Genetics of Marfan Syndrome Differential Diagnoses

Updated: Jan 07, 2021
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
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Diagnostic Considerations

The following disorders present considerable diagnostic challenges because of shared clinical features, overlapping phenotypes, similar inheritance patterns, and, at least for some, causation by mutations within the same gene, FBN1. [29]

Congenital contractural arachnodactyly (CCA or Beals syndrome) 

A rare autosomal dominant syndrome, CCA (OMIM #121050) has considerable clinical overlap with MFS. CCA results from heterozygous mutations in FBN2, the gene that codes for fibrillin-2, located on chromosome 5q23-q21.

Salient clinical features include the following:

  • Crumpled ears, with a folded upper helix

  • Arachnodactyly

  • Congenital contractures of small and large joints

  • Progressive kyphoscoliosis

  • Muscular hypoplasia

  • Mitral valve prolapse 

  • Absence of ectopia lentis

Mild aortic root enlargement has been reported, but further progression to dissection or rupture remains unclear.

Ehlers-Danlos syndrome, type III (benign hypermobility syndrome)

Major diagnostic criteria for Ehlers-Danlos syndrome, type III (OMIM #130020) are as follows:

  • Joint hypermobility

  • Soft or velvety skin with normal or slightly increased extensibility

Minor diagnostic criteria are as follows (these findings are supportive but alone are not sufficient to establish the diagnosis):

  • Autosomal dominant family history of similar features without skin abnormalities

  • Recurrent joint dislocation or subluxation

  • Chronic joint or limb pain

  • Easy bruising

  • Functional bowel disorders (functional gastritis, irritable bowel syndrome) [30]

  • Neurally mediated hypotension or postural orthostatic tachycardia

  • High, narrow palate

  • Dental crowding

Ehlers-Danlos syndrome, type IV (vascular type)

This condition (OMIM #130050) is caused by heterozygous mutation in the gene for type III collagen (COL3A1) located on chromosome 2q31.

Major diagnostic criteria include the following:

  • Thin, translucent skin

  • Arterial/intestinal/uterine fragility or rupture

  • Easy bruising

  • Facies with a tight-pinched appearance (large eyes, thin nose, thin lips and philtrum, small chin)

Minor diagnostic criteria are as follows:

  • Acrogeria

  • Hypermobility of small joints

  • Tendon and muscle rupture

  • Talipes equinovarus

  • Early-onset varicose veins

  • Arteriovenous, carotid-cavernous sinus fistula

  • Pneumothorax/pneumohemothorax

  • Chronic joint subluxations/dislocations

  • Gingival recession

  • A positive history that reflects an autosomal dominant inheritance pattern with history of sudden death in close relatives

Familial arterial tortuosity syndrome (ATS)

Features of this condition (OMIM #208050) are as follows:

  • Marked tortuosity of the aorta and its branches

  • Predisposition to aortic dissection

  • Telangiectasias on the cheeks

  • Lax skin

  • High-arched palate

  • Joint laxity

The genetic cause is mutations in SLC2A10, encoding glucose transporter 10 (GLUT10).

Familial ectopia lentis 1

Isolated ectopia lentis has been shown to segregate as a dominant trait in several families. Patients do not meet diagnostic criteria for MFS, although mild marfanoid skeletal features may be present. Lifelong follow-up by echocardiography is advised, as aortic root dilatation can occur later in life. Familial ectopia lentis 1 (OMIM #129600) is associated with mutations near the 3'-end of FBN1.

Familial mitral valve prolapse syndrome 1

This condition (OMIM #157700) occurs as an autosomal dominant trait, either isolated, or in association with an asthenic habitus (a body habitus distinguished by a slender physique, as well as long limbs, an angular profile, and prominent muscles or bones). Patients may develop aortic dilatation.

Familial pectus excavatum (OMIM 169300), familial scoliosis, and familial tall structure

This condition occurs in tall individuals with no systemic findings for other features of MFS or mutations in FBN1.

Familial thoracic aortic aneurysm/dissection

This is a progressive disorder (OMIM #132900, #607086) with either no or minor systemic findings. [31]  Patients with familial thoracic aortic aneurysm may have deformity of the thoracic cage (pectus excavatum, scoliosis). These skeletal features are also seen in patients with bicuspid aortic valve sequence. Patients are at risk for dissection or rupture of the aorta.

