Neuropsychological aspects of Marfan syndrome

We evaluated the neuropsychological status of 13 adult patients with Marfan syndrome. All subjects were administered the same neuropsychological test battery that included nine measures covering a broad range of cognitive abilities such as attention and concentration, learning and memory, and verbal and non-verbal abilities. Compared to a control group of 13 normal healthy subjects matched for sex, age and verbal intelligence, Marfan patients only performed significantly worse on tests measuring sustained visual attention and visuoconstruction. Although these tests use visual material and depend on visual perception and processing, the visual acuity problems associated with the syndrome could not explain these differences, nor could the use of beta-blocking medication or the presence of joint hypermobility. The findings suggest that problems with sustained visual attention and visuoconstruction may be present in Marfan syndrome over and above visual acuity problems and other phenomena associated with the disease. Further research on the neuropsychological aspects of Marfan syndrome is needed, using larger patient groups and more adequate control groups such as non-affected siblings and matched controls with similar visual impairment.     

Systematic review of the psychosocial aspects of living with Marfan syndrome

The purpose of this study was to explore the literature on the psychosocial aspects of Marfan syndrome (MFS), to critically appraise and to synthesize relevant literature. A mixed‐method systematic review was performed by searching the published literature databases using available medical, psychological, pedagogical and social databases and other sources. All studies that addressed psychosocial aspects of MFS, published in peer‐reviewed journals were assessed. Of 81 search results, 15 articles (four articles based on same study population) satisfied the eligibility criteria. All studies were cross‐sectional; no intervention or randomized controlled trial (RCT) studies were found. Most studies were of small sample sizes, had low response rate or participants without a verified diagnosis. Despite these limitations, all studies described, that MFS has a significant impact on the psychosocial aspects of people's lives: Decreased quality of life; challenges in education, work and family life, depression and anxiety. Some studies indicated that the subjective perception of discomfort did not necessarily match the medical severity of a disease. The research of the psychosocial aspects of MFS is limited in size and quality. More research is needed on the psychosocial aspects of MFS in samples with a verified diagnosis to develop evidence‐based knowledge and appropriate guidelines.     

Hiatus/paraesophageal hernias in neonatal Marfan syndrome

We report on an infant with neonatal Marfan syndrome (NMS) and hiatus/paraesophageal hernia who presented to a university hospital with an unusual early complication of this connective tissue disorder. An abnormal course of the nasogastric tube was noted on the first day of life by a radiograph of the chest and abdomen performed for bloody gastric drainage. The question of esophageal perforation was raised. Subsequent contrast study demonstrated a large hiatus/paraesophageal hernia with pronounced gastroesophageal reflux (GER). A part of the hernia was positioned posterior and to the right of the gastroesophageal junction (GEJ), presumably the location of the nasogastric tube as noted on the initial films. Although characterized by cardiac/aortic abnormalities, NMS can be a difficult diagnosis and should be considered in any infant with hiatus/paraesophageal hernia with or without GER. Am. J. Med. Genet. 72:156–158, 1997. © 1997 Wiley-Liss, Inc.     

