Marfan-like Phenotype Research Articles

Results of surgical treatment of children with lens subluxation

AIM: To assess the effectiveness of the surgical treatment of patients with lens subluxation, who were under 18 years old.
 MATERIAL AND METHODS: This study presented an analysis of the results of surgical treatment of eight patients with lens subluxation. The operations were performed in the Department of Ophthalmology of the State Healthcare Institution of Healthcare MCMC “Bonum,” carried out in 2020–2022. The inclusion criteria were as follows: age under 18 years, Marfan-like phenotype, stages 2–4 subluxation, absence of retinal changes and other eye pathologies, and surgical treatment performed in 2020–2022. The mean age at the detection of lens subluxation was 3.9±2.0 years, and the age during primary surgery was 5.4±1.9 years. All patients underwent phacoaspiration of the subluxated lens with anterior vitrectomy, simultaneous implantation, and sclerocorneal fixation of the intraocular lens by the same surgeon using the same equipment and consumables.
 RESULTS: The ophthalmological status was mainly assessed, and a statistical difference (p 0.05) was found between pre- and postoperative indicators. Before surgery, the maximum corrected visual acuity was 0.15±0.12 (min 0.02; max 0.5); spherical equivalent, 6.8±4.7 (min -15; max +16); total astigmatism value, 3.25±1.15 (min, 1; max, 6.5); and corneal astigmatism, 2.4±0.9 (min, 1; max, 3.9). After the surgical treatment, the maximum corrected visual acuity was 0.53±0.31 (min, 0.05; max, 0.9); spherical equivalent, −0.6±1.71 D (min −3.5; max +3); total astigmatism, -1.63±0.75 D (min, -0.25; max, −2.75); corneal astigmatism, 2.4±0.7 D (min 1; max 3.5). All operations were performed without complications. The postoperative period in patients was regarded as unreactive.
 CONCLUSION: The results show that sclerocorneal fixation allows for reliable and safe fixation of intraocular lenses without capsule support. A statistically significant increase in visual acuity was found after surgery; however, for optimal functional results in the postoperative period, refractive errors and pleoptic treatment must be controlled.

Aggressive Aortic Disease with Marfan-like Phenotype in Malaysian Patients with Loeys-Dietz Syndrome

Loeys- Dietz Syndrome (LDS, pronounced LOH-eez-DEETS) is a connective tissue disorder that was first described in 2005. In the past, many patients were misdiagnosed clinically as Marfan Syndrome (MFS) due to their overlapping phenotype. Distinguishing craniofacial features of LDS include hypertelorism, bifid uvula, cleft palate and absence of lens dislocation. Unlike MFS, aortic root dilatation with or without arterial tortuosity elsewhere are almost always present. Patient 1 was a 7-year- old boy, diagnosed with MFS at 4 years of age. Echocardiogram showed aortic root dilatation with no lens dislocation on eye assessment. He was initially started on β-blocker by the cardiologist, losartan was added on subsequently due to the increasing size of his aortic root diameter. Patient 2 was a 14-year-old boy, followed up for severe aortic root dilatation. He had a stormy neonatal period; diagnosed with tracheobronchomalacia, multiple joint dislocation, feeding intolerance, scoliosis and squint. He was followed up for many years as possible MFS. Genetic testing performed showed mutation at TGFBR2 gene, confirming a diagnosis of LDS in both patients. In addition to these families, another 6 families under our aortopathy clinic follow up have had their diagnosis of LDS confirmed molecularly. LDS is increasingly being described in patients with a more severe aortic disease and Marfan-like phenotype. The difference in disease severity highlights the importance of genetic testing in patients with suspected aortopathy, enabling timely implementation of therapeutic strategies.

