European Journal of Medical Genetics 62 (2019) 103727

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European Journal of Medical Genetics
journal homepage: www.elsevier.com/locate/ejmg

Novel pathogenic TGFBR1 and SMAD3 variants identified after
cerebrovascular events in adult patients with Loeys-dietz syndrome

T

Domenico Laterzaa, Marco Ritellib, Andrea Zinic,*, Marina Colombib, Maria Luisa Dell'Acquaa,
Laura Vandellia, Guido Bigliardia, Luca Vergantid, Stefano Valloned, Chiara Vincenzia,
Francesca Rosafioa, Ludovico Ciollia, Olga Calabresee, Paolo Frigio Nichellia, Livio Picchettoa
a
Stroke Unit, Neurology Clinic, Department of Neuroscience, Ospedale Civile "S. Agostino-Estense", Modena University Hospital, University of Modena and Reggio Emilia,
Modena, Italy
b
Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
c
IRCCS Istituto di Scienze Neurologiche di Bologna, Department of Neurology and Stroke Center, Maggiore Hospital, Bologna, Italy
d
Neuroradiology, Department. of Neuroscience, Ospedale Civile "S. Agostino-Estense", Modena University Hospital, University of Modena and Reggio Emilia, Modena, Italy
e
Medical Genetics Unit, University of Modena and Reggio Emilia, Modena, Italy

A R T I C LE I N FO

A B S T R A C T

Keywords:
Loeys-dietz syndrome
Stroke
Arterial dissection
TGFBR1
SMAD3

Introduction: Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder due to heterozygous pathogenic variants in transforming growth factor beta (TGFβ) signaling-related genes. LDS types 1–6 are
distinguished depending on the involved gene. LDS is characterized by multiple arterial aneurysms and dissections in addition to variable neurological and systemic manifestations.
Patient 1: a 68-year-old man was admitted due to an aphasic transient ischemic attack (TIA). Brain CT-scan
and CT angiography revealed a chronic and asymptomatic right vertebral artery dissection. Stroke diagnostic
panel was unremarkable. His history showed mild stroke familiarity. At age of 49, he was treated for dissectinganeurysm of the ascending aorta and started anticoagulation therapy. Seven years later, he underwent surgery
for dissecting aneurysm involving aortic arch, descending-thoracic aorta, left subclavian artery, and both iliac
arteries. Patient 2: a 47-year-old man presented a left hemiparesis due to right middle cerebral artery (MCA) and
anterior cerebral artery (ACA) occlusion caused by right internal carotid artery (ICA) dissection after sport
activity. Despite i.v. thrombolysis and mechanical thrombectomy, he developed malignant cerebral infarction
and underwent decompressive hemicraniectomy. Digital subtraction angiography showed bilateral carotid and
vertebral kinking, aneurysmatic dilatation on both common iliac arteries and proximal ectasia of the descending
aorta. His father and his uncle died because of an ischemic stroke and a cerebral aneurysm rupture with a
subarachnoid hemorrhage (SAH), respectively.
Discussion: in both cases, considering the family history and the multiple dissections and aneurysms, LDS molecular analysis was performed. In patient 1, the novel NM_005902.3 (SMAD3): c.840T > G; p.(Asn280Lys)
likely pathogenic variant was identified, thus leading to a diagnosis of LDS type 3. In patient 2, the novel
NM_004612.2 (TGFBR1): c.1225T > G; p.(Trp409Gly) likely pathogenic variant was found, allowing for a diagnosis of LDS type 1.
Conclusion: LDS is characterized by genetic and clinical variability. Our report suggests that this geneticallydetermined connective tissue disorder is probably underestimated, as it might firstly show up with cerebrovascular events, although mild systemic manifestations. These findings could lead to identify people at risk of
severe vascular complications (i.e., through genetic consult on asymptomatic relatives), in order to perform
adequate vascular assessments and follow-up to prevent complications such as stroke.