The molecular genetics of Marfan syndrome and related microfibrillopathies

Mutations in the gene for fibrillin-1 (FBN1) have been shown to cause Marfan syndrome, an autosomal dominant disorder of connective tissue characterised by pleiotropic manifestations involving primarily the ocular, skeletal, and cardiovascular systems. Fibrillin-1 is a major component of the 10-12 nm microfibrils, which are thought to play a role in tropoelastin deposition and elastic fibre formation in addition to possessing an anchoring function in some tissues.
  Fibrillin-1 mutations have also been found in patients who do not fulfil clinical criteria for the diagnosis of Marfan syndrome, but have related disorders of connective tissue, such as isolated ectopia lentis, familial aortic aneurysm, and Marfan-like skeletal abnormalities, so that Marfan syndrome may be regarded as one of a range of type 1 fibrillinopathies.
  There appear to be no particular hot spots since mutations are found throughout the entire fibrillin-1 gene. However, a clustering of mutations associated with the most severe form of Marfan syndrome, neonatal Marfan syndrome, has been noted in a region encompassing exons 24 to 32. The gene for fibrillin-2 (FBN2) is highly homologous to FBN1, and mutations in FBN2 have been shown to cause a phenotypically related disorder termed congenital contractural arachnodactyly. Since mutations in the fibrillin genes are likely to affect the global function of the microfibrils, the term microfibrillopathy may be the most appropriate to designate the spectrum of disease associated with dysfunction of these molecules.
  The understanding of the global and the molecular functions of the fibrillin containing microfibrils is still incomplete and, correspondingly, no comprehensive theory of the pathogenesis of Marfan syndrome has emerged to date. Many, but not all, fibrillin-1 gene mutations are expected to exert a dominant negative effect, whereby mutant fibrillin monomers impair the global function of the microfibrils. In this paper we review the molecular physiology and pathophysiology of Marfan syndrome and related microfibrillopathies.


Keywords: Marfan syndrome; fibrillin; microfibrillopathies     

Neuromuscular features in Marfan syndrome

Marfan syndrome is a clinically and allelic heterogeneous, heritable connective tissue disorder with infrequently reported neuromuscular features. This study is the first to delineate these symptoms in a non-selected population. Neuromuscular involvement was evaluated in 10 Marfan patients through a standardized questionnaire, physical examination, nerve conduction study (NCS), needle electromyography (EMG), muscle ultrasound, laboratory investigation, and muscle biopsy. Existing neuroimages were screened for dural ectasia and spinal meningeal cysts. Twenty healthy controls with similar age distribution completed the questionnaire.
The results showed that various neuromuscular symptoms occur more frequently in the patients. Four older patients reported muscle weakness, five patients had a mild-to-moderate reduction in vibration sense, and all older patients mentioned mild functional impairments. NCS showed axonal polyneuropathy in four and EMG myopathic and neurogenic changes in all patients. Increased echo intensity and atrophy on muscle ultrasound was found in more than half of the patients. Muscle biopsies obtained in two patients showed myopathic changes in the older, female patient.
In conclusion, the majority of Marfan patients exhibited neuromuscular symptoms characterized as myopathy or polyneuropathy or both, and signs of lumbosacral radiculopathy, with symptoms being most pronounced in the older patients. Although meriting corroboration, these findings indicate a need to further the awareness of neuromuscular involvement in this population.     

TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder characterized by manifestations in the cardiovascular, skeletal, ocular, and other organ systems. MFS type1 (MFS1) is caused by mutations in the gene encoding fibrillin (FBN1). Recently, the transforming growth factor-beta receptor-2 gene, TGFBR2, has been shown to be associated with a second type of this disorder with typically mild or absent ocular involvement (MFS type 2; MFS2). Several point mutations were found in the highly conserved serine/threonine kinase domain of TGFBR2. Mutations in both TGFBR1 and TGFBR2 are associated with Loeys-Dietz aortic aneurysm syndrome (LDS). We searched for TGFBR1 and TGFBR2 mutations in 41 unrelated patients fulfilling the diagnostic criteria of Ghent nosology or with the tentative diagnosis of Marfan syndrome, in whom mutations in the FBN1 coding region were not identified. In TGFBR1, two mutations and two polymorphisms were detected. In TGFBR2, five mutations and six polymorphisms were identified. Reexamination of patients with a TGFBR1 or TGFBR2 mutation revealed extensive clinical overlap between patients with MFS1, MFS2, and LDS.     

