Features Of Marfan Syndrome Research Articles

Etiology and pathogenesis of the Marfan syndrome: current understanding.

Much has changed regarding Marfan syndrome (MFS) over the past few decades. Once described solely as a heritable disorder of connective tissue, MFS is now one of a number of conditions recognized to be a disorder of abnormal signalling in the TGF-β pathway. The cardinal features of MFS, once encompassed by the ocular, skeletal and cardiovascular systems, are now known to encompass many more organ systems, especially as people with MFS grow older. They are growing older by several decades compared to the 1970's because of profound improvements in diagnosis and management of the cardiovascular features, especially dilatation of the aortic root. This dilatation can be detected first in infancy and followed up by echocardiography. Progressive enlargement increases the risk of type A dissection and aortic regurgitation, the major causes of early mortality, in untreated patients today. Medical therapy with β-adrenergic blockade, first shown to be effective in the 1980's, can retard this dilatation. In the past decade, angiotensin receptor blockade, which reduces aberrant signalling through one of the TGF-β pathways, also can be effective. However, when dilatation of the root becomes such that the risk of dissection increases to an unacceptable degree, surgical therapy becomes necessary. In the mid-1970's, the composite graft, introduced by Hugh Bentall, markedly reduced mortality. In the past decade, a valve-spring aortic root replacement, advanced by Tirone David, has become widely adopted. Mid-term results are quite encouraging. Other cardiovascular involvement, such as mitral valve prolapse, type B dissection, and dilatation and dissection of aortic branches, also require close monitoring. Currently, life-expectancy in people with MFS who are diagnosed early and treated prophylactically is approaching that of the general population.

Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections.

Marfan syndrome (MFS) due to mutations in FBN1 is a known cause of thoracic aortic aneurysms and acute aortic dissections (TAAD) associated with pleiotropic manifestations. Genetic predisposition to TAAD can also be inherited in families in the absence of syndromic features, termed familial TAAD (FTAAD), and several causative genes have been identified to date. FBN1 mutations can also be identified in FTAAD families, but the frequency of these mutations has not been established. We performed exome sequencing of 183 FTAAD families and identified pathogenic FBN1 variants in five (2.7%) of these families. We also identified eight additional FBN1 rare variants that could not be unequivocally classified as disease-causing in six families. FBN1 sequencing should be considered in individuals with FTAAD even without significant systemic features of MFS.

MG-114 First 2 years of experience of an integrated multidisciplinary clinic for adults with aortopathies in a canadian context

Background In 2012, the Montreal Heart Institute started an integrated multidisciplinary clinic for adults referred for suspicion of Marfan syndrome or other connective tissue disorders at risk of aortic disease. A heart team (cardiologist specialised in adult congenital heart disease, heart surgeons specialised in aortic surgery) and a genetics team (medical geneticist, genetic counsellor) work side-by-side. Both teams see patients with a family history of aortic disease or systemic features of Marfan syndrome. The heart team sees patients with presumed isolated aortic disease and determines if evaluation by the genetics team is needed. Objective Assess first two years of clinic activities. Methods Review of clinic database and patient charts for period between May 2012 and May 2014. Results 183 new patients were assessed, from 146 different families. Reasons for referral included suspicion of Marfan (72), Loeys-Dietz (15), or Ehlers-Danlos syndrome (8); TAAD (56); and sudden death in the family (6). All were seen by the heart team; 70 were seen by the geneticist for a dysmorphological exam. All had dedicated cardiovascular imaging in our centre. Genetic tests were ordered for 35 patients. Close links with the paediatric and prenatal genetic clinics have facilitated efficient cross-referrals: we referred eight children of our adult patients. Most importantly, we rapidly assessed three pregnant women at risk of aortic disease and eight affected parents (identified through their child) who had no active follow-up. Conclusions Our integrated multidisciplinary approach results in efficient access to specialised cardiac and genetic assessments and rapid management when required.

Analysis of Protrusio Acetabuli Using a CT-based Diagnostic Method in Korean Patients with Marfan Syndrome: Prevalence and Association with Other Manifestations.