1. Introduction

dominant genetic disorders of the connective tissue, firstly reported in
2005 (Loeys et al., 2005), and mainly characterized by multiple arterial
aneurysms and dissections in addition to variable neurological,

Loeys-Dietz syndrome (LDS) is a spectrum of six autosomal

*

Corresponding author.
E-mail address: a.zini@ausl.bologna.it (A. Zini).

https://doi.org/10.1016/j.ejmg.2019.103727
Received 14 January 2019; Received in revised form 30 June 2019; Accepted 13 July 2019
Available online 18 July 2019
1769-7212/ © 2019 Elsevier Masson SAS. All rights reserved.

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D. Laterza, et al.

currently lists a total of 101 mutations (queried on June 21, 2019).
LDS4-6 are the most recently identified types of LDS. LDS4, caused
by TGFB2 pathogenic variants, is usually characterized by aortic and
cerebral aneurysms and skeletal manifestations and it generally presents a milder phenotype (Lindsay et al., 2012; Ritelli et al., 2014;
Schepers et al., 2018). In LDS5, due to pathogenic TGFB3 variants, low
muscle mass, growth retardation and distal arthrogryposis have also
been described (Rienhoff et al., 2013; Matyas et al., 2014; BertoliAvella et al., 2015; Loeys and Dietz, 2008). Furthermore, rare pathogenic variants in the SMAD2 gene were lately reported as cause of LDS6
(Zaidi et al., 2013; Micha et al., 2015; Cannaerts et al., 2019; Fukuda
et al., 2018; Schepers et al., 2018). The anomalous development and
homeostasis of the extracellular matrix, due to abnormal TGFβ signaling, in patients with LDS, leads to multisystemic anomalies, mainly
characterized by vascular findings (cerebral, thoracic and abdominal
arterial aneurysms and/or dissections), skeletal manifestations (pectus
excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly,
talipes equinovarus, cervical spine malformation and/or instability)
and craniofacial (widely spaced eyes, strabismus, bifid uvula and/or
cleft palate and craniosynostosis) and cutaneous findings (velvety and
translucent skin, easy bruising, and dystrophic scars). Individuals with
LDS can show a predisposition for allergic/inflammatory disease including asthma, eczema, and hypersensitivities to food or environmental allergens. Wide variation in the distribution and severity of
clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant, suggesting the influence of genetic modifiers of disease that are
independent of the pathogenic variant itself (Loeys and Dietz, 2008).
Herein, we report two adult men with LDS, confirmed by the
identification of novel likely pathogenic variants in TGFBR1 and
SMAD3, which had been unrecognized until the patients presented to
our Stroke Unit with cerebrovascular events.

osteoarticular, musculoskeletal, gynecological, pregnancy related, cutaneous and craniofacial manifestations (Loeys and Dietz, 2008). LDS is
caused by mutations in TGFβ signaling pathway-related genes, i.e.
TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3. The TGFβ signaling is involved in the regulation of cell growth, differentiation, development and apoptosis in several biological systems. In this pathway,
the multifunctional cytokine TGFβ (TGFβ1, TGFβ2 and TGFβ3 isoforms, respectively encoded by TGFB1, TGFB2 and TGFB3) activates the
TGFβ receptor, a serine/threonine membrane receptor consisting of two
subunits, TGFβ receptor type 1 and TGFβ receptor type 2 (respectively
encoded by TGFBR1 and TGFBR2). The receptor, in turn, leads to a
downstream signaling cascade involving mothers against decapentaplegic homolog (SMAD) proteins such as SMAD2 and SMAD3.
This class of intracellular signaling proteins and transcription factors
are able to translocate into the cell nucleus to induce transcription of
different effectors (Schepers et al., 2018). Thus, mutations in genes
encoding different members of TGFβ signaling pathway, garbling the
physiological development of the extracellular matrix (Van de Laar
et al., 2011), lead to multisystemic abnormalities. For these reasons,
LDS shows genetic and clinical variability and is related to a significant
reduction of life expectancy. In particular, in LDS patients, rupture of
aneurysms and arterial dissections are the most common causes of
death. Mitral and aortic valvulopathies and rupture of bowel, spleen,
and uterus during pregnancy are other possible life-threatening manifestations (Loeys and Dietz, 2008; MacCarrick et al., 2014). While
various clinical presentations have been labeled in the past as LDS type
I (craniofacial features present), LDS type II (minimal to absent craniofacial features) (Loeys et al., 2005), and LDS type III (presence of
osteoarthritis) (Van de Laar et al., 2011), it is now recognized that LDS
caused by a heterozygous pathogenic variant in any of the six known
genes (TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3) is a
continuum in which affected individuals may have various combinations of clinical features (MacCarrick et al., 2014; Loeys and Dietz,
2008; Schepers et al., 2018). LDS1 and LDS2 are the most common
types and are due to pathogenic variants in TGFBR1 and TGFBR2, respectively (MacCarrick et al., 2014) TGFBR1 and TGFBR2 include 9 and
7 exons, respectively. The Human Gene Mutation Database Professional
(HGMD®) lists a total of 84 TGFBR1 and 154 TGFBR2 mutations
(queried on June 21, 2019; http://www.hgmd.cf.ac.uk).
LDS3, previously known as “Aneurysms-Osteoarthritis-Syndrome”
(AOS), is due to mutations in SMAD3. SMAD3 comprises 9 exons and
encoded protein consists of 425 amino acids included in two domains
called MH1 and MH2 (Van de Laar et al., 2011; Wischmeijer et al.,
2013). LDS3 is very frequently linked to mutations in the MH2-domain,
in particular in exon 6 (Schepers et al., 2018). The HGMD Professional

