Neonatal presentation of Loeys-Dietz syndrome: two case reports and review of the literature

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder described for the first time in 2005 [1]. This condition is typically characterized by a triad that consists of arterial tortuosity and aneurysms, hypertelorism and bifid uvula or cleft palate [2]. However, LDS’s phenotypic spectrum is highly variable, ranging from a precocious syndromic presentation in newborns and toddlers, with typical facial dysmorphisms and severe systemic features, to isolated aortic aneurysms incidentally discovered in adults.

Being the main causes of morbidity and early mortality in LDS, the cardiovascular manifestations are the key elements of this condition. Patients typically develop dilatations of the aorta and the pulmonary arteries, as well as a predisposition for aortic dissection. Arterial tortuosity is also present, and it is typically widespread, affecting a variety of aortic branches in the abdominal, pelvic, and intracranial area. It is estimated that around 50% of the subjects with LDS have an aneurysm distal from the aortic root that would have not been detected by echocardiography [3]. This extensive vascular involvement is a very distinct feature of LDS, and makes it differ from other connective tissue disorders, especially Marfan syndrome (MS). Furthermore, arterial tortuosity tends to appear early in LDS, so that it can be seen even on prenatal ultrasound. Indeed, an isolated aortic aneurysm detected in a fetus represents an indication to test for LDS [4]. Also, aortic dissections and rupture tend to develop with smaller aortic root’s dimensions compared to MS. Consequently, the mean age of death in LDS (26 years old) is significantly lower than MS [5]. As for the cardiac involvement, patent ductus arteriosus (PDA), atrial septal defects, mitral valve prolapse, and bicuspid aortic valve are also relatively common finding.

Craniofacial abnormalities include craniosynostosis, micro-retrognathia, cleft palate and bifid uvula, while eyes’ involvement is usually characterized by hypertelorism, strabismus and blue sclerae. Retinal hemorrhages and retinal detachment are also associated with this condition, while lens dislocation is not as typical as in MS. Generally, facial features in LDS patients are usually associated with a more aggressive and severe aortic disease [6].

The skeletal features of LDS are those typically associated with connective tissue disorders and include joint laxity (as well as congenital hip dislocation and recurrent joint subluxations) and joint contractures (camptodactyly, clenched hands, clubfeet), arachnodactyly and pectus excavatum or carinatum. Spinal abnormalities include cervical spine malformations, especially C2-C3 subluxations, spinal stenosis, and early-onset scoliosis [7].

Skin findings are similar to those in Ehlers-Danlos syndrome, including velvety and translucent skin, easy bruising and dystrophic scarring. Hernias occur at higher rate than the general population. Neurodevelopmental abnormalities are frequent, especially hypotonia and motor delays. Feeding issues are also common [8]. Lastly, patients with LDS are more prone to develop allergic diseases (such asthma, food allergies) and inflammatory bowel disease than the general population.

LDS is suspected by the recognition of both an aortic root enlargement or type A dissection and compatible systemic futures. The molecular diagnosis is established by the identification of a pathogenic variant in TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 or TGFB3 genes, encoding for components cooperating within the TGF-beta receptor signaling cascade to regulate cell differentiation and the development of many tissues, including bone, cartilage, blood vessels, heart [9]. Heterozygous, loss-of function variants in TGFBR1 and TGFBR2 are the most frequently identified in LDS patients and are responsible for up to 80% of the cases. Until now, there is no evidence of specific genotype-phenotype correlations.

LDS differential diagnosis includes other hereditary connective tissue disorders, mainly Marfan syndrome, but also Beals syndrome, Ehlers-Danlos syndrome, and Shprintzen-Goldberg syndrome.

Compared to Marfan syndrome, LDS patients usually don’t show significant long bone overgrowth and lens dislocation. On the other hand, Beals syndrome is typically not characterized by vascular abnormalities [10].

Currently there are not standardized treatments and consensus protocols for LDS patients, and only few clinical trials have been performed. Most of the information available can be inferred from studies regarding other connective tissue disorders, especially MS. Various medical approaches have been reported in the attempt to slow down the development of vascular abnormalities in these genetic conditions, including beta-blockers, ACE-inhibitors, and angiotensin receptor blockers (ARBs), especially losartan. Among patients with MS, beta-blockers and losartan showed efficacy in reducing aortic root dilatations and need for surgical interventions, especially starting therapies at a young age [11, 12]. When administered as a single therapy, no significant difference has been found comparing the two drug classes; however, the combination of a beta-blocker and losartan have showed to be more efficient than the beta-blocker alone [13, 14]. These clinical data confirm the positive expectations towards losartan, which previously showed the ability to fully correct vascular abnormalities on mouse models with MS [15]. In light of these findings, although beta-blockers remain the first line therapy for MS, some authors currently advocate a precocious losartan treatment as a valuable alternative [16].