A new CT-based diagnostic method of protrusio acetabuli (PA) was introduced. However, prevalence of PA by this method and correlation between PA and other manifestations of Marfan syndrome (MFS) is unknown in Korean MFS patients. This study aimed to investigate the prevalence of PA diagnosed by a CT-based method in Korean patients with MFS, the association of PA with other manifestations of MFS, and the contribution of PA to MFS diagnosis. We retrospectively reviewed the records of 146 MFS patients with the presence of a causative FBN1 mutation and 146 age- and sex-matched controls from a single tertiary care center. All MFS patients underwent a complete assessment of criteria based on the revised Ghent nosology. PA was assessed quantitatively using a CT-based circle-wall distance (CWD) method. PA was diagnosed in 77.4% of patients in the MFS group and in 11.0% of the control group. CWD was significantly different between the two groups (1.50 mm vs. -0.64 mm, P<0.001). The presence of PA did not correlate with the presence of ectopia lentis, aortic root diameter, or history of aortic dissection. The presence of PA did not have a significant impact on the final diagnosis of MFS. Even though the presence of PA does not related to the cardinal clinical features of MFS or influence MFS diagnosis, its presence may be helpful for the suspicion of MFS when aortic dissection or aneurysm is found on CT angiography of the aorta because of the high frequency of PA in MFS patients.

Facial and Ocular Features of Marfan Syndrome

Marfan syndrome is the most common inherited disorder of connective tissue affecting multiple organ systems. Identification of the facial, ocular and skeletal features should prompt referral for aortic imaging since sudden death by aortic dissection and rupture remains a major cause of death in patients with unrecognized Marfan syndrome. Echocardiography is recommended as the initial imaging test, and once a dilated aortic root is identified magnetic resonance or computed tomography should be done to assess the entire aorta. Prophylactic aortic root replacement is safe and has been demonstrated to improve life expectancy in patients with Marfan syndrome. Medical therapy for Marfan syndrome includes the use of beta blockers in older children and adults with an enlarged aorta. Addition of angiotensin receptor antagonists has been shown to slow the progression of aortic root dilation compared to beta blockers alone. Lifelong and regular follow up in a center for specialized care is important for patients with Marfan syndrome. We present a case of a patient with clinical features of Marfan syndrome and discuss possible therapeutic interventions for her dilated aorta.

Total serum transforming growth factor-β1 is elevated in the entire spectrum of genetic aortic syndromes.

Total serum transforming growth factor-beta 1 (tsTGF-β1) is increased in patients with Marfan syndrome (MFS), but it has not been assessed in thoracic aortic aneurysm and dissection (TAAD), Loeys-Dietz syndrome (LDS), and bicuspid aortic valve disease (BAVD). tsTGF-β1 is increased in genetic aortic syndromes including TAAD, LDS, MFS, and BAVD. We measured tsTGF-β1 and performed sequencing of the genes FBN1, TGFBR1, and TGFBR2 in 317 consecutive patients with suspected or known genetic aortic syndrome (167 men, 150 women; mean age 43 ± 14 years). TAAD was diagnosed in 20, LDS in 20, MFS in 128, and BAVD in 30 patients, and genetic aortic syndrome was excluded in 119 patients. Elevated tsTGF-β1 levels were associated with causative gene mutations (P = 0.008), genetic aortic syndrome (P = 0.009), and sporadic occurrence of genetic aortic syndrome (P = 0.048), whereas only genetic aortic syndrome qualified as an independent predictor of tsTGF-β1 (P = 0.001). The tsTGF-β1 levels were elevated in FBN1 and NOTCH1 mutations vs patients without mutations (both P = 0.004), and in NOTCH1 mutations vs ACTA2/MYH11 mutations (P = 0.015). Similarly, tsTGF-β1 levels were elevated in MFS (P = 0.003) and in BAVD (P = 0.006) vs patients without genetic aortic syndrome. In contrast to specific clinical features of MFS, FBN1 in-frame mutations (P = 0.019) were associated with increased tsTGF-β1 levels. tsTGF-β1 is elevated in the entire spectrum of genetic aortic syndromes. However, gradual differences in the increases of tsTGF-β1 levels may mirror different degrees of alteration of tsTGF-β1 signaling in different genetic aortic syndromes.

