Abstract
Loeys-Dietz syndrome (LDS) type 4 is a rare connective tissue disorder caused by mutations in the transforming growth factor β 2 gene. It is well-documented that LDS4 shares clinical features of Marfan syndrome (MFS), and vascular involvement is less significant compared to other types of LDS. However, information on the valvular characteristics is scarce due to the small number of reported cases. This case series presents five cases with LDS4, highlighting their cardiovascular manifestations. Multiple valve anomalies without aortic dilatation were manifested in three, whereas there was aortic arch dilatation without any valve involvement in two cases. We found missense mutations in the former two families and a frameshift mutation in transforming growth factor β 2 in the latter family. In LDS4, echocardiographic findings of the unique valve redundancy in multiple valves can be a key to diagnosing LDS4 if any Marfanoid features are suspected clinically, even without aortic dilatation found. Our cases suggest there may be a genotype-phenotype correlation in LDS4.
Learning objective
Clinical features of Loeys-Dietz syndrome (LDS) type 4 are generally milder than other types of LDS and known to manifest less vascular involvement and relatively more valvular diseases. If Marfanoid features are suspected, genetic testing should be offered for arrangements of the surgical timing and screening of family members. Echocardiographic assessment of cardiac valves in those patients can be a key to a successful diagnosis. Our cases suggest these types of variants may be related to phenotypes.
Keywords: Loeys-Dietz syndrome, Transforming growth factor β, Echocardiography, Redundant valve, Annuloaortic ectasia
Graphical abstract
Introduction
The Loeys-Dietz syndrome (LDS, MIM# 609192, 610168, 613795, 614816, 615582) is a rare connective tissue disease presenting wide-ranging clinical features similar to Marfan syndrome (MFS), including aortic arch enlargement (AAE), tortuosity of vessels, and skeletal and cutaneous manifestations. Several types of LDS and gene mutations have been reported to cause different manifestations [1]. Among them, loss-of-function mutations in the transforming growth factor β 2 ligand (TGFB 2) gene on chromosome 1q41 associated with LDS type 4 (LDS4). This has been shown with milder phenotypes of LDS type 1 and LDS type 2 [2]. Mechanisms and relationships with the loss of function of TGFβ pathways and genotype-phenotype correlations are still unclear, especially in cardiac presentations and detailed echocardiographic findings of cardiac valves.
This case series presents five cases of LDS4 in three families, with three cases exhibiting valve regurgitation at the mitral and aortic valves and two cases presenting aortic dilations only (Table 1).
Table 1.
Characteristics of cases with Loeys-Dietz syndrome type 4.
| Case | 1 | 2-1 | 2-2 | 3-1 | 3-2 |
|---|---|---|---|---|---|
| Variants |
NM_003238.6:c.905G>T p.Arg302Leu |
NM_003238.4:c.895C>T p.Arg299Trp |
NM_003238.4:c.895C>T p.Arg299Trp |
NM_003238.4:c.1147del p.Gln383fs |
NM_003238.4:c.1147del p.Gln383fs |
| Age (years), gender | 24,M | 56,F | 60,F | 50,M | 53,M |
| Height (cm, z score) | 175.2(0.56) | 167(1.94) | 172.8(3.06) | 180.6(1.57) | 175(0.85) |
| Hypertelorism | − | + | + | − | − |
| Broad uvula | + | + | − | − | + |
| Exotropia | − | − | − | − | − |
| Facial features | + | − | + | − | − |
| Scoliosis | + | + | + | − | − |
| Hind foot | + | − | − | − | + |
| Plain flat foot | + | − | − | − | − |
| Joint hypermobility | + | + | + | − | + |
| Dural ectasia | ND | + | + | − | ND |
| Pneumothorax | − | + | − | − | − |
| Inguinal hernia | − | − | − | − | − |
| Dissection | − | − | − | − | + |
| Arterial tortuosity | − | + | ± | − | + |
| Cardiac involvement | |||||
| Mitral valve (M) | +(severe MR) | +(severe MR) | +(severe MR) | − | − |
| Aortic valve (A) | − | +(severe AR) | +(BAV) | +(mild to moderate AR) | − |
| Tricuspid valve (T) | +(trivial TR) | +(trivial TR) | +(moderate TR) | − | − |
| Billowing feature of valves | M, T | A, M, T | M, T | − | − |
| AAE | + | − | − | + | + |
| Sinus of valsalva (cm, z score) | 4.2 (4.18) | 3.6 (1.71) | 3.4 (1.07) | 6.4 (11.2) | 5.4 (7.1)* |
| Other | +(VSD, moderate PR) | − | − | − | − |
A: aortic valve, AAE: aortic arch enlargement, AR: aortic valve regurgitation, Arg: arginine, BAV: bicuspid aortic valve, C: cytosine, G: guanine L: leucine, M: mitral valve, MR: mitral valve regurgitation, ND: not definable, NM: accession prefix for protein-coding transcripts, mRNA. PR: pulomonary valve regurgitation, T: tricuspid valve, or thymine, TR: tricuspid valve regurgitation, Trp: triptophan, VSD: ventricular septal defect.