Finally, dexamethasone has shown some results on in vitro studies, improving the extracellular matrix deposition in fibroblasts with TGFBR1 and TGFBR2 mutations [17, 18]. However, clinical studies to confirm the possible benefits in vivo have not been conducted yet.

In case of severe, rapidly progressing aneurysms, that do not respond to the medical therapy or that put the patient’s life at risk, an early and aggressive surgical intervention is required. Valve spearing procedures are generally preferred since they preclude the need for chronic anticoagulation.

In newborns, toddlers, and young children in general, especially with severe craniofacial features, aneurism’s rupture, aortic dissection, and intracerebral incidents can occur already in first months of life. Therefore, specific thresholds, based on age and clinical symptoms, have been established to plan surgical procedures (Table 1).

Apart from the vascular abnormalities, the remaining clinical features are managed according to the referring specialist.

To identify all the cases of LDS recognized in the neonatal period, we performed a research in the medical literature through Pubmed and PMC using the keywords “Loeys-Dietz” plus “neonatal”, “newborn”, “toddler” and “infant”. 31 articles came out from Pubmed and 320 from PMC, but only 11 of them were covering the topic [23‐31]. All of the compatible articles were case reports, except for a small case series. Two case reports discussed the clinical history of the same patient.

14 patients were identified from the literature, reaching, with the addition of the case reports described above, a total of 16 subjects (Table 2).

Although the exact timing of the diagnosis of LDS was not specified in most of the papers, it can be inferred that most of them were made in the very first years or even months of life, due to the precious appearance of systemic symptoms and clinical appearance. For instance, in 15 patients (93.7%) vascular abnormalities have been identified in the first year of life. In 3 subjects (18.7%) the initial recognition was through prenatal ultrasound, and in 2 individuals LDS was identified only post-mortem.

Genetic analyses are precisely described in 14 out 16 patients. TGFRB2 mutations were reported in 12 individuals (75%), while TGFBR1 and TGFB3 were involved in just one subject each. Four patients presented a guanine to adenine substitution (1583G > A) on exon 7 of TGFBR2 gene.

As for the differential diagnosis, arthrogryposis and Larsen syndrome were hypothesized as the original diagnosis in 4 cases each, while Beals syndrome in 2 cases.

14/16 individuals (87.5%) were alive at the time of the report. Of the 2 patients with negative outcome, one died at 21 days of life due to massive bleeding from the thoracic cavity caused by rupture of the right pulmonary artery, despite undergoing a bilateral artery bending at 9 days of age. The second one deceased at 9 years of age due to aortic dissection.

In terms of neonatal anthropometric measures, 4 subjects (25%) were small for gestation age (SGA) and 2 (12.5%) were large for gestational age (LGA).

Table 3 describes the clinical phenotype of the patients, including vascular and cardiac abnormalities.

The aorta was involved all but one patient (93.7%), mainly in its ascending component (75%) with a significant dilation or aneurysm, while the aortic arch was involved in 2 cases (12.5%). One patient presented an aortic coarctation and another one an interrupted aortic arch. The pulmonary circle was also frequently involved, since 9/16 patients (56.2%) presented some degree of dilation in one of its main arteries. Other vessels affected were the ductus arteriosus, in which an aneurysm was found in 2 patients (12.5%), the subclavian artery and carotid and vertebral artery, one time each. Arterial tortuosity was reported in 10/16 subjects (62.5%).

As for the cardiac involvement, patent ductus arteriosus was identified in 7 patients (43.7%), atrial septal defect and ventricular sept defect in 2 patients each (12.5%), cardiomegaly and congestive heart failure in 3 (18.7%), double outlet right ventricle in one. Overall, a cardiac murmur was reported in just 3 patients (18.7%).

All the patients except one (93.7%) presented one or more abnormalities of the bone or the joints. Arachnodactyly was described in 7 subjects (43.7%), articular contractions (such as camptodactyly and clenched hands) in 10 (62.5%), joint laxity with or without dislocations in 10 (62.5%), pectoral deformity in 2 (12.5%), marphanoid appearance, syndactyly, and absent distal phalanges in one patient each. Club feet were reported in 10 patients (62.5%), metatarsus abductus and genu recurvatum in 2 (12.5%). Translucent and thin skin was reported in 4 subjects (25%).

As for the head and eyes’ involvement, 13 patients (81.2%) presented with hypertelorism, 6 (37.5%) had strabismus and blue sclerae, 5 (31.2%) had macrocephaly and 2 (12.5%) had frontal bossing. Only one patient had a craniosynostosis. Occasionally, other clinical features were also described, such as palpebral downslanting, low set ears and deep-set eyes.

Bifid or broad uvula and/or cleft palate were present in 14 subjects (87.5%), while micro and/or retrognathia characterized 7 of them (43.7%).

