Loeys-Dietz syndrome

LDS shows a wide phenotypic spectrum, ranging from a severe syndromic presentation with significant extravascular findings in young children to predominantly thoracic aortic aneurysm and dissection in adults. Substantial intra- and interfamilial clinical variability is observed, even among relatives carrying the same pathogenic variant. The major sources of morbidity and early mortality are dilatation of the aorta at the level of the sinuses of Valsalva, predisposition to aortic dissection and rupture, mitral valve prolapse with or without regurgitation, and enlargement of the proximal pulmonary artery. Aortic dissection has been observed from early childhood (age ≥6 months) and at aortic dimensions that would not confer dissection risk in other connective tissue disorders such as . Arterial tortuosity is frequently generalised but most commonly involves the head and neck vessels. Craniofacial findings include hypertelorism and craniosynostosis, most often premature fusion of the sagittal suture with resulting dolichocephaly. Affected individuals are also predisposed to allergic disease, including asthma, food allergy, eczema, allergic rhinitis and eosinophilic gastrointestinal disease.

The estimated prevalence is 1/50,000.

LDS associated with pathogenic variants in TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3 is inherited in an autosomal dominant manner; LDS7, caused by biallelic variants in IPO8, is inherited in an autosomal recessive manner. For autosomal dominant LDS, approximately 75% of probands have a de novo pathogenic variant, while the remainder have inherited the variant from an affected parent. The recurrence risk for offspring of an affected individual is 50% in the autosomal dominant forms. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis of LDS is established in a proband by identification of a germline pathogenic variant in one of the known disease-associated genes through molecular genetic testing. Imaging plays a central role in defining the vascular phenotype: magnetic resonance angiography or CT angiography with three-dimensional reconstruction from head to pelvis is used to identify arterial aneurysms, dissections and arterial tortuosity throughout the arterial tree, while echocardiography is used to assess the aortic root and ascending aorta.

Main differential diagnoses include:

• : aortic root dilatation, dissection, mitral valve prolapse and tall stature with skeletal overgrowth; ectopia lentis is characteristic of Marfan but absent in LDS, while arterial aneurysms beyond the aortic root, generalised arterial tortuosity, hypertelorism, bifid uvula/cleft palate and dissection at smaller aortic diameters favour LDS; FBN1
• : craniosynostosis with marfanoid habitus overlapping LDS but distinguished by near-uniform developmental delay or mild-to-moderate intellectual disability and milder, less common aortic root dilatation; SKI
• Vascular : shares thin, translucent skin, easy bruising, aggressive arterial aneurysms and dissections (cerebral, thoracic, and abdominal) with LDS but is distinguished by the absence of prominent skeletal manifestations and craniofacial anomalies; COL3A1 (rarely COL1A1)

• Establishing the molecular genetic diagnosis confirms the clinical suspicion and provides the basis for individualised counselling.
• Identification of the underlying pathogenic variant enables specific and individualised surveillance and clinical management, with the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is known, predictive testing of at-risk relatives can clarify their genetic status and allow timely cardiovascular surveillance in those who carry the variant.

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• Gouda P, Kay R, Habib M, Aziz A, Aziza E, Welsh R. Clinical features and complications of Loeys-Dietz syndrome: A systematic review. International journal of cardiology. 2022;362:158-167. doi: 10.1016/j.ijcard.2022.05.065. PMID: .
• MacCarrick G, Black JH 3rd, Bowdin S, El-Hamamsy I, Frischmeyer-Guerrerio PA, Guerrerio AL, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genetics in medicine : official journal of the American College of Medical Genetics. 2014;16(8):576-87. doi: 10.1038/gim.2014.11. PMID: . PMCID: PMC4131122.