Congenital Connective Tissue Disorders Research Articles

G.O.21 - P4HA1 mutations cause a unique congenital disorder of connective tissue involving tendon, bone, muscle and the eye

G.O.21 - P4HA1 mutations cause a unique congenital disorder of connective tissue involving tendon, bone, muscle and the eye

Experimental/numerical study to assess mechanical properties of healthy and Marfan syndrome ascending thoracic aorta under axial and circumferential loading

Ascending thoracic aortic aneurysm (ATAA) can be a life threatening disease as it leads to a lack of function in most of the connective tissues. Marfan syndrome is a congenital connective tissue disorder that may have influence on the cardiovascular system. It has been shown that Marfan syndrome invokes a degradation of the elastin and collagen content of the aortic wall and, consequently, a remarkable weakness in the mechanical strength of the arterial wall. However, so far, the mechanical properties of the aortic wall due to Marfan syndrome have not been determined. Therefore, this study was aimed to perform a comparative experimental study to quantify the linear elastic and non-linear hyperelastic mechanical properties of the healthy and Marfan syndrome ATA. Eight healthy and Marfan aorta tissues were excised from the human body during invasive cardiac surgery and autopsy respectively. The tissue samples were subjected to the longitudinal and circumferential loadings until breakage occurred. The elastic modulus, maximum stress and strain of the ATA tissues were calculated. The non-linear mechanical behaviour of the ATA tissues was also computationally investigated using Mooney–Rivlin hyperelastic material model. The results showed that the healthy ATA tissues are stiffer in the longitudinal direction compared to the circumferential direction. The highest elastic modulus (764.10 N cm− 2) and maximum stress (298.18 N cm− 2) were observed for the Marfan ATA wall in the longitudinal direction, while the healthy ATA tissues showed the axial elastic modulus and maximum stress of 367.08 and 220.14 N cm− 2 respectively. The hyperelastic material model also well defined the non-linear mechanical behaviour of the ATA tissues. These results may have implications not only for understanding the mechanical properties of the healthy and Marfan ATA tissues but also for a wide range of clinical applications, including valve repair or replacement.

The face in Marfan syndrome: a 3D morphometric study

Marfan syndrome (MFS) is a rare congenital disorder of the connective tissue mainly caused by mutations in the FBN1 gene, resulting in an altered assembly of extracellular matrix microfibrils and TGF-beta signalling dysregulation. Major clinical manifestations of MFS involve the skeletal, ocular, and cardiovascular systems, with a high risk of life-threatening aortic dissection and rupture. An early recognition of the disorder is essential, but it could be difficult, due to the variable phenotypic expression of the disease and the current incomplete sensitivity of molecular genetic testing of FBN1. It has been suggested that craniofacial dysmorphism associated with MFS could facilitate obstructive sleep apnea, which in turn may promote aortic dilation. The study aimed to investigate the face in MFS through a 3D not invasive approach [1], identifying new morphometric features which could facilitate the early diagnosis of the disease. The 3D coordinates of 50 anatomical facial landmarks were obtained using a stereophotogrammetric system in 68 Italian subjects diagnosed with MFS, aged 4-64 years (27 males, mean ± SD age 29.6 ± 18.2 years; 41 females, mean ± SD age 37.2 ± 15.5 years). Subjects were divided in 11 non-overlapping age groups. Facial linear distances and angles were measured; z score values were calculated comparing patients with healthy Italian reference subjects (347 males, 388 females), matched for gender and age. Subjects with MFS showed a shorter mandibular ramus than controls (mean z score = -1.9), a greater facial divergence (mean z score = +2.0), a reduced ratio between posterior and anterior facial height (mean z score = -1.9), and a reduced ratio between facial width and facial height (mean z score = -1.5), together with an expected but overall mild increase of facial height (mean z score = +1.3). Noteworthy gender differences or age trends were not observed. Facial abnormalities pointed out in the current study could represent phenotypic traits of MFS; since they were observed also in young patients, their detection could facilitate the early recognition, management, and follow up of the disease. These promising findings need to be confirmed extending the study on more patients.