Homocysteinemia As An Independent Risk Factor For The Development Of Diabetic Kidney Damage In Diabetes Mellitus

The history of the study of hyperhomocysteinemia goes back half a century. It is interesting that the increased level of homocysteine as a factor of vascular damage was first noticed in pediatric practice. In 1969, Kilmer S. MeCully, a professor in the Department of Pathology at Harvard University, studying a rare genetic disorder manifested by homocysteinuria (increased levels of homocysteine in the urine), suggested a link between elevated serum homocysteine levels and arterial disease. Without treatment, these children usually die at an early age from myocardial infarction or cerebral strokes. During autopsy, it was found that their vessels were the same damaged and thickened as in elderly patients with cardiovascular diseases. Clinically, this disease is characterized by a marfan-like phenotype, connective tissue lesions (high growth, arachnodactyly, lens subluxation, chest deformities, heart defects), neuropsychiatric disorders, arterial thrombosis. The pathology is based on a defect in one of the metabolic enzymes of sulfur-containing methionine, mainly in the amino acid cystothionine-E-synthetase (classical tomocysteinuria). Subsequently, it was shown that moderate and mild homocysteinemia affects the vessels of various localization, leading to pathological changes in them.

Мутация в гене ADAMTSL4 у пациентки с марфаноподобным фенотипом (марфаноидной внешностью) без Ectopia lentis при несостоятельности рубца на матке после кесарева сечения

Мутация в гене ADAMTSL4 у пациентки с марфаноподобным фенотипом (марфаноидной внешностью) без Ectopia lentis при несостоятельности рубца на матке после кесарева сечения

К вопросу об этиопатогенетических причинах формирования марфаноподобного фенотипа (марфаноидной внешности)

К вопросу об этиопатогенетических причинах формирования марфаноподобного фенотипа (марфаноидной внешности)

Role of heritable connective tissue diseases phenotypes in assessing the risk for internal diseases

Aim. To identify the prevalence of main phenotypes of polygenic heritable connective tissue diseases in patients with internal diseases and to assess the prevalence of different internal diseases in such patients. Methods. The study involved 600 patients (254 males, 346 females) aged 18 to 64 years. Average age of males was 52±3.8 years, females - 47±2.2 years. Patients were examined to reveal the signs of different phenotypes of heritable connective tissue diseases in patients with internal diseases, as well as the severity of connective tissue diseases, and possibilities for it screening using the wrist and thumb hypermobility tests. Results. Signs of heritable connective tissue diseases were revealed in 147 (24.5%) patients with internal diseases. In females, those signs were observed in 104 (30.0%) cases, of which 44 (42.3%) were graded as mild, 35 (33.7%) - moderate, 25 (24.0%) - severe. In males, signs of heritable connective tissue diseases were revealed in 43 cases (16.9%), including mild - 17 (39.5%), moderate - 14 (32.5%) and severe - 12 (28.0%). Ehlers-like phenotype was the most common (52.0%), Marfan-like phenotype was observed in 14.0% of cases, primary mitral valve prolapse was diagnosed in 7.0% of patients, unclassifiable phenotype was observed in 11.0% of cases. Joint hypermobility syndrome was revealed in 31.0% of patients, presenting both as specific phenotypes (Marfan-like, Ehlers-like) and as a self-phenotype (31.9% of all the patients with heritable connective tissue diseases phenotype). Benign joint hypermobility was observed in 6.1% of cases. Symptoms of heritable connective tissue diseases were more frequent in patients with gastrointestinal and musculoskeletal diseases. Conclusion. The most common phenotype of heritable connective tissue diseases is Ehlers-like with skin, bone and systemic manifestations. Presence of heritable connective tissue diseases was most commonly associated with gastrointestinal and musculoskeletal diseases.

