Loeys–Dietz Syndrome - Causes, Symptoms, Diagnosis, and Treatment

Introduction

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder that is characterized by aortic, arterial tortuosity, hypertelorism, and uvula or palate deformities. The condition is caused due to mutations in TGF-β I, TGF-β II (transforming growth factors β-I and II), SMAD3, and TGF-β2 ligand genes. These mutations cause the cardiovascular, craniofacial, cutaneous, and skeletal manifestations associated with Loeys-Dietz syndrome.

What Are the Types of Loeys–Dietz Syndrome?

The proposed LDS classification categorizes the condition based on the gene involved and its corresponding manifestations:

• LDS 1 (TGFBR1 gene).

• LDS 2 (TGFBR2 gene).

• LDS 3 (SMAD3 gene).

• LDS 4 (TGFb2 gene).

Who Is Susceptible to Loeys–Dietz Syndrome?

Loeys-Dietz syndrome is a genetic disorder that can be inherited, but not always passed on to the progeny. The probability of LDS occurring for the first time in a family is 75 % with a 50 % probability of inheritance to the next generation. The accurate prevalence of LDS is unknown but LDS type 1 and type 2 are the most common occurrences. Approximately 15 % of the patients have cervical spine instability and 25 to 33 % of patients have gastrointestinal or allergic manifestations.

What Causes Loeys–Dietz Syndrome?

Loeys-Dietz syndrome has five distinct genetic mutations with five different variants. These five genes play major roles in a cell signaling pathway TGF-β pathway which directs the functions of the body's growth and development. The pathway also regulates the formation of the extracellular matrix and is important for tissue strength and repair. Mutations in the concerned genes result in the production of proteins with reduced efficiency. Even with inefficient protein, the TGF-β signaling pathway occurs at a very high intensity throughout the body. It is speculated that the increase in signaling may occur to compensate for the reduced protein synthesis. Overactivity of the TGF-β pathway disrupts the development of the extracellular matrix and various body systems which manifests the signs and symptoms of LDS.

What Are the Clinical Features of Loeys–Dietz Syndrome?

The signs and symptoms of Loeys-Dietz syndrome may be categorized based on the involvement of the organ system:

Head:

• Craniosynostosis (premature fusion of the skull bones).

• Bifid uvula.

• Cleft palate.

• High arch palate.

• Poor teeth enamel.

Ocular:

• Esotropia (eye misalignment).

• A blue tinge in the sclera.

• Myopia (near-sightedness).

• Retinal detachment.

Chest and Abdomen:

• Pectus excavatum (sunken chest).

• Pectus carinatum (bird-like chest)

• Pneumothorax (collapsed lung).

• Abdominal hernia (organ protruding into the abdominal cavity through the wall).

• Inguinal hernia (intestine protrudes into the inguinal canal).

• Incisional hernia (tissue protrusion at the site of incision).

• Hiatal hernia (stomach protrudes through the diaphragm muscle.).

• Inflammatory bowel disease.

• Food allergies.

• Asthma (breathing problems due to airway inflammation).

Hands and Feet:

• Arachnodactyly (slender curved fingers).

• Contractures.

Mucocutaneous:

• Translucent skin.

• Easy bruising.

• Poor wound healing.

• Atrophic scarring.

• Striae (indented, reddened streaks on the skin).

• Eczema.

• Stretch marks.

Cardiovascular:

• Aortic root aneurysm (bulging of the aortic root).

• Aortic root dissection (tear in the aorta).

• Arterial aneurysm (bulging of an artery).

• Arterial dissection.

• Arterial tortuosity.

• Congenital heart disease.

• Mitral valve prolapse.

Spine:

• Scoliosis (abnormal curvature of the spine).

• Kyphosis (hunchback spine).

• Disc degeneration.

• Cervical spine malformation or instability.

• Dural ectasia (ballooning or outpouching of the dura in the spine).

• Tarlov cyst (meningeal cysts in the spine).

Joints:

• Hypermobility.

• Joint dislocation or subluxation.

• Congenital hip dysplasia.

• Contractures.

• Osteoarthritis (degenerative joint disease).