Impact of aortic aneurysm on hospitalizations in patients with marfan syndrome: a multi-institutional study.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder affecting 1 in 3,000 people. Cardiovascular involvement is a prominent feature of MFS, with aortic dissection and/or rupture being the leading cause of death. Advances in the medical and surgical care of patients with MFS have improved survival. Hospital resource utilization and outcomes have not been evaluated in a large population of patients with MFS. We sought to analyze pediatric hospital resource utilization and outcomes in patients with MFS. Nationally distributed data from 43 pediatric hospitals in the 2004-2011 Pediatric Health Information System database were used to identify patients admitted to the hospital with International Classification of Diseases-9th Revision codes for a diagnosis of MFS. Aortic aneurysm (AA) with or without dissection, length of stay (LOS), and hospital charges were determined. During the study period, there were 1,978 admissions in 1,228 patients with MFS. AA was present in 217 (11%) admissions in 188 (15%) patients (63% male). Mean age of patients with AA was 13.8 ± 5.9 years. Aortic dissection or rupture was present in 15 (7% with AA) admissions in 15 (8% with AA) patients (mean age 15.7 ± 5.2 years). Other cardiac diagnoses occurred more commonly in the AA cohort (p < 0.0001), regardless of the reason for admission. Cardiothoracic surgical procedures were performed in 116 AA admissions (53%). Mean LOS, hospital charges per admission, and charges per day were significantly higher in AA cohort compared to those without AA. In-hospital mortality for AA was 2%. The presence of AA in patients with MFS increases hospital resource utilization. Cardiothoracic surgeries are commonly performed in this cohort. Other cardiovascular diagnoses are more prevalent in patients with AA suggesting a more severe phenotype.

First non-complicated thrombolysis in a young patient with Marfan syndrome and brainstem ischaemic stroke

The prevalence of neurovascular complications and their treatment in patients with Marfan syndrome (MS) is not well known. We have found only one report of a stroke patient with MS treated with thrombolysis, complicated by intracranial haemorrhage. We present, for the first time, a case of an effective intravenous thrombolysis in a young patient with MS and acute ischaemic brainstem stroke of probable cardioembolic aetiology. A 34-year-old patient with known MS was admitted to the emergency department with sudden onset of double vision and right face and tongue paresthesias that had developed 1.5 h before presentation (without any preceding head or neck trauma). Five months before, a successful Bentall procedure with biological conduit insertion was performed in the patient, to treat the aortic aneurysm and aortic valve dysfunction. He had been treated with oral anticoagulant (acenocumarolum) until 2 weeks before the stroke onset, when the anticoagulant was switched to acetylsalicylic acid. Echocardiography (ECHO) a month prior to the emergency admission had shown ejection fraction (EF) of 65% and no dysfunction of the conduit. Neurological examination revealed right central facial palsy, hypoesthesia in the second and third branch of the right trigeminal nerve, right ptosis with myopia, upward gaze restraint, and downward gaze paresis which suggested left trochlear nerve dysfunction. On general examination, the patient was haemodynamically stable (blood pressure 130/80 mm Hg, normal sinus rhythm 70/min) with typical features of MS — tall posture and long fingers. Initial magnetic resonance diffusion weighted imaging (DWI) did not show any areas of diffusion restriction, however, two small chronic lesions of probably vascular origin were found in the left hemisphere. 4 h and 20 min after the onset of symptoms, the patient received thrombolytic treatment with 80 mg (0.9 mg/kg bodyweight) of Alteplase. There were no complications of the treatment and the neurological symptoms resolved completely during the next 11 h. Control DWI performed 3 days later revealed a new, non-corresponding, discrete lesion in the left middle cerebellar peduncle (Fig. 1). The Doppler ultrasound test and the computed tomography angiography (Fig. 2) showed tight kinking of both internal carotid arteries and tortuous vertebral arteries, but without dissection. Transthoracic and transoesophageal ECHO did not reveal any abnormalities, and EF was 65%. Blood testing on possible prothrombotic state or autoimmune process was negative. The patient was discharged home 8 days after the incident with no remaining symptoms. The presented case of thrombolytic treatment in a MS patient was free of haemorrhagic complications, despite tortuous extracranial vessels and relatively short period between the Bentall operation and the Alteplase treatment. It is obvious, however, that the safety of ischaemic cerebral stroke Alteplase treatment in patients with MS remains to be confirmed.