2. Patient 1
A 68-year-old man was admitted at our hospital for sudden aphasia.
He was receiving anticoagulant drugs (warfarin, target INR range
2.5–3.5) and losartan therapy because, at the age of 49, he had been
treated for dissecting aneurysm of the ascending aorta (Bentall surgery
with mechanical aortic valve) and, in addition, seven years later, he had
undergone surgery for dissecting aneurysm involving aortic arch, descending-thoracic aorta, left subclavian artery and both iliac arteries (see
Fig. 1). In emergency room, urgent brain CT-scan was negative for
acute lesions. CT-angiography of supra-aortic and intracranial arteries
showed no vessel occlusion, aneurysms, or acute dissections, but

Fig. 1. Patient 1 features. 1a. CT angiography: sagittal reformat shows chronic dissection of the right vertebral artery.1b. CT angiography: 3D reformat shows a type
B aortic dissection.
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D. Laterza, et al.

Fig. 2. Patient 2 features. 2a. Digital subtraction angiography: anterior-posterior view shows a right carotid dissection with ipsilateral T occlusion. 2b. CT angiography: 2D reformal shows a left iliac artery ectasia.

disclosed. The patient was treated with intravenous thrombolysis and
mechanical thrombectomy (see Fig. 2a), but the right internal carotid
artery was recanalized just partially and brain-CT at 24 h showed a
wide right infarction in fronto-temporal, insular and parietal areas and
in lenticular nucleus. Because of the presence of malignant cerebral
edema, a decompressive craniotomy procedure was required. His clinical conditions gradually improved, and he started rehabilitation. The
anamnesis of the patient reported a history of myopia, morphoeic
epileptic seizures, obstructive sleep apnea and allergy to pumpkin.
Furthermore, he had an important family history of vascular disease on
his father's side who died from hemorrhagic stroke at 71 years old, in
addition one of his paternal uncles died from ruptured aortic aneurysm
at 67 years old and his paternal grandfather had an aortic aneurysm and
died of a lung cancer. Considering the vessel abnormalities together
with a suggestive family history, we suspected a genetic vascular disease. Thus, a thoraco-abdominal CT angiography was performed that
detected bilateral iliac tortuosity and a left iliac aneurysm (see Fig. 2b).
As a consequence, molecular analysis of TGFBR1, TGFBR2, SMAD3,
TGFB2, and TGFB3 was performed that disclosed in exon 7 of TGFBR1
the heterozygous g.101908861T > G, c.1225T > G (p.Trp409Gly)
variant (NM_004612.2, NP_004603.1). The variant, classified as likely
pathogenic (class 4) according to the guidelines of the ACMG, was not
reported in public databases (queried on June 21, 2019), and was
therefore submitted to the LOVD (https://databases.lovd.nl/shared/
genes/TGFBR1, variant identifier: #0000480117) as novel likely pathogenic variant associated with LDS1. Subsequently, mild dolichocephaly, malar hypoplasia, elongated uvula, light blue sclerae, striae
distensae, and small atrophic scars on knees were observed. Besides, a
screening for other potential manifestations of the disease was performed. In particular, echocardiogram showed minimal mitral regurgitation without other valvulopathies and dilatation of the sinuses of
Valsalva. Furthermore, ophthalmological exam detected myopia and
abnormality of the macular reflex.

