Introduction

Loeys-Dietz syndrome (LDS) is a rare genetic disorder that affects the connective tissue that holds the structures of your body together. LDS affects the following areas of the body: heart, blood vessels, bones, joints, skin, eyes, and face. 

People with LDS are born with it. Three out of four people with LDS are the first person in their family to have LDS. This is because a de novo or new genetic mutation (random gene error) occurs during conception – this is not inherited from the parents. However, a family history of LDS can increase the likelihood that someone will develop LDS as well. In a quarter of cases of LDS, people inherit an autosomal dominant variant of a gene (dominant faulty gene)  that leads to LDS development. Each child of a person with Loeys-Dietz Syndrome has a 50% chance of inheriting the faulty gene responsible for the condition.¹

Mutations in the TGFBR1 and TGFBR2 genes are the most common cause of Loeys-Dietz syndrome.¹ Understanding the genetics behind mutations that cause LDS will improve how the condition is diagnosed and managed. In this article, we will discuss how TGFBR1 and TGFBR2 mutations play a role in the development of Loeys-Dietz syndrome. 

What is Loeys-Dietz syndrome (LDS)?

Loeys-Dietz syndrome is a genetic disorder that affects connective tissues. It is named after the two clinicians who identified the condition in 2005.² People with LDS often have specific craniofacial features which affect the skull and facial bones. Typical features include hypertelorism (eyes positioned wider apart than usual) and a bifid uvula, where the small, teardrop-shaped tissue at the back of the throat is either broadened or split into two parts. Less common features include a cleft palate or club foot.² 

Clinical features

The primary clinical signs seen in Loeys-Dietz syndrome include:²

• Vascular (blood vessel) symptoms – aortic aneurysms and twisted or tortuous arteries 
• Craniofacial features may include eyes that are set unusually far apart (hypertelorism) and a uvula that is either split (bifid) or unusually wide

Physical features can include:² 

• Facial features  – cleft lip or palate
• Skeletal features – scoliosis (abnormal side-to-side curve of the spine), chest deformities, craniosynostosis (early fusion of skull bones)
• Skin features – unusually thin or translucent skin, along with a tendency to bruise or scar easily
• Club feet or flat feet
• Hyper-flexible joints 
• Long fingers and toes

Cause of LDS

Loeys-Dietz syndrome results from mutations in any one of five different genes, all of which produce proteins that play a role in the transforming growth factor beta (TGF-β) signaling pathway. The condition is classified into five subtypes, known as LDS types 1 through 5. The genetic mutations that correspond with the type of LDS they cause are listed below:

• LDS type 1 – transforming growth factor beta-receptor 1 (TGFBR1)
• LDS type 2 – transforming growth factor beta-receptor 2 (TGFBR2)
• LDS type 3 – mothers against decapentaplegic homolog (SMAD3)
• LDS type 4 – transforming growth factor beta 2 (TGFB2)
• LDS type 5 – transforming growth factor beta 2 (TGFB3)

The most common mutations that cause LDS are in the genes TGFBR1 and TGFBR2, which we will discuss in later sections of this article.¹

The TGF-β signalling pathway

What is TGF-β?

Transforming growth factor β (TGF-β) is a signalling molecule that is important for regulating various biological processes such as cell growth and tissue repair. TGF-β is a protein released by many types of cells to communicate with other cells to activate downstream processes in a chain of chemical reactions called a signalling cascade or signalling pathway. A cellular signalling pathway eventually leads to an action within the cells receiving the signal.³

TGF-β signalling and receptors

When TGF-β is released, it binds to TGF-β receptors on the surface of target cells.^3,4

 TGF-β receptor complexes are made up primarily of two main components: type I and type II TGF-β receptors (TGFBRI and TGFBRII, respectively). These receptors are controlled by molecular modifications and interactions with other proteins.^3,4

When TGF-β binds to the type II receptor, TGFBRII, this activates the type I receptor, TGFBRI. The type I and type II receptors then form a combined structure called a complex, consisting of 2 type I and 2 type II receptors.^3,4 After the TGFBRI is activated, it transmits a signalling cascade to induce change within the cell.³ 

The cell processes that TGF-β signalling can control include, but are not limited to cell division, cell differentiation (the process by which immature cells develop specific functions), programmed cell death (apoptosis), and more.

