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Loeys-Dietz syndrome

Reviewed July 2014

What is Loeys-Dietz syndrome?

Loeys-Dietz syndrome is a disorder that affects the connective tissue in many parts of the body. Connective tissue provides strength and flexibility to structures such as bones, ligaments, muscles, and blood vessels.

There are four types of Loeys-Dietz syndrome, labelled types I through IV, which are distinguished by their genetic cause. Regardless of the type, signs and symptoms of Loeys-Dietz syndrome can become apparent anytime in childhood or adulthood, and the severity is variable.

Loeys-Dietz syndrome is characterized by enlargement of the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. The aorta can weaken and stretch, causing a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection). People with Loeys-Dietz syndrome can also have aneurysms or dissections in arteries throughout the body and have arteries with abnormal twists and turns (arterial tortuosity).

Individuals with Loeys-Dietz syndrome often have skeletal problems including premature fusion of the skull bones (craniosynostosis), an abnormal side-to-side curvature of the spine (scoliosis), either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum), an inward- and upward-turning foot (clubfoot), flat feet (pes planus), or elongated limbs with joint deformities called contractures that restrict the movement of certain joints. Degeneration of the discs that separate the bones of the spine (vertebrae), often affecting the neck, is a common finding. Some affected individuals have prominent joint inflammation (osteoarthritis) that commonly affects the knees and the joints of the hands, wrists, and spine.

People with Loeys-Dietz syndrome may bruise easily and develop abnormal scars after wound healing. The skin is frequently described as translucent, often with stretch marks (striae) and visible underlying veins. Other characteristic features include widely spaced eyes (hypertelorism), a split in the soft flap of tissue that hangs from the back of the mouth (bifid uvula), and an opening in the roof of the mouth (cleft palate).

Individuals with Loeys-Dietz syndrome frequently develop immune system-related problems such as food allergies, asthma, or inflammatory disorders such as eczema or inflammatory bowel disease.

How common is Loeys-Dietz syndrome?

The prevalence of Loeys-Dietz syndrome is unknown. Loeys-Dietz syndrome types I and II appear to be the most common forms.

What genes are related to Loeys-Dietz syndrome?

The four types of Loeys-Dietz syndrome are distinguished by their genetic cause: mutations in the TGFBR1 gene cause type I, mutations in the TGFBR2 gene cause type II, mutations in the SMAD3 gene cause type III, and mutations in the TGFB2 gene cause type IV. These four genes play a role in cell signaling that promotes growth and development of the body's tissues. This signaling pathway also helps with bone and blood vessel development and plays a part in the formation of the extracellular matrix, an intricate lattice of proteins and other molecules that forms in the spaces between cells.

Mutations in the TGFBR1, TGFBR2, TGFB2, and SMAD3 genes result in the production of proteins with little or no function. Even though these proteins have severely reduced function, cell signaling occurs at an even greater intensity than normal. Researchers speculate that the activity of proteins in this signaling pathway is increased to compensate for the protein whose function is reduced; however, the exact mechanism responsible for the increase in signaling is unclear. The overactive signaling pathway disrupts the development of connective tissue, the extracellular matrix, and various body systems, leading to the varied signs and symptoms of Loeys-Dietz syndrome.

Related Gene(s)

Changes in these genes are associated with Loeys-Dietz syndrome.

  • SMAD3
  • TGFB2
  • TGFBR1
  • TGFBR2

How do people inherit Loeys-Dietz syndrome?

Loeys-Dietz syndrome is considered to have an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In about 75 percent of cases, this disorder results from a new gene mutation and occurs in people with no history of the disorder in their family. In other cases, an affected person inherits the mutation from one affected parent.

Where can I find information about diagnosis or management of Loeys-Dietz syndrome?

These resources address the diagnosis or management of Loeys-Dietz syndrome and may include treatment providers.

  • Gene Review: Loeys-Dietz Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1133)
  • Genetic Testing Registry: Loeys-Dietz syndrome (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2697932)
  • Genetic Testing Registry: Loeys-Dietz syndrome, type 4 (http://www.ncbi.nlm.nih.gov/gtr/conditions/CN143719)
  • Genetic Testing Registry: Loeys-Dietz syndrome 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2697933)
  • Genetic Testing Registry: Loeys-Dietz syndrome 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2674876)
  • Genetic Testing Registry: Loeys-Dietz syndrome type 3 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C3151087)
  • Johns Hopkins Medicine: Diagnosis of Craniosynostosis (http://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/pediatric_neurosurgery/conditions/craniosynostosis/diagnosis.html)
  • MedlinePlus Encyclopedia: Aortic Dissection (http://www.nlm.nih.gov/medlineplus/ency/article/000181.htm)
  • National Heart Lung and Blood Institute: How Is an Aneurysm Treated? (http://www.nhlbi.nih.gov/health/health-topics/topics/arm/treatment.html)

You might also find information on the diagnosis or management of Loeys-Dietz syndrome in Educational resources (http://www.ghr.nlm.nih.gov/condition/loeys-dietz-syndrome/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/loeys-dietz-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about Loeys-Dietz syndrome?

