# Cerebral dural arteriovenous fistulas in patients with PTEN -related hamartoma tumor syndrome

Anna Gerasimenko, Cyril Mignot, Olivier Naggara, Florence Coulet, Samar Ekram, Solveig Heide, Clarisse Sorato, Maxime Mazowiecki, Chrystelle Colas, Veronica Cusin, et al.

► To cite this version:

Anna Gerasimenko, Cyril Mignot, Olivier Naggara, Florence Coulet, Samar Ekram, et al. Cerebral dural arteriovenous fistulas in patients with PTEN -related hamartoma tumor syndrome. Clinical Genetics, 2024, 10.1111/cge.14515. hal-04487772

HAL Id: hal-04487772

https://hal.sorbonne-universite.fr/hal-04487772

Submitted on 4 Mar 2024

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# Cerebral dural arteriovenous fistulas in patients with PTEN -related hamartoma tumor syndrome

Anna Gerasimenko, Cyril Mignot, Olivier Naggara, Florence Coulet, Samar Ekram, Solveig Heide, Clarisse Sorato, Maxime Mazowiecki, Chrystelle Colas, Veronica Cusin, et al.

► To cite this version:

Anna Gerasimenko, Cyril Mignot, Olivier Naggara, Florence Coulet, Samar Ekram, et al. Cerebral dural arteriovenous fistulas in patients with PTEN -related hamartoma tumor syndrome. Clinical Genetics, 2024, 10.1111/cge.14515. hal-04487772

HAL Id: hal-04487772

https://hal.sorbonne-universite.fr/hal-04487772v1

Submitted on 4 Mar 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
SHORT REPORT

CLINICAL
GENETICS

WILEY

# Cerebral dural arteriovenous fistulas in patients with PTEN-related hamartoma tumor syndrome

Anna Gerasimenko¹,² ID | Cyril Mignot¹,² | Olivier Naggara³,⁴,⁵ |

Florence Coulet⁶,⁷ | Samar Ekram⁸ | Solveig Heide² | Clarisse Sorato² |

Maxime Mazowiecki² | Laurence Perrin⁹ | Chrystelle Colas¹⁰ | Veronica Cusin⁷ |

Frédéric Caux¹¹ | Antoine Dardenne¹² | Salima El Chehadeh¹³ ID |

Alain Verloes⁹,¹⁴ ID | Hélène Maurey¹⁵ | Alexandra Afenjar³¹ | Florence Petit¹⁶ |

Stéphane Barete¹⁷ | Odile Boespflug-Tanguy¹⁸,¹⁹ | Emmanuelle Bourrat²⁰ |

Yline Capri⁹ | Viorica Ciorna²¹ | Wallid Deb²² | Diane Doummar²³ |

Alexandre Perrier⁶,⁷ | Alexis Guédon²⁴ | Emmanuel Houdart²⁴ |

Bertrand Isidor²² | Marie-Line Jacquemont²⁵ | Camille Buffet²⁶ |

Sandra Mercier²² | Sandrine Passemard²⁷ | Audrey Riquet²⁸ | Lyse Ruaud⁹,¹⁴ ID |

Elise Schaefer²⁹ | Delphine Heron¹,² | Annouk Bisdorff²⁴,³⁰ | Patrick R. Benusiglio⁶,⁷

Correspondence

Anna Gerasimenko, Département de
Génétique médicale, Hôpital de la Pitié
Salpétrière, AP-HP, Sorbonne Université.
47-83 boulevard de l'hôpital, 75013 Paris,
France.

Email: anna.gerasimenko@aphp.fr

Abstract

Central nervous system (CNS) dural arteriovenous fistulas (DAVF) have been reported in *PTEN*-related hamartoma tumor syndrome (PHTS). However, PHTS-associated DAVF remain an underexplored field of the PHTS clinical landscape. Here, we studied cases with a *PTEN* pathogenic variant identified between 2007 and 2020 in our laboratory (n = 58), and for whom brain imaging was available. Two patients had DAVF (2/58, 3.4%), both presenting at advanced stages: a 34-year-old man with a left lateral sinus DAVF at immediate risk of hemorrhage, and a 21-year-old woman with acute intracranial hypertension due to a torcular DAVF. Interestingly, not all patients had 3D TOF/MRA, the optimal sequences to detect DAVF. Early diagnosis of DAVF can be lifesaving, and is easier to treat compared to developed, proliferative, or complex lesions. As a result, one should consider brain MRI with 3D TOF/MRA in PHTS patients at genetic diagnosis, with subsequent surveillance on a case-by-case basis.

KEYWORDS

cancer genetics, cerebrovascular disorders, Cowden syndrome, DAVF, dural fistula, genetic predisposition to disease, MRI, PHTS, PTEN

<figure><img src="image_2.png" /></figure>
SHORT REPORT

CLINICAL
GENETICS

WILEY

# Cerebral dural arteriovenous fistulas in patients with PTEN-related hamartoma tumor syndrome

Anna Gerasimenko¹,² ID | Cyril Mignot¹,² | Olivier Naggara³,⁴,⁵ |

Florence Coulet⁶,⁷ | Samar Ekram⁸ | Solveig Heide² | Clarisse Sorato² |

Maxime Mazowiecki² | Laurence Perrin⁹ | Chrystelle Colas¹⁰ | Veronica Cusin⁷ |

Frédéric Caux¹¹ | Antoine Dardenne¹² | Salima El Chehadeh¹³ ID |

Alain Verloes⁹,¹⁴ ID | Hélène Maurey¹⁵ | Alexandra Afenjar³¹ | Florence Petit¹⁶ |

Stéphane Barete¹⁷ | Odile Boespflug-Tanguy¹⁸,¹⁹ | Emmanuelle Bourrat²⁰ |

Yline Capri⁹ | Viorica Ciorna²¹ | Wallid Deb²² | Diane Doummar²³ |

Alexandre Perrier⁶,⁷ | Alexis Guédon²⁴ | Emmanuel Houdart²⁴ |

Bertrand Isidor²² | Marie-Line Jacquemont²⁵ | Camille Buffet²⁶ |

Sandra Mercier²² | Sandrine Passemard²⁷ | Audrey Riquet²⁸ | Lyse Ruaud⁹,¹⁴ ID |

Elise Schaefer²⁹ | Delphine Heron¹,² | Annouk Bisdorff²⁴,³⁰ | Patrick R. Benusiglio⁶,⁷

Correspondence

Anna Gerasimenko, Département de
Génétique médicale, Hôpital de la Pitié
Salpétrière, AP-HP, Sorbonne Université.
47-83 boulevard de l'hôpital, 75013 Paris,
France.

