Inherited Connective Tissue Disorders

Cutis laxa is a connective tissue disorder characterized by abnormally elastic tissue, causing skin to be loose. Like other connective tissue disorders it can affect the heart, eyes, and joints. The condition is caused by mutations to the FBLN5, EFEMP2, LTBP4, ATP6V0A2, PYCR1, or ALDH18A1 genes.

Ehlers-Danlos syndromes are a group of genetic conditions of the connective tissue. There are 13 different subtypes of EDS. These conditions usually present with hypermobility of joints (joints that move beyond the normal range of motion) and loose skin that is fragile and prone to injuries. Each subtype has a list of characteristics, which can involve many organs such as the heart and vessels, the skeletal system, or the eyes.

Dr. Forghani, our geneticist at Mount Sinai Medical Center is a board member at the EDS Society, an international nonprofit organization dedicated to patient support, scientific research, advocacy, and increasing awareness for Ehlers-Danlos syndromes and hypermobility spectrum disorders. Alongside other esteemed experts in the field, she spearheads an educational program on the genetics and genomics of EDS.

Patients with familial TAAD have problems with the aorta, the largest blood vessel that sends the blood from the heart to the rest of the body. Familial TAAD can be caused by defects in multiple genes, responsible for the integrity of the aortic wall. The condition most commonly affects the top part of the aorta, but it can involve other parts of the aorta or other blood vessels besides the aorta.

The defects in the genes responsible for the strength of the aorta weaken the vessel wall, leading to a bulge called an aneurysm. Aortic enlargement can also cause aortic dissection, a rapid tearing of the layers of the artery that is life-threatening. TAAD is the major health concern in some inherited connective tissue disorders like Marfan syndrome and Loeys-Dietz syndrome. But this condition is not always associated with these syndromes. In some genetic conditions, it can occur as an isolated issue without affecting any other organs. Diagnosis of isolated TAAD relies on genetic testing because enlargement of aorta is the only abnormality — and most of the affected patents are asymptomatic at earlier stages of the disease. Unfortunately, only 5% of familial TAAD cases are symptomatic prior to having a rupture in their aorta. Identifying the genetic causes in a family with TAAD is extremely important. When the gene is identified in one family member, we can track other family members who may carry the gene defect.

Early diagnosis and prevention is crucial in TAAD. By close monitoring, as well as with preventive medical and surgical management, aortic ruptures can usually be prevented. While there has been significant progress in understanding the genetic causes of aortic disease in recent years, there are still some families with TAAD whose specific genetic defect has yet to be identified. Research in this area is ongoing, and it is essential for the development of effective diagnostic and treatment strategies. Here at Mount Sinai, we collaborate with other researchers to discover new genes and treatment guidelines for familial TAAD.

Loeys-Dietz syndrome is a genetic disease caused by mutations to the TGFBR1, TGFBR2, SMAD3, TGFB2, or TGFB3 genes, which control the production of proteins that help connective tissue be strong and flexible. LDS can be classified into five subtypes, each based on the specific gene defect. Like other inherited connective tissue disorders, LDS can involve many organs such as the skeletal system, ligaments, heart and vascular system, and the eyes.

Marfan syndrome is a genetic disorder that affects the connective tissue primarily in the heart, eyes, blood vessels, and skeleton. People with Marfan syndrome have mutations in the FBN1 gene, which makes fibrillin, a protein that helps connective tissue stretch and stay strong.

The aorta, the largest blood vessel in the body, is frequently affected, which can be life-threatening if it becomes too inflexible and tears or ruptures. In addition, patients may have eye problems or a curved spine or chest wall that sinks in or out. Affected people are usually tall and have a thin build with long arms, legs, fingers, and toes. Evaluation and lifelong monitoring are required in a multidisciplinary Marfan Clinic, which integrates doctors of various specialties, such as cardiologists, heart surgeons, eye doctors, spine surgeons, and geneticists.

Here at Mount Sinai Medical Center, we have a multidisciplinary clinic in addition to the genetic team who help patients with diagnosis and management. Our team includes cardiologists, cardiothoracic surgeons, orthopedic surgeons, and physical therapists.

Osteogenesis imperfecta, which is also known as “brittle bone disease,” is caused by mutations to the genes responsible for making collagen and other proteins involved in bones’ structure. People with osteogenesis imperfecta have defects in these proteins and as a result, they have weaker bones that can break easily. The condition can vary in severity. In mild forms of OI, affected people may experience only a few fractures during their lifetime. In more severe cases, patients can have hundreds of bone breaks that happen without any real trauma. Bone-strengthening medications, physical therapy, and certain surgeries can help.