Feet and Toes:

• Club foot.

• Flat feet.

How to Diagnose Loeys–Dietz Syndrome?

Loeys-Dietz syndrome can be diagnosed by observing the clinical history, and further physical and medical history which should be followed with various diagnostic procedures.

The presence of aortic root enlargement is the most common finding and is diagnostic of LDS. The patient should be grilled through a physical exam and any medically relevant history along with a detailed familiar history.

Angiogram: Angiograms can be performed to closely monitor the arteries to detect aneurysms or arterial tortuosity.

Echocardiogram: Ultrasound waves can be used to take pictures to look for structural myocardial defects.

Eye examinations: Can be used to detect ocular defects and deformities.

Imaging Studies: Studies with MRA (magnetic resonance angiography) and CTA (computed tomography angiogram) with 3D reconstruction from the head to the pelvis can be done to identify arterial aneurysm, dissection, or arterial tortuosity throughout the arterial tree.

Genetic Testing and Counseling: This involves the evaluation of the genes involved in LDS that involved a combination of gene-targeted testing and genomic testing.

How to Treat Loeys–Dietz Syndrome?

Since Loeys-Dietz syndrome is a genetic disorder, the treatment involves a focus on reducing stress on the aorta, and arterial tree, managing skeletal and muscular difficulties, any associated complications, and immune response.

For smaller aneurysms, observation, and monitoring may be the best course of treatment which includes an echocardiogram every six months and pharmacotherapy for possible symptoms. Angiotensin II receptor blockers may be prescribed against hypertension. In the case of larger aneurysms, surgical interventions may be warranted. The type of surgery depends on the location of the aneurysm and the patient’s overall health. Patent ductus arteriosus and septal defect intervention can be done as per protocol. Valve-sparing aortic root replacement can be done in the case of aortic annulus in young children.

Repeated imaging every three to five years to determine the spine deformities and their progression. Clubfoot and contracture interventions as per protocols. Osteoarthritis may be treated symptomatically. In case of fractures, without any trauma, a dual-energy X-ray absorptiometry scan can be performed. Hard shoe support or shoes can be used to provide good arch support.

Allergies can be treated symptomatically. Additionally, EpiPen (Epinephrine injection) should be kept handy for emergencies. In case of rare splenic or bowel ruptures, surgical repair with mesh should be indicated.

Genetic counseling and close monitoring of pregnancy are necessary to avoid any complications for the mother and child. Preconception genetic counseling is necessary for family planning to prepare for any outcome as LDS can be inherited or may occur without any familial history.

What Is the Prognosis of Loeys–Dietz Syndrome?

Loeys-Deitz syndrome portrays a poor prognosis. The estimated life expectancy of patients is 37 years. Some patients can live a longer life with micro-management of LDS symptoms. Patients with vascular surgery do extremely well with vascular surgery.

What Are the Differential Diagnosis of Loeys–Dietz Syndrome?

• Marfan syndrome.

• Shprintzen-Goldberg syndrome.

• BGN-associated aortic aneurysm syndrome.

• MASS phenotype.

• Ehlers-Danlos syndrome.

• Congenital contractural arachnodactyly.

• Arterial tortuosity syndrome.

• Turner syndrome.

• Noonan syndrome.

• Cutis laxa.

• Fibromuscular dysplasia.

• Persistent patent ductus arteriosus with thoracic aortic aneurysm.

• Familial thoracic aortic aneurysm and dissection.

What Are the Complications of Loeys–Dietz Syndrome?

• Collapsed lung (pneumothorax).

• Perforated bowel.

• Retinal detachments.

• Ruptured spleen.

• Death.

• Aortic regurgitation

• Severe aortic valve regurgitation.

Conclusions

Loeys-Deitz syndrome is a potentially life-threatening condition with a trend of inheritance. The patients are advised to restrict exercises and most of the symptoms require regular monitoring and follow-ups. The management regime requires a team of specialists treating symptoms pertaining to their own specialty. Pertaining to its poor prognosis, the patients require utmost care and vigilance. Any symptom or visible aberrancy should be reported immediately and required protocols may be implemented to nullify any potential complications.