Introduction

LDS was first described in 2005 as a genetic connective tissue disorder with two distinct subtypes [1]. Type I LDS referred to patients with the characteristic triad of arterial tortuosity and aneurysms, hypertelorism and bifid uvula/cleft palate, while type II LDS referred to patients with bifid uvula and less severe vascular abnormalities but without other craniofacial manifestations. Further studies have demonstrated greater phenotypical heterogeneity than initially described [2–4], and identical mutations can lead to both type I and type II LDS, indicating that LDS exists along a single clinical continuum [5]. The exact prevalence of LDS is unknown, but may be greater than initially thought, as significant phenotypical overlap with better-recognized genetic syndromes exists and contributes to misdiagnosis [6].

Several radiographically evident cardiovascular, neuroradiological and musculoskeletal abnormalities have been associated with LDS. In constellation, these imaging findings allow for distinction from similar connective tissue disorders such as Marfan (MFS) or vascular subtype of Ehlers-Danlos syndromes (vEDS), and the diagnosis of LDS may be first suggested by the radiologist. Early recognition is important as LDS carries a worse prognosis than similar connective tissue disorders and warrants more frequent follow-up imaging and earlier surgical intervention.

Genetics and pathophysiology

LDS is caused by autosomal-dominant heterozygous mutations in the genes encoding transforming growth factor beta (TGF-β) receptor type 1 (TGFBR1), found on chromosome 9q22, or receptor type 2 (TGFBR2) found on chromosome 3p22 [1, 7, 8]. Additional genetic anomalies, such as duplication of the TGFBR1 gene in the absence of TGFBR1/TGFBR2 mutations, have also been associated with bifid uvula and facial dysmorphic features seen in LDS [9]. Somatic mosaicism of the TGFBR2 mutation resulting in phenotypical features of LDS has also been reported [10]. The TGF-ß family of signaling molecules, including the related Smad proteins, controls an extensive set of cellular processes ranging from maintenance of the extracellular matrix (e.g., collagen deposition, elastin architecture) to tissue morphogenesis, including cartilage, bone, and vasculature [11]. Recent evidence has shown that the degree to which individual TGFBR2 mutations affect signaling in the Smad and related ERK pathways may correlate with the disease severity in LDS and related disorders [12].

Abnormalities in elements of the TGF-ß signaling pathway have been implicated in a wide array of pathological processes, including abnormal angiogenesis [13], cardiac defects [14, 15], embryonic anomalies [16] and craniosynostosis [17]—all sequelae that can be seen in LDS. LDS-associated TGF-ß receptor mutations specifically lead to dysfunctional downstream signaling in blood vessels [1], resulting in histological findings of elastic fiber disarray, diffuse medial degeneration, and increased collagen deposition in the arterial media predisposing to dilatation, dissection and/or rupture [18]. This is in contrast to the less severe aortic histopathology seen in MFS, caused by an autosomal-dominant mutation in the gene encoding fibrillin-1, which controls TGF-ß activation and encodes fibrillar collagens and collagen-modifying enzymes [19]. Predictably, arterial pathology is more aggressive and widespread in LDS than in MFS, with dissections occurring at a younger age and at smaller aortic diameters [1, 18, 20].

Immunohistochemical markers seen in LDS (pSmad2) are also present in other “TGF-ß-opathies,” including but not limited to MFS, arterial tortuosity syndrome and the berry aneurysms associated with autosomal-dominant polycystic kidney disease [18]. TGF-ß also plays a role in the expression of procollagen type III, abnormalities of which are implicated in vEDS [21, 22]. Other radiologically evident diseases linked to dysfunction in TGF-ß signaling include hereditary hemorrhagic telangiectasia (HHT) and Camurati-Engelmann disease/progressive diaphyseal dysplasia [23, 24]. Recent evidence demonstrates that haploinsufficiency of SMAD4 may result in increased risk for not only HHT, but also juvenile polyposis syndrome and cardiac valvular dysfunction, highlighting the diversity of the TGF-ß signaling network extending well beyond vascular remodeling and maintenance of the extracellular matrix to transcriptional regulation of tumorigenesis and countless other functions [25].

