The packet lists FBN1 (chromosome 15) as the only known gene, with a ClinGen validity of Definitive. Its molecular mechanism is described as pathogenic variants in FBN1 encoding fibrillin-1, a component of extracellular matrix microfibrils, with defective fibrillin-1 leading to abnormal TGF-beta signaling and connective tissue weakness.

Inheritance is autosomal dominant. GeneReviews states that approximately 75% of individuals diagnosed have an affected parent and approximately 25% have a de novo pathogenic variant, consistent with the packet's statement about de novo origin. Parental germline mosaicism is described, and absence of a known family history does not preclude the diagnosis.

On genotype and phenotype, GeneReviews states that few correlations exist and none is definitive. A variant causing in-frame loss or gain of central coding sequence is generally associated with more severe disease; premature termination codon variants have been associated with presentations from mild to classic, and ectopia lentis is less common with haploinsufficiency. GeneReviews states that identifying the precise variant has limited prognostic value and has not been proven to reliably guide individual management. It describes high clinical penetrance, although intrafamilial variability can be extensive.

The packet lists the revised Ghent criteria, echocardiography of the aortic root, slit-lamp examination for ectopia lentis, FBN1 sequencing, and family history evaluation as diagnostic methods. GeneReviews states that consensus clinical diagnostic criteria have been published. Marfan syndrome is described as suspected in the presence of aortic root enlargement (z score of 2.0 or higher), ectopia lentis, or a systemic score of 7 or higher, or with a family history consistent with autosomal dominant inheritance.

GeneReviews states that the diagnosis of FBN1-related Marfan syndrome is established in a proband who has an FBN1 pathogenic variant known to be associated with Marfan syndrome and either aortic root enlargement (z score of 2.0 or higher) or ectopia lentis. Because many manifestations emerge with age, the chapter describes tentative designations in people under age 20 who do not quite reach diagnostic thresholds, such as nonspecific connective tissue disorder or potential Marfan syndrome.

Its differential diagnosis includes Loeys-Dietz syndrome, in which aortic aneurysms are described as dissecting or rupturing at small dimensions and in early childhood, and Shprintzen-Goldberg syndrome, which features developmental delay. The packet contains no newborn-screening designation.

The packet lists no FDA-approved treatment for Marfan syndrome. Its orphan drug records include two designations for Marfan syndrome, enzastaurin (Aytu BioPharma, Inc.) and losartan (National Marfan Foundation), both with status DESIGNATED, which is not marketing approval. Other records in that field carry other indications and are not treated here as Marfan syndrome therapies.

The packet's foundational therapies are beta-blocker therapy (atenolol, propranolol) to reduce aortic wall stress, losartan as an alternative or adjunct for aortic protection, annual echocardiographic assessment of the aortic root, prophylactic aortic root surgery when diameter reaches a threshold, activity modification regarding contact sports and isometric exercise, and ophthalmologic management of lens dislocation. GeneReviews states that no comprehensive or widely adopted clinical practice guidelines have been published and that management is most effectively accomplished through a multidisciplinary team including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon.

By manifestation, GeneReviews describes spectacle correction for refractive errors, surgical lens removal in some cases of lens dislocation, bracing or surgical stabilization for severe scoliosis, and surgical repair of the aorta in childhood when the rate of aortic root enlargement approaches 0.5-1.0 cm per year or severe regurgitation progresses, and in adults when the maximum measurement approaches 5.0 cm, the rate approaches 1.0 cm per year, or regurgitation progresses. It states that no effective therapies for symptomatic dural ectasia currently exist.

Surveillance is described separately: growth and chest wall assessment at each visit, ophthalmologic and dental examination at least annually, and echocardiography annually when the aorta is relatively small and enlarging slowly, and more often with an aortic root near 4.5 cm, faster enlargement, or valve disease. CT or MR angiography of the entire aorta begins intermittently in young adulthood. GeneReviews lists circumstances flagged as risks, including contact sports, isometric exercise, fluoroquinolone antibiotics, and LASIK eye surgery.

The packet does not certify life expectancy or survival figures for Marfan syndrome. GeneReviews states that the major morbidity and early mortality relate to the cardiovascular system, and its frequency table reports aortic tear or rupture in 25% of adults. The phenotypic continuum is described as ranging from mild disease in a few systems to rapidly progressive multiorgan disease in neonates. The chapter states that the precise variant has limited prognostic value for individual management. The packet supports no statement about the course in any individual case.

ClinicalTrials.gov records in the packet list 14 active studies, ten with full detail. Those specific to Marfan syndrome or closely related groups include NCT05700175, a transcriptomic study of adults with Marfan syndrome (IRCCS Policlinico S. Donato; active, not recruiting); NCT07495267, Nutritional Ketosis Marfan (Washington University School of Medicine; not yet recruiting); NCT04970459, a biological collection for Marfan and related syndromes (University Hospital, Toulouse; recruiting); and NCT04194619, a study of pregnancy in women with rare multisystemic vascular diseases (Hospices Civils de Lyon; recruiting). The packet's research directions list TGF-beta signaling modulators, novel surgical techniques for aortic repair, and gene therapy approaches, and the research digest classifies 309 publications, mainly basic science and preclinical work.