Email: anna.gerasimenko@aphp.fr

Abstract

Central nervous system (CNS) dural arteriovenous fistulas (DAVF) have been reported in *PTEN*-related hamartoma tumor syndrome (PHTS). However, PHTS-associated DAVF remain an underexplored field of the PHTS clinical landscape. Here, we studied cases with a *PTEN* pathogenic variant identified between 2007 and 2020 in our laboratory (n = 58), and for whom brain imaging was available. Two patients had DAVF (2/58, 3.4%), both presenting at advanced stages: a 34-year-old man with a left lateral sinus DAVF at immediate risk of hemorrhage, and a 21-year-old woman with acute intracranial hypertension due to a torcular DAVF. Interestingly, not all patients had 3D TOF/MRA, the optimal sequences to detect DAVF. Early diagnosis of DAVF can be lifesaving, and is easier to treat compared to developed, proliferative, or complex lesions. As a result, one should consider brain MRI with 3D TOF/MRA in PHTS patients at genetic diagnosis, with subsequent surveillance on a case-by-case basis.

KEYWORDS

cancer genetics, cerebrovascular disorders, Cowden syndrome, DAVF, dural fistula, genetic predisposition to disease, MRI, PHTS, PTEN

<figure><img src="image_2.png" /></figure>
# 1 | INTRODUCTION

PTEN-related hamartoma tumor syndrome (PHTS) is an overgrowth and cancer susceptibility syndrome associated with heterozygous germline pathogenic variants (PV) in the *PTEN* gene. The umbrella term of PHTS includes overlapping syndromes referred to as Cowden (OMIM #158350) macrocephaly/autism (OMIM #605309), and Bannayan-Riley-Ruvalcaba syndromes. PHTS is characterized by macrocephaly, and manifestations of variable penetrance such as neurodevelopmental delay, breast, endometrial, thyroid and renal cancer, colorectal polyps, skin and mucosal papillomas, dysplastic ganglioma of the cerebellum (Lhermitte-Duclos disease), as well as extracerebral and cerebral vascular anomalies.<sup>1,2</sup>

Benign developmental venous anomalies are the most frequent cerebral vascular anomalies.<sup>3,4</sup> Dural arteriovenous fistulas (DAVF), which are the focus of this manuscript, are also reported, sometimes with dramatic outcomes (Table S1). DAVF consist of arteriovenous communications between the meningeal arteries and dural venous sinuses and/or subarachnoid veins. In the general population, they are rare, with an estimated annual incidence of 0.16 per 100.000, and occur at a median age of 64 years (range 24–83),<sup>5</sup> in most cases, with no known etiology. Annual rate of neurological events, such as hemorrhagic stroke, or acute edema, is 15%.<sup>6</sup> In PHTS, DAVFs are likely caused by the loss of inhibition of PTEN on the mTOR-pathway,<sup>1</sup> triggering angiogenesis through secretion of angioproliferative factors.

DAVFs have been described in several PHTS patients. Prats-Sanchez et al. reported a 46 year-old man with PHTS and an acute left anterior temporal hemorrhage associated with a left parasagittal subarachnoid hemorrhage.<sup>7</sup> Imaging revealed an advanced lesion with multiple dural and epidural high-flow arteriovenous fistulas. Despite multiple procedures of embolization, the patient died of status epilepticus. As for case series, Tan et al. observed one right posterior DAVF with bilateral transverse sinus occlusion in a 9-year-old boy, out of nine PHTS patients who had brain MRI with contrast.<sup>8,9</sup> Dhamija et al. studied 22 patients with suspected PHTS, of which seven were proven PTEN PV carriers.<sup>3</sup> Two had evidence of DAVF on brain MRI.

To get more insight into DAVF prevalence and manifestations in PHTS, we retrospectively studied brain imaging in 58 patients with a variety of neurodevelopment and tumor phenotypes.

# 2 | MATERIALS AND METHODS

All cases in whom a *PTEN* (likely) pathogenic variant (L)PV), according to ACMG criteria,<sup>10</sup> had been identified at the Cancer and Vascular Genetics laboratory, Sorbonne Université, and for whom brain imaging was available, were selected. Whenever possible, we also included first-degree relatives of index cases who had been tested elsewhere and obligate carriers. Patients' images were reviewed by an expert neuroradiologist (A.B.). A second expert reviewed images of the two patients with DAVF (O.N.).

All patients (or their legal representatives) had signed a genetic testing informed consent form, mentioning a potential use of their

DNA/data for research purposes related to their phenotype. An information note for this study with a possibility to opt out was sent to patients. Given the retrospective nature of the study, French law did not require ethics committee approval.

# 3 | RESULTS

## 3.1 | Genetics

We identified 58 PTEN (L)PV carriers from 50 families. There were 39 males and 19 females. Brain MRI was available in 57 cases, CT angiography (CTA) in one. Mean age at PHTS diagnosis was 16 years (range 6 months–58 years). Primary reported cause for genetic exploration was neurodevelopmental delay (n = 24), cascade testing (n = 13), malignant or benign tumor (n = 7, e.g., breast cancer or colorectal polyps), macrocephaly (n = 4), LDD (n = 4), and soft-tissue hamartoma (n = 1). It was unknown in four cases. One individual was an obligate carrier. Among the PTEN PV, 14 were frameshift (n = 18 patients), 10 nonsense (n = 13), 19 missense (n = 22), 3 splicing (n = 3), and 2 were intragenic deletions (n = 2) (Table S2).

