3
Marfan Syndrome and Related Hereditary Aortopathies
Marfan syndrome (MFS) is an autosomal-dominant disorder that affects multiple organ systems, especially the ocular, cardiovascular, and skeletal systems. Absent appropriate diagnosis and management, severe disability and early death are common. MFS shares features with several related hereditary disorders of connective tissue (HDCTs) called hereditary aortopathies, including Loeys-Dietz syndrome (LDS), congenital contractural arachnodactyly (CCA; also known as Beals-Hecht syndrome), and Shprintzen-Goldberg syndrome (SGS), particularly in the cardiovascular and skeletal systems. This chapter describes the history, diagnosis, and characteristics of MFS and related hereditary aortopathies, and reviews their treatment, their management, and those disease manifestations that are potentially disabling. An overview of these disorders is provided in Annex Table 3-1 at the end of the chapter.
HISTORY OF MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES
In 1896, the French pediatrician Antoine Marfan described a young girl with unusually long digits (arachnodactyly) and joint contractures from birth. He did not note any problems with her heart or eyes. Soon after, his colleagues termed this condition “Marfan syndrome.” Over the next five decades, some patients with arachnodactyly were also found to have dislocation of the lens of the eye (ectopia lentis); leakage of heart valves; and, most worrisome, enlargement (dilatation) of the aorta at the point where it exits the heart (aortic aneurysm). When the dilatation progressed to a severe
degree, the wall of the aorta would tear (aortic dissection), which was often fatal. Consequently, it became clear that MFS resulted in a markedly reduced life expectancy, by one-third to one-half, with some patients dying in childhood. Of interest, by the 1960s it was clear that Marfan’s original patient had a different but overlapping condition—CCA—which generally has none of the severe complications of MFS, particularly aortic dissection (Takeda et al., 2015). Since the late 1970s, steady progress has been made in the medical and surgical management of MFS.
The genetic cause of MFS was discovered in 1991 (Dietz et al., 1991; Lee et al., 1991). The syndrome is caused by pathogenic variants in the gene that encodes the connective tissue protein fibrillin-1 (FBN1). These variants are heterozygous—that is, alterations are seen in only one copy of the FBN1 gene, while the other copy is unaffected. About three-quarters of patients have an affected parent (autosomal-dominant inheritance), while the remaining roughly 25 percent represent new pathogenic variants in a family. Each offspring of an affected individual has a 50 percent risk of inheriting the condition.
Over the past few decades, people with aortic aneurysms, often with a parental history of the same phenotype, have been found to demonstrate a wide spectrum of features sometimes overlapping with classic MFS. This observation has given rise to recognition of a separate set of syndromes called the aortopathies, the most severe of which is LDS. All share the risk of aortic dilatation and aortic dissection, although the risk varies within families and among individuals who carry a pathogenic variant in the same gene.
DIAGNOSIS OF MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES
Diagnosis of Marfan Syndrome
The current diagnostic criteria for MFS are based on clinical and molecular features, summarized most recently in the 2010 revised Ghent nosology, also known as the Ghent II criteria (Loeys et al., 2010). The Ghent II criteria address the presence of family history and aortic root dilatation, as well as pathogenic variants in FBN1 (see Box 3-1), and include a scoring system that assigns points to defined clinical characteristics of MFS (see Box 3-2). Genetic testing involves analyzing FBN1 for pathogenic and likely pathologic variants (mutations).
Diagnosis of Related Hereditary Aortopathies
As with MFS, the most severe hereditary aortopathies (e.g., LDS, CCA [see below]) can often be diagnosed on the basis of clinical examination and family history. Differences in clinical findings may be subtle, however, and final diagnosis and management depend on the results of genetic testing. Currently, pathogenic variants in more than two dozen genes other than FBN1 have been discovered to be causative of the aortopathies. To date, pathogenic variants in five different genes have been found to cause different types of LDS: TGFBR1 (LDS1) (Loeys et al., 2005), TGFBR2 (LDS2) (Loeys et al., 2005), SMAD3 (LDS3) (Regalado et al., 2011), TGFB2 (LDS4) (Lindsay et al., 2012), and TGFB3 (LDS5) (Bertoli-Avella et al., 2015; Matyas et al., 2014; Rienhoff et al., 2013). CCA is caused by pathogenic variants in the FBN2 gene (Gupta et al., 2002), and Shprintzen-Goldberg syndrome results from pathogenic variants in the SKI gene (Doyle et al., 2012).