A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm

A number of autosomal dominantly inherited disorders, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), are associated with predisposition to thoracic aortic aneurysms and dissections (TAADs). In the majority of cases, mutations in genes encoding components of the transforming growth factor-β (TGF-β) signaling pathway, such as FBN1, TGFBR1, TGFBR2 and SMAD3, underlie the disease. Recently, a familial syndromic form of TAAD with other clinical features that overlap the MFS-LDS spectrum has been described to be caused by heterozygous loss-of-function mutations in TGFB2, encoding the TGF-β2 ligand of TGF-β serine/threonine kinase receptors (TGFBRs). We analyzed the TGFB2 gene by sequencing in a cohort of 88 individuals with a Marfan-like phenotype and/or TAAD, who did not have mutations in known genes causing thoracic aortic disease. We identified the novel heterozygous c.1165dupA mutation in exon 7 of TGFB2 in three members of a family, a 51-year-old male, his brother and nephew with aortic aneurysms, cervical arterial tortuosity and/or skeletal abnormalities as well as craniofacial dysmorphisms. The 1-bp duplication causes a frameshift leading to a stable transcript with a premature stop codon after seven TGF-β2-unrelated amino acids (p.Ser389Lysfs*8). As the resulting protein is unlikely functional and by considering data from the literature, we support the notion that functional haploinsufficiency for TGF-β2 predisposes to thoracic aortic disease. Taken together, TGFB2 is a rarely mutated gene in patients with syndromic TAAD, and the clinical features of our TGFB2 mutation-positive individuals fit in the scheme of LDS, rather than MFS-related disorders.

Genotype-Phenotype Correlation of 2q37 Deletions Including NPPC Gene Associated with Skeletal Malformations

Coordinated bone growth is controlled by numerous mechanisms which are only partially understood because of the involvement of many hormones and local regulators. The C-type Natriuretic Peptide (CNP), encoded by NPPC gene located on chromosome 2q37.1, is a molecule that regulates endochondral ossification of the cartilaginous growth plate and influences longitudinal bone growth. Two independent studies have described three patients with a Marfan-like phenotype presenting a de novo balanced translocation involving the same chromosomal region 2q37.1 and overexpression of NPPC. We report on two partially overlapping interstitial 2q37 deletions identified by array CGH. The two patients showed opposite phenotypes characterized by short stature and skeletal overgrowth, respectively. The patient with short stature presented a 2q37 deletion causing the loss of one copy of the NPPC gene and the truncation of the DIS3L2 gene with normal CNP plasma concentration. The deletion identified in the patient with a Marfan-like phenotype interrupted the DIS3L2 gene without involving the NPPC gene. In addition, a strongly elevated CNP plasma concentration was found in this patient. A possible role of NPPC as causative of the two opposite phenotypes is discussed in this study.

Acute Aortic Dissection Associated with Cystic Medial Necrosis of Unknown Etiology

A 61-year-old man without a Marfan-like phenotype was admitted to the hospital because of acute Stanford type A aortic dissection. The patient underwent surgical repair with total arch replacement. Histological examination of the excised aorta showed a connective tissue abnormality, which could have contributed to the development of aortic dissection. The cause of the connective tissue abnormality could not be determined through physical examination. Recently, however, many novel gene mutations have been found to be related to aortic diseases that do not always produce physical signs and symptoms. In this case, unknown causes of connective tissue abnormalities might be existed.

Classical familial homocystinuria in an adult presenting as an isolated lens subluxation

To report a case of late diagnosis of a classical familial homocystinuria based on an ophthalmologic examination. A 35-year-old male with Marfan-like phenotype complained of a progressive increase of myopia during the previous 2years. Ophthalmologic exploration showed a bilateral subluxation of the lens with inferior and nasal displacement. Biochemical study detected a profile of increased amino acid levels (homocysteinemia) consistent with suspected homocystinuria. Vascular and skeletal studies ruled out Marfan syndrome. Response to treatment demonstrated B(6)-non-responsive homocystinuria. Molecular study showed compound heterozygous T353N and D444N mutations of the cystathionine beta-synthase (CBS) gene, and also a C667T homozygous mutation of the methylenetetrahydrofolate-reductase (MTHFR) gene. Family study showed classical homocystinuria in his father and sister, although they did not present any systemic or ocular features of the disease. Homocystinuria is a metabolic disease usually presenting at an early age as vascular, skeletal and neuropsychiatric abnormalities, as well as ectopia lentis. Our case is atypical because of the absence of thromboembolism and the mild phenotype, in spite of being B(6)-non-responsive, and the association of a rare compound heterozygous mutation of the CBS gene and also an homozygous mutation of the MTHFR gene. It is necessary to rule out homocystinuria in patients with ectopia lentis, even in the absence of systemic symptoms.

