Loeys-Dietz syndrome with a novel in-frame SMAD3 deletion diagnosed as a result of postpartum aortic dissection: A case report.

OBJECTIVE: Loeys-Dietz syndrome (LDS) is a rare, autosomal dominant connective tissue disorder which can aggressively affect the aortic vasculature. Limited information is available regarding its impact on pregnancy and postpartum outcomes. CASE REPORT: A pregnant 38-year-old nulliparous woman with mild aortic regurgitation and family history of aortic aneurysms presented with an aortic root measuring 49 mm. Despite concerns of an underlying connective tissue disorder, a definitive diagnosis was not reached. She delivered under strict blood pressure control, developed intractable uterine atony, and underwent uterine artery embolization. On the second postpartum day, aortic dissection was incidentally diagnosed, and aortic root replacement surgery was performed. Genetic testing revealed a novel in-frame SMAD3 deletion [NM_005902.4: c.703_708del, (p.Ile235_Ser236del)], leading to a diagnosis of LDS type 3. CONCLUSION: This case highlights the high postpartum aortic dissection risk in women with LDS, emphasizing the importance of early diagnosis in pregnant women with few clinical symptoms.

Arterial tortuosity in pediatric Loeys-Dietz syndrome patients.

Loeys-Dietz syndrome (LDS) is an autosomal connective tissue disorder commonly presenting with hypertelorism, bifid uvula, aortic aneurysms, and arterial tortuosity. The aim of the present study was to investigate differences in tortuosity index (TI) between genotypes of LDS, possible progression over time and its use as an adjunctive prognostic tool alongside aortic dimensions to aid timely surgical planning in pediatric patients. A retrospective observational study of pediatric LDS patients referred to our center (November 2012-February 2021) was conducted. Using magnetic resonance angiography (MRA) with 3D maximum intensity projection volume-rendered angiogram, arterial TI was measured. Twenty three patients had genetically confirmed LDS with at least one head and neck MRA and 19 had no less than one follow-up MRA available. All patients presented arterial tortuosity. Patients with TGFBR2 variants had greater values of TI compared to patients with TGFB2 variants (p = 0.041). For patients who did not undergo surgery (n = 18), z-scores at the level of the sinus of Valsalva showed a significant correlation with vertebral TI (rs = 0.547). There was one death during follow-up. This study demonstrates that patients with LDS and TGFBR2 variants have greater values of TI than patients with TGFB2 variants and that greatest values of TI are associated with increased aortic root z-scores. Furthermore, as TI decreases over time, less frequent neuroimaging follow-up can be considered. Nevertheless, additional studies are needed to better define more accurate risk stratification and long-term surveillance in these patients.

[Depressive and anxiety symptoms in hereditary connective tissue disorders : case description and systematic literature review]. / Depressieve en angstklachten bij erfelijke bindweefselaandoeningen: casus en systematisch literatuuroverzicht.

Hereditary connective tissue disorders are a broad group of congenital disorders that are characterized by a pathological weakness of the connective tissue as a result of an incorrect genesis, leading to multisystem complaints. We describe a 14-year-old patient with the hereditary connective tissue disorder Loeys-Dietz syndrome who was admitted to a child psychiatric crisis unit because of depressive and anxiety symptoms. A systematic literature search was carried out to analyze the prevalence of depressive and anxiety symptoms in individuals with hereditary connective tissue disorders Loeys-Dietz syndrome, Ehlers-Danlos syndrome and Marfan syndrome, to identify a possible association between these disorders and explanations for this. We conclude that there is an increased incidence of depression and anxiety symptoms in which pain, fatigue, social support and functioning, quality of life and functional limitations seem to play a role. There is a need for further research to determine exactly which factors contribute and how these can be targeted in prevention and treatment.

Ten-year follow-up study of a young woman with loeys-dietz syndrome: a case report.

We herein report the 10-year surgical course of a 27-year-old woman who underwent two surgeries after being diagnosed with Loeys-Dietz syndrome. As described in previous cases, this patient developed ectopic arterial enlargement. We followed her temporal changes over a 10-year period, including the changes in computed tomography, pathology, and surgery.