CHARACTERISTICS OF MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES
Marfan Syndrome
Clinical Picture
The majority of MFS patients have notable involvement of the cardiovascular, musculoskeletal, and ocular systems, as well as abnormalities in the respiratory and central nervous systems (Loeys et al., 2010). Although MFS typically manifests in multiple body systems, the severity of the manifestations may vary among body systems within a given individual (Bruno et al., 1984). In other words, within a given patient, there may be a lack of correlation between, for example, the severity of aortic dilatation and the degree of joint hypermobility. In addition, the range and timing of clinical symptoms experienced by individual patients can be broad. For example, some patients present in the neonatal period with rapidly progressive or severe multisystem disease, whereas others with more limited manifestations may go undiagnosed until they experience a sentinel event, such as aortic dissection, in adulthood (Dietz, 2022). Musculoskeletal and ocular abnormalities in patients with MFS are often identified in childhood, while respiratory abnormalities typically manifest in adulthood. The age at time of diagnosis ranges from the prenatal period to the eighth decade of life (Groth et al., 2015). Most patients demonstrate joint laxity throughout life, although paradoxically, some have reduced mobility in certain joints, such as the digits or elbows (Dietz, 2022). Investigation for MFS is
warranted in young people with unexplained aortic dissection, as data from the International Registry of Acute Aortic Dissection have shown that MFS accounts for half of patients under age 40 with this condition (Januzzi et al., 2004). When diagnosed early, and with appropriate management, most people with classic MFS have a relatively normal life expectancy. However, many of the other findings in the condition (e.g., ectopia lentis, glaucoma, joint laxity, pes planus/planovalgus, scoliosis, acetabular protrusion, dural ectasia, and pulmonary complications) contribute to the risk of long-term disabling clinical issues, only some of which, such as ectopia lentis, can be reliably managed by medical and surgical intervention (Esfandiari et al., 2019).
Epidemiology
MFS affects males and females with equal frequency, although overall severity may be somewhat greater in males (Roman et al., 2017). The true prevalence of MFS is unclear, but current estimates are 1 to 5 per 10,000 population (Judge and Dietz, 2005; NORD, 2021), with no gender, race, or ethnic origin preference (Chiu et al., 2014).
Given the wide range of organ systems potentially affected by MFS and the marked variability in expression of pathologic variants in FBN1, there is no “average age” of appearance of manifestations. In the most severe form of MFS (often termed “neonatal MFS”), severe ocular, skeletal, and cardiovascular features are present at birth, and life expectancy is markedly reduced, even with early and aggressive treatment. In less severe forms, some features (e.g., aortic dilatation, disproportionately tall stature) may
be present in infancy and worsen with age, while others are not evident until childhood (e.g., ectopia lentis, scoliosis) or even adulthood (e.g., dural ectasia, weaking of the covering of the spinal root).
Manifestations
This section describes some of the physical and mental manifestations associated with MFS and how they may interfere with daily life. Chapter 5 contains additional information related to the physical and mental secondary impairments associated with and functional implications of MFS and related hereditary aortopathies (see Annex Tables 5-3–5-16 at the end of that chapter).
Cardiovascular features of MFS include aortic root aneurysm, aortic root dissection, mitral valve prolapse, premature calcification of the mitral
annulus, and pulmonary artery dilation (Loeys et al., 2010; Stuart and Williams, 2007). Echocardiography findings demonstrate aortic root dilation in most pediatric MFS patients by the age of 19 and adult MFS patients (Aburawi and O’Sullivan, 2007). Aortic root dilation typically increases with age and is often accompanied by aortic regurgitation (Jeremy et al., 1994; Jondeau et al., 1999). Aortic pathology may lead to aneurysmal formation; dilation; and ultimately dissection, the primary cause of patient morbidity and mortality (Adams and Trent, 1998). Mitral valve prolapse with elongated leaflets also occurs frequently in patients with MFS, although it is considered a nonspecific finding given the frequent observation of mitral valve prolapse in the general population (Rybczynski et al., 2010). Associated mitral valve regurgitation may be present and progressive, sometimes leading to heart failure in children with the most severe presentation. Less commonly, patients may have cardiomyopathy unrelated to valvular disease (Alpendurada et al., 2010). The increased risk of aortic aneurysm and dissection limits many physical activities, in particular those that elevate heart rate or blood pressure and/or involve impact (Bitterman and Sponseller, 2017). Aortic or mitral regurgitation, if severe and untreated, may lead to chronic heart failure. Management of MFS requires lifestyle modifications, and it is recommended that physical activity be reduced to about 50 percent of capacity (Milewicz et al., 2021). Aortic root dilatation is more common in males than in females, whereas mitral valve prolapse is more common in females than in males (Roman et al., 2017).
