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Loeys-Dietz Syndrome.

Authors

Loeys BL1, Dietz HC2.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
2008 Feb 28 [updated 2013 Jul 11].

Author information

1
Center Medical Genetics, Antwerp University Hospital, Antwerp, Belgium
2
Victor A McKusick Professor of Medicine and Genetics, Institute of Genetic Medicine, Howard Hughes Medical Institute, Departments of Pediatrics, Medicine, and Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland

Excerpt

CLINICAL CHARACTERISTICS:

Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus). Approximately 75% of affected individuals have LDS type I with craniofacial manifestations (widely spaced eyes, bifid uvula/cleft palate, craniosynostosis); approximately 25% have LDS type II with systemic manifestations of LDSI but minimal or absent craniofacial features. LDSI and LDSII form a clinical continuum. The natural history of LDS is characterized by aggressive arterial aneurysms (mean age at death 26.1 years) and a high incidence of pregnancy-related complications, including death and uterine rupture.

DIAGNOSIS/TESTING:

The diagnosis of LDS is based on characteristic clinical findings in the proband and family members and molecular genetic testing of TGFBR1,TGFBR2, SMAD3, and TGFB2. No differences in phenotype are observed between individuals with a pathogenic variant in TGFBR1 and TGFBR2; it has been suggested that persons with a pathogenic variant in SMAD3 are at higher risk for osteoarthritis and those with a pathogenic variant in TGFB2 present a milder phenotype.

MANAGEMENT:

Treatment of manifestations: Important considerations when managing cardiovascular features of LDS: aortic dissection occurs at smaller aortic diameters than observed in Marfan syndrome; vascular disease is not limited to the aortic root; beta-adrenergic blockers or other medications are used to reduce hemodynamic stress; and aneurysms are amenable to early and aggressive surgical intervention. Surgical fixation of cervical spine instability may be necessary to prevent spinal cord damage. Treatment is standard for club feet and severe pes planus. Management by a craniofacial team is preferred for treatment of cleft palate and craniosynostosis. Prevention of secondary complications: Consider subacute bacterial endocarditis (SBE) prophylaxis in those undergoing dental work or other procedures expected to contaminate the bloodstream with bacteria. Because of a high risk for cervical spine instability, an x-ray of the cervical spine should be performed prior to intubation or any other procedure involving manipulation of the neck. Surveillance: All individuals with LDS require echocardiography at frequent intervals to monitor the status of the ascending aorta; the frequency of magnetic resonance angiography (MRA) or computerized tomography angiography (CTA) evaluation to image the entire arterial tree depends on clinical findings. Individuals with cervical spine instability and severe or progressive scoliosis should be followed by an orthopedist. Agents/circumstances to avoid: Contact sports, competitive sports, and isometric exercise; agents that stimulate the cardiovascular system including routine use of decongestants; activities that cause joint injury or pain. Evaluation of relatives at risk: If the causal variant is known in the proband, molecular genetic testing can be used to clarify genetic status of family members at risk; if the pathogenic variant is not known, relatives at risk should be evaluated for signs of LDS, including echocardiography and extensive vascular imaging if findings suggest LDS or if findings were subtle in the index case. Pregnancy management: Pregnancy can be dangerous for women with LDS; increased frequency of aortic imaging is recommended, both during pregnancy and in the weeks following delivery.

GENETIC COUNSELING:

LDS is inherited in an autosomal dominant manner. Approximately 25% of individuals diagnosed with LDS have an affected parent; approximately 75% of probands have LDS as the result of a de novo pathogenic variant. Each child of an individual with LDS has a 50% chance of inheriting the pathogenic variant and the disorder. Prenatal diagnosis for pregnancies at increased risk for LDS is possible if the pathogenic variant in the family is known.

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