Metacarpophalangeal pattern profile analysis in Sotos and Marfan syndrome

Patients with Sotos and Marfan syndrome have unusually long metacarpals and phalanges which may make the differential diagnosis difficult in younger children. Using Q-scores, we compared metacarpophalangeal pattern profile (MCPP) analysis in these two syndromes and identified distinct and different pattern profiles. This illustrates that the MCPPs are specific in these syndromes, even at an early age, and not related solely to the unusually long metacarpals and phalanges. For this study we used data from 50 Sotos patients (34 from the United Kingdom and 16 from the Netherlands, with a total of 95 hand films) and 36 Marfan patients (from the Netherlands, with 98 hand films). Of all patients over age 3 years the bone length (including the epiphysis) was determined. The patients under 7½ years (29 Sotos and 12 Marfan) were also measured without inclusion of the epiphysis. The patients measured without epiphysis had a relative short metacarpal 1 (MC1) and long distal phalanx 1 (DPh1) in Sotos syndrome, and a relative long MC1 and short DPh1 in Marfan syndrome. Between age 3 and 7½ years more than 90% of the films could be classified correctly using these two variables. Of the roentgenograms measured with epiphyses, about 80% were classified correctly. © 1994 Wiley-Liss, Inc.     

Metacarpophalangeal pattern profile in Marfan syndrome and Marfan-like patients

Marfan syndrome (MFS) is an autosomal dominant trait due to mutations in the fibrillin gene (FBN1). The MFS expressivity is variable, and its diagnosis relies completely on clinical criteria. Atypical cases and Marfan-like (marfanoid) clinical presentations are commonly found. The metacarpophalangeal pattern profile (MCPP), a radiological method in which the 19 tubular hand bones are assessed, has been used in the diagnosis of various syndromes. To investigate whether the MCPP was adequate to discriminate between MFS and Marfan-like subjects, we studied 38 patients who were referred to our service because they had an MFS diagnosis, diagnostic hypothesis, or differential diagnosis or had arachnodactyly with dolichostenomelia. Two groups were formed: 1) MFS: 21 patients with a mean age of 18.3 (10.8 S.D.) years and 2) Marfan-like syndromes: 16 patients who did not meet the current criteria, with a mean age of 14.6 (4.6 S.D.) years. The MCPP was performed in each case following the classical technique, and a characteristic mean profile was obtained for group I (MFS), with Z scores ranging from 0.69 to 2.73 (1.80 ± 0.50; mean ± S.D.). In group I, three cases had no correlation with the typical MFS pattern. In group II, three cases had an MFS pattern. The correlation with the mean MCPP of MFS permitted the differential diagnosis of MFS and marfanoid syndromes with 86% sensitivity, 81% specificity, and 86% positive and 81% negative predictive values. The results suggest that MCPP can be used effectively as an auxiliary tool in the nosology of these conditions and, because there is no change in MCPP with age, can be helpful in early diagnosis. Am. J. Med. Genet. 72:159–163, 1997. © 1997 Wiley-Liss, Inc.     

Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies

Fibrillin is the major component of extracellular microfibrils and is widely distributed in connective tissue throughout the body. Mutations in the fibrillin-1 FBN1) gene, on chromosome 15q21.1, have been found to cause Marfan syndrome, a dominantly inherited disorder characterised by clinically variable skeletal, ocular, and cardiovascular abnormalities. Fibrillin-1 mutations have also been found in several other related connective tissue disorders, such as severe neonatal Marfan syndrome, dominant ectopia lentis, familial ascending aortic aneurysm, isolated skeletal features of Marfan syndrome, and Shprintzen-Goldberg syndrome. Mutations are spread throughout the gene and, with the exception of neonatal Marfan syndrome, show no obvious clustering or phenotypic association. Hum Mutat 10:415–423, 1997. © 1997 Wiley-Liss, Inc.     

Marfan综合征的基因突变及基因诊断

Marfan综合征是常染色体显性遗传性结缔组织疾病,发病率为0.2‰～0.3‰,病变主要涉及骨骼、眼睛、心血管系统,有时也涉及肺部、皮肤和硬脑脊膜等器官.目前研究认为Marfan综合征发病主要原因为原纤维蛋白基因(fibrillin-1,FBN1)的突变.本文主要介绍了与Marfan综合征相关的FBN1基因及突变特点,重点对目前基因诊断研究情况加以概述.     