Clinical musculoskeletal features in MFS typically include tall stature, disproportionately long limbs and digits, abnormal curvature of the spine (scoliosis), indentation or protrusion of the breast bone (pectus excavatum or carinatum, respectively), medial displacement of the head of the femur within the hip joint (protrusio acetabuli), unusual flexibility and/or restriction of joints, flat feet (pes planus/planovalgus), reduced elbow extension, and finger contractures (Bitterman and Sponseller, 2017). Musculoskeletal manifestations may contribute to pain and are likely to increase over time. Scoliosis and arachnodactyly are more prevalent in females than in males (Roman et al., 2017). Scoliosis can limit the ability to bend at the waist or chest. Joint laxity contributes to progressive degenerative arthritis, especially with repetitive bending or carrying under strain.
Ocular involvement is seen in the majority of MFS patients. Ectopia lentis is seen in 50–80 percent of patients; this condition is progressive, can impair vision, and often requires surgical intervention (Agarwal and Narang, 2014; Dietz, 2022; Sandvik et al., 2019). Other ophthmalogic abnormalities include amblyopia, strabismus (Izquierdo et al., 1994), myopia, increased globe length, and corneal flattening (Loeys et al., 2010). An elongated globe contributes to severe myopia and a risk of retinal detachment, which may lead to visual impairment or permanent blindness. Early
cataract formation may also be observed (Dietz, 2022). In addition, the risk of developing glaucoma, a known complication of MFS, is significantly increased after surgical repair of retinal detachment (Tranos et al., 2004). High-impact activities can lead to lens displacement or dislocation (Bitterman and Sponseller, 2017).
Neurologic manifestations commonly include dural ectasia, an enlargement of the dural sac around the spinal cord, and spinal arachnoid cysts or diverticula (Meester et al., 2017). Severe dural ectasia and meningoceles can cause lower back and radicular pain and leg weakness, especially with prolonged standing and walking.
Other findings include facial manifestations (high arched palate, teeth crowding, flattening of the midface, small and receding lower jaw). Lung or pulmonary complications can result from chest wall abnormalities (pectus excavatum) that contribute to restrictive lung disease. Widening of the lung spaces can result in spontaneous pneumothorax that in turn can lead to cardiopulmonary instability (Huang et al., 2014). MFS patients may develop emphysematous changes in the airway as they age, with histologic evidence of pathology apparent in early or middle adulthood (Dyhdalo and Farver, 2011). Respiratory involvement may also cause sleep-disordered breathing in adults with MFS, ultimately contributing to mental impairment and disability (Sowho et al., 2020). Skin abnormalities include changes in the skin due to thinning of the underlying connective tissues, otherwise known as “stretch marks” (striae atrophicae).
Chronic pain is experienced by 47–92 percent of patients with MFS (Velvin et al., 2016a) and may significantly impair daily functioning. Participants in a study by Speed and colleagues (2017) reported poor physical and mental health functioning and moderate pain-related disability. And while 89 percent of respondents reported experiencing pain, 41 percent reported never receiving a pain diagnosis. Chronic fatigue is another common manifestation of MFS, frequently comorbid with chronic pain and orthostatic intolerance; MFS patients with versus those without chronic pain report higher levels of chronic fatigue (Bathen et al., 2014). Chronic fatigue may in turn result in impaired cognitive functioning. Chronic fatigue has been found to interfere with daily functioning and to be associated with less participation in the workforce, younger age at retirement, and increased likelihood of receiving disability benefits (Bathen et al., 2014; Velvin et al., 2015).