These 58 cases were part of a series of 137 carriers identified in our laboratory. Reason for brain imaging was documented in 56/58 cases: macrocephaly and/or neurodevelopmental delay (n = 40), peripheral vascular malformations (n = 1), routine imaging following PHTS diagnosis (n = 9), and CNS symptoms (e.g., ataxia, hypoacousia, headaches, seizures, n = 6). It was unknown in two cases.

## 3.2 | Brain imaging and DAVF

The brain MRI protocol included at least one fluid attenuated inversion recovery (FLAIR) or Fast Spin Echo sequence (n = 56/57), and in most patients either gradient echo T2 (T2*) or susceptibility-weighted imaging (n = 45/57). However, 3D time-of-flight (TOF)/MRA images were only performed in 6 of 57 patients. 3D TOF/MRA are the optimal sequences to detect high-flow DAVF, which are characterized by a hyperintense signal within intracranial venous structures. As for contrast-enhanced images, they had been performed in 20 of 57 patients. They provide indirect evidence of DAVF since they show venous congestion, illustrated by enlarged tortuous pial veins over the cerebral or cerebellar convexities. One patient underwent CTA.

Two patients had DAVF (2/58, 3.4%). In both cases, DAVF was diagnosed at advanced stages, strongly suggesting that earlier diagnosis would have prevented severe clinical manifestations.

The first patient was a 34-year-old man with macrocephaly and learning difficulties who presented to the emergency department after a first episode of seizures (Patient 58, Table S2). Brain MRI, including T2 FLAIR and angiography, showed multiple DAVFs, in particular a right lateral sinus DAVF with significant reflux into the cortical veins, posing a substantial risk of subsequent brain hemorrhage (Figure 1A–D). The patient underwent several endovascular embolizations. He died aged 42 after accidental leakage of the embolization
# 1 | INTRODUCTION

PTEN-related hamartoma tumor syndrome (PHTS) is an overgrowth and cancer susceptibility syndrome associated with heterozygous germline pathogenic variants (PV) in the *PTEN* gene. The umbrella term of PHTS includes overlapping syndromes referred to as Cowden (OMIM #158350) macrocephaly/autism (OMIM #605309), and Bannayan-Riley-Ruvalcaba syndromes. PHTS is characterized by macrocephaly, and manifestations of variable penetrance such as neurodevelopmental delay, breast, endometrial, thyroid and renal cancer, colorectal polyps, skin and mucosal papillomas, dysplastic ganglioma of the cerebellum (Lhermitte-Duclos disease), as well as extracerebral and cerebral vascular anomalies.<sup>1,2</sup>

Benign developmental venous anomalies are the most frequent cerebral vascular anomalies.<sup>3,4</sup> Dural arteriovenous fistulas (DAVF), which are the focus of this manuscript, are also reported, sometimes with dramatic outcomes (Table S1). DAVF consist of arteriovenous communications between the meningeal arteries and dural venous sinuses and/or subarachnoid veins. In the general population, they are rare, with an estimated annual incidence of 0.16 per 100.000, and occur at a median age of 64 years (range 24–83),<sup>5</sup> in most cases, with no known etiology. Annual rate of neurological events, such as hemorrhagic stroke, or acute edema, is 15%.<sup>6</sup> In PHTS, DAVFs are likely caused by the loss of inhibition of PTEN on the mTOR-pathway,<sup>1</sup> triggering angiogenesis through secretion of angioproliferative factors.

DAVFs have been described in several PHTS patients. Prats-Sanchez et al. reported a 46 year-old man with PHTS and an acute left anterior temporal hemorrhage associated with a left parasagittal subarachnoid hemorrhage.<sup>7</sup> Imaging revealed an advanced lesion with multiple dural and epidural high-flow arteriovenous fistulas. Despite multiple procedures of embolization, the patient died of status epilepticus. As for case series, Tan et al. observed one right posterior DAVF with bilateral transverse sinus occlusion in a 9-year-old boy, out of nine PHTS patients who had brain MRI with contrast.<sup>8,9</sup> Dhamija et al. studied 22 patients with suspected PHTS, of which seven were proven PTEN PV carriers.<sup>3</sup> Two had evidence of DAVF on brain MRI.

To get more insight into DAVF prevalence and manifestations in PHTS, we retrospectively studied brain imaging in 58 patients with a variety of neurodevelopment and tumor phenotypes.

# 2 | MATERIALS AND METHODS

All cases in whom a *PTEN* (likely) pathogenic variant (L)PV), according to ACMG criteria,<sup>10</sup> had been identified at the Cancer and Vascular Genetics laboratory, Sorbonne Université, and for whom brain imaging was available, were selected. Whenever possible, we also included first-degree relatives of index cases who had been tested elsewhere and obligate carriers. Patients' images were reviewed by an expert neuroradiologist (A.B.). A second expert reviewed images of the two patients with DAVF (O.N.).

All patients (or their legal representatives) had signed a genetic testing informed consent form, mentioning a potential use of their

DNA/data for research purposes related to their phenotype. An information note for this study with a possibility to opt out was sent to patients. Given the retrospective nature of the study, French law did not require ethics committee approval.

# 3 | RESULTS

## 3.1 | Genetics

We identified 58 PTEN (L)PV carriers from 50 families. There were 39 males and 19 females. Brain MRI was available in 57 cases, CT angiography (CTA) in one. Mean age at PHTS diagnosis was 16 years (range 6 months–58 years). Primary reported cause for genetic exploration was neurodevelopmental delay (n = 24), cascade testing (n = 13), malignant or benign tumor (n = 7, e.g., breast cancer or colorectal polyps), macrocephaly (n = 4), LDD (n = 4), and soft-tissue hamartoma (n = 1). It was unknown in four cases. One individual was an obligate carrier. Among the PTEN PV, 14 were frameshift (n = 18 patients), 10 nonsense (n = 13), 19 missense (n = 22), 3 splicing (n = 3), and 2 were intragenic deletions (n = 2) (Table S2).

