Table 6.

Other Connective Tissue Disorders of Interest in the Differential Diagnosis of FBN1-Related Marfan Syndrome

Gene(s)DisorderMOIClinical Features / Comments
ACTA2
FOXE3
LOX
MAT2A
MFAP5
MYH11
MYLK
PRKG1
TGFB3
(selected HTAD-
related genes 1)		Other causes of heritable thoracic aortic disease (HTAD)Primarily ADHTAD refers to TAAD caused by mutation of a gene that confers a high risk for TAAD. ≤20% of individuals w/TAAD who do not have features of MFS, vascular EDS, or LDS have a family history of TAAD. ~30% of families w/HTAD who do not have a clinical diagnosis of MFS or another syndrome have a causative pathogenic variant in one of the known HTAD-related genes. 1
BGN Meester-Loeys syndrome (OMIM 300989)XLEarly-onset TAAD, hypertelorism, pectus deformity, joint hypermobility, contractures, & mild skeletal dysplasia
CBS Homocystinuria caused by cystathionine β-synthase (CBS) deficiency ARVariable ID, ectopia lentis &/or severe myopia, skeletal abnormalities (incl excessive height & limb length), & a tendency for intravascular thrombosis & thromboembolic events. ~50% of those affected are responsive to pharmacologic doses of vitamin B6, highlighting need to consider this diagnosis. Overlap w/MFS can be extensive & incl an asthenic (long & lean) body habitus, pectus deformity, scoliosis, mitral valve prolapse, highly arched palate, hernia, & ectopia lentis. Thromboembolic events can be life threatening.
COL2A1
COL9A1
COL9A2
COL9A3
COL11A1
COL11A2 		Stickler syndrome AD
AR 2		May incl ocular findings (myopia, cataract, & retinal detachment); hearing loss that is both conductive & sensorineural; midfacial hypoplasia & cleft palate (either alone or as part of Pierre Robin sequence); & mild spondyloepiphyseal dysplasia &/or precocious arthritis. The diagnosis is clinically based.
COL3A1 Vascular EDS (vEDS)AD 3Joint laxity (often limited to small joints in hands), translucent skin w/easily visible underlying veins, easy bruising, wide & dystrophic scars, characteristic facies (prominent eyes & a tight or "pinched" appearance), organ rupture (spleen, bowel, gravid uterus), & a tendency for aneurysm &/or dissection of any medium-to-large muscular artery throughout the body. Unlike in MFS or LDS, there is no particular tendency for involvement of aortic root, although this location is not spared from risk. The tissues can be extremely friable, often contributing to surgical catastrophe. Arteries often tear or rupture w/o prior dilatation.
COL5A1
COL5A2
(COL1A1)		Classic EDS (cEDS)ADSkin hyperextensibility, abnormal wound healing, smooth velvety skin, & joint hypermobility; aortic root dilatation reported, apparently more common in young persons & rarely progressing
FBN1 MASS syndrome (OMIM 604308)ADSee Genetically Related Disorders.
FBN2 Classic congenital contractural arachnodactyly (CCA)ADMarfan-like appearance & long, slender fingers & toes. Most affected persons have "crumpled" ears w/folded upper helix, & most have contractures of knees & ankles at birth that usually improve w/time. Proximal interphalangeal joints also have flexion contractures, as do toes. Hip contractures, adducted thumbs, & clubfoot may occur. Kyphosis/scoliosis, present in ~50%, begins as early as infancy & is progressive. Majority of affected persons have muscular hypoplasia. Mild dilatation of aorta is rarely present.
FMR1 Fragile X syndrome XLModerate ID in affected males & mild ID in affected females. Males have large testes (postpubertally), and may have characteristic appearance (large head, long face, prominent forehead & chin, protruding ears) & connective tissue findings (joint laxity) that suggest MFS phenotype. Behavior abnormalities, sometimes incl ASD, are common.
PLOD1 PLOD1-related kyphoscoliotic EDS (kEDS)ADFriable, hyperextensible skin, thin scars, & easy bruising; generalized joint laxity; severe muscular hypotonia at birth; progressive scoliosis, present at birth or w/in 1st yr of life; & scleral fragility w/↑ risk of rupture of globe. Intelligence is normal; life span may be normal, but affected persons are at risk for rupture of medium-sized arteries & respiratory compromise if kyphoscoliosis is severe.

AD = autosomal dominant; AR = autosomal recessive; ASD = autism spectrum disorder; EDS = Ehlers-Danlos syndrome; ID = intellectual disability; LDS = Loeys-Dietz syndrome; MFS = Marfan syndrome; MOI = mode of inheritance; TAAD = thoracic aortic aneurysms and aortic dissections; XL = X-linked

1.

To date, 16 genes are known to predispose to TAAD (see Table 1 in Heritable Thoracic Aortic Disease Overview). Note that many families with a family history of TAAD do not have a pathogenic variant in one of these 16 genes: additional HTAD-related genes are yet to be identified.

2.

Stickler syndrome caused by pathogenic variants in COL2A1, COL11A1, or COL11A2 is inherited in an autosomal dominant manner; Stickler syndrome caused by pathogenic variants in COL9A1, COL9A2, or COL9A3 is inherited in an autosomal recessive manner.

3.

Vascular EDS is almost always inherited in an autosomal dominant manner, but rare examples of biallelic inheritance have been reported.

From: FBN1-Related Marfan Syndrome

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