Intramural aortic hematoma in an 11-years-old girl with Marfan′s syndrome

Marfan's syndrome is a rare congenital connective tissue disorder. It occurs worldwide with no sex predilection. Mutation in the fibrillin genes result in production of abnormal elastic tissue, which predisposes the aorta to cystic medial degeneration and may result in dissection, rupture, or aneurysm formation. Other vascular structures like the heart valves may also be involved causing aortic regurgitation and mitral valve prolapse and regurgitation. Aortic dissection is rare in children even in those with Marfan's syndrome. We report a case of an 11-years-old girl with Marfan's syndrome who had an intramural aortic hematoma.

NON-SPECIFIC CONGENITAL CONNECTIVE TISSUE DISORDERS AS AN INDEPENDENT PREDICTOR OF STRUCTURAL AND FUNCTIONAL ARTERIAL CHANGES

Aim. To assess the impact of non-specific congenital connective tissue disorders (CCTD) on the changes in arterial stiffness and endothelial function; to study the role of CCTD as an independent predictor of structural and functional arterial changes.Material and methods. The study included 147 18–50-year-old men and women with CCTD and 85 healthy volunteers, comparable by age and gender (controls). All participants underwent a screening assessment of cardiovascular risk factors (RFs) and the assessment of heart rate variability (HRV), pulse wave velocity (PWV) at baseline (PWVbas) and after sublingual administration of nitroglycerin (PWVntg), and endothelium-dependent vasodilatation (EDVD), assessed by photopletismography.Results. Compared to the control group, CCTD patients had lower values of body mass index (p<0,001), waist circumference, WC (p<0,001), hip circumference, HC (p<0,001), WC/HC ratio (p<0,005), systolic blood pressure (p<0,05), total cholesterol (p<0,001), low-density lipoprotein cholesterol (p<0,005), atherogenicity index (p<0,05), and triglycerides (p<0,005). Moreover, CCTD patients were characterized by sympathetic activation, increased PWVbas (p<0,001), PWVntg (p<0,05), and EDVD (p<0,001). According to the results of stepwise multivariate analyses of the whole sample data, CCTD was a significant independent predictor of PWVbas (p<0,001), PWVntg (p<0,005), and EDVD (p<0,005 and <0,05 in men and women, respectively).Conclusion. Patients with CCTD demonstrated increased arterial stiffness and endothelium-dependent vasodilatation, compared to healthy controls. Independently from cardiovascular RFs and autonomic dysregulation, CCTD is a significant predictor of structural and functional arterial changes and can also have a prognostic value. These findings should be taken into account in the studies which assess vascular parameters.

Endovascular Repair of Bilateral Iliac Artery Aneurysms in a Patient With Loeys–Dietz Syndrome

Loeys-Dietz syndrome (LDS) is a rare congenital connective tissue disorder (CTD) caused by mutations in the gene encoding for transforming growth factor-β receptors I and II. This recently described syndrome is characterized by aortic aneurysms anddissections, arterial tortuosity, and spontaneous organ perforation. The technical feasibility of endovascular interventions, particularly endovascular aneurysm repair (EVAR), in CTDs is relatively unknown. A 38-year-old man presented with asymptomatic bilateral common iliac artery aneurysms measuring 5.3 cm on the right and 4.3 cm on the left. The patient had an extensive surgical and medical history, including a recently repaired Stanford type-A aortic dissection, total colectomy with end ileostomy for a colonic perforation, splenectomy for rupture, and cirrhosis secondary to chronic hepatitis C. The patient's CTD, multiple abdominal surgeries performed in the past, and ileostomy made him a poor candidate for open repair. We elected to offer him a complex endovascular repair and hoped to preserve his pelvic circulation by using "double-barrel" configuration of stent-grafts in the right iliac artery system. Successful deployment of the devices and repair of femoral access allowed routine discharge on postoperative day 2. At 6-month follow-up, the patient's pelvic circulation has been maintained, the aneurysms are excluded without endoleak, and sac regression has been shown. LDS is a rare connective tissue disorder characterized by vascular aneurysms and arterial tortuosity. When vascular reconstruction is necessary, open techniques are often preferred given the lack of data on endovascular procedures. In the present case, we report the first successful abdominal EVAR in a high-risk patient with LDS, providing excellent short-term results.