These 58 cases were part of a series of 137 carriers identified in our laboratory. Reason for brain imaging was documented in 56/58 cases: macrocephaly and/or neurodevelopmental delay (n = 40), peripheral vascular malformations (n = 1), routine imaging following PHTS diagnosis (n = 9), and CNS symptoms (e.g., ataxia, hypoacousia, headaches, seizures, n = 6). It was unknown in two cases.

## 3.2 | Brain imaging and DAVF

The brain MRI protocol included at least one fluid attenuated inversion recovery (FLAIR) or Fast Spin Echo sequence (n = 56/57), and in most patients either gradient echo T2 (T2*) or susceptibility-weighted imaging (n = 45/57). However, 3D time-of-flight (TOF)/MRA images were only performed in 6 of 57 patients. 3D TOF/MRA are the optimal sequences to detect high-flow DAVF, which are characterized by a hyperintense signal within intracranial venous structures. As for contrast-enhanced images, they had been performed in 20 of 57 patients. They provide indirect evidence of DAVF since they show venous congestion, illustrated by enlarged tortuous pial veins over the cerebral or cerebellar convexities. One patient underwent CTA.

Two patients had DAVF (2/58, 3.4%). In both cases, DAVF was diagnosed at advanced stages, strongly suggesting that earlier diagnosis would have prevented severe clinical manifestations.

The first patient was a 34-year-old man with macrocephaly and learning difficulties who presented to the emergency department after a first episode of seizures (Patient 58, Table S2). Brain MRI, including T2 FLAIR and angiography, showed multiple DAVFs, in particular a right lateral sinus DAVF with significant reflux into the cortical veins, posing a substantial risk of subsequent brain hemorrhage (Figure 1A–D). The patient underwent several endovascular embolizations. He died aged 42 after accidental leakage of the embolization
**FIGURE 1** Dural arteriovenous fistula and *PTEN*-related hamartoma tumor syndrome. (A-D) 34-year-old male. Serpiginous dilated cortical veins are seen as flow voids on T2 FLAIR (A) and after contrast (B) in the posterior fossa and temporal lobe, associated with an enlarged right lateral sinus. 3D-TOF images (C, D) show a high-flow arteriovenous shunt with abnormal early venous filling of cerebellar cortical veins and lateral sinus. (E-G) 21-year-old female. Computed tomography and angiography show left lateral ventricle intraventricular hemorrhage and longitudinal cerebral fissure subdural hematoma (E), associated with diffuse bilateral white matter hypodensity. Angiography (F-G): abnormal torcular opacification with superior sagittal sinus retrograde opacification, confirming the presence of a torcular DAVF.

<figure><img src="image_3.png" /></figure>

product during a procedure. He was an obligate *PTEN* PV carrier since (i) his sister, the index case referred to clinical cancer genetics with a history of bilateral breast cancer, thyroidectomy, and macrocephaly, carried the p.His118Profs*8* *PTEN* PV, and (ii) the PV was identified in the patient's three children.

The second patient was a 21-year-old woman with intracranial hypertension symptoms (Patient 46, Table S2). A DAVF of the torcular was observed on CTA, alongside diffuse vasogenic edema and intracranial hemorrhage (Figure 1E-G). Treatment consisted of DAVF endovascular occlusion. She subsequently developed epilepsy, which was considered a sequela of the DAVF. Other PHTS features were a multinodular goiter, labial papillomatosis, and macrocephaly.

4 | DISCUSSION

DAVFs have been reported in at least 10 patients with PHTS to date (Table S1) with a median age at diagnosis of 27 years among the five patients with in whom age is documented (range 9-46). In this study, we report on brain imaging in a series of 58 PHTS cases ascertained

mainly through cancer and neurodevelopment phenotypes: two had DAVF at ages 21 and 34 years (3.4%).

In both our cases, DAVF presented at advanced stages and were associated with severe clinical manifestations; seizures and intracranial hypertension respectively. DAVF also had long-term consequences in both. The first patient underwent successive embolization procedures, while the second had secondary epilepsy. It is likely that earlier DAVF diagnosis and treatment would have led to improved outcomes.

Actual DAVF prevalence in PHTS is hard to estimate. Selection bias in our study might have led to prevalence overestimation, since imaging was, in a minority of cases, performed for reasons potentially associated with DAVF. Admittedly, the two reported DAVF cases did present with acute of subacute symptoms, that is, seizures, headaches. On the other hand, only a minority of brain MRI included optimal sequences for DAVF detection. Six out of 57 and 20 of 57 included 3D TOF/MRA and contrast-enhanced sequences, respectively. 3D TOF/MRA are the best sequences to identify DAVF, with an estimated sensitivity of 80%-90%.¹¹,¹² DAVF-albeit asymptomatic or paucisymptomatic at the time of study—might thus have been
**FIGURE 1** Dural arteriovenous fistula and *PTEN*-related hamartoma tumor syndrome. (A-D) 34-year-old male. Serpiginous dilated cortical veins are seen as flow voids on T2 FLAIR (A) and after contrast (B) in the posterior fossa and temporal lobe, associated with an enlarged right lateral sinus. 3D-TOF images (C, D) show a high-flow arteriovenous shunt with abnormal early venous filling of cerebellar cortical veins and lateral sinus. (E-G) 21-year-old female. Computed tomography and angiography show left lateral ventricle intraventricular hemorrhage and longitudinal cerebral fissure subdural hematoma (E), associated with diffuse bilateral white matter hypodensity. Angiography (F-G): abnormal torcular opacification with superior sagittal sinus retrograde opacification, confirming the presence of a torcular DAVF.

<figure><img src="image_3.png" /></figure>

product during a procedure. He was an obligate *PTEN* PV carrier since (i) his sister, the index case referred to clinical cancer genetics with a history of bilateral breast cancer, thyroidectomy, and macrocephaly, carried the p.His118Profs*8* *PTEN* PV, and (ii) the PV was identified in the patient's three children.

