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29: Loeys-Dietz Syndrome

Gretchen Oswald; Harold C. Dietz

Key Points

  • Disease summary:

    • Loeys-Dietz syndrome (LDS) is a connective tissue disorder characterized by vascular features (aortic aneurysm or dissection and arterial tortuosity with risk of aneurysm throughout the arterial tree) in addition to a variety of skeletal (scoliosis, pectus deformity, joint laxity, clubfoot or varus deformities, cervical spine instability) and cutaneous features (skin translucency, hernias, abnormal scarring). A proportion of individuals who come to medical attention at young ages have severe craniofacial anomalies (craniosynostosis, cleft palate, hypertelorism) typically associated with more severe vascular disease. The spectrum of physical manifestations is broad.

    • LDS is caused by mutations in TGFBR1, TGFBR2, SMAD3, and TGFB2 genes.

  • Hereditary basis:

    • LDS is an autosomal dominant disorder.

  • Differential diagnosis:

    • It is important to differentiate between LDS and other aortic aneurysm syndromes as systemic manifestations, imaging management, and surgical intervention guidelines differ according to diagnosis.

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria

Diagnostic criteria have not been established. Molecular genetic testing plays an important role in distinguishing LDS from other aortic aneurysm syndromes. For the differential diagnosis for LDS, see Table 29-1.

Table 29-1Genetic Differential Diagnosis
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Table 29-1 Genetic Differential Diagnosis
Syndrome Gene Associated Features
Marfan syndrome FBN1

Cardiovascular: aortic root aneurysm

Skeletal: scoliosis, pectus deformity, flat feet, arachnodactyly, tall stature

Other: ocular lens dislocation
Familial thoracic aortic aneurysm disease (FTAAD) ACTA2, MYH11, MYLCK(TGFBR1, TGFBR2, SMAD3, TGFB2)a

Cardiovascular: aortic root aneurysm, bicuspid aortic valve (BAV) or patent ductus arteriosus (PDA), vascular occlusive disease

Skeletal: none

Other: livedo reticularis, iris flocculi
Ehlers-Danlos syndrome, vascular type COL3A1, TGFB2

Cardiovascular: typically lack aortic root aneurysm; aneurysm or dissection throughout arterial tree

Skeletal: finger joint hypermobility

Cutaneous: abnormal scarring, translucent skin, easy bruising

Other: bowel or uterine rupture
Arterial tortuosity syndrome SLC2A10

Cardiovascular: significant and widespread arterial tortuosity, pulmonary artery and other arterial stenosis; rare aortic aneurysm

Skeletal: joint hypermobility

Cutaneous: soft, doughy or hyperextensible skin

Other: hernias
BAV and ascending aneurysm NOTCH1 (rare); largely unknown

Cardiovascular: family or personal history of BAV, aortic coarctation, left-sided heart defects, ascending aortic aneurysm

Skeletal: none

Cutaneous: none
Shprintzen-Goldberg syndrome Unknown SKI

Cardiovascular: mitral valve prolapse, rare aortic aneurysm

-Skeletal: scoliosis, pectus deformity, arachnodactyly, contractures, joint hypermobility

-Other: craniosynostosis, prominent lateral palantine edge, intellectual disability

aGene mutations in these genes have been reported in both LDS and FTAAD.

Gene names: FBN1, fibrillin 1; COL3A1, collagen, type 3, alpha-1; ACTA2, smooth muscle aortic alpha-actin; MYH11, myosin, heavy chain 11, smooth muscle; TGFBR1, transforming growth factor beta receptor 1; TGFBR2, transforming growth factor beta receptor 2, SMAD3, mothers against decapentaplegic, Drosophila, homolog of, 3; SKI, SK oncogene; SLC2a10, solute carrier family 2, member 10; NOTCH1, notch, Drosophila, homolog of, 1.

Clinical Characteristics

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