Loeys-Dietz syndrome

Further

delineation of Loeys-Dietz syndrome type 4 in a family with mild vascular involvement and a TGFB2 splicing mutation. Clinical and radiological features of the proband and her daughter. (A) Clinical phenotype of the proband including microretrognathia, and elongated philtrum (a, b), mild generalized skin hyperextensibility (c), joint hypermobility (d, e). (B) MRI in the proposita showed dural ectasia of the lumbar tract (a), MRA disclosed tortuosity and ectasia of carotid, vertebral, and cerebral arteries (b, c) and marked tortuosity of both segmental pulmonary arteries (d). (C) Clinical presentation of the 34 years-old proband’s daughter: hypotelorism, elongated philtrum and malar hypoplasia (a, b), mild skin hyperextensibility over the neck (c), atrophic post-surgical scar and ecchymosis (d), arachnodactyly with positive wrist and thumb signs (e, f).

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Loeys-Dietz syndrome is an autosomal dominant connective tissue disorder which has many features similar to Marfan syndrome.

The disease is characterized by skeletal manifestations and vasculopathies. Although Loeys-Dietz syndrome shares many similarities with Marfan syndrome, the course is often more aggressive with respect to vasculopathy and is more likely to affect peripheral arteries.

The classical triad of Loeys-Dietz syndrome is described as :

arterial tortuosity and aneurysms
hypertelorism
bifid uvula or cleft palate

Epidemiology

Loeys-Dietz syndrome is rare, with prevalence estimated at less than one per 100,000.

Clinical presentation

Disease spectrum and associated features include:

Craniofacial

hypertelorism
cleft palate
bifid uvula
craniosynostosis
malar hypoplasia
blue sclerae
Chiari I malformation
hydrocephalus

Cardiovascular

aortic dissection
aortic dilatation
non-aortic aneurysms (a distinguishing feature of Loeys-Dietz syndrome), including:
- popliteal artery aneurysm
- internal thoracic artery aneurysm
- common iliac aneurysm
- splenic artery aneurysm
- intracranial aneurysm
arterial tortuosity
associated congenital cardiac abnormalities:
- patent ductus arteriosus
- atrial septal defects
mitral valve prolapse
left ventricular hypertrophy

Musculoskeletal

arachnodactyly
camptodactyly
pectus carinatum
scoliosis
talipes equinovarus
joint laxity
dolichostenomelia (unusually long limbs)
cervical spine instability

Other

developmental delay
environmental allergies
dural ectasia

Pathology

It is caused by mutations in the genes encoding transforming growth factor-beta receptor 1 (TGFBR1) or 2 (TGFBR2). Although Loeys-Dietz syndrome is inherited in an autosomal dominant pattern, de novo mutations account for approximately 75% of cases.

Subtypes

Loeys-Dietz syndrome can be subdivided into four subtypes depending on their genetic mutations and resulting phenotypic features.

type I: predominantly craniofacial features
- TGFBR1 mutation; chromosome 9q22
type II: predominantly cutaneous features
- TGFBR2 mutation; chromosome 3p22
type III: predominantly aneurysm-osteoarthritis features
- SMAD3 mutation; chromosome 15q
type IV: predominantly Marfanoid features
- TGFB2 mutation; chromosome 1q41