Clinical features

Several abnormalities have been associated with LDS in addition to the triad of arterial aneurysms, hypertelorism and bifid uvula/cleft palate. Characteristic findings include cardiac anomalies, vertebral artery tortuosity, hydrocephalus, cervical instability, Chiari malformations, scoliosis, pectus deformities and congenital hip dislocation. These can be broadly organized into cardiovascular, neuroradiological and musculoskeletal manifestations (Table 1) as detailed below. Joint hypermobility, translucent skin, blue sclerae [1], developmental delay [20] and facial skin cysts termed facial milia [26] are additional clinical findings in LDS that may be radiographically occult.

Table 1 Summary of common clinical findings in Loeys-Dietz syndrome
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Cardiovascular abnormalities

Aortic root aneurysms

The most severe abnormality in LDS is aneurysmal dilation of the aortic root, which frequently results in dissection and rupture. Aortic root aneurysms have been reported in 98% of patients with LDS [20]. Thoracic aortic dissection is the most common cause of death in LDS patients [1]. Aneurysmal dilation of the aortic root may also occur in utero, and has been reported on prenatal US performed on a 19-week-old fetus with LDS [27]. Progressive dilation of the aortic root may occur in the neonatal period [28]. Infantile aortic aneurysms can dissect at a very early age, and have been reported in infants as young as 3 months old [29].

Other cardiovascular abnormalities

In addition to the aorta, aneurysmal dilation and dissections can occur distantly along the arterial tree, as demonstrated in the example below (Fig. 1). Dilation of the main pulmonary artery can also be seen in LDS (Fig. 1) [28, 30]. More than half of patients with LDS have distant aneurysms [20]. A quarter to a third of LDS patients have been reported to have other cardiac anomalies, including patent ductus arteriosus, ductus aneurysms, bicuspid aortic valve, bicuspid pulmonary valve, atrial septal defect, mitral valve prolapse and coronary artery aneurysms [1, 20, 30].

Fig. 1
figure 1

LDS type 1 in a 6-year-old. a Sagittal maximum-intensity projection (MIP) of an aortic CTA demonstrates fusiform aneurysmal dilation of the proximal SMA. b CTA sagittal 3-D reconstruction reveals “corkscrew” tortuosity of left common carotid arising from an ectatic distal ascending aorta. Ao = aorta, PA = main pulmonary artery, RCCA = right common carotid artery, LCCA = left common carotid artery

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Neuroradiological abnormalities

Craniofacial malformations

Multiple craniofacial abnormalities have been reported in LDS. The most common are hypertelorism and cleft palate/bifid uvula; they are considered characteristic features of LDS. Mild hypertelorism can be appreciated in our example patient (Fig. 2).

Fig. 2
figure 2

Three-dimensional CT. a Volumetric reconstructions in the same 6-year-old with LDS demonstrate mild hypertelorism. Mild malar hypoplasia can also be appreciated. b Calvarial deformity is apparent, likely from premature fusion of the left lambdoid and sagittal sutures

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Craniosynostosis, malar hypoplasia, retrognathia and high-arched palate are also commonly seen [20]. Of the craniosynostoses, premature fusion of the sagittal suture (dolichocephaly/scaphocephaly) is the most common, seen in two-thirds of cases, including our example patient (Fig. 2) [31].

A craniofacial severity index has been used to quantify the severity of craniofacial malformations in LDS by determining the degree of hypertelorism, craniosynostosis and uvular malformations. This index has clinical value, as more severe craniofacial malformations correlate to worse cardiovascular outcomes [20]. The severity of craniofacial malformations may be used to determine thresholds for prophylactic cardiac surgery [32], and is discussed later.

Neurovascular abnormalities

Neurovascular abnormalities are commonly seen in patients with LDS. Tortuosity of the carotid, vertebrobasilar, and/or subclavian arteries was demonstrated in all patients in a study of 25 patients with LDS. A third of these patients had neurovascular aneurysms, almost all intracranial [31]. Evaluating vertebral artery tortuosity may be more specific, since normal young patients do not have tortuous vertebral vessels [33]. Vertebral artery tortuosity may be used to distinguish between LDS and MFS, as it has been shown to occur at a significantly greater frequency in patients with LDS compared to those with MFS [33]. Carotid and vertebral artery tortuosity can be appreciated in Fig. 1.