Siblings with profound connective tissue disease: First report of biallelic TGFBR1-related Loeys-Dietz syndrome.

Heterozygous missense variants in TGFBR1, encoding one subunit of the transforming growth factor-beta receptor, are a well-established cause of Loeys-Dietz syndrome (LDS)-an autosomal dominant disorder with variable phenotypic expression. Patients with LDS have compromised connective tissues that can result in life-threatening arterial aneurysms, craniosynostosis, characteristic craniofacial and skeletal anomalies, skin translucency, and abnormal wound healing. We report a full sibship with a biallelic type of TGFBR1-related disease. Each born at 38 weeks had aortic root dilation, congenital diaphragmatic hernia (CDH), skin translucency, and profound joint laxity at birth. Both had progressive dilation of the aorta and recurrence of a diaphragmatic defect after plication early in infancy. Patient 1 died at 66 days of age and Patient 2 is alive at 4 years and 4 months of age with multiple morbidities including cystic lung disease complicated by recurrent pneumothoraces and ventilator dependence, craniosynostosis, cervical spine instability, progressive dilation of the aorta, worsening pectus excavatum, large lateral abdominal wall hernia, and diffuse aortic ectasia. Fibroblasts cultured from Patient 2 showed decreased TGF-ß responsiveness when compared to control fibroblasts, consistent with previous observations in cells from individuals with autosomal dominant LDS. Whole genome copy number evaluation and sequencing for both patients including their parents as reference revealed compound heterozygous variants of uncertain clinical significance in exon 2 of TGFBR1 (c.239G>A; p.Arg80Gln paternal and c.313C>G; p.His105Asp maternal) in both siblings in trans. Each parent with their respective variant has no apparent medical issues and specifically no LDS characteristics. Neither of these variants have been previously reported. Thousands of patients have been diagnosed with LDS-an established autosomal dominant disease. These siblings represent the first reports of biallelic TGFBR1-related LDS and expand the differential diagnosis of CDH.

Retinal detachment in Loeys-Dietz syndrome.

Loeys-Dietz syndrome (LDS) is an autosomal-dominant connective-tissue disorder with vascular and musculoskeletal abnormalities similar to Marfan syndrome. However, unlike Marfan, retinal detachment (RD) is rarely reported, and screening protocols do not currently feature ophthalmic assessment or RD counseling. We report a 5-generation family affected by LDS, where RD occurred in six eyes of four individuals. The proband was an 84-year-old male recently diagnosed with type-V LDS (TGFß3 pathogenic variant c.899G>A, p.(Arg300Gln)). Further investigation was undertaken into the family's medical history. The proband experienced bilateral rhegmatogenous RD at age 60, requiring emergency surgical repair. Other notable ophthalmic features include unusual keratometry, abnormal biometry, and severe hayfever requiring long-term sodium cromoglycate treatment. The proband's sister, father, and uncle had also experienced RDs, all prior to LDS diagnosis. This series demonstrates that RD risk may be significant in LDS, and on occasion the presenting clinical feature. We suggest ophthalmic examination should be added to the initial assessment LDS patients, and patients informed of the early warning symptoms of retinal detachment. As in Marfan syndrome, LDS patients may exhibit cornea plana and abnormal corneal topography, producing atypical biometry. They may also present with allergic conjunctivitis, and awareness of these signs might facilitate earlier diagnosis.

Infant with Loeys-Dietz syndrome treated for febrile status epilepticus with COVID-19 infection: first reported case of febrile status epilepticus and focal seizures in a patient with Loeys-Dietz syndrome and review of literature.