You may find the following resources about Loeys-Dietz syndrome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for Loeys-Dietz syndrome?

  • LDS
  • Loeys-Dietz aortic aneurysm syndrome

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about Loeys-Dietz syndrome?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding Loeys-Dietz syndrome?

aneurysm ; aorta ; aortic dissection ; arteries ; autosomal ; autosomal dominant ; bifid ; cell ; cleft palate ; clubfoot ; connective tissue ; craniosynostosis ; eczema ; extracellular ; extracellular matrix ; gene ; hypertelorism ; immune system ; inflammation ; inheritance ; joint ; joint inflammation ; mutation ; new gene mutation ; palate ; pattern of inheritance ; pectus excavatum ; prevalence ; protein ; scoliosis ; syndrome ; tissue ; tortuosity ; translucent ; uvula ; veins

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Frischmeyer-Guerrerio PA, Guerrerio AL, Oswald G, Chichester K, Myers L, Halushka MK, Oliva-Hemker M, Wood RA, Dietz HC. TGFβ receptor mutations impose a strong predisposition for human allergic disease. Sci Transl Med. 2013 Jul 24;5(195):195ra94. doi: 10.1126/scitranslmed.3006448. (http://www.ncbi.nlm.nih.gov/pubmed/23884466?dopt=Abstract)
  • Kalra VB, Gilbert JW, Malhotra A. Loeys-Dietz syndrome: cardiovascular, neuroradiological and musculoskeletal imaging findings. Pediatr Radiol. 2011 Dec;41(12):1495-504; quiz 1616. doi: 10.1007/s00247-011-2195-z. Epub 2011 Jul 23. Review. (http://www.ncbi.nlm.nih.gov/pubmed/21785848?dopt=Abstract)
  • Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, Kempers MJ, Fishman EK, Chen Y, Myers L, Bjeda D, Oswald G, Elias AF, Levy HP, Anderlid BM, Yang MH, Bongers EM, Timmermans J, Braverman AC, Canham N, Mortier GR, Brunner HG, Byers PH, Van Eyk J, Van Laer L, Dietz HC, Loeys BL. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet. 2012 Jul 8;44(8):922-7. doi: 10.1038/ng.2349. (http://www.ncbi.nlm.nih.gov/pubmed/22772368?dopt=Abstract)
  • Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, De Backer JF, Oswald GL, Symoens S, Manouvrier S, Roberts AE, Faravelli F, Greco MA, Pyeritz RE, Milewicz DM, Coucke PJ, Cameron DE, Braverman AC, Byers PH, De Paepe AM, Dietz HC. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006 Aug 24;355(8):788-98. (http://www.ncbi.nlm.nih.gov/pubmed/16928994?dopt=Abstract)
  • MacCarrick G, Black JH 3rd, Bowdin S, El-Hamamsy I, Frischmeyer-Guerrerio PA, Guerrerio AL, Sponseller PD, Loeys B, Dietz HC 3rd. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014 Aug;16(8):576-87. doi: 10.1038/gim.2014.11. Epub 2014 Feb 27. (http://www.ncbi.nlm.nih.gov/pubmed/24577266?dopt=Abstract)
  • van de Laar IM, van der Linde D, Oei EH, Bos PK, Bessems JH, Bierma-Zeinstra SM, van Meer BL, Pals G, Oldenburg RA, Bekkers JA, Moelker A, de Graaf BM, Matyas G, Frohn-Mulder IM, Timmermans J, Hilhorst-Hofstee Y, Cobben JM, Bruggenwirth HT, van Laer L, Loeys B, De Backer J, Coucke PJ, Dietz HC, Willems PJ, Oostra BA, De Paepe A, Roos-Hesselink JW, Bertoli-Avella AM, Wessels MW. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet. 2012 Jan;49(1):47-57. doi: 10.1136/jmedgenet-2011-100382. (http://www.ncbi.nlm.nih.gov/pubmed/22167769?dopt=Abstract)
  • Van Hemelrijk C, Renard M, Loeys B. The Loeys-Dietz syndrome: an update for the clinician. Curr Opin Cardiol. 2010 Nov;25(6):546-51. doi: 10.1097/HCO.0b013e32833f0220. Review. (http://www.ncbi.nlm.nih.gov/pubmed/20838339?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: July 2014
Published: November 24, 2014