The revised ghent nosology; reclassifying isolated ectopia lentis

Inherited ectopia lentis (EL) is most commonly caused by Marfan syndrome (MFS), a multisystemic disorder caused by mutations in FBN1. Historically the diagnosis for patients with EL who have no systemic features of MFS is isolated EL (IEL). However, the Ghent nosology for MFS was updated in 2010 and made some important alterations. In particular, patients with EL and a FBN1 mutation are now categorically diagnosed with MFS, if their mutation has previously been described with aortic dilation/dissection. This carries significant systemic implications, as many patients previously diagnosed with IEL are now reclassified. We provide a review of all published cases of IEL caused by FBN1 mutations over the last 20 years to assess what impact the new Ghent nosology has on these. Indeed, 57/123 probands (46.3%) are now classified as MFS according to the revised Ghent nosology and 37/96 mutations (38.5%) reported to cause isolated EL have also been found in patients with aortic dilation/dissection. These findings suggest that EL caused by mutations in FBN1 is actually part of a spectrum of fibrillinopathies with MFS, and the term 'IEL' should be avoided in such cases.

Juvenile idiopathic arthritis, mitral valve prolapse and a familial variant involving the integrin‐binding fragment of FBN1

Mutations in Fibrillin 1 (FBN1) are associated with Marfan syndrome and in some instances with the MASS phenotype (myopia, mitral valve prolapse, borderline non-progressive aortic root dilatation, skeletal features, and striae). Potential confusion over diagnosis and management in patients with borderline features has been addressed through the revised Ghent nosology, which emphasizes the importance of aortic root dilatation and ectopia lentis as features of Marfan syndrome. The overlapping and more common mitral valve prolapse syndrome is precluded by ectopia lentis or aortic dilatation. Among these clinically related conditions, there is no compelling evidence that genotype predicts phenotype, with the exception of neonatal Marfan syndrome, mutations in which cluster within FBN1 exons 24-32. Recent reports also link two very different phenotypes to changes in FBN1. Heterozygous mutations in transforming growth factor β-binding protein-like domain 5 (TB5) can cause acromicric or geleophysic dysplasias-and mutations in the TB4 domain, which contains an integrin binding RGD loop, have been found in congenital scleroderma/stiff skin syndrome. We report on a variant in an evolutionarily conserved residue that stabilizes the integrin binding fragment of FBN1, associated with juvenile idiopathic arthritis, mitral valve prolapse or apparently normal phenotype in different family members.