Loeys-Dietz syndrome (LDS) is a rare, autosomal dominant multisystem disorder that is caused by mutations of transforming growth factor-ß receptors. Mutations in SMAD3 and TGFB3 have been recently reported.LDS is characterised by the triad of arterial tortuosity, hypertelorism and a bifid uvula or cleft palate among other cardiovascular, craniofacial and orthopaedic manifestations. Patients with LDS show clinical and genetic variability and there is a significant risk of reduced life expectancy due to widespread arterial involvement, aortic root dilation, aneurysms and an aggressive vascular course. Thus early genetic testing is warranted if clinical signs and history are suggestive of this potentially catastrophic disorder.LDS predisposes patients to aortic aneurysms and early death due to vascular malformations, but neurological emergencies, such as seizures and febrile status epilepticus, have not been reported.Febrile status epilepticus is the most common neurological emergency in childhood. Neurological manifestations of COVID-19 in the paediatric population are not as well described in medical literature.To the best of our knowledge, this is the first reported case of febrile status epilepticus with COVID-19 infection in an infant with LDS. Our patient had focal epileptiform activity emanating over the left posterior hemisphere, which evolved into an electrographic seizure on video EEG. Such patients have a heightened risk of epilepsy in the future, and this occurrence is consistent with a diagnosis of focal epilepsy. Neurological complications such as epilepsy and status epilepticus in a patient with LDS have never been reported before.A brief review of literature is also given here.

Intracranial Aneurysms in Loeys-Dietz Syndrome: A Multicenter Propensity-Matched Analysis.

BACKGROUND: Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by a classic triad of hypertelorism, bifid uvula and/or cleft palate, and generalized arterial tortuosity. There are limited data on the prevalence and rupture risk of intracranial aneurysms (IAs) in the setting of LDS, with no established guidelines. OBJECTIVE: To analyze the prevalence and rupture risk of IA in LDS. METHODS: Electronic medical records of patients with a confirmed diagnosis of LDS and available cerebrovascular imaging were reviewed. Patients were divided into 2 groups based on the presence of IA. Unmatched and propensity-matched analyses were used to identify potential risk factors for aneurysm formation. RESULTS: Records of 1111 patients were screened yielding a total of 60 patients with a diagnosis of LDS. Eighteen (30%) patients had IA, 4 (22.2%) of whom had multiple aneurysms for a total of 24 IAs. Twenty-three (95.8%) aneurysms were located in the anterior circulation; none of them were ruptured. On unmatched analysis, age ( P = .015), smoking history ( P = .034), hypertension ( P = .035), and number of extracranial aneurysms ( P < .001) were significantly higher in patients with IA. After matching for age, sex, race, stroke history, family history, and extracranial aneurysms, smoking history ( P = .009) remained significant. CONCLUSION: Patients with LDS have an increased risk of IAs, especially with a history of smoking. The prevalence rate of IAs in our series was 30%. Screening imaging should be considered at diagnosis, and patients should be encouraged to abstain from smoking. Further studies are needed to elucidate the risk of IA rupture and treatment considerations in this unique population.

Clinical features and complications of Loeys-Dietz syndrome: A systematic review.

INTRODUCTION: Loeys-Dietz syndrome (LDS) is a connective tissue disorder that arises from mutations altering the transforming growth factor ß signalling pathway. Due to the recent discovery of the underlying genetic mutations leading to LDS, the spectrum of characteristics and complications is not fully understood. METHODS: Our search included five databases (Pubmed, SCOPUS, Web of Science, EMBASE and google scholar) and included variations of "Loeys-Dietz Syndrome" as search terms, using all available data until February 2021. All study types were included. Three reviewers screened 1394 abstracts, of which 418 underwent full-text review and 392 were included in the final analysis. RESULTS: We identified 3896 reported cases of LDS with the most commonly reported features and complications being: aortic aneurysms and dissections, arterial tortuosity, high arched palate, abnormal uvula and hypertelorism. LDS Types 1 and 2 share many clinical features, LDS Type 2 appears to have a more aggressive aortic disease. LDS Type 3 demonstrated an increased prevalence of mitral valve prolapse and arthritis. LDS Type 4 and 5 demonstrated a lower prevalence of musculoskeletal and cardiovascular involvement. Amongst 222 women who underwent 522 pregnancies, 4% experienced an aortic dissection and the peripartum mortality rate was 1%. CONCLUSION: We observed that LDS is a multisystem connective tissue disorder that is associated with a high burden of complications, requiring a multidisciplinary approach. Ongoing attempts to better characterise these features will allow clinicians to appropriately screen and manage these complications.

