What does Loeys-Dietz Syndrome Look Like?

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An Overview into the Phenotypic Differences Across LDS Subtypes

8 min. read

Do the different types of Loeys-Dietz syndrome (LDS) have different features? Research has now shown that there are both similarities and differences between the types of LDS.

Keep reading to find the phenotypes (features) associated with LDS, the types of LDS, and other connective tissue disorders like Marfan syndrome and Ehlers-Danlos syndrome.


What is Loeys-Dietz Syndrome?

Loeys-Dietz syndrome (LDS) is a rare genetic disorder that affects the body’s connective tissue.

How? There are six genes associated with LDS. These genes control the production of proteins that help to form and maintain connective tissue throughout the body.

The six different subtypes of LDS and their associated genes are:

LDS Subtype Associated Gene
Loeys-Dietz syndrome 1 TGFBR1
Loeys-Dietz syndrome 2 TGFBR2
Loeys-Dietz syndrome 3 SMAD3
Loeys-Dietz syndrome 4 TGFB2
Loeys-Dietz syndrome 5 TGFB3
Loeys-Dietz syndrome 6 SMAD2


When certain mutations occur in these six genes, it causes Loeys-Dietz syndrome. People with LDS often exhibit certain physical features that are known as the signs and symptoms of LDS.


What is a Phenotype? What is a Genotype?

A phenotype refers to the observable physical, behavioral, and biochemical characteristics of an organism. These traits come from a combination of the organism’s genetic makeup (genotype) and their environment. Phenotypes can range from visible physical traits like eye color, hair texture, and height, to more complex traits like intelligence, personality, and disease risk.

This article covers the various phenotypes and clinical manifestations that are present due to a genetic diagnosis of Loeys-Dietz syndrome.


What are the Different Phenotypes of LDS?

From Head to Toe

LDS is a condition that can manifest in many ways. It affects an individual from head to toe. Most notably, LDS is characterized by the following:

  • Aortic aneurysms or dissections: This is the most common and dangerous characterization of LDS. It involves the weakening and enlargement of the aorta, the largest artery in the body, which can lead to a life-threatening rupture or tear. Aneurysms and dissections can also occur throughout the body’s arteries, from head to pelvis.
  • Connective tissue abnormalities: This can include soft, velvety skin that is easily bruised, joint hypermobility (increased flexibility), and abnormal scarring
  • Skeletal abnormalities: This can include scoliosis, joint laxity, cervical spine malformation, osteoarthritis, etc.
  • Craniofacial abnormalities: This can include widely spaced eyes, a cleft palate, a highly arched palate, a small lower jaw, and a tendency towards a “long” face shape
  • Ocular abnormalities: This can include nearsightedness, farsightedness, and/or a lens dislocation
  • Allergic/Inflammatory issues: Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including inflammatory bowel disease and eosinophilic esophagitis, gastritis, and colitis.
  • Other cardiovascular abnormalities: This can include arterial tortuosity, a bicuspid aortic valve (a heart valve with only two leaflets instead of the normal three); mitral valve prolapse, and dilation of other blood vessels

It is important to note that not all individuals with LDS will have all of these symptoms, and the severity of these symptoms can vary greatly even within families with the same genetic mutation. If you suspect you or a loved one may have LDS, it is important to consult a healthcare professional for proper diagnosis and management.

To learn more about the signs and symptoms of LDS, click here.


LDS Subtypes: Phenotypes

Do the different subtypes of Loeys-Dietz syndrome have different features? Research shows that while there are similarities, there are also differences between the subtypes of LDS.

The table below shows a list of features associated with the types and genetic mutations:

LDS1 (Mutations in TGFBR1) LDS2 (Mutations in TGFBR2) LDS3 (Mutations in SMAD3) LDS4 (Mutations in TGFB2) LDS5 (Mutations in TGFB3) LDS6 (Mutations in SMAD2)
o    Characterized by the presence of craniofacial features (cleft palate, hypertelorism, bifid uvula)

o    Most severe form of LDS

o    Most commonly reported features: aortic aneurysms, arterial tortuosity, pectus excavatum/carinatum, broad or bifid uvula, long, thin toes and fingers, joint laxity, aneurysms in the vasculature beyond the aorta, and retrognathia

o    Onset of disease is significantly younger

o    More likely to present with vascular disease beyond the aorta

o    Reported neurodevelopmental issues (more common than LDS2 and LDS3)

