Familial thoracic aortic aneurysm 4 (FTAA4) is a hereditary disease associated with patent ductus arteriosus, thoracic aortic aneurysm and/or aortic dissection. FTAA4 is caused by mutations in the MYH11 gene and is inherited in an autosomal dominant manner. While patent ductus arteriosus may be diagnosed in infancy, thoracic aortic aneurysm and aortic dissection usually occur in adulthood. If diagnosed in a timely manner, these conditions may be treated, but they bear the risk of aortic rupture and sudden death. Thus, cardiological surveillance is highly recommended for known carriers of pathogenic MYH11 mutations.
Patent ductus arteriosus, thoracic aortic aneurysm, and aortic dissection are the hallmarks of FTAA4. Whereas the former may be diagnosed in early life, aortic aneurysm and aortic dissection don't usually occur in pediatric patients. Nevertheless, those with patent ductus arteriosus may not show any symptoms at all. The severity of clinical disease largely depends on the volume of blood that passes through this type of left-to-right shunt. Severe shunting may lead to hypotension, hypoxemia, and cardiovascular insufficiency. The auscultation of patients suffering from patent ductus arteriosus reveals a continuous systolic heart murmur.
FTAA4-related thoracic aortic aneurysm and aortic dissection develop in mid-adulthood, but it should be noted that an increased stiffness of the aortic wall and a higher pulse wave velocity may already be depicted in young adulthood or even adolescence  . Thoracic aortic aneurysm and aortic dissection may be incidentally diagnosed in asymptomatic patients , or they may cause aortic regurgitation and left ventricular failure, exertional dyspnea, paroxysmal nocturnal dyspnea and chest pain . Space-occupying arterial dilation may cause the compression of intrathoracic organs, triggering hoarseness, dyspnea and cough, dysphagia, and myocardial infarction. Even though affected individuals may be asymptomatic, both aortic aneurysm and aortic dissection are life-threatening conditions. They may develop acutely and result in aortic rupture, severe hemorrhage, and death . In an affected family from France, anomalies of the aortic wall were limited to the ascending part of the artery, whereas aortic dissection extended to the abdominal aorta in American patients  .
Furthermore, aortic disease is a risk factor for thromboembolism. Thus, carriers of deleterious FTAA4 mutations may have an increased risk of stroke and other forms of thromboembolic episodes. Data obtained by familial anamnesis seem to support this hypothesis, although the rarity of FTAA4 doesn't allow for a reliable conclusion .
Entire Body System
Wischmeijer A, Van Laer L, Tortora G, Bolar NA, Van Camp G, Fransen E, et al. Thoracic aortic aneurysm in infancy in aneurysms-osteoarthritis syndrome due to a novel SMAD3 mutation: further delineation of the phenotype. [karger.com]
Camp N.J. Farnham J.M. MacDonald J. Abtin K. Rowe K.G. A genealogical assessment of heritable predisposition to aneurysms.J Neurosurg. 2003; 99: 637-643 Vaughan C.J. Casey M. He J. et al. [annalsthoracicsurgery.org]
Severe shunting may lead to hypotension, hypoxemia, and cardiovascular insufficiency. The auscultation of patients suffering from patent ductus arteriosus reveals a continuous systolic heart murmur. [symptoma.com]
habitus and isolated ectopia lentis. [bmcmedgenet.biomedcentral.com]
Left Ventricular Dysfunction
ventricular dysfunction 0005162 Patent ductus arteriosus 0001643 Showing of 11 Last updated: 3/1/2020 Making a diagnosis for a genetic or rare disease can often be challenging. [rarediseases.info.nih.gov]
murmur (SM)収縮期雑音 t tachycardia 頻拍（脈） tachypnea呼吸頻数、頻呼吸 technetium (Tc)テクネシ（チ）ウム temporal resolution時間分解能 terminal portion終末部 tetralogy of Fallot (T/F, TOF) ファロー四徴［症］ thallium (Tl)タリウム thoracic aorta 胸［部］大動脈 thoractomy開胸［術］ thrill振戦 thromboangiitis obliterans [tokyo-med.ac.jp]
Jaw & Teeth
The diagnosis of FTAA4 requires the identification of the causal mutation of the MYH11 gene. In case of members of families known to harbor MYH11 mutations, the respective molecular biological studies are realized to determine the patients' carrier state. However, such a straightforward approach is rarely chosen in the absence of a familial history of aortic disease, which highlights the importance of a detailed familial anamnesis. The medical history of the index patient should also be considered: concomitant patent ductus arteriosus and thoracic aortic aneurysm may raise suspicion as to a syndromic disease, even though familial data cannot be provided. The familial thoracic aortic aneurysm gene panel comprises genes MYH11, ACTA2, MYLK, PRKG1, MFAP5, LOX, FOXE3, FBN1, COL3A1, TGFBR1, TGFBR2, SMAD3, and TGFB2. Negative results in the setting of a positive family history demonstrate the limits of testing and the existence of knowledge gaps regarding the genetic causes of hereditary thoracic aortic disease .