The second patient was a 21-year-old woman with intracranial hypertension symptoms (Patient 46, Table S2). A DAVF of the torcular was observed on CTA, alongside diffuse vasogenic edema and intracranial hemorrhage (Figure 1E-G). Treatment consisted of DAVF endovascular occlusion. She subsequently developed epilepsy, which was considered a sequela of the DAVF. Other PHTS features were a multinodular goiter, labial papillomatosis, and macrocephaly.

4 | DISCUSSION

DAVFs have been reported in at least 10 patients with PHTS to date (Table S1) with a median age at diagnosis of 27 years among the five patients with in whom age is documented (range 9-46). In this study, we report on brain imaging in a series of 58 PHTS cases ascertained

mainly through cancer and neurodevelopment phenotypes: two had DAVF at ages 21 and 34 years (3.4%).

In both our cases, DAVF presented at advanced stages and were associated with severe clinical manifestations; seizures and intracranial hypertension respectively. DAVF also had long-term consequences in both. The first patient underwent successive embolization procedures, while the second had secondary epilepsy. It is likely that earlier DAVF diagnosis and treatment would have led to improved outcomes.

Actual DAVF prevalence in PHTS is hard to estimate. Selection bias in our study might have led to prevalence overestimation, since imaging was, in a minority of cases, performed for reasons potentially associated with DAVF. Admittedly, the two reported DAVF cases did present with acute of subacute symptoms, that is, seizures, headaches. On the other hand, only a minority of brain MRI included optimal sequences for DAVF detection. Six out of 57 and 20 of 57 included 3D TOF/MRA and contrast-enhanced sequences, respectively. 3D TOF/MRA are the best sequences to identify DAVF, with an estimated sensitivity of 80%-90%.¹¹,¹² DAVF-albeit asymptomatic or paucisymptomatic at the time of study—might thus have been
<table><caption>TABLE 1 Propositions for brain neuroimaging in PTEN-related hamartoma tumor syndrome (PHTS).</caption><thead><tr><td>Imaging modality</td><td>Sequences</td><td>Starting age</td><td>Long-term surveillance</td></tr></thead><tbody><tr><td>Brain MRI</td><td>T2 FLAIR<br/>T2*/susceptibility-weighted imaging<br/>Large 3D TOF/MRA</td><td>At PHTS diagnosis</td><td>Case-by-case basis<br/>Attention to symptoms of intracranial hypertension</td></tr></tbody></table>

missed in our series. In addition, none of our cases had PTEN germline testing specifically because of CNS DAVF. What we mean here is that neuroradiologists and neurologists rarely refer their patients with DAVF for genetic testing, as there are no data on PHTS prevalence in this context. One could imagine that a subset of PHTS cases do have DAVF as the main phenotype (alongside macrocephaly), and that these cases are rarely identified, leading to prevalence underestimation.

Given the potentially devastating consequences of DAVF in PHTS,¹³ one should consider brain MRI at PHTS diagnosis in all patients. Early diagnosis of DAVF is paramount, given the potential for cure using mainly endovascular approaches.¹⁴ Our study highlights the necessity for a specific protocol sensitive to DAVF detection. MRI should include at least 3D TOF/MRA sequences in addition to T2 FLAIR and susceptibility-weighted imaging (Table 1). Another advantage of routine brain MRI would be the identification of other PHTS-related CNS abnormalities (Lhermitte-Duclos disease or LDD, Arnold-Chiari malformations).⁴ We do acknowledge the risk of overdiagnosis should our proposition be adopted, for example of asymptomatic LDD. We also recognize that systematic MRI might induce anxiety in some patients.

Subsequent surveillance should be discussed on a case-by-case basis, as there is the possibility of new lesions appearing with time. Naturally, one must be attentive to symptoms suggestive of intracranial hypertension, such as headache, pulsatile tinnitus, or double vision. Prospective, multinational studies are warranted to better define DAVF prevalence and screening indications and modalities. The physiopathology of DAVF should also be investigated, as it could lead to targeted therapy perspectives for affected cases.

## AUTHOR CONTRIBUTIONS

Study conception and design: PB, CM, Data collection: all authors; Analysis and interpretation of results: AG, Manuscript preparation: AG, CM, PB, Supervision: PB, CM, Reanalysis of brain imaging: AB, ON. The manuscript has been read and approved by all authors. All persons who satisfied authorship criteria are listed.

## AFFILIATIONS

¹Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpital la Pitié Salpêtrière, Paris, France

²APHP.Sorbonne Université, GH Pitié Salpêtrière et Trousseau, Service de Génétique, Centre de référence "déficiences intellectuelles de causes rares", Paris, France

³Université Paris Cité, INSERM UMR 1266 IMA-BRAIN, GHU Paris, Service de Neuroradiologie, Paris, France

⁴APHP.Université Paris Cité, Institut Imagine, INSERM U1000, Hôpital Necker - Enfants Malades, Service de Radiologie Pédiatrique UMR 1163, Paris, France

⁵APHP.Université Paris Cité, Centre Français pour les AVC Pédiatriques, INSERM U894, Paris, France

⁶Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 et SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Paris, France

⁷Département de Génétique Médicale, APHP.Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France

⁸Department of Medical Genetics, College of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia

⁹APHP.Université Paris Cité, Hôpital Robert-Debré, Service de Génétique, Paris, France

¹⁰Université Paris Sciences Lettres, Institut Curie, Service de Génétique, Paris, France

¹¹GH Paris Seine-Saint-Denis, INSERM UMR1125, Service de Dermatologie, Bobigny, France

¹²APHP.Sorbonne Université, Hôpital Saint-Antoine, Oncologie Digestive, Paris, France

¹³Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Institut de Génétique Médicale d'Alsace (IGMA), Service de Génétique Médicale, Strasbourg, France