o    Clubfoot is common

o    Joint flexibility is common

o    Reported Allergic and GI disease

o    Reported eye muscle problems

o    Reported cervical spine instability

o    Less likely to have hernias

o    Less likely to have osteoarthritis

o   Less likely to have spondylolisthesis

o   Less likely to have scoliosis

o   Most commonly reported features: aortic aneurysms, arterial tortuosity, pectus excavatum/carinatum, broad or bifid uvula, long, thin toes and fingers, joint laxity, hypertelorism, scoliosis, velvety skin, easy bruising, malar hypoplasia, and a high arched palate

o   Minimal to absent craniofacial features

o   More likely to dissect at smaller diameters than the other subtypes

o   Reported neurodevelopmental issues

o   Clubfoot is common

o   High presence of oro-dental abnormalities (dental crowding, enamel defects, delayed eruption of permanent teeth)

o   Reported eye muscle problems

o   Reported cervical spine instability

o   Joint flexibility is common

o   Reported allergic and GI disease

o   Less likely to have hernias

o   Less likely to have osteoarthritis

o   Less likely to have spondylolisthesis


o   Most commonly reported features: early onset osteoarthritis, osteochondritis dissecans, aortic aneurysms, arterial tortuosity, velvety skin, striae, varices, broad or bifid uvula, abnormal palate, scoliosis, and pes planus

o   Most likely of all types to experience mitral valve prolapse

o   Craniofacial features are only somewhat common

o   Reported neurodevelopmental issues

o   Osteoarthritis is very common

o   Reported neurovascular abnormality

o   Spondylolisthesis is common

o   Hernias are common

o   Less likely to have clubfoot

o   Less likely to have joint flexibility

o    Most commonly reported features: aortic aneurysms, pectus excavatum/carinatum, joint laxity, scoliosis, pes planus, high arched palate, long, thin toes and fingers, and inguinal and umbilical hernias

o    Craniofacial features are only somewhat common

o    Clubfoot is common

o    Systemic findings similar to Marfan Syndrome

o    Reported cerebral aneurysms

o    Joint flexibility is common

o    Hernias are common

o    Scoliosis is common

o    Less likely to have osteoarthritis

o    Less likely to have spondylolisthesis



o    Most commonly reported features: aortic aneurysms, excavatum/carinatum, joint laxity, pes planus, long, thin toes and fingers, hypertelorism, and broad or bifid uvula

o    Least severe form of LDS

o    Fewer skeletal features

o    Lower risk of aneurysm rupture

o    Recently identified – still much to learn

o    Higher risk of aortic aneurysm rupture than some of the other subtypes

NOTE: All subtypes have reported similar levels of pectus deformity, presence of aortic root aneurysm, and arterial tortuosity


LDS affects each individual differently. Therefore, even though this table describes features associated with the different types of LDS, not all individuals will experience all the features of their type of LDS.

If an individual exhibits features of LDS or of a specific type of LDS, it does not necessarily mean they have LDS or that type of LDS. Clinical evaluation and/or genetic testing are necessary to confirm a diagnosis of Loeys-Dietz syndrome.

Loeys-Dietz syndrome (LDS) has been categorized into different subtypes based on clinical presentations such as LDS type I (presence of craniofacial features), LDS type II (minimal to absent craniofacial features), and LDS type III (presence of osteoarthritis). These subtypes indicate the range of disease severity, with LDS1 being the most severe and LDS5 being the least severe. LDS4 exhibits systemic findings that are similar to Marfan syndrome but may be less severe. Although the implicated gene can broadly correlate with disease severity, there are limited specific genotype-phenotype correlations in LDS. In general, LDS1 is the most severe, in which the onset of disease is significantly younger and is more likely to present with vascular disease elsewhere. However, LDS2 patients are more likely to dissect at smaller diameters than individuals with LDS1. Furthermore, LDS5 have a milder form of the syndrome, with fewer skeletal features and a lower risk of aortic aneurysm rupture. Moreover, LDS6 was recently identified and there is still much to learn about it, but there is evidence that it may have higher risk of aortic aneurysm rupture than some other subtypes.

Although there have been limited data reported in regard to neurodevelopmental issues in LDS, recent studies are starting to show that neurodevelopmental issues are actually common in patients with LDS. However, LDS1 appears to have worse neurodevelopmental issues than those with either LDS2 or LDS3. In addition, a longitudinal 10-year study in the Netherlands on adults with LDS3 showed that majority of these individuals had some form of neurovascular abnormality. Based on these findings, LDS patients need neurodevelopmental and neurovascular monitoring through their healthcare providers.