Other neuroradiological abnormalities

Congenital upper cervical abnormalities and instability have been described in LDS [3, 34] and can be seen in our example patient manifested by dysplasia of the dens and clivus (Fig. 4). Approximately 10% of patients with LDS have Chiari malformations, including our example patient, resulting in the formation of a syrinx (Fig. 3) [20, 31]. Communicating hydrocephalus in LDS patients is thought to result from the underlying connective tissue disorder, rather than from Chiari malformations [31]. Dural ectasia is seen in two-thirds of LDS patients [34, 35]. Additionally, submandibular branchial cysts have been associated with LDS [20].

Fig. 3
figure 3

Midsagittal T2-W MRI in the same 6-year-old with LDS demonstrates a Chiari I malformation and a prominent multiseptated syrinx (arrows). The child had prior suboccipital craniectomy performed for surgical decompression

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Musculoskeletal abnormalities

Several musculoskeletal findings have been reported in 195 patients with LDS. Half of patients with LDS have cervicospinal instability including anterior and posterior C1 arch defects, rotatory subluxation of C1 on C2 (Fig. 4), and/or anterior subluxation of C2 on C3 [34]. The most common spinal abnormality is scoliosis, which is seen in half of LDS patients. Marked scoliosis can result in pulmonary restriction (Fig. 5) [20, 31, 34]. A study of 55 patients demonstrated an average Cobb angle of 30° [34]. Two-thirds of patients demonstrate pectus deformities [18, 20], sometimes severe enough to warrant surgical correction [18]. Approximately 5% of patients have developmental hip dysplasia [18]. Mild protrusio acetabulae has been described in a third of patients [34]. Mild coxa valga and genu valgum have been described in patients with LDS and may be secondary to joint laxity [3].

Fig. 4
figure 4

Basilar invagination and rotator subluxation. a Sagittal CT, bone windows, in the same 6-year-old with LDS demonstrates basilar invagination, concave dysplasia of the clivus and a markedly dysplastic and shortened dens. Clivus, C1 = anterior arch of C1, C2 = dens of C2. b Three-dimensional CT volumetric reconstruction also demonstrates rotatory subluxation of C1 on C2

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Fig. 5
figure 5

Frontal radiograph in the same 6-year-old with LDS demonstrates severe dextroscoliosis of the thoracic spine and levoscoliosis of the lumbar spine

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Elongated limbs and fingers as well as contractures (camptodactyly) are seen in LDS patients [20]. A study of five children with LDS found that all had advanced carpal ossification with delayed or normal radial and phalangeal ossification, while two of the five had marked metaphyseal cupping notable at the distal ulna [3].

Foot deformities, including talipes equinovarus, hindfoot valgus and pes planus, are seen in approximately 40% of LDS patients [20]. An association between skeletal fragility and osteoporosis has also been reported in patients with LDS [36].

Differential diagnoses

Marfan syndrome (MFS)

MFS is an autosomal-dominant connective-tissue disorder caused by mutations in FBN1 encoding fibrillin-1, and is primarily associated with ocular, musculoskeletal and cardiovascular abnormalities. Similar to LDS, MFS patients can have craniofacial abnormalities and cardiovascular pathology, especially aortic root aneurysms and dissections. The latest revision of the Ghent nosology for diagnosing MFS assigns the greatest weight for making the diagnosis to ectopia lentis and cardiovascular manifestations, particularly aortic root aneurysms and mitral valvulopathy [37]. While approximately two-thirds of patients affected with MFS suffer lens dislocation, it occurs rarely in patients with LDS [1]. Additionally, mitral valve prolapse with mitral regurgitation is more common in MFS patients than in LDS patients [38]. Patients with LDS frequently have aneurysms and dissections throughout the arterial tree, whereas aneurysms and dissections in patients with MFS are typically confined to the aortic root [1, 32, 39]. As noted previously, the histopathological changes in the arterial media of MFS patients are less severe relative to those of LDS patients, explaining why dissections occur at younger ages and at smaller aortic diameters in LDS vs. MFS. Several other radiographically apparent features are associated with LDS patients but are rarely seen in those with MFS, such as Chiari malformation, cervical instability, cleft palate/bifid uvula and craniofacial abnormalities (e.g., malar hypoplasia, retrognathia). Despite some of these clinical differences, significant overlap exists between MFS and LDS and the revised Ghent nosology heavily weights the importance of molecular testing to establish the diagnosis of MFS.