incidentally it detected chronic right vertebral artery dissection (see Fig
1). His electrocardiogram was normal. INR was 2.30. Symptoms regressed within 12 h. Brain CT-scan performed 24 h after admission was
unchanged. Thus, a diagnosis of transient ischemic attack (TIA) was
given and the patient continued anticoagulation therapy with warfarin.
Trans-esophageal echocardiogram was negative for thoracic aorta aneurysms and dissections, cardiac thrombosis and further valvular abnormalities. Considering both vertebral and aortic dissections and patient's clinical history, we suspected a vascular connective tissue
disorder. On examination, pectus carinatum and flat feet were detected
in the absence of other osteoarticular, craniofacial and cutaneous features. Furthermore, after resolution of TIA, neurological examination
was normal. In particular, there were no signs of central or peripheral
deficit (i.e., polyneuropathy). Moreover, patient's clinical history included two inguinal hernias treated with hernioplasty at the age of 20
and a bilateral operation for varicose vein at the age of 30. Besides, he
was affected by arterial hypertension and chronic obstructive bronchitis. The patient reported that both his mother and one maternal
uncle had died from stroke at 51 and 65 years old, respectively; he is a
single child and one of his two sons, who had suffered from migraine
and depression, died from a car accident at the age of 30. His family
history was negative for other neurological and arterial diseases. The
historical and clinical findings induced a suspicion of LDS; thus molecular analysis of TGFBR1, TGFBR2, SMAD3, TGFB2 and TGFB3 was
performed by Sanger sequencing that revealed the heterozygous
g.67473760T > G; c.840T > G; p.(Asn280Lys) SMAD3 variant (reference sequences: NM_005902.3; NP_005893.1) in exon 6 of SMAD3.
The variant, classified as likely pathogenic (class 4) according to the
guidelines of the American College of Medical Genetics and Genomics
(ACMG), was not reported in public databases (queried on June 21,
2019), and was therefore submitted to the Leiden Open Variation Database (https://databases.lovd.nl/shared/genes/SMAD3, variant identifier: #0000480118) as novel likely pathogenic variant associated with
LDS3.

4. Discussion and conclusion
3. Patient 2
LDS has an unknown prevalence and presents a wide phenotypic
spectrum in which affected individuals may have various combinations
of clinical features ranging from a severe syndromic presentation with
significant extravascular systemic findings in young children to a presentation with predominantly thoracic aortic aneurysms/dissections
occurring in adults. In 2018 Loeys and Dietz, following subtype designations provide a general indication of the spectrum of disease severity,
from most to least severe: LDS1 = LDS2 > LDS3 > LDS4 > LDS5.
Table 1 shows potential clinical findings described in LDS subtypes

A 47-year-old man was hospitalized for sudden dysarthria and left
hemiparesis. Brain-CT performed in emergency room detected early
signs of cerebral infarction in the right lenticular nucleus with evident
core/penumbra mismatch at CT perfusion maps. CT angiography
showed dissection of the right internal carotid artery and embolic occlusion of homolateral carotid syphon, middle and anterior cerebral
arteries (“T” occlusion). Furthermore, severe tortuosity and multiple
kinking in epiaortic arteries and vertebro-basilar dolichoectasia were
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D. Laterza, et al.