LDS manifestations also include oro-dental abnormalities, such as high-arched and narrow palate, enamel defects, bifid uvula, cleft palate, dental crowding, and delayed eruption of permanent teeth. Studies show that oro-dental manifestations in LDS2 has the most severity affected phenotype. This extensive characterisation, as well as some identified distinguishing features can significantly aid dental and medical care providers in the diagnosis and clinical management of patients with this rare connective tissue disorder.


Heritable Connective Tissue Disorders: Phenotypical Similarities and Differences

Three examples of heritable (genetic) connective tissue disorders are Marfan syndrome (MFS), Ehlers-Danlos syndrome (EDS), and LDS. These syndromes can affect multiple systems in the body and show some degree of phenotypical overlap of cardiovascular, skeletal, and cutaneous (skin) features.

Studies have shown that LDS manifestations tend to be more severe than MFS or EDS.  Consequently, genetic testing and an accurate diagnosis is highly important in order for the right interventions to take place at the appropriate time. To receive an accurate genetic diagnosis, a multigene Marfan syndrome / LDS / familial aortic aneurysms and dissections panel is recommended. A medical professional like a geneticist or genetic counsellor can order testing and pick a panel that is right for you.

It is important to note that the symptoms and severity of these three syndromes can vary widely from person to person, even within the same family. If you suspect that you or your family member may have LDS, EDS, or MFS, it is important to speak with a healthcare provider who can provide a diagnosis and appropriate treatment plan.


MFS & LDS: Phenotypes

MFS (caused by mutations in FBN1 gene) and LDS both involve:

  • aortic aneurysm and dissection.
  • Scoliosis
  • pes planus (flat feet)
  • anterior chest deformity
  • tall stature
  • osteoarthritis
  • spontaneous pneumothorax (collapsed lung)
  • dural ectasia

However, while there is some overlap in physical features, LDS can be distinguished from MFS by the unique presence of:

  • hypertelorism (widely spaced eyes)
  • bifid (split) or broad uvula
  • cleft palate
  • translucent or thin skin
  • widespread aortic and arterial aneurysm, dissection, and tortuosity. In LDS, dissections can occur at smaller diameters and at a younger age than in MFS, and so it is important for medical professionals to treat LDS more aggressively.


EDS & LDS: Phenotypes

EDS (caused by mutations in genes associated with collagen) and LDS both involve:

  • skin-related findings such as easy bruising, soft or velvety skin texture, wide scarring, translucent skin, and skin hyperextensibility (stretchiness)
  • clubfoot
  • joint hypermobility
  • tissue fragility
  • some cases of sudden organ rupture
  • For LDS and the vascular type of EDS (vEDS), vascular complications (aneurysm, dissection, rupture of blood vessel), but the risk and severity of these complications tend to be higher in LDS.

People with LDS may also exhibit hypertelorism (widely-spaced eyes) and bifid (split) or broad uvula, unlike people with EDS.

While both EDS and LDS can affect lifespan and quality of life, LDS is generally a more severe condition with a higher risk of cardiovascular complications and affected individuals may require closer monitoring and earlier interventions.


Embracing your Uniqueness

It is worth noting that having a LDS mutation and experiencing various phenotypes should not affect your incredible qualities. Instead, acknowledging your uniqueness can help you overcome the challenges you face. And, self-acceptance provides an opportunity to share your personal story and help educate and inspire others.

The ability to embrace uniqueness further proves that those with LDS have no limits to what they can accomplish. By embracing your journey, you can contribute to society in your own way and share your talents, skills, and perspectives.

For psychological and social resources to empower your journey, click here.


Treating the Physical Manifestations

Multidisciplinary Clinics

After going through the various manifestations of LDS, it is evident that LDS is a complex condition that can affect multiple systems in the body. Due to this nature, treating the manifestations requires involving multiple medical specialists who collaborate to address the patient’s concerns. Multidisciplinary clinics bring together a team of healthcare professionals, who work together to create an individualized treatment planthat address the needs of each patient. This approach can lead to better outcome for patients, as it allows for more coordinated care and communication between healthcare providers, as well as a more holistic approach to patient care.

To find a clinic near you, visit our Find a Clinic Directory



  • For the Foundation’s LDS helpline, call us at 1-888-LDS-FCAN.
  • For peer support, visit a community-run, private Facebook group: Loeys-Dietz Families.
  • For the Foundation’s resource directory, click here.
  • For clinics familiar with LDS, click here.
  • For signs and symptoms of LDS, check out our diagnostic Head to Toe and learn about the Signs and Symptoms of LDS



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