The diagnostic procedures for patent ductus arteriosus, aortic aneurysm, and aortic dissection are not different from those carried out to confirm sporadic variants of these diseases:
- Echocardiography is the most important tool to visualize a patent ductus arteriosus, to assess its dimensions and the volume of blood that is redirected to the pulmonary artery. At the same time, echocardiographic images may reveal structural and functional anomalies of the aortic wall. Media degeneration has been confirmed in asymptomatic carriers of MYH11 mutations; it results in low compliance and distensibility and an increased stiffness of the aorta  .
- Other imaging techniques employed to evaluate cardiovascular anatomy and function comprise aortography, computed tomography, and magnetic resonance imaging .
- Cardiac imaging should always be complemented by electrocardiography and standard analyses of blood samples.
Aortic tissue samples may be obtained during surgical interventions or autopsy to relate clinical findings to histological anomalies. The main findings in FTAA4 patients are cystic medial necrosis with an accumulation of Alcian
blue–positive mucopolysaccharides, low counts of smooth muscle cells in the corresponding layer of the arterial wall, disruption of the medial elastic fibers, and fibromuscular dysplasia with an increased size of vasa vasorum of the aorta    .
Besides watchful waiting, surgery is the only option to treat thoracic aortic aneurysm. Watchful waiting is generally recommended in case of small aneurysms, i.e., in case of lesions measuring less than 5.5 cm in diameter, but specific guidelines regarding the therapeutic approach to FTAA4-related aortic disease have not yet been established. In general, familial aortic aneurysm syndromes have been shown to be associated with particularly aggressive aortic disease. The rapid growth of aneurysms, whose diameter may increase >2mm per year, should be considered as a risk factor for sudden death when evaluating treatment options . Thus, 4.5 cm has been proposed as a cut-off value for surgical interventions in case of familial aortic aneurysm syndromes .
Acute aortic dissection usually constitutes a surgical emergency, especially if located in the ascending aorta. Chronic aortic dissection and dissections affecting the descending part of the thoracic aorta may warrant a conservative approach to treatment. Similar to what has been said above, data regarding the risks implicated in a wait-and-see approach in FTAA4 patients are not available.
Patients are to be included in surveillance programs. The detection and successful treatment of a thoracic aortic aneurysm or dissection do not impede recurrence .
Thoracic aortic aneurysm and aortic dissection are important causes of sudden death, as is stroke, a common complication of arterial disease . Genetic testing and regular cardiological examinations should be offered to members of affected families to avoid these detrimental consequences of FTAA4. If this could be achieved, carriers of pathogenic MYH11 mutations might have near-to-normal life expectancies. The reality looks somewhat different, and patients have stated multiple reasons for not complying with surveillance programs, so they remain at risk of sudden death at any time in adulthood.
FTAA4 has first been mapped to the short arm of chromosome 16 and later been linked to mutations of the MYH11 gene  . This gene encodes for myosin heavy chain 11, a protein which is part of a hexameric myosin complex that mediates contractility in smooth muscle. The backbone of this complex consists of two heavy chains that form a coiled-coil helix, which is characteristic of class II myosins. A total of four essential and regulatory myosin light chains bind to the neck region of the heavy-chain backbone to form a functional myosin molecule. It has been suggested that FTAA4-related mutations of the MYH11 gene interfere with the formation of the coiled-coil helix and the assembly of the myosin molecule .
In detail, the American patients described by Glancy et al. were found to carry an in-frame deletion in exon 28. In the French kindred, two heterozygous mutations affecting the same allele have been found. One of them was a substitution at the splice-donor site of intron32, the other a missense mutation in exon 37 . Both Japanese families harboring FTAA4-related variants of the MYH11 gene were found to present in-frame deletions similar to the patients from the United States .