Professional parachuting: the risk of acute aortic dissection

Acute aortic dissection is a rare disease, but if it occurs rapid diagnosis and therapy are needed. It is usually seen in elderly patients with long-term persistent arterial hypertension. In younger patients, it is mainly caused by congenital connective tissue disorders, such as Marfan syndrome, or by trauma. We present here a 34-year-old male patient with an acute type A aortic dissection. This patient was a professional parachutist and had carried out a large number of parachute jumps during his lifetime. He was admitted to the emergency department with acute chest pain. The symptoms were not related in time to a parachute jump. During a computed tomography scan, an aortic dissection was diagnosed. The patient was immediately referred to the operating room, and the ascending aorta was replaced by a conduit. After a regular postoperative course, the patient was discharged and recovered completely. Although acute aortic dissection is rare in young patients, it has to be considered in cases of acute chest pain. An immediate diagnosis and adequate therapy are essential to offer the patient a good clinical outcome and long-term survival.

Is aortopathy in bicuspid aortic valve disease a congenital defect or a result of abnormal hemodynamics? A critical reappraisal of a one-sided argument

Although there is adequate evidence that bicuspid aortic valve (BAV) is an inheritable disorder, there is a great controversy regarding the pathogenesis of dilatation of the proximal aorta. The hemodynamic theory was the first explanation for BAV aortopathy. The genetic theory, however, has become increasingly popular over the last decade and can now be viewed as the clearly dominant one. The widespread belief that BAV disease is a congenital disorder of vascular connective tissue has led to more aggressive treatment recommendations of the proximal aorta in such patients, approaching aortic management recommendations for patients with Marfan syndrome. There is emerging evidence that the 'clinically normal' BAV is associated with abnormal flow patterns and asymmetrically increased wall stress in the proximal aorta. Recent in vitro and in vivo studies on BAV function provide a unique hemodynamic insight into the different phenotypes of BAV disease and asymmetry of corresponding aortopathy even in the presence of a 'clinically normal' BAV. On the other hand, there is a subgroup of young male patients with BAV and a root dilatation phenotype, who may present the predominantly genetic form of BAV disease. In the face of these important findings, we feel that a critical review of this clinical problem is timely and appropriate, as the prevailing BAV-aortopathy theory undoubtedly affects the surgical approach to this common clinical entity. Thorough analysis of the recent literature shows a growing amount of evidence supporting the hemodynamic theory of aortopathy in patients with BAV disease. Data from recent studies requires a reevaluation of our overwhelming support of the genetic theory, and obliges us to acknowledge that hemodynamics plays an important role in the development of this disease process. Given the marked heterogeneity of BAV disease, further studies are required in order to more precisely determine which theory is the 'correct' one for explaining the obviously different types of BAV-associated aortopathy.

Total Hip Arthroplasty in Young Adults with Stickler Connective Tissue Disorder: Review of Literature and Case

Connective tissue disorders such as Stickler syndrome cause the premature development of musculoskeletal diseaseresembling spondyloepiphyseal dysplasia, in some cases requiring surgical intervention for premature developmentof osteoarthritis. Total hip arthroplasty is a routine procedure regarded as highly successful in maintaining mobilityin elderly patients. When hip replacement is required in the young, unique challenges are presented to the surgeonincluding efforts to maximize the life of the first prosthesis while also considering that multiple revisions will likelybe necessary. A 17 year old male patient presented with a connective tissue disorder, exhibiting symptoms of Sticklersyndrome. The patient suffered from acute episodes of pain and dysfunction including mechanical clicking andoccasional locking, originally seeking orthopaedic assessment at 14 years old. Total hip arthroplasty was performedafter the patient’s femoral growth plate had fused radiologically and is presented as an option to treat the multifacetedabnormal hip joint caused by Sticklers syndrome. In this way, hip mobility and functionality can be vastlyimproved in young adults with debilitating congenital connective tissue disorders.

Anatomical repair of a congenital aneurysm of the distal abdominal aorta in a newborn

Congenital (primary) neonatal abdominal aortic aneurysm (AAA) is an extremely rare truncular arterial abnormality among numerous congenital vascular malformations. Only seven cases have been reported as congenital origin in newborns. This report presents the case of a male infant in whom a 33-mm congenital AAA was diagnosed prenatally and was successfully treated 10 days after birth without exogenous graft material or aneurysmorrhaphy. Follow-up study at 39 months demonstrated excellent clinical, ultrasound scan, and computed tomography scan findings. Anatomic reconstruction with native vessels is the preferred surgical technique to ensure the child's potential for harmonious growth.

Diagnostik und Therapie der Osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a congenital connective tissue disorder with an incidence of up to 1:30,000. Patients suffer from deformities and fractures, and many of them never reach ambulation. The therapy consists of conservative, medicamentous and operative procedures that are described in this article.