Case 1
A 24-year-old male diagnosed with a ventricular septal defect at birth, which was surgically closed in his childhood. In his teens, he developed pulmonary valve regurgitation (PR) and right ventricle dilatation, but he was asymptomatic for years. In his recent follow-up, he was found to have moderate mitral regurgitation (MR) due to valve prolapse. The Marfanoid features were distinct when he reached adulthood. Further examination revealed hypermobility of joints, high-arched palate, micrognathia and scoliosis. However, his height (175.2 cm, z = 0.56) was within normal range. Transthoracic and transesophageal echocardiogram (TEE) revealed dilatation of the sinus of Valsalva (42 mm, z = 4.18), redundant tricuspid valve (Fig. 1A), severe MR due to billowing leaflets and torn chordae tendineae at P3 (Fig. 1B, C), and moderate PR with reduced right ventricular function. Cardiovascular computed tomography (CT) images showed no apparent tortuosity in other vessels. The diagnosis of LDS4 was confirmed by genetic tests showing a likely pathogenic missense mutation in the gene of TGFB2 (NM_003238.6:c.905G>T) p.(Arg302Leu). Mitral valvuloplasty and pulmonary valve replacement were performed.
Fig. 1.
Transesophageal echocardiographic images of valves (Cases 1, 2-1, 2-2). (A) Redundant tricuspid valve, with trivial regurgitation. (B) Commissure view of mitral valve; billowing and redundant valvular tissues and torn chords of P3 shown causing severe mitral valve regurgitation (white arrow). (C) 3D en face view of mitral valve showing billowing features of bileaflets (Case1: A-C). (D) Floppy aortic valve causing severe aortic valve regurgitation. No dilatation was noted in sinus of Valsalva. (E) Commissure view of the mitral valve showed billowing leaflets causing severe mitral valve regurgitation (Case 2-1: D, E). (F) Billowing tricuspid valve causing moderate tricuspid valve regurgitation in Case 2-2.
Case 2-1
A mid-50s female was referred with systolic heart murmur. Further assessment revealed moderate MR and mild aortic regurgitation with left ventricular dilatation. She experienced occasional exertional dyspnea that gradually worsened. Her mother also had MR, and her sister had mitral valve surgery with suspicion of MFS (Case 2-2). Her clinical features, including thorax deformity, micrognathia, and dural ectasia, suggested MFS. TEE showed severe aortic valve regurgitation with floppy tricuspid leaflets. Additionally, severe MR with billowing bi-leaflets was demonstrated (Fig. 1D, E). Genetic testing revealed a pathogenic variant in TGFB2 (NM_003238.4:c.895C>T) p.(Arg299Trp). Aortic valve replacement confirmed a myxomatous change of valves.
Case 2-2
The sister of Case 2 had a heart murmur in her teens, but no cardiac diseases were found until she was in her forties. She exhibited features suggestive of MFS, including her tall height (172.8 cm, z = 3.06), hypertelorism, micrognathia, arachnodactyly, and dural ectasia. However, there were no ocular findings or AAE. Echocardiography revealed bicuspid aortic valve, redundant mitral valve with severe regurgitation, and moderate tricuspid valve regurgitation that had required mitral valvuloplasty and tricuspid valve annuloplasty about 15 years before (Fig. 1F). There was no need to intervene in the aortic valve. She did not have any genetic examinations at the time of her own surgery, but they were performed after her sister's (Case 2-1) diagnosis of LDS, which identified the same mutation in TGFB2.
Case 3-1
A male in his early fifties presented with aortic valve regurgitation and AAE (6.4 cm, z = 11.2). While his tall height (180 cm, z = 1.57) and loosened joints suggested MFS with his brother's past history, other clinical features did not fulfill the revised Ghent criteria [3]. Genetic testing confirmed a frameshift mutation [TGFB2 (NM_003238.4:c.1147del)p. (Gln383fs)], which was a likely pathogenic variant of unknown significance. Valve-sparing root reconstruction was performed successfully.