Shprintzen-Goldberg syndrome (SGS) (i.e. marfanoid craniosynostosis syndrome)

Craniofacial abnormities in LDS may also resemble those seen in SGS and cardiovascular anomalies such as mitral valve prolapse may be seen; however, SGS is not associated with cleft palate/bifid uvula, or aortic/arterial aneurysm, tortuosity and/or dissection [1, 38, 40]. Another distinction is that patients with SGS demonstrate developmental delay, which is seen in only a minority of patients with LDS [41]. Finally, many patients with true SGS syndrome do not have TGFBR1/2 mutations [1, 42].

Vascular type Ehlers-Danlos syndrome, type IV (vEDS)

This phenotype is characterized by cutaneous findings (easy bruising, thin or translucent skin) and the characteristic facial appearance of thin lips and philtrum, large eyes and narrow cheeks. Fragility and tendency toward rupture of tendons/muscles, intestines, arteries and uterus are also characteristic [43]. Musculoskeletal complications in vEDS include clubfoot, congenital hip dislocation and hypermobility of small joints [39]. Neuroradiological manifestations in vEDS include hemorrhage associated with intracranial aneurysms, carotid-cavernous fistulas and cervical artery dissections [44]. Discriminating features that are relatively specific to LDS include cervical instability, widespread aortic/arterial tortuosity, craniosynostosis and Chiari malformations.

Familial thoracic aortic aneurysm and dissections (FTAAD)

Cardinal features of FTAAD include progressive dilation of the ascending aorta and thoracic aortic dissections [45]. Unlike LDS, cardiovascular abnormalities are typically the only manifestations of disease. Five genes and several loci have been associated with this disease, notably TGFBR1/2 mutations identified in families with this condition. Although family members with TGFBR1/2 mutations did not have the characteristic craniofacial, skeletal or cutaneous findings of LDS upon clinical assessment, mild marfanoid features are variably present; additionally, other investigations such as whole-body 3-D imaging to survey for arterial tortuosity were not regularly performed in these patients, so the precise degree of phenotypic overlap in these cases remains uncertain [46–48]. In patients with FTAAD caused by mutation in the ACTA2 gene encoding smooth muscle alpha-actin, unique clinical findings including livedo reticularis and iris flocculi, may be seen as well as findings also in LDS, such as cerebral aneurysm and persistent ductus arteriosus [45, 49]. Aortic dissection has occurred at diameters less than 5.5 cm in a subset of these patients, similar to the more aggressive course seen in LDS patients [45, 49].

Congenital contractural arachnodactyly (CCA)

CCA overlaps significantly in terms of musculoskeletal phenotype with MFS (tall and slender body habitus, dolichostenomelia, arachnodactyly). LDS and CCA share many features, including not only arachnodactyly but also camptodactyly, club foot, scoliosis and aortic dilation that may progress over time [45, 50]. Whereas aortic tortuosity/aneurysms are typically widespread in patients with LDS, dilation is restricted to the aorta in CCA and is not present in all individuals; moreover, no dissections have so far been reported in CCA patients [45].

Other syndromes

Several other syndromes are associated with ascending aortic aneurysms and should be considered in the differential diagnosis based on clinical presentation, including Turner and Noonan syndromes, persistent patent ductus arteriosus with thoracic aortic aneurysm, and the recently described aneurysms-osteoarthritis syndrome caused by mutations in SMAD3 [38, 51]. Arterial tortuosity syndrome, a rare autosomal-recessive disorder with a clinical phenotype of aortic/arterial tortuosity, skeletal and cutaneous involvement, may closely resemble LDS as well [52].

Workup and management

Genetic testing

Given the extensive clinical overlap between LDS and related phenotypes, radiological evaluation and genetic testing are recommended to confirm a presumptive diagnosis [19, 37]. TGFBR1/2 testing should be performed for not only patients with the characteristic triad of hypertelorism, cleft palate/bifid uvula, and aortic/arterial aneurysms/tortuosity, but also for patients with aortic/arterial aneurysm and a variable combination of the other features summarized in Table 1 (e.g., craniosynostosis, easy bruising, joint hypermobility), patients with a vEDS-like phenotype but normal collagen III biochemistry, patients with a MFS-like phenotype not fulfilling the Ghent nosological criteria, and patients with a family history of autosomal-dominant thoracic aortic aneurysms, particularly in cases with vascular disease beyond the aortic root [5].