MFS affects many organ systems, in particular the cardiovascular, nervous, respiratory, musculoskeletal, and ocular systems, and can result in impairments in daily functioning. The chronic pain and chronic fatigue experienced by many MFS patients can affect work participation and education-related activities; Rao and colleagues (2016), for example, found that chronic fatigue was associated with reduced work capacity. Research has
shown that children and adolescents with MFS may be unable to participate in many physical activities as a result of the physical manifestations of their disease, and these limitations can in turn affect their psychosocial functioning (Nielsen et al., 2019). Additional research on the relative benefits versus risks of participation in common childhood activities (e.g., contact sports, gymnastics, dance) would inform management of the disease in this area. Severe back and neck pain, in addition to frequent headaches, may result from a number of manifestations of MFS, also affecting physical and mental functioning (Nielsen et al., 2019). Common as well among those with MFS are cardiac problems; spine issues, including back pain; and generalized fatigue (Rao et al., 2016). MFS may also result in difficulties with executive function, particularly mental fatigue (Ratiu et al., 2018) and cognitive difficulties, that diminish quality of life and affect a patient’s ability to work (Nielsen et al., 2019). Several studies of a Norwegian cohort of men and women with MFS have shown that both physical and mental impairments associated with the disease result in poorer quality of life that increases with age (Rand-Hendriksen et al., 2010; Vanem et al., 2020; Velvin et al., 2016b). MFS has been associated with less employment, younger age at retirement, more disability benefits (Velvin et al., 2015), and reduced work hours (Rao et al., 2016). Studies in other populations with MFS have also found increased pain, anxiety and depression, and reduced mobility compared with patients with other chronic conditions (Andonian et al., 2021).
Loeys-Dietz Syndrome
Clinical Picture
The clinical findings of LDS are similar to those of MFS, and these syndromes show a considerable degree of phenotypical overlap, particularly in cardiovascular, skeletal, and cutaneous findings. Overlapping features include cardiac complications, scoliosis, pes planus, anterior chest deformity, spontaneous pneumothorax, and dural ectasia (Meester et al., 2017).
There are, however, important differences between the two syndromes. Individuals with LDS can experience aortic dissection earlier in life and with smaller aortic diameters relative to those with MFS. Other cardiovascular manifestations seen in LDS but not in MFS include tortuous arteries in multiple anatomic locations (Loeys and Dietz, 2018). Certain craniofacial features of LDS (e.g., widely spaced eyes [hypertelorism] and cleft palate [bifid uvula]), as well as the absence of ectopia lentis, also distinguish it from MFS (Meester et al., 2017). Additionally, skeletal overgrowth is less pronounced and arachnodactyly less common with LDS than with MFS (Erkula et al., 2010).
Epidemiology
LDS occurs without regard to gender, race, or ethnic origin (Loeys and Dietz, 2018). Its true prevalence is unknown. As with MFS, the onset of secondary impairments associated with LDS can range from childhood (typically severe cases) to adulthood.
Manifestations
In addition to hypertelorism and bifid uvula, craniofacial features of LDS include strabismus and craniosynostosis. Craniosynostosis may involve any of the suture lines, but most often affects the sagittal suture, leading to dolicocephaly (long narrow-shaped head) (Loeys and Dietz, 2018). Other facial features include retrognathia (receding jaw), malar flattening (midface), tall and broad forehead, downsloping palpebral fissures, and frontal bossing with a high anterior hairline.
The vascular features of LDS include rapidly progressive aortic and peripheral arterial aneurysmal disease that can lead to dissection (Loeys and Dietz, 2018; Loughborough et al., 2018). Patients with LDS show diffuse arterial involvement, and a large proportion of patients develop aneurysms of the iliac, mesenteric, and intracranial arteries (Loughborough et al., 2018). Additionally, bicuspid aortic valve, atrial septal defect, and patent ductus arteriosus are observed more frequently in LDS than in the general population (MacCarrick et al., 2014).
Neurologic manifestations of LDS may include dural ectasia and Chiari malformation, as well as migraines, intracranial hypertension and hypotension, and spinal disorders (atlanto-occipital instability, atlanto-axial instability, basilar invagination, and instability/malformation of the cervical spine).
Skeletal features of LDS include an indented or protruding sternum, scoliosis, joint laxity, arachnodactyly, club foot (talipes equinovarus), and cervical spine malformation and/or instability (Loeys and Dietz, 2018). Cutaneous features of LDS include velvety and translucent skin, easy bruising, and dystrophic scars (Loeys and Dietz, 2018).
Other important manifestations of LDS include a high incidence of allergic or inflammatory diseases such as asthma, eczema, and food or environmental allergies (Frischmeyer-Guerrerio et al., 2013). Patients with LDS also show an increased predisposition to gastrointestinal inflammation, including eosinophilic esophagitis and gastritis or inflammatory bowel disease (Wang et al., 2021). In addition, the disease carries an increased risk of pregnancy complications (MacCarrick et al., 2014; Meester et al., 2017).
