38: LOEYS DIETZ SYNDROME AND RELATED DISORDERS

PATIENT STORY

A 26-year-old woman was referred for evaluation of a possible connective tissue disorder. She first came to medical attention in early childhood when she was diagnosed with a pectus excavatum and joint hypermobility. Additional history included mitral valve prolapse, inguinal and umbilical hernias, as well as scoliosis. She carried the diagnosis of hypermobile Ehlers-Danlos syndrome (EDS) for many years yet had normal collagen studies for EDS type IV. At the age of 19 years, mitral valve repair for severe mitral valve regurgitation was performed. Six years later, she presented to the emergency room for evaluation of sudden-onset tachycardia and chest pain. Echocardiogram revealed a dilated aorta, and computed tomographic (CT) scan showed bilateral subclavian artery aneurysms. The physical examination was notable for normal height, weight, and body mass index (BMI). Marfan syndrome assessment revealed a systemic score of 6 with points for increased arm span to height ratio, pectus excavatum, positive wrist sign, mitral valve prolapse, and hindfoot deformity. Additional physical examination findings were notable for a bifid uvula and normal palate. A transforming growth factor beta (TGF-β) spectrum disorder was suspected and a c.1363T>A mutation in the TGFβR2 gene consistent with the diagnosis of Loeys Dietz syndrome (LDS) was confirmed on sequencing.

EPIDEMIOLOGY

• The prevalence of LDS is unknown. There is no enrichment in any particular ethnic or racial group or gender.

ETIOLOGY AND PATHOPHYSIOLOGY

• Due to point mutations and (rarely) deletions in the TGFβR1, TGFβR2, TGFβ2, or SMAD3 genes.

• Autosomal dominant disorder.

• Highly variable disorder even within families with incomplete penetrance.

• Mutations in other genes involved in the TGF-β signaling pathway are likely to emerge as disease contributing.

CLINICAL FEATURES

LDS is a disorder of connective tissue characterized by:¹

Vascular

• Dilatation or dissection of the aorta most commonly thoracic (Figure 38-1)

• Other arterial aneurysms and dissections (Figure 38-1)

• Arterial tortuosity

Skeletal

• Pectus excavatum or pectus carinatum

• Scoliosis

• Joint laxity

• Arachnodactyly

• Talipes equinovarus or hindfoot deformity

• Osteoarthritis (SMAD3)

• Cervical spine instability

Craniofacial

• Ocular hypertelorism

• Bifid uvula or cleft palate (Figure 38-2)

• Craniosynostosis

Cutaneous

• Translucent skin (Figure 38-3)

• Easy bruising

• Dystrophic