Aortic microcalcification is associated with elastin fragmentation in Marfan syndrome

Marfan syndrome (MFS) is a connective tissue disorder in which aortic rupture is the major cause of death. MFS patients with an aortic diameter below the advised limit for prophylactic surgery (<5 cm) may unexpectedly experience an aortic dissection or rupture, despite yearly monitoring. Hence, there is a clear need for improved prognostic markers to predict such aortic events. We hypothesize that elastin fragments play a causal role in aortic calcification in MFS, and that microcalcification serves as a marker for aortic disease severity. To address this hypothesis, we analysed MFS patient and mouse aortas. MFS patient aortic tissue showed enhanced microcalcification in areas with extensive elastic lamina fragmentation in the media. A causal relationship between medial injury and microcalcification was revealed by studies in vascular smooth muscle cells (SMCs); elastin peptides were shown to increase the activity of the calcification marker alkaline phosphatase (ALP) and reduce the expression of the calcification inhibitor matrix GLA protein in human SMCs. In murine Fbn1^C1039G/+ MFS aortic SMCs, Alpl mRNA and activity were upregulated as compared with wild‐type SMCs. The elastin peptide‐induced ALP activity was prevented by incubation with lactose or a neuraminidase inhibitor, which inhibit the elastin receptor complex, and a mitogen‐activated protein kinase kinase‐1/2 inhibitor, indicating downstream involvement of extracellular signal‐regulated kinase‐1/2 (ERK1/2) phosphorylation. Histological analyses in MFS mice revealed macrocalcification in the aortic root, whereas the ascending aorta contained microcalcification, as identified with the near‐infrared fluorescent bisphosphonate probe OsteoSense‐800. Significantly, microcalcification correlated strongly with aortic diameter, distensibility, elastin breaks, and phosphorylated ERK1/2. In conclusion, microcalcification co‐localizes with aortic elastin degradation in MFS aortas of humans and mice, where elastin‐derived peptides induce a calcification process in SMCs via the elastin receptor complex and ERK1/2 activation. We propose microcalcification as a novel imaging marker to monitor local elastin degradation and thus predict aortic events in MFS patients. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Identification of 9 novel FBN1 mutations in German patients with Marfan syndrome

We report 9 new mutations in German patients presenting with classical Marfan syndrome. All mutations occur in exons with calcium‐binding (cb) epidermal growth factor‐like (EGF) domains. Five mutations are missense involving exons 12, 27, 30, 44, and 52 with the resultant substitution of cysteine by phenylalanine (C504F), cysteine by tyrosine (C1129Y), tyrosine by cysteine (Y1261C), cysteine by serine (C1833S), and cysteine by tyrosine (C2142Y), respectively. The other four mutations are single base deletions in exons 39, 43, 48, and 58, at nucleotide A4826, C5311, T6018, and A7291, respectively, each resulting in frameshift with premature termination. Four mutations were detected in sporadic cases and are likely to be de novo. Hum Mutat 14:181, 1999. © 1999 Wiley‐Liss, Inc.     

马凡综合征新发变异一例

目的:对1例不明原因生长发育过快及心脏畸形的患儿进行临床表型及遗传学病因分析。方法:对先证者进行全外显子测序分析,应用Sanger测序技术对全外显子筛出的可疑致病基因的变异位点进行验证,并利用生物信息学软件进行功能预测分析。结果:全外显子测序结果显示,先证者在 FBN1基因的第48外显子上存在c.5846_...     

Safety and cardiovascular behavior during pulmonary function in patients with Marfan syndrome