¹⁴INSERM U1141, Hôpital Robert-Debré, Paris, France

¹⁵Hôpitaux Universitaires Paris Saclay, Hôpital Bicêtre, Centre National de Référence pour les Maladies Rares du Cerveau et de la Moelle Épinière, Service de Neurologie Pédiatrique, Le Kremlin Bicêtre, France

¹⁶APHP.Sorbonne Université, GH Trousseau, Département de Génétique, Centre de référence "déficiences intellectuelles de causes rares", Paris, France

¹⁷Université de Lille, ULR7364 RADEME, CHU Lille, Clinique de Génétique, Guy Fontaine, Lille, France

¹⁸APHP.Sorbonne Université, GH Pitié-Salpêtrière, Service de Dermatologie, Paris, France

¹⁹APHP.Université Paris Cité, Hôpital Robert Debré, Service de Neuropédiatrie, Paris, France

²⁰Université Paris Cité, NeuroDiderot, UMR 1141, Paris, France

²¹Hôpital-Saint Louis, CRMR MAGEC Nord St Louis, Service de Dermatologie, Paris, France

²²CHR Metz-Thionville, Service de Génétique, Metz, France

²³CHU Nantes, Service de Génétique Médicale, Nantes, France

²⁴APHP.Sorbonne Université, CHU Armand Trousseau, Service de Neuropédiatrie-Pathologie du développement, Centre de Référence Maladies Rares Neurogénétiques, Paris, France
<table><caption>TABLE 1 Propositions for brain neuroimaging in PTEN-related hamartoma tumor syndrome (PHTS).</caption><thead><tr><td>Imaging modality</td><td>Sequences</td><td>Starting age</td><td>Long-term surveillance</td></tr></thead><tbody><tr><td>Brain MRI</td><td>T2 FLAIR<br/>T2*/susceptibility-weighted imaging<br/>Large 3D TOF/MRA</td><td>At PHTS diagnosis</td><td>Case-by-case basis<br/>Attention to symptoms of intracranial hypertension</td></tr></tbody></table>

missed in our series. In addition, none of our cases had PTEN germline testing specifically because of CNS DAVF. What we mean here is that neuroradiologists and neurologists rarely refer their patients with DAVF for genetic testing, as there are no data on PHTS prevalence in this context. One could imagine that a subset of PHTS cases do have DAVF as the main phenotype (alongside macrocephaly), and that these cases are rarely identified, leading to prevalence underestimation.

Given the potentially devastating consequences of DAVF in PHTS,¹³ one should consider brain MRI at PHTS diagnosis in all patients. Early diagnosis of DAVF is paramount, given the potential for cure using mainly endovascular approaches.¹⁴ Our study highlights the necessity for a specific protocol sensitive to DAVF detection. MRI should include at least 3D TOF/MRA sequences in addition to T2 FLAIR and susceptibility-weighted imaging (Table 1). Another advantage of routine brain MRI would be the identification of other PHTS-related CNS abnormalities (Lhermitte-Duclos disease or LDD, Arnold-Chiari malformations).⁴ We do acknowledge the risk of overdiagnosis should our proposition be adopted, for example of asymptomatic LDD. We also recognize that systematic MRI might induce anxiety in some patients.

Subsequent surveillance should be discussed on a case-by-case basis, as there is the possibility of new lesions appearing with time. Naturally, one must be attentive to symptoms suggestive of intracranial hypertension, such as headache, pulsatile tinnitus, or double vision. Prospective, multinational studies are warranted to better define DAVF prevalence and screening indications and modalities. The physiopathology of DAVF should also be investigated, as it could lead to targeted therapy perspectives for affected cases.

## AUTHOR CONTRIBUTIONS

Study conception and design: PB, CM, Data collection: all authors; Analysis and interpretation of results: AG, Manuscript preparation: AG, CM, PB, Supervision: PB, CM, Reanalysis of brain imaging: AB, ON. The manuscript has been read and approved by all authors. All persons who satisfied authorship criteria are listed.

## AFFILIATIONS

¹Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpital la Pitié Salpêtrière, Paris, France

²APHP.Sorbonne Université, GH Pitié Salpêtrière et Trousseau, Service de Génétique, Centre de référence "déficiences intellectuelles de causes rares", Paris, France

³Université Paris Cité, INSERM UMR 1266 IMA-BRAIN, GHU Paris, Service de Neuroradiologie, Paris, France

⁴APHP.Université Paris Cité, Institut Imagine, INSERM U1000, Hôpital Necker - Enfants Malades, Service de Radiologie Pédiatrique UMR 1163, Paris, France

⁵APHP.Université Paris Cité, Centre Français pour les AVC Pédiatriques, INSERM U894, Paris, France

⁶Sorbonne Université, INSERM, Unité Mixte de Recherche Scientifique 938 et SIRIC CURAMUS, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Paris, France

⁷Département de Génétique Médicale, APHP.Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France

⁸Department of Medical Genetics, College of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia

⁹APHP.Université Paris Cité, Hôpital Robert-Debré, Service de Génétique, Paris, France

¹⁰Université Paris Sciences Lettres, Institut Curie, Service de Génétique, Paris, France

¹¹GH Paris Seine-Saint-Denis, INSERM UMR1125, Service de Dermatologie, Bobigny, France

¹²APHP.Sorbonne Université, Hôpital Saint-Antoine, Oncologie Digestive, Paris, France

¹³Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Institut de Génétique Médicale d'Alsace (IGMA), Service de Génétique Médicale, Strasbourg, France

¹⁴INSERM U1141, Hôpital Robert-Debré, Paris, France

¹⁵Hôpitaux Universitaires Paris Saclay, Hôpital Bicêtre, Centre National de Référence pour les Maladies Rares du Cerveau et de la Moelle Épinière, Service de Neurologie Pédiatrique, Le Kremlin Bicêtre, France

¹⁶APHP.Sorbonne Université, GH Trousseau, Département de Génétique, Centre de référence "déficiences intellectuelles de causes rares", Paris, France

¹⁷Université de Lille, ULR7364 RADEME, CHU Lille, Clinique de Génétique, Guy Fontaine, Lille, France