Table 1
Clinical feature of LDSs.

et al., 2018), as the novel variant identified in our patient 2.
Functional studies performed in tissues derived from individuals
and mouse strains with TGFBR1 and TGFBR2 mutations showed not
only structural weakness and abnormal deposition of collagen, but also
overactivation of TGFβ signaling pathway with overexpression of
SMAD2 phosphorylated, especially in aortic tissues; besides progressive
upregulation of SMAD2 phosphorylation was associated with increasing
enlargement of aneurysms (Loeys et al., 2005; Gallo et al., 2014;
Takeda et al., 2018).
LDS1, together with LDS2, has worse prognosis than other LDS
types, mostly because of vascular manifestations. The risk is higher in
affected individuals with severe craniofacial abnormalities (Loeys and

and the estimated proportion attributed to each causal gene.
The mechanisms by which the tissue matrix presents an altered
development in LDS are complex and not completely clarified and cause
a systemic illness with reduction of life expectancy, mainly because of
vascular events.
In this article, we reported a novel likely pathogenic variant in
TGFBR1 and SMAD3, respectively, in two adult patients presented with
cerebrovascular accident and without major extravascular systemic
findings. A positive family history was present in both patients and
patient 1 suffered from several previous major vascular events.
LDS1 is very frequently associated with TGFBR1 missense mutations
clustering especially in the serine-threonine kinase domain (Takeda
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D. Laterza, et al.

Dietz, 2008; MacCarrick et al., 2014). Incidence of aortic and intracranial aneurysms and dissections and craniofacial dysmorphisms in
LDS1 (and LDS2) is greater than other types (MacCarrick et al., 2014;
Loeys and Dietz, 2008); our patient with LDS1 presented all these
clinical features. The most frequent craniofacial findings in these patients comprise cleft palate, craniosynostosis, bifid uvula, and hypertelorism. Retinal abnormalities have been described in LDS1 and
LDS2; ectopia lentis is common in Marfan syndrome (MFS) but not in
LDS. Vascular aneurysms, dissections and tortuosity could be widespread in LDS1, while aneurysms involve especially the sinuses of
Valsalva in MFS (Loeys et al., 2005; Loeys and Dietz, 2008; MacCarrick
et al., 2014; Meester et al., 2017; Longmuir et al., 2014). Skeletal and
other clinical features of LDS1 are shown in Table 1.
SMAD3 encodes a protein-member of TGFβ pathway regulating
gene transcription, such as in arterial wall cells (Van de Laar et al.,
2011).
Several studies have investigated how SMAD3 mutations cause osteoarthritis and structural and functional vascular abnormalities (Ye
et al., 2013). In particular, fiber fragmentation, collagen fiber reorganization and inflammatory infiltrations in vessel walls have been
detected in experimental models with SMAD3 deficiency (Lindsay et al.,
2012).
Cases of LDS3 have been reported almost exclusively in Caucasian
families, like our patient 1. LDS3 could have a phenotypic variability
and wide spectrum of severity: widespread arterial dissections, aneurysms and tortuosity and valvulopathies are common; cardiopathies can
display an aggressive course; early-onset ostheoartrhritis is more frequent with respect to the patients with LDS1 and LDS2 (Loeys and
Dietz, 2008; Van de Laar, 2011; Schepers et al., 2018), as shown also in
Table 1.
In summary, we reported a likely novel pathogenic variant in
TGFBR1 and in SMAD3 identified respectively in two Italian patients
with LDS presented because of cerebrovascular accident and we described their clinical characterization, thus expanding both the
knowledge of the clinical phenotype of LDS1 and LDS3 and their allelic
repertoire. The genetically determined connective tissue disorders are
probably underestimated causes of cerebrovascular disease. Patient 1,
for example, could perform genetic testing for a suspected connective
tissue disorder only at age 68, despite previous recognition of multidistrict vascular and extravascular abnormalities and a suggestive family history. Identification of patients and relatives with LDS could help
to perform strict vascular assessment and periodic follow-up and/or
surgical treatment to prevent fatal complications for people at risk of
arterial dissections, aneurysms, stroke and other severe pathological
manifestations.
Moreover, as already proposed in another work (Kuzmik et al.,
2010), identifying arterial dissections (especially “spontaneous” dissections, multiple dissections and multiorgan dissections) in patients
with a cerebrovascular accident should be a red flag for clinicians to
look for other clinical abnormalities potentially related to a heritable
connective tissue disorder and, eventually, perform appropriate genetic
analyses.
Acknowledgments: This manuscript has not been published and is
not under consideration for publication elsewhere. Its publication is
approved by all the authors. All declare that they have no conflict of
interest. This research didn't receive a specific grant from any institution or funding agency. MC and MR thank the Fazzo Cusan family for its
generous support.

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