29: Loeys-Dietz Syndrome

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 29-1 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

Clinical Characteristics

The majority of individuals with LDS will present with aortic root aneurysm or dissection. With three-dimensional computed tomography angiography or magnetic resonance angiography, arterial tortuosity can be a diagnostic clue. The presence of additional skeletal, cutaneous, or allergy findings should prompt genetic evaluation and testing. The first cohort of patients described in 2005 had more severe craniofacial features (LDS1), while other patients presented with more prominent cutaneous features (LDS2). SMAD3 mutations were described in 2011 and TGFB2 mutations in 2012, leading to renaming of subtypes of LDS based on genotype (mutations in TGFBR1, TGFBR2, SMAD3 and TGFB2 causing LDS 1, 2, 3, and 4, respectively). All four types of LDS show a broad continuum of associated features. Unless noted, percentages noted in Table 29-2 are reported in individuals with TGFBR1/2 mutations.