) multiple cutaneous and mucosal telangiectasias; (3) internal organ AVMs; and (4) a family history of HHT. A definite diagnosis is established when three or more criteria are met. The presence of two criteria suggests a suspected case [4]. Most cases present no clinical symptoms before adolescence. With age developing, over 90% of patients initially present with epistaxis. Vascular malformations in HHT often involve organs, particularly the lungs, liver, and brain. At least 50% of patients with HHT have pulmonary AVMs (PAVMs). These are often asymptomatic, though severe cases may present with hypoxemia, cardiac failure, paradoxical ischemic strokes, or even brain abscesses [5]. TTCE with bubbles is preferred for screening PAVMs and its sensitivity is approximately 93%–100%. Subsequent contrast‐enhanced chest CT scan or digital subtraction angiography (DSA) is recommended when TTCE is positive. A positive TTCE while with a normal thoracic CT was considered as the evidence of microscopic PAVMs, which are detectable by TTCE but too small to be visualized on CT or angiography [6]. Patients with microscopic PAVMs are recommended to undergo follow‐up thoracic CT every 1–5 years. However, some studies have shown that PAVM enlargement occurs less frequently than previously expected. A longer interval between follow‐up CT scans may be considered; nevertheless, the most appropriate surveillance schedule has not yet been determined and long‐term follow‐up data merit further evaluation [7]. The patient in this case presented with recurrent spontaneous epistaxis, cutaneous telangiectasia, microscopic pulmonary arteriovenous malformations, and a family history with her mother exhibiting identical clinical manifestations, so the case fulfills the diagnostic criteria for HHT.

HHT can cause cerebral hemorrhage by involving cerebrovascular malformations, though some studies revealed a predominance of acute ischemic strokes and transient ischemic attacks over hemorrhage in HHT [8]. Stroke in HHT arises primarily from paradoxical embolism shunting through PAVMs. It has been reported that ischemic stroke incidence per 1000 patient‐year is 9.52 for macroscopic PAVM, 2.08 for microscopic PAVM, and 1.52 for no PAVM. Macroscopic PAVM significantly increases risk of ischemic stroke 9.77‐fold, while microscopic PAVM showed no significant correlation but a slight incidence elevation than no PAVM [9]. In this study, no other significant embolic factors were identified, so the acute cerebral infarction was suspected to be caused by a paradoxical embolism originating from the PAVMs. Currently, there are no specific guidelines about the thrombolytic therapy for acute ischemic stroke in patients with HHT. HHT per se is not considered as a contraindication to thrombolysis except known cerebral AVMs (CAVMs) and active gastrointestinal bleeding [10]. Therefore, patients with HHT who present with acute cerebral infarction may be considered for thrombolytic therapy. This patient acquired improvement in weakness and slurred speech after receiving thrombolytic therapy within the window period.

Ongoing technological progress improves the growing role of gene sequencing in HHT diagnosis. A causative genetic variant has been identified in more than 90% of patients with a clinical HHT diagnosis [4, 11]. It is usually a heterozygous pathogenic variant in one of three primary genes (ENG, ACVRL1, or SMAD4) involved in the TGF‐β pathway. The “second‐hit” model posits that germline heterozygosity confers susceptibility, whereas a local somatic event causes biallelic loss and vascular lesions, with inflammation, shear stress, and trauma as potential triggers [12]. The majority of genotyped HHT patients have loss‐of‐function variants in the genes of ENG, resulting in what is referred to as HHT1 characterized by PAVMs and CAVMs, or ACVRL1 that cause HHT2 where hepatic AVMs are more prevalent. A smaller proportion is attributed to SMAD4 variants, which give rise to a combined syndrome of juvenile polyposis and HHT (JP‐HHT) [13].

Recently, GDF2 variants have been identified as another infrequent cause of HHT, named as HHT‐like syndrome or HHT5, through encoding BMP9, which is an activating ligand in the TGF‐β pathway [14]. Nowadays, only few cases of GDF2‐related HHT have been reported, thus, the complete phenotypic spectrum associated with GDF2 variants remains to be fully elucidated. Its clinical features resembles HHT1, yet characterized by an earlier onset of epistaxis and a distinct topographic distribution of cutaneous vascular lesions, predominantly located on the trunk, upper forelimbs, and head [3]. In 2013, GDF2 was firstly identified as a rare genetic cause for HHT [15]. Wooderchak‐Donahue et al. reported a heterozygous missense variant in GDF2 (c.1282T > C) was detected in three members in 191 individuals with features of HHT and negative for ENG, ACVRL1, and SMAD4 variants through whole genome sequencing [14]. In this work, we identified a heterozygous frameshift mutation of GDF2 gene in a patient with HHT. We suspect the GDF2 variant may be involved in the HHT pathogenesis. Regretfully, the patient's BMP‐9 plasma levels and her families’ gene variants were not detected further, which is a limitation of this study.

4. Conclusion

To our knowledge, this mutation has never been reported before, thereby broadening the known clinical spectrum of HHT associated with GDF2 variants. This finding supports the likelihood of a confirmatory molecular diagnosis for patients who fulfill the Curaçao criteria. Further studies will be essential to elucidate the genotype–phenotype relationship in HHT with GDF2 variants.

Author Contributions

H.Z. contributed to collection of data, data analysis, and manuscript writing. L.Q. contributed to data analysis and manuscript writing. J.J., L.W., X.L., Y.C., X.W., and Q.D. contributed to collection of data and interpretation. J.G. contributed to study design and data analysis. M.S. contributed to study conception, writing – editing. All authors reviewed the manuscript and approved the manuscript for submission.

Funding

This work was supported by the Young Elite Scientists Sponsorship Program by CAST of Jiangsu Province (No. JSTJ‐2025‐300).

Consent

Written informed consent for publication of this case report was obtained from the patient.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data are available upon reasonable request.