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

BACKGROUND: Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder characterized by cardiovascular manifestations, especially aortic dilatations and arterial tortuosity, craniofacial and skeletal features, joint laxity or contractures, skin abnormalities, hypotonia and motor delay. Its diagnosis is established by the identification of a pathogenic variant in TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 or TGFB3 genes. In newborns and toddlers, vascular complications such as aneurism rupture, aortic dissection, and intracerebral incidents, can occur already in the weeks of life. To avoid these events, it is crucial to precociously identify this condition and to start an apunderwent a surgical procedurepropriate treatment which, depending on the severity of the vascular involvement, might be medical or surgical. CASE PRESENTATION: We report two cases of Loeys-Dietz syndrome precociously diagnosed. The first describes a male, born at 38 + 1 weeks of gestation, with hypotonia, joint hypermobility, arachnodactyly, and fingers joint contractures, as well as senile appearance and facial dysmorphisms. In the suspect of a connective tissue disorder, an echocardiography was performed and revealed an aortic root dilatation of 13 mm (Z score + 3). A trio based Whole Exome Sequencing found a novel de novo variant in the TGFBR2 gene. Despite the onset of a low-dose angiotensin receptor blocker therapy, the aneurysm progressed. The second case describes a female, born at 41 + 3 weeks of gestation. During the neonatal examination a cleft palate was noticed, as well as minor dysmorphisms. Since the family history was suspicious for connective tissue disorders, a genetic panel was performed and identified a pathogenetic variant in TGFB3 gene. In this case, the echocardiography revealed no abnormalities. CONCLUSIONS: In addition to our cases, we identified 14 subjects with neonatal LDS in the medical literature. All of them had aortic involvement. Skeletal and face abnormalities, including eyes and palate malformations, were also highly frequent. Overall, 10 subjects required medical therapy to avoid aneurysm progression, and 8 patients underwent surgical procedures. Benefits of an early diagnosis of LDS are various and imply a potential modification of the natural history of the disease with early interventions on its complications.

Loeys-Dietz syndrome caused by 1q41 deletion including TGFB2 is associated with a neurodevelopmental phenotype.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder that commonly results in a dilated aorta, aneurysms, joint laxity, craniosynostosis, and soft skin that bruises easily. Neurodevelopmental abnormalities are uncommon in LDS. Two previous reports present a total of four patients with LDS due to pure 1q41 deletions involving TGFB2 (Gaspar et al., American Journal of Medical Genetics Part A, 2017, 173, 2289-2292; Lindsay et al., Nature Genetics, 2012, 44, 922-927). The current report describes an additional five patients with similar deletions. Seven of the nine patients present with some degree of hypotonia and gross motor delay, and three of the nine present with speech delay and/or intellectual disability (ID). The smallest deletion common to all patients is a 785 kb locus that contains two genes: RRP15 and TGFB2. Previous studies report that TGFB2 knockout mice exhibit severe perinatal anomalies (Sanford et al., Development, 1997, 124, 2659-2670) and TGFB2 is expressed in the embryonic mouse hindbrain floor (Chleilat et al., Frontiers in Cellular Neuroscience, 2019, 13). The deletion of TGFB2 may be associated with a neurodevelopmental phenotype with incomplete penetrance and variable expression.

[A pedigree study of Loeys-Dietz syndrome type 4 with skeletal deformity related to a novel TGFß2 mutation].

Objective: Loeys-Dietz syndrome is a rare type of hereditary connective tissue disease. This study was aimed to analyze the clinical characteristics and gene mutations in a family of Loeys-Dietz syndrome with skeletal deformity. Methods: Clinical data of the proband and family members were collected and biochemical measurements and radiological examinations were conducted. Genomic DNA was extracted from peripheral blood of the family members. Whole-exome sequencing was performed to determine the mutation sites in the proband, and Sanger sequencing was applied to verify the candidate mutation in the other family members. Results: The proband is a 34-year-old man with deformities of lower extremities for more than 30 years. Physical examinations showed dolichostenomelia, pes planus, joint laxity and scoliosis. Echocardiography revealed the dilatation of aortic root at the level of the sinuses of Valsalva. A heterozygous missense mutation (c. 220A>C, p.Thr74Pro) in exon 1 of TGFß2 gene was identified in the proband. The same mutation was detected in his sister and niece with similar clinical features such as deformities of lower extremities and pes planus. This novel mutation has not been reported in ExAC or 1000G and was predicted to be deleterious, supporting a diagnosis of Loeys-Dietz syndrome type 4. Conclusions: Loeys-Dietz syndrome type 4 is caused by TGFß2 mutations. Skeletal deformity is one of the distinctive features. Genetic testing is helpful for the early diagnosis and differential diagnosis from other connective tissue diseases.