FTAA4 is a rare disease and has so far only been described in a handful of families from the United States, France, and Japan    . According to recent estimations, mutations of the MYH11 gene account for 1-2% of cases of familial thoracic aortic aneurysm and dissection . The penetrance of deleterious MYH11 mutations is assumed to be incomplete and age-dependent .
The ascending aorta has to resist and compensate for major increases in pressure during the systole of each cardiac cycle . Maximum compliance and distensibility are required to fulfill this task, and they are mainly conferred by elastic fibers and smooth muscles in the medial layer of the aortic wall, the tunica media. After the systolic expansion of the aorta, these elements contract, transform the stored potential energy to kinetic energy, and thus maintain blood flow throughout the diastole. The degeneration of elastic fibers and loss of smooth muscle cells, which can be observed in FTAA4 patients, predispose to a dilatation of the ascending aorta. This condition is associated with an increase in wall tension, which induces remodeling processes and favors further dilatation .
Any limitation of the compliance and distensibility of the aortic wall may, therefore, lead to the formation of thoracic aortic aneurysm and aortic dissection. Smooth muscle cells fulfill similar functions in other vessels and non-vascular tissues, but nowhere are they placed under such high mechanical stress as in the thoracic part of the aorta.
Affected families may benefit from genetic counseling. Parents-to-be should be informed about the disease, about the high risk of patent ductus arteriosus and adult-onset aortic disease, which are curable conditions. They should be offered a prenatal determination of the child's carrier state and be given a chance to decide if they seek such a diagnosis.
Known carriers of FTAA4 mutations should be included in surveillance programs. They should be checked for patent ductus arteriosus in infancy and undergo regular cardiological examinations during adulthood, whereby monitoring should be intensified in pregnant women   . Additionally, FTAA4 patients should be educated about the risks of hypertension and may be prescribed β-sympatholytics or vasodilators to relieve the aortic wall. In fact, lifelong therapy with β-sympatholytics has been proposed as a measure to prevent thoracic aortic aneurysm and aortic dissection in FTAA4 patients. Individuals at highest risks of life-threatening aortic disease may eventually be identified by measurements of aortic compliance and distensibility: Particularly low values may indicate a greater need for prophylactic β-blockade therapy .
Beyond medical prophylaxis, certain lifestyle decisions may help to diminish the risk of fatal aortic disease. In this context, FTAA4 patients should be recommended to avoid major physical efforts and to prefer sports that don't involve dynamic movements or body collision . Affected individuals should also refrain from smoking.
In the absence of connective tissue disorders like Marfan syndrome, Ehlers-Danlos syndrome, or Loeys-Dietz syndrome, it is not always possible to determine the triggers of thoracic aortic aneurysm or aortic dissection . In this context, it has been estimated that genetic components are involved in about 20% of all cases, with underlying hereditary conditions being of variable penetrance and expressivity  . High penetrance and expressivity result in strikingly high familial incidences of aortic diseases, which led to the definition of familial aortic aneurysm syndromes. One of them is FTAA4.
FTAA4 has first been described by Glancy and colleagues in 2001. Although the authors were unaware of the underlying mutation, they noted a striking accumulation of patent ductus arteriosus in three generations of family from the United States. Several family members were additionally diagnosed with aortic diseases, so the cardiologists postulated that they were facing a unique syndrome, presumably inherited in an autosomal dominant manner . Similar observations have subsequently been made in a French kindred, in Japanese and few other families   . In 2006, the cause of FTAA4 was identified: Affected individuals were shown to carry pathological mutations of the MYH11 gene .
Patent ductus arteriosus, thoracic aortic aneurysm, and aortic dissection are cardiovascular diseases:
- Patent ductus arteriosus is a remnant from fetal circulation and may cause cardiovascular insufficiency after birth. It is a curable condition.
- Thoracic aortic aneurysm and aortic dissection refer to tears in the wall of the aorta, the main artery originating from the heart. They may not cause any symptoms at all, but they are life-threatening conditions that may lead to acute chest pain, aortic rupture, severe hemorrhage, and death.
In some families, these diseases occur rather frequently. This is the case when genes are passed from generation to generation that alter the structure of the arterial walls and predispose to aortic disease. If such a predisposition is caused by mutations in the MYH11 gene, the family is affected by familial thoracic aortic aneurysm 4. It is important to identify family members who carry pathogenic variants of the MYH11 gene, so they can be included in surveillance programs to avoid the detrimental consequences of thoracic aortic aneurysm and aortic dissection.
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