Occasionally, FBN1 mutations have been identified. In addition, mutations in the TGFβR2 gene have been implicated as a rare cause (5%) of familial thoracic aortic aneurysm. In these cases, widespread vascular disease and aneurysms and dissections of the descending aorta/middle-sized arteries are seen. Mutations in the MYH11 gene have also been described with this condition. [32]

Loeys-Dietz syndrome 1 (LDS1)

LDS1 (OMIM #609192) is an autosomal dominant aortic aneurysm syndrome. [11]  It is characterized by the triad of hypertelorism, bifid uvula/cleft palate, and arterial tortuosity with ascending aortic aneurysm/dissection. Differences between LDS1 and MFS are the absence of significant long bone overgrowth and lens dislocation.

In LDS1, there are multiple other findings, such as craniosynostosis, Chiari malformation, club feet, patent ductus arteriosus, and aneurysms/dissection throughout the arterial tree, that are not present in MFS. LDS1 is caused by heterozygous mutation in the TGFβR1 gene, located on chromosome 9q22.

Loeys-Dietz syndrome 2 (LDS2)

In contrast to LDS1, some patients with LDS2 (OMIM #610168) have fewer craniofacial abnormalities, but have prominent skin and joint manifestations. [33]  LDS2 is more reminiscent of vascular Ehlers-Danlos syndrome.

Patients with LDS2 are characterized by velvety translucent skin, easy bruising, widened atrophic scars, uterine rupture, severe peripartal bleedings, and arterial aneurysm/dissections throughout the arterial circulation.

LDS2 is caused by a heterozygous mutation in the TGFβR2 gene, located on chromosome 3p22. The natural history of patients with LDS1 and LDS2 is more aggressive than that of patients diagnosed with MFS or vascular Ehlers-Danlos syndrome, with a mean age at death of 26.1 years. Aortic dissections occur in young childhood and/or at smaller aortic dimensions (< 40 mm), and the incidence of pregnancy-related complications is high.

Loeys-Dietz syndrome 3 (LDS3)

LDS3 (OMIM #613795) is caused by a heterozygous mutation of the SMAD3 gene, located on chromosome 15q22.33. This condition is characterized by arterial aneurysm/dissection with early onset osteoarthritis.

Loeys-Dietz syndrome 4 (LDS4)

LDS4 (OMIM #614816) is caused by a heterozygous mutation in the TGFB2 gene, located on chromosome 1q41. This condition is characterized by aortic and cerebral aneurysms with arterial tortuosity and skeletal manifestations. No ectopia lentis is present.

Mitral valve prolapse, myopia, aortic dilation, skin, and skeletal (MASS) phenotype

The MASS phenotype (OMIM #604308) is a constellation of features, namely mitral valve prolapse, myopia, mild nonprogressive aortic root dilatation, and marfanoid skeletal and skin (striae atrophicae) findings. [34, 35]

This phenotype may segregate as a dominant trait and remain stable over time. Most patients diagnosed with MASS have no progressive aortic root dilatation or aortic dissection. In rare instances, FBN1 mutations have been identified.

Stickler syndrome (OMIM #108300 [type I], #604841 [type II], #609508 [type I, nonsyndromic], #184840 [type III])

Overlapping features of Stickler syndrome and MFS are retrognathia, myopia, retinal detachment, and mitral valve prolapse. Other clinical findings include conductive and sensorineural hearing loss, midface hypoplasia, cleft palate, mild spondyloepiphyseal dysplasia, and/or precocious arthritis.


Homocystinuria (OMIM #236200) is an autosomal recessive metabolic disorder. It is characterized by ectopia lentis, long bone overgrowth, mental impairment, high predisposition to thromboembolism and coronary artery disease, in the absence of aortic root dilation. Light skin and hair are described in affected patients. [36]

There are two main phenotypes: a milder pyridoxine (vitamin B6)-responsive form, and a more severe vitamin B6-nonresponsive form. B6 is a cofactor for the cystathionine beta-synthase (CBS) enzyme and aids in the conversion of homocysteine to cysteine. 

Biochemical diagnostic features are increased urinary homocystine and methionine. Homocystinuria is due to either a homozygous or compound heterozygous mutation in the gene encoding CBS, located on chromosome 21q22.3.

Shprintzen-Goldberg syndrome

Shprintzen-Goldberg syndrome (OMIM #182212) typically includes craniosynostosis, hypertelorism, and, rarely, aortic root dilatation. Other features are exophthalmos, maxillary and mandibular hypoplasia, low-set ears, arachnodactyly, abdominal hernias, and intellectual disability. Patients do not have ectopia lentis. Patients differ from MFS patients in that they usually have some level of intellectual disability. Shprintzen-Goldberg syndrome is caused by a heterozygous mutation in the SKI gene, located on chromosome 1p36. [37, 38, 39]

Differential Diagnoses