Dissecting aortic aneurysm in a 23 year-old hypertensive woman

A 23 year-old woman was admitted to our hospital after loss of consciousness with chest pain in a stress situation (the woman’s wedding ceremony). The patient had been irregularly treated for mild hypertension from the age of eight. Secondary causes of hypertension were never diagnosed. There were no morphological features of Marfan syndrome in the patient. She had been operated upon for vesicoureteral reflux in childhood. The patient was admitted in a stable condition. Her physical examination revealed diastolic aortic murmur and tachycardia, blood pressure was normal. Transthoracic echocardiography showed expansion of ascending aorta to 43 mm and thoracic aorta dissection (Fig. 1). Chest computed tomography demonstrated thoracic aorta dissection, which began 15 mm above the aortic valve, expansion of ascending aorta to 44 mm, expansion of arch of aorta to 28 mm and pseudocanal of the descending aorta to 6.5 mm (Fig. 2). The dissection included brachiocephalic trunk, both common carotid arteries, left subclavian artery and abdominal aorta to the celiac trunk (Fig. 3). The patient was operated upon immediately. A dissecting aneurysm DeBakey I type was diagnosed intraoperatively. The Bentall de Bono procedure was done with implantation CompositGraft St. Jude Medical 25. The early postoperative period was complicated by bleeding, requiring rethoracotomy and low output syndrome. Because of this, the patient was treated with pressor amines. In the following days, postoperative acute kidney failure occurred and patient was subjected to dialysis. Tamponade occurred and a puncture was performed with evacuation of liquid. The antihypertensive treatment was modified and vitamin K antagonist therapy was initiated. The patient was discharged from hospital on the 26th day of treatment. Aortal dissection is one of the most life-threatening complications of hypertension. The commonest causes of aortal dissection are arterial wall abnormalities, which had not been demonstrated in histopathology in our patient. Long term, inadequately treated hypertension was the only aetiology factor of aortic dissection in this young woman.

Arachnodactyly—a key to diagnosing heritable disorders of connective tissue

Arachnodactyly literally means spidery fingers, and describes the long, slender fingers typical of patients with Marfan syndrome (MFS). Many clinicians regard arachnodactyly as pathognomonic of MFS; however, this view is misleading as arachnodactyly is a key element of the marfanoid habitus, which is present in several heritable disorders of connective tissue (HDCTs). Other features of the marfanoid habitus include long hands and feet, increased skin stretch, joint hypermobility and characteristic changes in the physiology of the pectum. Here, we focus on the differential diagnosis of diseases with features of the marfanoid habitus. Ectopia lentis (lens dislocation) and aortic root dilation or dissection are cardinal features of MFS. Distinguishing MFS from other HCDTs has important implications for treatment, as cardiovascular and ocular complications commonly seen in patients with MFS are not seen in all HDCTs. Joint hypermobility syndrome and Ehlers-Danlos syndrome are also HDCTs, neither of which is associated with ectopia lentis or aortic changes. Some of the rarer forms of Ehlers-Danlos syndrome are associated with severe vascular, dental and skin pathologies. This Review serves as a guide for correctly diagnosing members of the HDCT family.

Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations

Dilation or aneurysm of the ascending aorta can progress to acute aortic dissection (Thoracic Aortic Aneurysms and Aortic Dissections, TAAD). Mutations in genes encoding TGF-β-related proteins (TGFBR1, TGFBR2, FBN1, and SMAD3) cause syndromic and inherited TAAD. SMAD4 mutations are associated with juvenile polyposis syndrome (JPS) and a combined JPS-hereditary hemorrhagic telangiectasia (HHT) known as JPS-HHT. A family with JPS-HHT was reported to have aortic root dilation and mitral valve abnormalities. We report on two patients with JPS-HHT with SMAD4 mutations associated with thoracic aortic disease. The first patient, an 11-year-old boy without Marfan syndrome features, had JPS and an apparently de novo SMAD4 mutation (c.1340_1367dup28). Echocardiography showed mild dilation of the aortic annulus and aortic root, and mild dilation of the sinotubular junction and ascending aorta. Computed tomography confirmed aortic dilation and showed small pulmonary arteriovenous malformations (PAVM). The second patient, a 34-year-old woman with colonic polyposis, HHT, and features of Marfan syndrome, had a SMAD4 mutation (c.1245_1248delCAGA). Echocardiography showed mild aortic root dilation. She also had PAVM and hepatic focal nodular hyperplasia. Her family history was significant for polyposis, HHT, thoracic aortic aneurysm, and dissection and skeletal features of Marfan syndrome in her father. These two cases confirm the association of thoracic aortic disease with JPS-HHT resulting from SMAD4 mutations. We propose that the thoracic aorta should be screened in patients with SMAD4 mutations to prevent untimely death from dissection. This report also confirms that SMAD4 mutations predispose to TAAD.