Cervical spine abnormalities, especially vertebral subluxations, were described in 6 patients (37.5%). Congenital scoliosis was described in one patient. Hernias, whether inguinal or umbilical, appeared in 9 patients (56.2%).

Lastly, hypotonia, diffuse or marked, was reported in 6 patients (37.5%), and neurodevelopmental delay in 3 (18.7%).

In terms of treatment, 10 patients (62.5%) started a medical therapy (Table 4). Overall, angiotensin II receptor blockers (ARBs) were the most frequently used (31.2%), followed by ACE-inhibitors and beta-blockers (25% each). 3 patients required more than one drug. 3 patients remained clinically stable under medical treatment, and one even improved while taking a losartan.

Eight patients (50%) underwent surgical procedure. The type of surgical management and the surgical timing are all reported in Table 4.

LDS is a rare autosomal dominant condition, and its neonatal presentation is even rarer. However, its precocious cardiovascular phenotype, sometimes recognizable even with prenatal ultrasound, might be extremely severe and put a newborn’s life in danger since its very first days of life. Hence, LDS is a disorder that pediatricians and neonatologists should be able to suspect. We suggest that in a newborn or a fetus with abnormalities compatible with connective tissue disorders, and even more if vascular abnormalities are precociously detected, Loeys-Dietz syndrome should be the first diagnosis to take into consideration. Moreover, as our review of the literature suggested, when arthrogryposis is suspected early in life or even prenatally, it is reasonable to include LDS in the differential diagnosis process. Benefits of an early and specific diagnosis of LDS are various and imply a potential modification of the natural history of the disease with early interventions on its complications.

To our knowledge, the first case described in our paper is the only clinical report of an LDS clinically suspected and a molecularly confirmed within the first month of life. Of course, the in-trio- WES approach has significantly speeded up the diagnostic process and its cost-effectiveness in the neonatal clinical setting is undeniable. In that case was detected a novel variant in TGFBR2. This gene encodes for a key TGF-beta transmembrane receptor, regulating cell proliferation and differentiation and extracellular matrix production. Most of the already described pathogenic TGFBR2 LDS variants are located in the intracellular kinase domain where is also located the herein reported variant. Interestingly, another variant involving the same nucleotide and responsible of a different aminoacidic modification (p.R460C) has been reported as responsible of isolated familial thoracic aortic aneurysms and dissections, Marfan-syndrome related disorder and rarely to classic LDS [32‐34]. Moreover, other two variants in the following nucleotide, but involving the same amino acid (p.R460H, p.R460L) have been described, highlighting that the amino acid 460 is strategically located within a highly conserved region of the protein domain and its substitutions interfere with the receptor’s ability to transduce signals [17‐28]. For this reason, the detected variant has been considered as pathogenic (according to the ACMG guidelines).

The importance of an early diagnosis of LDS relies on the possibility of tackling the otherwise inevitable progression of its vascular abnormalities with a medical therapy. As discussed above, various drugs have shown some degree of efficacy in preventing the evolution of aneurysms to rupture or dissection in connective tissue disorders. Although there’s still small evidence of this efficacy in LDS, essentially because of the lack of dedicated clinical trials, the possible benefits of beta-blockers or ARBs should encourage their immediate start when vascular abnormalities are detected. This is even more true considering that both drugs have a positive safety profile in newborns and young children, with very few adverse effects. Delaying a pharmacological approach could allow a progression of the vascular lesions and lead to cardiac symptoms, congestive heart failure, and to the need of early surgery. Although, as reported previously in Table 4, most of the surgical procedures described in the literature occurred without complications, LDS subjects present a peculiar vascular fragility that put them at higher risk of vessel rupture. Ideally, surgery should be performed only on those subjects who did not respond to a medical therapy, or on subjects with high-risk vascular abnormalities. Moreover, considering that aortic tissues from affected patients show evidence of increased TGFβ signaling, new personalized options for the implementation insisting on this pathway are worth to consider [35].

As described in the second case report, LDS features might not be evident from the very first days of life, since the syndrome’s phenotype is extremely broad. On that occasion, the key to the precocious diagnosis was the family history highly suspicious for connective tissue disorders. Based on these premises, we suspect that LDS might be underdiagnosed especially during childhood, when marphanoid features can be less clear. A suggestive family history, even if in presence of mild dysmorphisms, can be crucial to start an appropriate genetic evaluation. In fact, about one third of LDS cases are familiar and generally characterized by milder clinical signs than sporadic cases. Indeed, the variant identified in the second case has already been reported in patients with isolated thoracic aortic disorders and a mild spectrum of LDS [36, 37].

Finally, we hope that new clinical trials will be conducted to finally assess the utility of the already used medical therapy in LDS patients, and to identify new molecules and targets that may be more efficient in preventing the progression of vascular abnormalities.