Loeys-Dietz and Shprintzen-Goldberg syndromes: analysis of TGF-ß-opathies with craniofacial manifestations using an innovative multimodality method.

BACKGROUND: Elevated transforming growth factor-beta (TGF-ß) signalling has been implicated in the pathogenesis of Loeys-Dietz syndrome (LDS) and Shprintzen-Goldberg syndrome (SGS). In this study, we provide a qualitative and quantitative analysis of the craniofacial and functional features among the LDS subtypes and SGS. METHODS: We explore the variability within and across a cohort of 44 patients through deep clinical phenotyping, three-dimensional (3D) facial photo surface analysis, cephalometric and geometric morphometric analyses of cone-beam CT scans. RESULTS: The most common craniofacial features detected in this cohort include mandibular retrognathism (84%), flat midface projection (84%), abnormal eye shape (73%), low-set ears (73%), abnormal nose (66%) and lip shape (64%), hypertelorism (41%) and a relatively high prevalence of nystagmus/strabismus (43%), temporomandibular joint disorders (38%) and obstructive sleep apnoea (23%). 3D cephalometric analysis demonstrated an increased cranial base angle with shortened anterior cranial base and underdevelopment of the maxilla and mandible, with evidence of a reduced pharyngeal airway in 55% of those analysed. Geometric morphometric analysis confirmed that the greatest craniofacial shape variation was among patients with LDS type 2, with distinct clustering of patients with SGS. CONCLUSIONS: This comprehensive phenotypic approach identifies developmental abnormalities that segregate to mutation variants along the TGF-ß signalling pathway, with a particularly severe phenotype associated with TGFBR2 and SKI mutations. Multimodality assessment of craniofacial anomalies objectively reveals the impact of mutations of the TGF-ß pathway with perturbations associated with the cranium and cranial base with severe downstream effects on the orbit, maxilla and mandible with the resultant clinical phenotypes.

Ocular findings in two Chinese children with Loeys-Dietz syndrome.

BACKGROUND: Loeys-Dietz syndrome (LDS) is a type of connective tissue disease with systemic symptoms similar to Marfan syndrome. Ocular findings are rarely reported especially fundus and extraocular muscles. CASE PRESENTATION: A 6-month old boy with systemic skeletal development delay was found peripheral non-perfusion and neovascularization in the both eyes, and gaven intravitreal injection of ranibizumab and laser. Fundus examination revealed a mild straightening of the temporal vessel in the both eyes. A 22-month old girl with confirmed connective tissue disorder presented to our hospital for strabismus and showed congenital hypoplasia of extraocular muscles. She also had arteriovenous anastomosis in the retinal. The diagnosis of LDS was supported by the genetic DNA examination. CONCLUSION: His is the first report of LDS with congenital hypoplasia of extraocular muscles, meanwhile, ocular examination especially fundus should be paid attention to.

Meester-Loeys Syndrome.

Meester-Loeys syndrome is an X-linked form of syndromic thoracic aortic aneurysm, characterized by the involvement of multiple organ systems. More specifically, the cardiovascular, skeletal, craniofacial, cutaneous and neurological systems are affected. Clear clinical overlap with Marfan syndrome and Loeys-Dietz syndrome is observed. Aortic dissections occur typically at young ages and are most often observed in males. Meester-Loeys syndrome is caused by loss-of-function mutations in BGN, encoding the small leucine-rich proteoglycan biglycan. Although functional consequences of these mutations remain largely elusive, increased TGF-ß signaling has been observed. Novel insights will provide opportunities for preventive therapeutic interventions.