¹⁸APHP.Sorbonne Université, GH Pitié-Salpêtrière, Service de Dermatologie, Paris, France

¹⁹APHP.Université Paris Cité, Hôpital Robert Debré, Service de Neuropédiatrie, Paris, France

²⁰Université Paris Cité, NeuroDiderot, UMR 1141, Paris, France

²¹Hôpital-Saint Louis, CRMR MAGEC Nord St Louis, Service de Dermatologie, Paris, France

²²CHR Metz-Thionville, Service de Génétique, Metz, France

²³CHU Nantes, Service de Génétique Médicale, Nantes, France

²⁴APHP.Sorbonne Université, CHU Armand Trousseau, Service de Neuropédiatrie-Pathologie du développement, Centre de Référence Maladies Rares Neurogénétiques, Paris, France
<sup>25</sup>APHPUniversité Paris Cité, Service de Neuroradiologie
Diagnostique et Interventionnelle, CHU Lariboisière, Paris, France

<sup>26</sup>Service de Génétique Médicale, CHU Ste-Justine, Montréal, Canada

<sup>27</sup>APHP.Sorbonne Université, Service de pathologies Thyroïdiennes et Tumorales Endocrines, Hôpital La Pitié-Salpêtrière, Paris, France

<sup>28</sup>APHPUniversité Paris Cité, Inserm UMR 1141,
NeuroDiderotFrance, Hôpital Robert Debré, Service de Neurologie
Pédiatrique, DMU INOV-RDB, Paris, France

<sup>29</sup>Département de Neurologie Pédiatrique, GHICL, Hôpital
Saint Vincent de Paul, Lille, France

<sup>30</sup>CHU de Strasbourg, Service de Génétique Médicale, IGMA,
Strasbourg, France

<sup>31</sup>Groupe d'Étude Interdisciplinaire pour les Malformations
Vasculaires, Hôpitaux Lariboisière, Bichat, Saint-Joseph, Clinique
Alma, Paris, France

## ACKNOWLEDGMENTS

We would like to thank the patients and their families for their invaluable contribution to this work.

## CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

## PEER REVIEW

The peer review history for this article is available at https://www.
webofscience.com/api/gateway/wos/peer-review/10.1111/cge.
14515.

## DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

## ORCID

Anna Gerasimenko https://orcid.org/0000-0001-7873-0992

Salima El Chehadeh https://orcid.org/0000-0003-1613-6570

Alain Verloes https://orcid.org/0000-0003-4819-0264

Lyse Ruaud https://orcid.org/0000-0003-4940-5896

## REFERENCES

1. Marsh DJ, Kum JB, Lunetta KL, et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. *Hum Mol Genet.* 1999;8(8):1461-1472. doi:10.1093/hmg/8.8.1461

2. Hendricks LAJ, Hoogerbrugge N, Mensenkamp AR, et al. Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome. *J Natl Cancer Inst.* 2023;115(1):93-103. doi:10.1093/jnci/djac188

3. Dhamija R, Weindling SM, Porter AB, Hu LS, Wood CP, Hoxworth JM. Neuroimaging abnormalities in patients with Cowden syndrome: retrospective single-center study. *Neurol Clin Pract.* 2018; 8(3):207-213. doi:10.1212/CPJ.0000000000000463

4. Lok C, Viseux V, Avril MF, et al. Brain magnetic resonance imaging in patients with Cowden syndrome. *Medicine* (Baltimore). 2005;84(2): 129-136. doi:10.1097/01.md.0000158792.24888.d2

5. Al-Shahi R, Bhattacharya JJ, Currie DG, et al. Prospective, population-based detection of intracranial vascular malformations in adults. *Stroke*. 2003;34(5):1163-1169. doi:10.1161/01.STR.0000069018.90456.C9

6. Koch MJ, Stapleton CJ, Guniganti R, et al. Outcome following hemorrhage from cranial dural arteriovenous fistulas. *Stroke*. 2021;52(10):e610-e613. doi:10.1161/STROKEAHA.121.034707

7. Prats-Sánchez LA, Hervás-García JV, Becerra JL, et al. Multiple intracranial arteriovenous fistulas in Cowden syndrome. *J Stroke Cerebrovasc Dis.* 2016;25(6):e93-e94. doi:10.1016/j.jstrokecerebrovasdis.2016.03.048

8. Srinivasa RN, Burrows PE. Dural arteriovenous malformation in a child with Bannayan-Riley-Ruvalcaba syndrome. *AJNR Am J Neuroradiol.* 2006;27(9):1927-1929.

9. Tan WH, Baris HN, Burrows PE, et al. The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management. *J Med Genet.* 2007;44(9):594-602. doi:10.1136/jmg.2007.048934

10. Mester JL, Ghosh R, Pesaran T, et al. Gene-specific criteria for PTEN variant curation: recommendations from the ClinGen PTEN expert panel. *Hum Mutat.* 2018;39(11):1581-1592. doi:10.1002/humu.23636

11. Azuma M, Hirai T, Shigematsu Y, et al. Evaluation of intracranial Dural arteriovenous fistulas: comparison of unenhanced 3T 3D time-of-flight MR angiography with digital subtraction angiography. *Magn Reson Med Sci.* 2015;14(4):285-293. doi:10.2463/mrms.2014-0120

12. Ryu B, Sato S, Mochizuki T, Niimi Y. Relative signal intensity on time-of-flight magnetic resonance angiography as a novel indicator of aggressive presentation of intracranial dural arteriovenous fistulas. *J Cereb Blood Flow Metab.* 2021;41(6):1428-1436. doi:10.1177/0271678X20969218

13. Kobayashi A, Al-Shahi SR. Prognosis and treatment of intracranial dural arteriovenous fistulae: a systematic review and meta-analysis. *Int J Stroke.* 2014;9(6):670-677. doi:10.1111/ijs.12337

14. Baharvahdat H, Ooi YC, Kim WJ, Mowla A, Coon AL, Colby GP. Updates in the management of cranial dural arteriovenous fistula. *Stroke Vasc Neurol.* 2020;5(1):50-58. doi:10.1136/svn-2019-000269

## SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

**How to cite this article:** Gerasimenko A, Mignot C, Naggara O, et al. Cerebral dural arteriovenous fistulas in patients with PTEN-related hamartoma tumor syndrome. *Clinical Genetics.* 2024;1-5. doi:10.1111/cge.14515
<sup>25</sup>APHPUniversité Paris Cité, Service de Neuroradiologie
Diagnostique et Interventionnelle, CHU Lariboisière, Paris, France

<sup>26</sup>Service de Génétique Médicale, CHU Ste-Justine, Montréal, Canada

<sup>27</sup>APHP.Sorbonne Université, Service de pathologies Thyroïdiennes et Tumorales Endocrines, Hôpital La Pitié-Salpêtrière, Paris, France

<sup>28</sup>APHPUniversité Paris Cité, Inserm UMR 1141,
NeuroDiderotFrance, Hôpital Robert Debré, Service de Neurologie
Pédiatrique, DMU INOV-RDB, Paris, France

<sup>29</sup>Département de Neurologie Pédiatrique, GHICL, Hôpital
Saint Vincent de Paul, Lille, France

<sup>30</sup>CHU de Strasbourg, Service de Génétique Médicale, IGMA,
Strasbourg, France

<sup>31</sup>Groupe d'Étude Interdisciplinaire pour les Malformations
Vasculaires, Hôpitaux Lariboisière, Bichat, Saint-Joseph, Clinique
Alma, Paris, France

## ACKNOWLEDGMENTS

We would like to thank the patients and their families for their invaluable contribution to this work.

## CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

## PEER REVIEW

The peer review history for this article is available at https://www.
webofscience.com/api/gateway/wos/peer-review/10.1111/cge.
14515.

## DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

## ORCID

Anna Gerasimenko https://orcid.org/0000-0001-7873-0992

Salima El Chehadeh https://orcid.org/0000-0003-1613-6570

Alain Verloes https://orcid.org/0000-0003-4819-0264

Lyse Ruaud https://orcid.org/0000-0003-4940-5896

## REFERENCES

1. Marsh DJ, Kum JB, Lunetta KL, et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. *Hum Mol Genet.* 1999;8(8):1461-1472. doi:10.1093/hmg/8.8.1461

2. Hendricks LAJ, Hoogerbrugge N, Mensenkamp AR, et al. Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome. *J Natl Cancer Inst.* 2023;115(1):93-103. doi:10.1093/jnci/djac188

3. Dhamija R, Weindling SM, Porter AB, Hu LS, Wood CP, Hoxworth JM. Neuroimaging abnormalities in patients with Cowden syndrome: retrospective single-center study. *Neurol Clin Pract.* 2018;8(3):207-213. doi:10.1212/CPJ.0000000000000463

4. Lok C, Viseux V, Avril MF, et al. Brain magnetic resonance imaging in patients with Cowden syndrome. *Medicine* (Baltimore). 2005;84(2):129-136. doi:10.1097/01.md.0000158792.24888.d2

5. Al-Shahi R, Bhattacharya JJ, Currie DG, et al. Prospective, population-based detection of intracranial vascular malformations in adults. *Stroke*. 2003;34(5):1163-1169. doi:10.1161/01.STR.0000069018.90456.C9

6. Koch MJ, Stapleton CJ, Guniganti R, et al. Outcome following hemorrhage from cranial dural arteriovenous fistulas. *Stroke*. 2021;52(10):e610-e613. doi:10.1161/STROKEAHA.121.034707

7. Prats-Sánchez LA, Hervás-García JV, Becerra JL, et al. Multiple intracranial arteriovenous fistulas in Cowden syndrome. *J Stroke Cerebrovasc Dis.* 2016;25(6):e93-e94. doi:10.1016/j.jstrokecerebrovasdis.2016.03.048

8. Srinivasa RN, Burrows PE. Dural arteriovenous malformation in a child with Bannayan-Riley-Ruvalcaba syndrome. *AJNR Am J Neuroradiol.* 2006;27(9):1927-1929.

9. Tan WH, Baris HN, Burrows PE, et al. The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management. *J Med Genet.* 2007;44(9):594-602. doi:10.1136/jmg.2007.048934

10. Mester JL, Ghosh R, Pesaran T, et al. Gene-specific criteria for PTEN variant curation: recommendations from the ClinGen PTEN expert panel. *Hum Mutat.* 2018;39(11):1581-1592. doi:10.1002/humu.23636

11. Azuma M, Hirai T, Shigematsu Y, et al. Evaluation of intracranial Dural arteriovenous fistulas: comparison of unenhanced 3T 3D time-of-flight MR angiography with digital subtraction angiography. *Magn Reson Med Sci.* 2015;14(4):285-293. doi:10.2463/mrms.2014-0120

12. Ryu B, Sato S, Mochizuki T, Niimi Y. Relative signal intensity on time-of-flight magnetic resonance angiography as a novel indicator of aggressive presentation of intracranial dural arteriovenous fistulas. *J Cereb Blood Flow Metab.* 2021;41(6):1428-1436. doi:10.1177/0271678X20969218

13. Kobayashi A, Al-Shahi SR. Prognosis and treatment of intracranial dural arteriovenous fistulae: a systematic review and meta-analysis. *Int J Stroke.* 2014;9(6):670-677. doi:10.1111/ijs.12337

14. Baharvahdat H, Ooi YC, Kim WJ, Mowla A, Coon AL, Colby GP. Updates in the management of cranial dural arteriovenous fistula. *Stroke Vasc Neurol.* 2020;5(1):50-58. doi:10.1136/svn-2019-000269

## SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

**How to cite this article:** Gerasimenko A, Mignot C, Naggara O, et al. Cerebral dural arteriovenous fistulas in patients with PTEN-related hamartoma tumor syndrome. *Clinical Genetics.* 2024;1-5. doi:10.1111/cge.14515