314 Outcomes and prognosis in patient with TGFBR2 or FBN1 gene mutation

TGFBR2 mutations were recently recognized among patients with a Marfan-like phenotype and have been associated with poor cardiovascular prognosis (early deaths, aortic dissections or early surgery for thoracic ascending aorta aneurysm). Clinical features and outcomes were analysed in a group of 71 patients (including 22 children) with a TGFBR2 mutation. Patients were compared with age- and gender-matched patients harbouring the FBN1 mutation (FBN1 group n=243). The proportion of patients with aortic dilatation was similar in the TGFBR2 group and in the FBN1 group in both adults [74% vs. 76%] and children [86%vs. 86%] and aortic dilatation was very variable in both TGFBR2 and FBN1 groups. The incidence and average age of thoracic aortic surgery for aortic dissection or aortic dilatation were similar in the 2 groups (31% vs. 27% and 35±16 vs. 39±13 years, NS). Both the frequency and the age of occurrence of aortic dissection were similar in the TGFBR2 and the FBN1 groups for the ascending aorta [14% vs. 10%, p=0.26; 38±12 vs. 39±9 years, p=0.82] and for the descending aorta (3/71 vs. 8/243, p=0.72; 34±6 vs. 44±10 years, p=0.16). In contrast, aortic dilatation, dissection or sudden death was the index event leading to genetic diagnosis within the family in 65% of families with TGFBR2 mutations and only 32% in families with FBN1 mutations (p = 0.002). When these family members were included in the survival analysis, mortality was worse in TGFBR2 families than in FBN1 families (p= 0.017) whereas it was similar if only patients benefiting for preventive care (i.e. in whom the mutation had been identified) were included (p = 0.39). The wide clinical spectrum of patients with TGFBR2 gene mutations underscores the importance of molecular biology for early diagnosis. The prognosis of a patient depends on the clinical expression of the disease and not solely on the presence of a mutation in the TGFBR2 gene.

Comparison of Clinical Presentations and Outcomes Between Patients With TGFBR2 and FBN1 Mutations in Marfan Syndrome and Related Disorders

TGFBR2 mutations were recognized recently among patients with a Marfan-like phenotype. The associated clinical and prognostic spectra remain unclear. Clinical features and outcomes of 71 patients with a TGFBR2 mutation (TGFBR2 group) were compared with 50 age- and sex-matched unaffected family members (control subjects) and 243 patients harboring FBN1 mutations (FBN1 group). Aortic dilatation was present in a similar proportion of patients in both the TGFBR2 and FBN1 groups (78% versus 79%, respectively) but was highly variable. The incidence and average age for thoracic aortic surgery (31% versus 27% and 35+/-16 versus 39+/-13 years, respectively) and aortic dissection (14% versus 10% and 38+/-12 versus 39+/-9 years) were also similar in the 2 groups. Mitral valve involvement (myxomatous, prolapse, mitral regurgitation) was less frequent in the TGFBR2 than in the FBN1 group (all P<0.05). Aortic dilatation, dissection, or sudden death was the index event leading to genetic diagnosis in 65% of families with TGFBR2 mutations, versus 32% with FBN1 mutations (P=0.002). The rate of death was greater in TGFBR2 families before diagnosis but similar once the disease had been recognized. Most pregnancies were uneventful (without death or aortic dissection) in both TGFBR2 and FBN1 families (38 of 39 versus 213 of 217; P=1). Seven patients (10%) with a TGFBR2 mutation fulfilled international criteria for Marfan syndrome, 3 of whom presented with features specific for Loeys-Dietz syndrome. Clinical outcomes appear similar between treated patients with TGFBR2 mutations and individuals with FBN1 mutations. Prognosis depends on clinical disease expression and treatment rather than simply the presence of a TGFBR2 gene mutation.