Case 3-2
The elder brother of Case 3-1, presented with aortic dissections in his mid-forties and had a Bentall procedure before. He did not show any clinical features of Marfanoid habitus except talipes planus. However, he had a history of myocardial infarction and dissections of carotid arteries. His genetic results performed after his brother's (Case 3-1) diagnosis showed the same mutation.
Discussion
LDS is a rare connective tissue disorder caused by mutations usually in the TGFBR1 or 2 gene, which is initially described as a syndrome characterized by arterial tortuosity, hypertelorism, and bifid uvula [1]. The clinical features of LDS overlap with MFS, however, broad variations in phenotypes and mutations in SMAD3 and TGFB2 have been reported. Several types of LDS have been reported with each genetic variant in TGFβ signaling pathways. Among them, LDS4, caused by mutations in TGFB2, is known to show milder forms than LDS1, 2, and 3.
Valve involvement in LDS4
The cardiovascular findings in LDS1 and 2 predominantly involve AAE and tortuosity, and valve regurgitation occasionally. As LDS4 cases have been reported recently, the possible incidence of associated aortic dissection is known. However, little has been reported on its valvular features [4]. Renard et al. reported four cases of significant mitral valve prolapse, in which two patients required surgical valve replacement [4]. In our Cases 1, 2-1, and 2-2, at least two valves showed billowing features (Fig. 1), requiring surgical interventions, while Cases 3-1 and 3-2 did not show these valvular features. Cases 2-1 and 2-2 showed valvular manifestations mainly. Thus, various features were previously reported with the similar mutation sites [5].
Aortic manifestations in LDS4
In LDS, earlier onset of aortic dissections than MFS has been reported. However, vascular involvement is less common. Our Cases 3-1 and 3-2 showed AAE in middle-age requiring surgery, which is more like the features of LDS1 or 2 [6]. Case 1 showed mild dilatation, but never manifested dissections. Cases 2-1 and 2-2 showed no dilatations (Fig. 2).
Fig. 2.
Ascending aorta images by thoracic enhanced-computed tomography (Cases 1, 2-1, 3-1, and 3-2). Cases 1 (A) and 2 (B) had mutations at the RKKR motif, there was mild aortic dilatation shown in (A), however, there was normal sinus of Valsalva in (B). Cases 3-1 (C) and 3-2 (D) had a frameshift. Aortic dilatation was noted in Case 3-1, and aortic dissection was seen in Case 3-2.
Congenital heart diseases in LDS4
Concomitant congenital cardiac diseases (CHD) in LDS are sporadically reported [7]. Case 1 had a ventricular septal defect and Case 2-2 had a bicuspid aortic valve. Both cardiac lesions are common as a CHD, which may not be related to LDS.
Genotype-phenotype correlations
The phenotype-genotype relationship among LDS4 patients is still unclear. New mutations, in which around there were 20–30 % of missense, nonsense, and frameshift for each, have been reported [8]. Mature TGFβ is not properly released from the latency-associated peptide if mutations occur at the RKKR motif of the furin protease cleavage site [8]. In our Cases 1, 2-1, and 2-2, mutations were found within this motif. In Cases 2-1 and 2-2, however, their clinical manifestations were different even with the same mutation site. On the other hand, the mutation found in Cases 3-1 and 3-2 caused a frameshift in the C-terminal peptide, which is in the cytokine domain, not in the RKKR motif. They manifested AAE mainly without valve features. Overall, their phenotypes were milder than those of MFS or LDS1/2.
Difficulty of diagnosis
The diagnosis of LDS could be easily missed due to its mild clinical features if detailed interviews of patients' medical and family history are not well performed. In particular, LDS4 was less frequently reported, and the symptoms reported were not consistent. In one review, Gouda et al. reported that aortic aneurysm was found in around 60 %, but mitral valvar prolapse was found in only 22 % of all patients [9]. Thus, the definitive diagnosis usually cannot be made from any symptoms but requires a genetic diagnosis. Multimodality imaging as screening should be performed if any suspicious phenotypes are shown, because the echocardiographic descriptions of valves and vessels would be helpful to reach the diagnosis of LDS. Our cases showed distinctive valvular deformities in multiple valves: billowing and redundant. It is common to observe the features in one, usually in the mitral valve, but uncommon in more than two valves among normal populations.