A study from Norway reports on a combined cohort of persons with vascular Ehlers-Danlos syndrome (vEDS) and LDS who responded to a
questionnaire on physical function and psychosocial aspects of hereditary thoracic aortic disease (Johansen et al., 2020). The authors found that 21/34 respondents with LDS were receiving disability pensions, rehabilitation benefits, partial disability pensions, or were retired; 29/34 respondents reported chronic musculoskeletal pain. No associations were found between age or gender and chronic musculoskeletal pain in the combined cohort with LDS and vEDS. A score for the respondents’ multi–organ system burden, including chronic musculoskeletal pain, neck instability, joint problems, scoliosis, vision problems, hearing problems, pneumothorax, hernia, rupture of internal organs, skin problems, allergies, and abdominal pain, was calculated based on a range from 0 (least burden) to 12 (greatest). The median score for LDS1 and 2 was 5, for LDS3 was 3.5, and for LDS4 was 6.
Congenital Contractural Arachnodactyly
Clinical Picture
The features of CCA often overlap with those of the other disorders discussed in this chapter. CCA is characterized by external ear anomalies, arachnodactyly, camptodactyly, contractures, muscle weakness, a high arched palate, and occasional cardiovascular complications (Callewaert et al., 2009).
Epidemiology
Inheritance is autosomal-dominant, and males and females are equally affected. The true prevalence of CCA is unknown (Callewaert, 2019), but its distinctive physical features often result in earlier diagnosis relative to other HDCTs. One study found the mean age of diagnosis to be 10.6 years (Callewaert et al., 2009).
Manifestations
The most prominent skeletal features of CCA are malformations of the hands and spine (Callewaert et al., 2009). Contractures of joints (typically elbows, fingers, and knees), elongated fingers and toes, external ear malformation, and protruding sternum are often detected at birth (Tunçbilek and Alanay, 2006). Contractures for individuals with CCA generally improve over time, while scoliosis and kyphosis are usually progressive (Callewaert et al., 2009), necessitating aggressive management.
Cardiovascular malformations have been identified with CCA, but with less frequency than with MFS and LDS (Callewaert et al., 2009). Aortic root
dilation has been reported in as many as 10–15 percent of cases of CCA with fibrillin-2 (FBN2) pathogenic variants (Callewaert, 2019).
Shprintzen-Goldberg Syndrome
Clinical Picture
SGS shows considerable phenotypic overlap with MFS and LDS, but also manifests in developmental delays, mild to moderate intellectual disability, and severe skeletal muscle hypotonia (Greally, 2020). It is characterized by a marfanoid habitus; craniosynostosis; and skeletal, neurologic, and cardiovascular abnormalities (Doyle et al., 2012; Greally, 2020).
Epidemiology
Inheritance of SGS is autosomal-dominant, and males and females are equally affected, with no ethnic predisposition (NORD, 2017). Its prevalence is unknown (Greally, 2020).
Manifestations
This disorder is often recognized early in life (Adès et al., 1995). Clinical findings include marfanoid habitus, craniosynostosis, hydrocephalous, arachnodactyly, camptodactyly (bent fingers), undersized lower jaw, protruding eyes, abnormal external ears, indented or protruding sternum, scoliosis, mitral valve prolapse, occasional aortic root dilatation and aneurysms, occasional aneurysms beyond the aorta, multiple abdominal wall hernias, infantile hypotonia, intellectual disability, bone loss, decreased subcutaneous tissues, and obstructive sleep apnea (Greally, 2020; Loeys et al., 2005; Robinson et al., 2005).
TREATMENT AND MANAGEMENT
MFS and related hereditary aortopathies manifest in multiple body systems, and individuals with these disorders may experience a variety of secondary impairments that, individually or in combination, can cause functional limitations of varying severity. Appropriate management of the HDCTs and treatment of associated secondary impairments are important for managing functional limitations and reducing HDCT-related disability. This section addresses the management of MFS, LDS, CCA, and SGS. Chapter 5 addresses the relationship among secondary impairments associated with these disorders, their potential effects on function, and considerations relevant to Social Security Administration disability.