An Anesthetic Experience of Intraoperative Hypercapnia in a Patient with Larsen Syndrome: A case report

Larsen syndrome is a rare congenital connective tissue disorder which is characterized by multiple dislocation of major joints, typical facial appearance, cervical spine narrowing and instability, and respiratory difficulties secondary to laryngo-tra-cheomalacia. We describe a case of general anesthesia for orthopedic operations in female infant consistent with Larsen syn-drome. The patient showed hypercapnia intraoperatively, but recovered without any sequelae.

Anesthetic management in fibrodysplasia ossificans progressiva (FOP): a case report

Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder of connective tissue, which has significant implications on anesthetic management of affected patients, e.g., application of difficult airway algorithm, avoiding any trauma during venous cannulation. FOP has received very limited reviews in the published anesthesia literature. We describe perioperative care of a 21-year-old female with established diagnosis of FOP presenting for hysteroscopy followed by dilatation and curettage. Multiorgan abnormalities of FOP are reviewed and available anesthetic options are analyzed and compared.

Divertículo vesical congénito y Síndrome de ehlers-danlos: una rara asociación

The existence of a vesical diverticulum in the context of a congenital connective tissue disorder such as Ehlers-Danlos syndrome led us to consider the possibility of a relationship. Four types of diverticula can be found in the literature: congenital, acquired, iatrogenic and syndrome-associated. Within the later, Ehlers-Danlos syndromes type IV and IX, even type V, are associated to the existence of vesical diverticula. The potential spontaneous rupture of the diverticulum is a typical feature, as well as post-surgery relapse. The attitude towards such diverticula should be one of watchful waiting, and simple, plasty-free diverticulectomy on the bladder's neck is indicated when performing a surgical procedure.

Increased Proliferation of Bone Marrow-Derived Fibroblasts in Primitive Hypertrophic Osteoarthropathy With Severe Myelofibrosis

Pachydermoperiostosis or primary hypertrophic osteoarthropathy (HOA) is a rare congenital growth disorder of connective tissue. We report a case of severe myelofibrosis in a patient with HOA. When cultured in vitro, patient bone marrow-derived fibroblasts displayed a high proliferative potential with a shortened doubling time (24 hours v 36 to 48 hours for normal fibroblasts). The role of platelet-derived growth factor (PDGF), previously implicated in the pathogenesis of secondary acquired myelofibrosis, was studied. HOA fibroblasts expressed an increased number of PDGF-BB binding sites (300,000 sites/cell v 200,000 sites/cell for normal fibroblasts) without any modification of affinity. The increased expression of PDGF-R beta appeared to result from an accelerated rate of PDGF-R beta resynthesis with normal kinetics of endocytosis. As a consequence, a several-fold increase of PDGF-R beta tyrosine kinase activity was observed. No autocrine mechanism of growth was suspected as neither spontaneous PDGF-R beta autophosphorylation nor mitogenic activity in HOA fibroblast-conditioned medium was detected. Patient serum and platelet lysate were less potent than controls in inducing [3H]thymidine incorporation into HOA fibroblasts. This was inconsistent with a paracrine mechanism of growth. In vitro, human serum or PDGF-BB were not more mitogenic for HOA than normal fibroblasts. High levels of cyclin D1, a putative oncogene, were detected in serum-deprived HOA fibroblasts. Cyclin D1 overexpression could be implicated in the accelerated growth of these cells. Our results suggest that the mechanism of fibroblastic proliferation observed in this case of myelofibrosis might differ from those reported in other acquired myeloproliferative syndromes and could be associated with an intrinsic abnormality of HOA fibroblast growth.

Familial Elastosis Perforans Serpiginosa

Elastosis perforans serpiginosa (EPS) is an uncommon skin disease characterized by transepidermal elimination of abnormal elastic fibers. The disease is frequently associated with congenital connective tissue disorders or Down's syndrome. The pathogenesis of EPS is still unclear. There are a few reports in the literature about a familial occurrence of EPS in which different modes of inheritance are suggested. To support the hypothesis of a congenital origin of the disease, we have studied another family with EPS. In this study, we describe a family in which two sisters and a brother were affected by EPS. The father and three paternal uncles were most probably affected by the same disease. There were no signs of other congenital connective tissue disease in the family members. An autosomal dominant mode of inheritance with variable expression of EPS is suggested.