Surgical outcome
Long-term outcomes in LDS4 and the progression of vessel dilatations and valvular diseases are not well understood. In Case 2-2, there was no apparent deterioration after mitral valvuloplasty and tricuspid valve annuloplasty for more than a decade. Early surgical intervention potentially prevents further degenerative valvular changes and avoids valve replacement.
On the contrary, the best timing for aortic interventions in LDS4 is not well established. Some recommend earlier preventive surgeries when the size of AAE reaches 40 mm in LDS overall, or 45 mm for LDS4, because of the potential dissection risk without enlargement [10]. Also, some patients could have repeat dissections at distal vessels before and after arch repairs as we saw in Case 3-2. However, Cases 2-1 and 2-2 did not manifest AAE. For understanding better indications for each cardiac lesion in LDS4 and phenotype correlations, further study and follow-up data are needed.
Conclusion
LDS4 is a rare connective tissue disease associated with milder vascular involvement compared to other types of LDS or MFS. Our cases showed two phenotypes with two genotypes in three families, showing excessive features of valves without severe AAE with missense variants, or aortic dilatations like MFS with frameshifts without valve features. In the missense group, both atrioventricular and semilunar valves were affected. Among the patients with any Marfanoid features shown, regardless of the presence of AAE, genetic testing should be offered. Moreover, careful echocardiographic assessment of the valve redundancy in multiple valves can be a key to a successful diagnosis of connective tissue disease.
Consent statement
Written informed consent was obtained from the patients. The institutional ethical review of Sakakibara Heart Institute approved this case-series report (#20-089).
Declaration of competing interest
The authors declare that there is no conflict of interest.
Acknowledgments
MS contributed data curation, conceptualization, the original draft of the manuscript, and the preparation of images. YM provided genetic descriptions, conceptualization, and expressions of clinical features. KK, YI, and MT contributed to the review and editing of manuscript and echocardiographic descriptions of the valve.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jccase.2024.07.001.
Appendix A. Supplementary data
The following are the supplementary data related to this article.
4-D transesophageal echocardiographic image of mitral valve in en-face view (Case 1). Bileaflet prolapse and degenerative change and the torn chorda of posteromedial scallop are shown.
Transesophageal echocardiographic image of tricuspid valve (Case 1). Billowing and elongated leaflets were shown without annular dilatation. The caudal part of sternal bone protruded toward inside, compressing anterior part of right ventricle.
Transesophageal echocardiographic long-axis view of mitral valve, showing severe regurgitation with prominent flow convergence region in the left ventricle (Case 1).
Transesophageal echocardiographic image of aortic valve showing severe regurgitation with wide vena contracta. Aortic valve prolapse was also noted without dilatation of sinus of Valsalva (Case 2-1).
The short-axis view of aortic valve in transesophageal echocardiography showed fluttering and excessive movements of cusps (Case 2-1).
4-D transesophageal echocardiographic view of aortic valve (Case 3-1). Dilated sinus of Valsalva, especially in right coronary cusp was shown. Wide effective regurgitant orifice was shown.
Prominently dilated sinus of Valsalva was shown by transesophageal echocardiography (Case 3-1).
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Associated Data
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Supplementary Materials
4-D transesophageal echocardiographic image of mitral valve in en-face view (Case 1). Bileaflet prolapse and degenerative change and the torn chorda of posteromedial scallop are shown.
Transesophageal echocardiographic image of tricuspid valve (Case 1). Billowing and elongated leaflets were shown without annular dilatation. The caudal part of sternal bone protruded toward inside, compressing anterior part of right ventricle.
Transesophageal echocardiographic long-axis view of mitral valve, showing severe regurgitation with prominent flow convergence region in the left ventricle (Case 1).
Transesophageal echocardiographic image of aortic valve showing severe regurgitation with wide vena contracta. Aortic valve prolapse was also noted without dilatation of sinus of Valsalva (Case 2-1).
The short-axis view of aortic valve in transesophageal echocardiography showed fluttering and excessive movements of cusps (Case 2-1).
4-D transesophageal echocardiographic view of aortic valve (Case 3-1). Dilated sinus of Valsalva, especially in right coronary cusp was shown. Wide effective regurgitant orifice was shown.
Prominently dilated sinus of Valsalva was shown by transesophageal echocardiography (Case 3-1).