Genetic mutations in TGFBR1 and TGFBR2

Functions of TGFBR1 and TGFBR2

TGFBR1 and TGFBR2 are genes that encode, or provide instructions to build, a specific protein for the receptors for TGF-β. Loeys-Dietz syndrome type 1 is caused by a mutation in TGBR1, while LDS type 2 is caused by a mutation in TGBR2. These mutations lead to issues in the normal production of TGF-β receptors by cells and disrupt the TGF-β signalling pathway.^5,6 LDS and similar diseases, such as Marfan syndrome (MFS) and familial thoracic aortic aneurysm and dissection (TAAD), arise from changes in TGF-β signalling.³ 

Nature of TGFBR1 and TGFBR2 mutations

Genetic mutations for TGFBR1 and TGFBR2 that cause LDS are typically heterozygous and autosomal dominant.⁵ Mutations can occur de novo during conception or be inherited from a parent that already possesses the mutation.¹ 

Missense, splice site, and nonsense mutations in TGFBR1 and TGFBR2 have been reported.⁶ Most missense mutations in these genes occur in or next to the serine-threonine kinase domain of either TGF-β receptor.⁶ More than one mutation in the same gene is also possible.⁶

Impact of TGFBR1 and TGFBR2 mutations

While LDS types 1 and 2 overlap in many clinical symptoms, LDS type 1 (TGFBR1) mainly involves craniofacial symptoms, while LDS type 2 (TGFBR2) mainly involves minimal craniofacial symptoms and symptoms of the skin.^1,2,7 Scoliosis, velvety skin and easily bruised skin are frequent features of LDS type 2.⁷

Individuals with LDS type 2 seem to have more aggressive aortic disease, according to a comprehensive evaluation of LDS clinical characteristics.⁷ People with LDS type 1 and type 2 have a similar risk of aortic dissection, a tear in the aorta. Among patients with LDS type 1, people assigned male at birth (AMAB) have a greater risk of aortic complications than people assigned female at birth (AFAB).⁷

Neurodevelopmental concerns are an under-reported aspect of LDS. One study reported that 42% of patients with LDS had hearing loss, with conductive hearing loss being predominant in LDS types 1 and 2.⁷ 

Diagnosis of LDS

Healthcare professionals utilise the following methods to diagnose LDS:^1,2,7

• Physical exam for physical symptoms
• Family medical history
• Genetic testing to distinguish LDS from other similar conditions
• Blood testing

Genetic counselling is recommended for people who are suspected of having LDS. Early diagnosis and genetic testing can prevent vascular complications and provide interventions as needed.⁷

Importance of genetic counselling

Diagnosis of LDS and genetic counselling for the specific mutation causing the syndrome are important considerations for an LDS patient’s health. Individuals with LDS are more likely to get an early aortic dissection. Surgical intervention for cardiovascular complications is generally successful, but mutations in TGFBR1 and TGFBR2 can manifest in different presentations of LDS.⁶ Diagnosis of LDS patients and their families with a risk of arterial dissection is crucial for improved intervention, counselling, and clinical management tailored to the individual.⁶

Providing additional support during pregnancy is crucial for families affected by Loeys-Dietz syndrome. In most cases, inherited LDS is autosomal dominant in nature, meaning a parent with LDS has a 50% chance of passing on the genetic mutation that causes LDS.^6,7 Pregnant people with LDS have an increased risk of stress to the heart and blood vessels.⁸

Management

Although there isn't a cure for Loeys-Dietz syndrome, there are ways to manage its symptoms and avoid consequences.

Physical activity

The effects of LDS on the aorta and connective tissues can be exacerbated by vigorous exercise. Low- or moderate exercises, such as hiking, biking and swimming, are suggested for people with LDS. Generally, contact sports, exercising to the point of exhaustion and planks or wall sits are not recommended for people with LDS.²

Medication

Beta-blockers and angiotensin II receptor blockers (ARBs) are commonly used to help manage the cardiovascular complications associated with Loeys-Dietz syndrome.^1,2

Monitoring

LDS affects the heart, blood vessels, eyes, and skeletal system. Routine medical check-ups will help your healthcare team detect changes or complications in these areas and address them early on. Echocardiograms to check the health of the heart, heart valves and aorta are usually recommended yearly.⁸

Quality of life

Gastrointestinal issues and food allergies are commonly reported amongst those with LDS. Hearing loss may also appear, especially in LDS types 1 and 2.⁷

Summary

Loeys-Dietz syndrome (LDS) is an inherited condition that impacts the body’s connective tissues. It is caused by an inherited genetic mutation in certain genes. Mutations in the genes TGFBR1 and TGFBR2 are the most common causes of LDS, causing LDS type 1 and type 2, respectively. TGFBR1 and TGFBR2 mutations can occur de novo, in a person without a previous family history of LDS, or be inherited from a parent who has LDS. TGFBR1 and TGFBR2 are genes that encode for receptors of the signalling molecule TGF-β, which is involved in tissue repair and cell growth. TGFBR1 and TGFBR2 mutations cause issues with the TGF-β signalling system, especially with TGF-β receptors, which receive and amplify the TGF-β signal. While LDS types 1 and 2 share many clinical symptoms, LDS type 1 mainly has craniofacial symptoms, while type 2 has minimal craniofacial symptoms and skin symptoms. Both LDS types 1 and 2 have an increased risk of aortic dissection, or tearing. Early diagnosis and genetic counselling are recommended to manage LDS symptoms and complications.