Pharmacological treatment

LDS patients are typically managed medically with beta-blockers and exercise restriction to reduce hemodynamic stress [5, 19]. The role of medications targeting the underlying TGF-ß abnormalities, such as losartan, an anti-hypertensive medication with TGF-ß signal blocking, is still being defined [53] as clinical trials are ongoing [54]. An in vitro study has shown substantial improvement in the defective function of LDS fibroblasts following dexamethasone administration [55], suggesting a role for in utero treatment since prenatal diagnosis is possible based on imaging [27] and parental genetics.

Imaging recommendations

Annual surveillance of the arterial tree has been recommended for patients with LDS given the aggressive course of aneurysms. This should be performed with CTA or MRA from the head to at the least the pelvis [19, 32]. Since iliac artery aneurysms have been reported [30], run-off studies may also be considered. Three-dimensional renderings can be helpful for visualizing associated musculoskeletal and vascular anomalies [30]. MR evaluation may be preferred due to concerns about radiation dose, since follow-up imaging involves a large body area and is recommended annually [56].

Echocardiograms are recommended every 3 to 6 months to evaluate for valvular disease and aortic root dilation if initial aortic root measurements taken at diagnosis are abnormally large [32]. If initial measurements are normal, current practice is to repeat echo at 6 months and annually thereafter if there is minimal progression depending on phenotype severity [5]. Similarly close follow-up has been recommended after aortic grafting [32]. Cervical instability, scoliosis/spondylolisthesis and osteopenia are all abnormalities associated with LDS that should be excluded with flexion-extension cervical radiographs, thoracolumbar spinal imaging and DEXA scan, respectively [3]. It is particularly critical to exclude cervical instability in LDS patients who may undergo general anesthesia and/or elective surgery, such as pregnant women [5]. Recommendations for surveillance imaging are summarized in Table 2.

Table 2 Recommendations for surveillance imaging and surgical management
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Surgical intervention

A 4.0-cm threshold for prophylactic aortic root grafting has been suggested for adolescents and adults with LDS [30, 32]. This is less than the 5.0-cm threshold used for MFS patients. A lower threshold is used because multiple lethal aortic ruptures have been reported with aortic root diameters less than 4.5 cm [32]. However, there are recent data to suggest that a threshold of 5.0 cm is safe in adult patients with a less severe phenotype [5, 57]. Patients with LDS have been reported to better tolerate surgical intervention compared to patients with vEDS [32, 58], where friable vascular tissue is associated with intra- and postoperative failure [59].

Aortic root dissection has been reported in infants as young as 3 months [29] and death from aortic root dissection in patients as young as 6 months [32]. Surgery is performed once the ascending aorta exceeds the 99th percentile and the aortic annulus is at least 1.8 cm [20] in young children with extensive vascular abnormalities or severe craniofacial abnormalities [32]. Rapid enlargement of greater than 0.5 cm/year may also warrant surgical intervention [32]. Precise timing depends on the presence or absence of a TGFBR mutation, family history and ability to place graft of sufficient size to permit growth, among other factors [5, 32].

Uterine rupture and damage to pelvic structures as well as ante- or postpartum hemorrhage and delayed wound healing are important considerations for pregnant LDS patients, and elective early cesarean section may be recommended [2]. Additional recommendations include referral to a high-risk OB/GYN clinic with delivery in a tertiary care center and prenatal diagnosis if the disease-causing mutation is known [2, 5]. Recommendations for surgical intervention are summarized in Table 2.

Prognosis

Patients with LDS have a median survival of 37 years, which is substantially lower than patients with vEDS (48 years) or treated MFS (70 years) [20]. There are preliminary data to suggest that progression of disease and overall survival varies based on gender in patients with a TGFBR1 but not a TGFBR2 mutation, with men dying younger and more frequently presenting with thoracic aortic aneurysms and dissections [48]. Current recommendations do not differentiate between individuals with TGFBR1 and TGFBR2 mutations, but as our understanding of receptor gene mutations continues to improve, differences in management and outcome based on the specific TGFBR that is mutated may eventually emerge.

Conclusion

Loeys-Dietz syndrome (LDS) is characterized by aggressive aortic and distal arterial aneurysms predisposed to early dissection and rupture. The constellation of cardiovascular, neuroradiological and musculoskeletal findings seen in LDS is radiologically distinctive from those seen in related disorders such as Marfan or vascular subtype of Ehlers-Danlos syndromes. Early diagnosis, frequent follow-up imaging and prophylactic surgical intervention are essential in preventing catastrophic cardiovascular complications.