Cipriano GFB, Peres PAT, Cipriano G Jr, Arena R, Carvalho AC. Safety and cardiovascular behavior during pulmonary function in patients with Marfan syndrome. Marfan syndrome (MS) is a dominant autosomal connective tissue disease that impacts multiple systems, such as the cardiovascular system, tissue viscoelastic properties, bone calcification matrix and, most specific to the present investigation, pulmonary parenchyma. The aim of the present study was to evaluate pulmonary function (PF) in patients with MS and relate it to thoracic cage abnormalities (TCA) and the occurrence of cardiac arrhythmias during the spirometric exam (SE). A sample of 75 subjects (46 with MS) underwent clinical, anthropometric, echocardiographic, radiographic and PF evaluation; 51 subjects (33 with MS) had their electrocardiogram (ECG) information evaluated during PF. These individuals were matched and compared with a healthy control group (CG). Forced vital capacity (FVC) and forced expiratory volume (FEV) in the first second (FEV₁) in the patients with MS were significantly lower in comparison with the CG (p = 0.012 and 0.0006) and predicted values (p = 0.04 and 0.003). Subgroup analysis based on TCA revealed differences between patients with MS with two combined abnormalities (scoliosis + pectus) in comparison with both the CG (p = 0.012 and 0.002) and patients without abnormalities (p = 0.05 and 0.006). There were no differences regarding the occurrence of arrhythmia during exertion on the SE. There was a correlation between clinical history, cardiovascular behavior and PF. PF is reduced in patients with MS, and deformities in the thoracic cage appear to contribute to this reduction. Despite the apparent structural alterations in the cardiovascular system in this population, exertion during the SE appears to be safe.     

The molecular genetics of Marfan syndrome and related disorders

Marfan syndrome (MFS), a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin-1 (FBN1). The leading cause of premature death in untreated individuals with MFS is acute aortic dissection, which often follows a period of progressive dilatation of the ascending aorta. Recent research on the molecular physiology of fibrillin and the pathophysiology of MFS and related disorders has changed our understanding of this disorder by demonstrating changes in growth factor signalling and in matrix-cell interactions. The purpose of this review is to provide a comprehensive overview of recent advances in the molecular biology of fibrillin and fibrillin-rich microfibrils. Mutations in FBN1 and other genes found in MFS and related disorders will be discussed, and novel concepts concerning the complex and multiple mechanisms of the pathogenesis of MFS will be explained.     

A suggestion of linkage between the Marfan syndrome and the rhesus blood group

The linkage relationships of the locus for the Marfan Syndrome were investigated with 19 marker loci in 17 families. Close linkage with several marker loci was excluded. There was a suggestion of linkage between the locus for the Marfan Syndrome and Rh.     

Systematic review of chronic pain in persons with Marfan syndrome

The purpose of this study was to explore the literature on chronic pain in adults with Marfan syndrome (MFS), critically appraising and synthesizing relevant literature. A systematic review was conducted by searching the published literature databases using available medical, physical, psychological, social databases and other sources. All studies that addressed pain in MFS, published in peer‐reviewed journals were assessed. Of 351 search results, 18 articles satisfied the eligibility criteria. All studies were cross‐sectional and quantitative; no randomized controlled trials or intervention studies were found. Most studies had small sample sizes, low response rates and mainly dealt with other aspects of the diagnosis than pain. Only one article dealt mainly with pain. The research on chronic pain in MFS is limited in size and quality. Despite these limitations, studies describe that the prevalence of pain in patients with MFS is high, varying from 47 to 92% and affecting several anatomic sites. In addition, chronic pain limits daily function and few studies describe treatment options for pain in patients with MFS. Research is needed to obtain more evidence‐based knowledge for developing more appropriate rehabilitation programs for people with MFS.     

马凡综合征两种新的原纤维蛋白-1基因突变

目的对9例马凡综合征(Marfansyndrome,MFS)患者的原纤维蛋白-1(fibrillin-1,FBN1)基因进行突变筛查,以发现新的FBN1基因突变。方法应用变性高效液相色谱法对MFS患者FBN1基因65个外显子中的35个进行突变筛查,对变性高效液相色谱图形异常的PCR扩增片段用DNA测序鉴定突变位置及性质,并用等位基因特异性PCR以及限制性片段长度多态性分析等方法进一步证实突变。结果在两例MFS患者中发现两种新的FBN1基因突变。其中一种为第34外显子4307～4308位4个碱基TCGT的插入突变(4307insTCGT),另一种为第43外显子5309位的点突变5309G>A。结论FBN1基因移码突变(4307insTCGT)与点突变(5309G>A)分别是这两例MFS患者的发病原因。