The UMD-TGFBR1 mutations database
The clinics

The mutations of TGFBR1 gene have been found in association with a continuum of clinical features such as Marfan syndrome (OMIM #154700), Loeys-Dietz syndrome type I (OMIM #609192) or type II (OMIM #608967), vascular Ehlers-Danlos syndrome, Furlong syndrome and TAAD.

1. Marfan syndrome

Marfan syndrome (MFS) (OMIM#154700), the founding member of heritable disorders of connective tissue, is an autosomal dominant connective-tissue disorder. It involves predominantly three systems: skeletal, ocular, and cardiovascular.
Squeletal features: increased height, disproportionately long limbs and digits, anterior chest deformity, mild-to-moderate joint laxity, vertebral column deformity (scoliosis and thoracic lordosis), and a narrow, highly arched palate with crowding of the teeth.
Ocular features: myopia, increased axial globe length, corneal flatness, and subluxation of the lenses (ectopia lentis).
Cardiovascular features: mitral valve prolapse, mitral regurgitation, dilatation of the aortic root, and aortic regurgitation are cardiovascular features.
Other common or peculiar manifestations include striae distensae, pulmonary blebs (which predispose to spontaneous pneumothorax) and spinal arachnoid cysts or diverticula.

2. Loeys-Dietz Syndrome

This aortic aneurysm syndrome is characterized by hypertelorism, bifid uvula and/or cleft palate, and generalized arterial tortuosity with ascending aortic aneurysm and dissection (Loeys et al 2005) (OMIM #609192). The syndrome showed autosomal dominant inheritance and variable clinical expression. Other findings in multiple systems included craniosynostosis, structural brain abnormalities, developmental delay, congenital heart disease, and aneurysms with dissection throughout the arterial tree. Mutations in TGFBR2 (OMIM 190182) and in TGFBR1 (OMIM #190181) have been found (Loeys et al 2005 and 2006).

3. Thoracic Aortic Aneurysm And Dissections (TAAD)

Thoracic aortic aneurysms leading to aortic dissections (TAAD) (OMIM #608967) is a complication of some known genetic disorders, such as Marfan syndrome but the majority of familial cases are not due to a known genetic syndrome. TAAD are a major cause of morbidity and mortality. Familial TAAD is inherited in an autosomal dominant manner with decreased penetrance and variable expression.

4. Shprintzen-Goldberg syndrome (SGS)

Shprintzen-Goldberg syndrome (OMIM #182212) is one of a group of disorders characterized by craniosynostosis (premature fusion of skull sutures) and marfanoid habitus (features resembling Marfan syndrome). Other craniofacial features such as micrognathia (small lower jaw), maxillary hypoplasia, low-set ears, soft tissue hypertrophy of the palatal shelves, ocular hypertelorism (increased distance between the eyes), and exophthalmos (protruding eyes) may also be seen.

5. vascular Ehlers-Danlos syndrome (vEDS)

Vascular Ehlers-Danlos syndrome, also known as Ehlers-Danlos syndrome type IV or cutis hyperelastical, is a life-threatening inherited disorder of connective tissue, resulting from mutations in the COL3A1 gene coding for type III procollagen but also TGFBR1 gene. Vascular EDS causes severe fragility of connective tissues with arterial and gastrointestinal rupture, and complications of surgical and radiological interventions. In adulthood, four main clinical findings, including a striking facial appearance, easy bruising, translucent skin with visible veins and rupture of vessels, gravid uterus or intestines contribute to the diagnosis.
Loeys et al. (2006) undertook the clinical and molecular characterization of the families of 40 probands presenting with typical manifestations of the Loeys-Dietz syndrome (LDS1A). In view of the phenotypic overlap between this syndrome and vascular Ehlers-Danlos syndrome (EDS; 130050), they screened an additional cohort of 40 patients who had been diagnosed provisionally with vascular EDS but lacked the characteristic abnormalities of type III collagen (120180). Of these 40 probands, 4 carried a heterozygous mutation in TGFBR1 (3 of which involved codon 487; see, e.g., 190181.0004 and 190181.0007) and were classified as Loeys-Dietz syndrome type 2 (see LDS2A, 608967)

6. Furlong syndrome

The Furlong syndrome (OMIM #609192) is a very rare autosomal dominant genetic syndrome characterized by the association of premature fusion of skull bones with Marfanoid features. The disorder arises from abnormal connective tissue.
Furlong et al. (1987) described a male of normal height and intelligence with dolichocephaly, a high palate, dolichostenomelia, a mild scoliosis, L4-5 spondylolisthesis, long thorax, prominent pectus carinatum, camptodactyly, pes planus, mitral valve insufficiency, bilateral recurrent inguinal herniae, myopia with normal lenses, mitral valve prolapse, and a dilated aortic root which subsequently dissected at age 18 years. Features atypical for Marfan syndrome (154700) included multisutural craniosynostosis, ptosis, hypertelorism, and hypospadias. Ades et al. (2006) found that 2 patients with a phenotype resembling Furlong syndrome were heterozygous for the same de novo missense mutation in the TGFBR1 gene (190181.0005).