Management of MFS and related hereditary aortopathies involves specialists in numerous physical and mental health disciplines. For example, cardiologists and cardiovascular surgeons diagnose, monitor, and treat mitral valve prolapse and aortic root dilatation. Orthopedists monitor and manage the development of scoliosis, protrosio acetabuli, pes planus, and associated issues of joint hypermobility. If necessary, thoracic surgeons manage and treat deformity of the anterior chest wall, particularly if it causes chest pain or affects breathing. Ophthalmologists diagnose and manage ectopia lentis, myopia, and strabismus in childhood, and monitor adults for the development of cataracts, glaucoma, and retinal tears. Physical and occupational therapists can provide interventions to mediate impairments and functional limitations. Overall management should be coordinated by a medical geneticist or physician with knowledge of and experience with these disorders.
Marfan Syndrome
No curative treatment currently exists for MFS. Management of the disorder involves early recognition and aggressive monitoring and treatment of manifestations in multiple organ systems, treatment of associated secondary impairments present at the time of diagnosis, and measures to reduce or prevent problems that may occur with age. Management is lifelong (as summarized in Milewicz et al., 2021), including routine eye examinations and imaging of the aorta. Pharmacologic therapies and prophylactic surgeries can prevent aortic dissections. Skeletal complications should be treated as they arise (Milewicz et al., 2021). Conservative treatment of musculoskeletal manifestations is preferred whenever possible because of higher complication rates following surgical intervention among persons with MFS relative to the general population (Bitterman and Sponseller, 2017). An important component of lifelong management is genetic counseling, as there is about a 50 percent chance of transmitting the pathologic FBN1 variant to offspring with each pregnancy.
The types of treatment necessary for a given patient vary widely based on the severity of the disease complications and the age at which they present. Severe, progressive scoliosis, for example, requires early and aggressive bracing, as well as careful clinical and radiologic monitoring during childhood and adolescence and when necessary, surgical stabilization of the vertebral column to prevent progression (Bitterman and Sponseller, 2017).
The most life-threatening complication of MFS is dilatation of the ascending aorta, which predisposes to aortic dissection. Monitoring of the diameter of the ascending aorta, typically with echocardiography, should be initiated as soon as the diagnosis of MFS is established; the frequency of monitoring depends on the severity and pace of progression of enlargement.
Prophylactic treatment with beta-adrenergic blockade, angiotensin receptor blockade, or both should be considered as soon as the diagnosis of MFS is made. Once the aortic diameter has reached a certain size (typically 45–50 mm in an adult), prophylactic aortic root replacement is recommended (Hiratzka et al., 2010; Hoskoppal et al., 2018).
Management of patients with MFS changes over time, as many features associated with the disease worsen or become apparent only with aging. Some manifestations (e.g., sleep apnea, central obesity, dural ectasia) do not appear or cause problems until adulthood. Some features become apparent only because life expectancy for persons with MFS has been increasing as a result of effective management of cardiovascular complications (Pyeritz, 2019).
Loeys-Dietz Syndrome
The management of LDS and other hereditary aortopathies is similar to that of MFS. The more aggressive nature of aortic root dilatation and dissection in LDS warrants close monitoring, and surgery is recommended at an earlier stage of aortic dilation because of the increased likelihood of catastrophic events. Unlike management of MFS, management of LDS includes diagnostic or baseline vascular imaging with magnetic resonance angiography or computed tomography angiography of the head, neck, chest, abdomen, and pelvis to assess for aneurysms throughout the aorta and arterial tree and to look for arterial tortuosity (MacCarrick et al., 2014). Some individuals with an abdominal aortic aneurysm may require surgery before root replacement, underscoring the need for whole-body surveillance (Beaulieu, et al., 2017). Since LDS patients have a strong predisposition toward allergic and inflammatory diseases, appropriate management of those conditions should be included in care plans for these patients. Cutaneous findings in LDS are more severe than those seen in MFS, and wound healing can be delayed, with atrophic scars resulting.
Congenital Contractural Arachnodactyly
During childhood, spinal deformity resulting from CCA should be followed closely by physical examination and radiography. If it is severe or progressive, an orthopedist with special expertise in abnormal spinal curvature should be consulted. Bracing should be considered, as should surgery if bracing is ineffective. Because of the increased incidence of aortic root dilatation with CCA, periodic echocardiography is recommended.
Shprintzen-Goldberg Syndrome
Management of SGS is currently limited to symptom treatment. Patients should be monitored with echocardiograms and bone scans. Treatments include surgical repairs as necessary for the cardiovascular and skeletal systems. Medications may be considered if the patient shows abnormal aortic growth. Patients should be assessed and receive early intervention for developmental delays, and may need occupational, physical, and speech therapy. Because of the severe muscle hypotonia associated with SGS, bracing of the feet and spine may be necessary to help with ambulation. A feeding tube may be required for adequate nutrition. Continuous positive airway pressure is recommended for obstructive sleep apnea. Individuals with SGS may also need to avoid contact sports and other activities that stress their cardiovascular system or may result in injury or pain in their joints (Greally, 2020).