LRP1 Functions as an Atheroprotective Integrator of TGFβ and PDGF Signals in the Vascular Wall: Implications for Marfan Syndrome

BackgroundThe multifunctional receptor LRP1 controls expression, activity and trafficking of the PDGF receptor-β in vascular smooth muscle cells (VSMC). LRP1 is also a receptor for TGFβ1 and is required for TGFβ mediated inhibition of cell proliferation.Methods and Principal FindingsWe show that loss of LRP1 in VSMC (smLRP−) in vivo results in a Marfan-like syndrome with nuclear accumulation of phosphorylated Smad2/3, disruption of elastic layers, tortuous aorta, and increased expression of the TGFβ target genes thrombospondin-1 (TSP1) and PDGFRβ in the vascular wall. Treatment of smLRP1− animals with the PPARγ agonist rosiglitazone abolished nuclear pSmad accumulation, reversed the Marfan-like phenotype, and markedly reduced smooth muscle proliferation, fibrosis and atherosclerosis independent of plasma cholesterol levels.Conclusions and SignificanceOur findings are consistent with an activation of TGFβ signals in the LRP1-deficient vascular wall. LRP1 may function as an integrator of proliferative and anti-proliferative signals that control physiological mechanisms common to the pathogenesis of Marfan syndrome and atherosclerosis, and this is essential for maintaining vascular wall integrity.

The FBN1 (R2726W) mutation is not fully penetrant

The R2726W mutation in the fibrillin 1 (FBN1, Marfan syndrome) gene segregates with isolated skeletal features of Marfan syndrome and/or high stature. Here we report a family in which two out of four individuals, an 18-year-old son and his mother, a 41-year-old woman, had the R2726W mutation of FBN1. Both family members carrying the mutation were of average height. The son had a Marfan-like phenotype, but his mother did not. The FBN1 R2776W mutation, which is associated with skeletal features of Marfan syndrome, appears incompletely penetrant. Consequently, genetic counselling in the presence of this mutation is difficult.

Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy.

Marfan syndrome (MFS) is a disorder of the extracellular matrix caused by mutations in the gene encoding fibrillin-1 (FBN1). Recent studies have illustrated the variability in disease severity and clinical manifestations of MFS. Useful genotype-phenotype correlations have been slow to emerge. We screened 57 unrelated patients with MFS or a Marfan-like phenotype using a combination of SSCP and/or DHPLC. We detected 49 different FBN1 mutations, 30 (62%) of which were novel. The mutations comprised 38 substitutions (78%), 10 deletions (20%), and one duplication (2%). There were 28 missense (57%), nine frameshift (18%), eight splice site (16%), and four nonsense mutations (8 %). Genotype-phenotype analysis revealed that patients with an identified FBN1 mutation were more likely to have ectopia lentis and cardiovascular complications compared to those without an identifiable mutation (relative risks of 4.6 and 1.9, respectively). Ectopia lentis was also found to be more prevalent in patients whose mutations involved a cysteine substitution (relative risk 1.6) and less prevalent in those with premature termination mutations (relative risk 0.4). In our hands, we achieved 93% mutation detection for DHPLC analysis of patients who fulfilled the Ghent criteria. Further analysis of detailed clinical information and mutation data may help to anticipate the clinical consequences of specific FBN1 mutations.

Defective expression of HLA class I and CD1a molecules in boy with Marfan-like phenotype and deep skin ulcers

We report the case of a boy with low expression of HLA class I molecules on peripheral blood mononuclear cells, which is associated with immunodeficiency. The patient, who had a Marfan-like phenotype, had chronic deep skin ulcers and sinobronchiectasis. Immunohistologic examination of the ulcerated skin showed a dense perivascular infiltrate composed of normal mature lymphocytes and macrophages. All cells in the infiltrate showed an apparently normal expression of HLA class I molecules, but intraepidermal dendritic Langerhans' cells were negative for CD1a, an antigen that is a highly specific marker for these cells and is abundantly expressed in some self-healing forms of cutaneous lesions. It is therefore speculated that a defective expression of CD1a molecules can contribute to the chronic persistence of deep skin ulcers, which have already been reported in association with defective expression of HLA class I molecules.