Evaluation of the adolescent or adult with some features of Marfan syndrome

Disclaimer: ACMG standards and guidelines are designed primarily as an educational resource for medical geneticists and other health care providers to help them provide quality medical genetic services. Adherence to these standards and guidelines does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticists should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient’s record the rationale for any significant deviation from these standards and guidelines.Individuals who are suspected of having Marfan syndrome are often referred to a medical geneticist for further evaluation and diagnosis. However, there are a number of conditions that share physical manifestations with those of Marfan syndrome; therefore, an approach to diagnosis and evaluation is crucial to the proper long-term follow-up of these individuals. This practice guideline provides guidance for the approach to this cadre of individuals.Genet Med 2012:14(1):171–177

Mitral Valve Disease in Marfan Syndrome and Related Disorders

Marfan syndrome (MFS) is a systemic disorder of the connective tissue with pleiotropic manifestations due to heterozygous FBN1 mutations and consequent upregulation of TGFβ signaling in affected tissues. Myxomatous thickening and elongation of the mitral valve (MV) leaflets commonly occur in this condition. Investigation of murine models of this disease has led to improved understanding of the mechanisms that underlie many of the phenotypic features of MFS, including MV disease. Loeys-Dietz syndrome (LDS) is a related disorder due to heterozygous mutations in the genes encoding subunits of the TGFβ receptor, and it may also involve the MV leaflets with similar elongation and thickening of the MV leaflets. Although the genetic basis and pathogenesis of nonsyndromic MV prolapse has been elusive to date, insights derived from monogenic disorders like MFS and LDS can be informative with regard to novel gene discovery and investigation into the pathogenesis of MV disease. This manuscript will review the prevalence of MV disease in MFS, its pathogenic basis as determined in mice with Fbn1 mutations, and ongoing studies that seek to better understand MV disease in the context of fibrillin-1 deficiency or excessive TGFβ signaling.

Further evidence for a marfanoid syndrome with neonatal progeroid features and severe generalized lipodystrophy due to frameshift mutations near the 3′ end of the FBN1 gene

We report on a 20-year-old man who presented in infancy with severe generalized lipodystrophy with a progeroid appearance and some Marfanoid features. He subsequently was diagnosed with bilateral lens subluxations at the age of 16 years which prompted analysis of the FBN1 gene. This analysis showed him to have a novel heterozygous, de novo, c.8156_8175del, p.Lys2719ThrfsX12, frameshift mutation in exon 64 of his FBN1 gene. His phenotype is similar to a patient described by Graul-Neumann et al. [2010] who was found to have a de novo, heterozygous, c.8155_8156del deletion in exon 64 of FBN1. Both mutations result in a truncated protein with an extremely charged C-terminus, containing two positive and four negative charges in the last eight amino acids. This most likely has a profound impact on protein–protein interactions, which are very important in the extracellular matrix. The similarities in the phenotypes, and overlapping molecular defects, provides further evidence that the phenotype with features of Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy is a distinct clinical entity due to frameshift mutations in exon 64 of the FBN1 gene.

Dysfunctional Voiding as a Presenting Feature of Marfan Syndrome: A Rare Case

Dysfunctional Voiding as a Presenting Feature of Marfan Syndrome: A Rare Case

Giant aortic root aneurysm in Marfan syndrome: A rare complication in early childhood