EMERGING TREATMENTS
Better medications to protect the aorta remain an important and ongoing goal of research in MFS and related hereditary aortopathies; at present, beta blockers and angiotensin-converting enzyme blockage remain the mainstay of treatment. Surgical approaches to repair aortic aneurysms are highly effective, but aortic dissection remains a difficult problem to treat. Efforts are under way to develop noninvasive methods for assessing the strength of the enlarged aorta to identify those patients most at risk of dissection (Baliga et al., 2014). ClinicalTrials.gov (NLM, 2022) is a database of more than 400,000 clinical trials being conducted in the 50 U.S. states and 220 other countries and territories. As of May 2022, more than 20 clinical trials related to MFS, 5 trials related to LDS, and 1 trial related to CCA were either recruiting, actively ongoing, or completed.
FINDINGS AND CONCLUSIONS
Findings
3-1. Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), congenital contractural arachnodactyly (CCA; also known as Beals-Hecht syndrome), and Shprintzen-Goldberg syndrome (SGS) affect multiple body systems, often with cardiovascular, skeletal, and ocular manifestations.
3-2. Diagnosis of MFS, LDS, CCA, and SGS is based on established clinical criteria and can be confirmed through genetic testing.
3-3. Many manifestations of hereditary aortopathies worsen over time, with some not appearing until adulthood.
3-4. No curative treatments currently exist for MFS, LDS, CCA, SGS, or other hereditary aortopathies. Management of these disorders involves early diagnosis and aggressive monitoring and treatment of manifestations in multiple organ systems, including treatment of associated physical and mental secondary impairments present at the time of identification and measures to reduce or prevent problems that may occur with age.
3-5. Management of MFS and related hereditary aortopathies is lifelong and involves specialists across multiple physical and mental health disciplines.
3-6. As the life spans of patients with these syndromes increase with improvements in management of previously fatal complications (e.g., aortic rupture, spontaneous pneumothorax), concurrent increases are seen in the occurrence and severity of age-related secondary impairments.
3-7. Hereditary aortopathies can affect individuals’ everyday physical and mental functioning, often impacting multiple body systems. MFS frequently manifests in cardiovascular, nervous, respiratory, musculoskeletal, and ocular system impairments. LDS and CCA manifest particularly in cardiovascular, cerebrovascular, respiratory, musculoskeletal, craniofacial, ocular, and neurological impairments. SGS manifests in developmental delays and intellectual disability, as well as impairments associated with the other hereditary aortopathies.
3-8. Pregnancy can be a high-risk condition in some individuals with hereditary aortopathies.
Conclusions
3-1. MFS and related hereditary aortopathies have multiple physical and mental manifestations that, individually or in combination, can cause functional limitations of varying severity. Some manifestations may become apparent only with age, and the severity of manifestations may, and often does, progress with age. Treatment can be successful in reducing impairments in selected cases.
3-2. Management of MFS and related hereditary aortopathies requires a multidisciplinary approach and involves early diagnosis of the multisystem findings associated with these syndromes, treatment of associated physical and mental secondary impairments, and measures to reduce or prevent problems that may present with aging.