FIGURE 1. Chest x-ray demonstrating the aneurysmal dilation of the ascending aorta. A 7-year-old girl presented with shortness of breath on exertion and palpitations. Features of Marfan syndrome were noted on physical examination. The chest x-ray revealed marked cardiomegaly with a widened mediastinum (Figure 1). Echocardiography showed a gigantic dilatation of the aortic root (Figure 2). The aortic valve annulus measured 3.7 cm (Z-scoreþ12), and the maximal diameter at the sinuses of Valsalva measured 8.7 cm (Z-score þ14), with severe aortic regurgitation, left ventricular dilatation, and depressed left ventricular function. Cardiac magnetic resonance imaging was impressive for severe dilatation of the ascending aorta (Figure 3) comprising the annulus, sinuses of Valsalva, sinotubular junction, and tubular ascending aorta, with severe aortic regurgitation (regurgitant fraction, 44%), severe left ventricular dilatation, and depressed systolic function (ejection fraction, 36%). The child was brought to the operating room. Given the proximity of the giant aneurysm to the sternum, the child was placed on cardiopulmonary bypass by femoral vessel cannulation, and adequate drainage of the heart was confirmed before sternotomy. The aortic root and ascending aorta were replaced with a 28-mm Gelweave Valsalva tube graft (Terumo Cardiovascular Systems Corporation, Ann Arbor, Mich) using the David valve-sparing root replacement operation, remodeling the annulus with multiple subannular sutures. Post-bypass echocardiography showed moderate aortic regurgitation and severe left ventricular dysfunction and dilatation. The reimplanted native valve had to be replaced with a Carpentier-Edwards Perimount Magna 21-mm bioprosthesis (Edwards Lifesciences LLC, Irvine, Calif) within the Valsalva graft. Because of severe left ventricular dysfunction, the child could not be

The diagnostic value of the facial features of Marfan syndrome

We examined the prevalence of known facial features of Marfan syndrome (MFS)-dolicocephaly, malar hypoplasia, enophthalmos, retrognathia, and down-slanting palpebral fissures-and the diagnostic utility (sensitivity, specificity, accuracy, predictive values, and likelihood ratios) of using them for screening and diagnosis. Frontal and lateral photographs of 76 subjects with MFS (average age 18.3years) and of 76 age- and gender-matched controls were obtained, randomized, and compiled into an online survey. Three physicians experienced with MFS rated each photograph for the presence of each feature and indicated whether each photograph triggered a suspicion for MFS. Eight non-expert orthopaedic surgeons reviewed a subset of those photographs and indicated if each triggered a suspicion for MFS. Half of the non-experts then received a brief diagnosis instructional sheet, and all non-experts were retested. The results were compared using Chi-square tests and t-tests with a significance level of P<0.05. Using facial features alone, the accuracy of experienced physicians in identifying individuals with MFS was 73%. Facial features had a 54% sensitivity, a 91% specificity, an 86% positive predictive value (PPV), a 67% negative predictive value (NPV), a 6.9% positive likelihood ratio (PLR), and a 50% negative likelihood ratio (NLR) for MFS. There was no significant difference in the diagnostic accuracy between non-experts receiving and not receiving instructions. Facial features are more specific than sensitive for MFS. Therefore, the recognition of facial features of MFS can be used as an initial screening tool, but facial features do not have a high sensitivity for MFS.

The clinical spectrum of complete FBN1 allele deletions

The most common mutations found in FBN1 are missense mutations (56%), mainly substituting or creating a cysteine in a cbEGF domain. Other mutations are frameshift, splice and nonsense mutations. There are only a few reports of patients with marfanoid features and a molecularly proven complete deletion of a FBN1 allele. We describe the clinical features of 10 patients with a complete FBN1 gene deletion. Seven patients fulfilled the Ghent criteria for Marfan syndrome (MFS). The other three patients were examined at a young age and did not (yet) present the full clinical picture of MFS yet. Ectopia lentis was present in at least two patients. Aortic root dilatation was present in 6 of the 10 patients. In three patients, the aortic root diameter was on the 95th percentile and in one patient, the diameter of the aortic root was normal, the cross-section, however, had a cloverleaf appearance. Two patients underwent aortic root surgery at a relatively young age (27 and 34 years). Mitral valve prolapse was present in 4 of the 10 patients, and billowing of the mitral valve in 1. All patients had facial and skeletal features of MFS. Two patients with a large deletion extending beyond the FBN1 gene had an extended phenotype. We conclude that complete loss of one FBN1 allele does not predict a mild phenotype, and these findings support the hypothesis that true haploinsufficiency can lead to the classical phenotype of Marfan syndrome.