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Annex Table 3-1
Overview of Marfan Syndrome and Related Hereditary Aortopathies
| Selected HDCTs | Description | Documentation (e.g., laboratory tests, diagnostic criteria) |
|---|---|---|
| Marfan syndrome | Marfan syndrome is a heritable genetic disorder associated with multiorgan syndrome dysfunctions and inherited in an autosomal dominant manner. Abnormalities seen in this disorder include ectopia lentis, myopia, corneal flatness, retinal detachment, early-onset glaucoma and cataracts, trabeculodysgenesis, strabismus, aortic valve regurgitation, mitral valve regurgitation and prolapse, congestive heart failure, tricuspid valve prolapse, premature calcification of the mitral annulus, aortic root dilatation and dissection, ascending aortic root aneurysm, pulmonary artery dilatation, emphysema, pneumothorax, pulmonary blebs, pectus abnormalities, recurrent hernias, scoliosis, spondylolithesis, lumbar dural ectasia, protrusion acetabulae, long-bone overgrowth, joint hypermobility and contractures, hammer toes, pes planus and pes cavus, and decreased muscle mass. | Diagnostic criteria 2010 Revised Ghent Nosology Laboratory genetic (mutation) testing Fibrillin 1 (FBN1) |
| Loeys-Dietz syndrome | Loeys-Dietz syndrome is an autosomal dominant inherited arthropathy syndrome with widespread systemic involvement. Abnormalities seen in this disorder include micrognathia, hypertelorism, exotropia, blue sclerae, proptosis, malar hypoplasia, bifid uvula, cleft palate, atrial septal defect (uncommon), bicuspid aortic valve (uncommon), bicuspid pulmonary valve (rare), mitral valve prolapse (uncommon), arterial tortuosity (generalized), patent ductus arteriosus, ascending aortic aneurysm and dissection, pulmonary artery aneurysm, descending aortic aneurysm, cerebral aneurysm, pectus deformity, joint laxity, craniosynostosis (uncommon), scoliosis, arachnodactyly, camptodactyly, postaxial polydactyly (rare), talipes equinovarus, velvety textured and translucent skin, mental retardation (uncommon), developmental delay (uncommon), Chiari malformation (uncommon), hydrocephalus (uncommon), headaches, asthma, food allergy, eczema, allergic rhinitis, increased incidence of eosinophilic gastrointestinal disease and other gastrointestinal complaints, pneumothorax and restrictive lung disease, and increased fracture risk. |
Diagnostic criteria Heterozygous mutation in one of the genes listed below and either of the following:
Laboratory genetic (mutation) testing TGFBR1; TGFBR2; SMAD2; SMAD3; TGFB2; TGFB3 |
| Congenital contractural arachnodactyly (also known as Beals-Hecht syndrome) | Congenital contractural arachnodactyly is an autosomal dominant disorder characterized primarily by contractures and musculoskeletal and cardiac complications. Abnormalities seen in this disorder include marfanoid habitus (dolichostenomelia); dolichocephaly; micrognathia; crumpled appearing ears; ectopia lentis; myopia; high-arched palate; mitral valve prolapse; mitral regurgitation; atrial and ventricular septal defect; bicuspid aortic valve; patent ductus arteriosus; aortic root dilatation; interrupted aortic arch; pectus carinatum; duodenal or esophageal atresia (including intestinal malrotation); osteopenia; congenital kyphoscoliosis; hip, elbow, and knee contractures; subluxation of patella; arachnodactyly; camptodactyly; adducted thumbs; flexion contractures of proximal interphalangeal joints; metatarsus varus; talipes equinovarus; and motor developmental delay. | Diagnostic criteria Arachnodactyly (wrist and thumb sign) Marfanoid habitus (dolichostenomelia)—decreased upper to lower segment ratio (<0.85 in white adults; <0.78 in black adults) Laboratory genetic (mutation) testing Fibrillin 2 (FBN2) |
| Shprintzen Goldberg syndrome | Shprintzen Goldberg syndrome is an ultrarare autosomal dominant disorder characterized by craniofacial, skeletal, and cardiovascular abnormalities. Clinical findings include craniosynostosis (premature fusion of cranial bones in infancy), craniofacial features (maxillary hypoplasia, micrognathia, ptosis), mitral valve prolapse, aortic dilation, rare arterial tortuosity, obstructive apnea, pectus excavatum or carinatum, marfanoid habitus, joint laxity and/or contractures, umbilical and abdominal hernias, scoliosis, osteopenia, talipes equinovarus, pes planus, hyperelastic skin, lack of subcutaneous tissue, intellectual disability, Chiari malformation, hydrocephalus, and severe muscle hypotonia. | Diagnostic criteria No formal diagnostic criteria Considerable phenotypic overlap with Marfan syndrome and Loeys-Dietz syndrome with additional findings of intellectual disabilities and severe muscle hypotonia Laboratory genetic (mutation) testing SKI Protooncogene (SKI) |
NOTE: HDCT = heritable disorder of connective tissue and disability.
SOURCES: Bertoli-Avella et al., 2015; Callewaert, 2019; Doyle et al., 2012; Frischmeyer-Guerrerio et al., 2013; Greally, 2020; Gupta et al., 2002; Lindsay et al., 2012; Loeys and Dietz, 2018; Loeys et al., 2005, 2010; Matyas et al., 2014; Regalado et al., 2011; Rienhoff et al., 2013; Tan et al., 2013; Van Hemelrijk et al., 2010.
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