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3 Marfan Syndrome and Related Hereditary Aortopathies Marfan syndrome (MFS) is an autosomal-dominant disorder that af- fects 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 contrac- tural 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 char- acteristics 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 âMarfan syndrome.â Over the next five decades, some patients with arachnodactyly were also found to have dis- location 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 47
48 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE degree, the wall of the aorta would tear (aortic dissection), which was of- ten 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 Marfanâs original patient had a different but overlapping conditionâCCAâwhich 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 heterozygousâthat 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 mo- lecular features, summarized most recently in the 2010 revised Ghent nosol- ogy, 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).
MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES 49 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 differ- ent 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 patho- genic 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 cardio- vascular, 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 mani- festations 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 manifesta- tions may go undiagnosed until they experience a sentinel event, such as aortic dissection, in adulthood (Dietz, 2022). Musculoskeletal and ocu- lar 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 through- out life, although paradoxically, some have reduced mobility in certain joints, such as the digits or elbows (Dietz, 2022). Investigation for MFS is
50 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE BOX 3-1 Revised Ghent Criteria for Diagnosis of Marfan Syndrome and Related Conditions In the absence of family history: 1. Aortic root dilatation (Z score â¥ 2) AND ectopia lentis = Marfan syndrome* â¢ âThe presence of aortic root dilatation (Z-score â¥ 2 when standard- ized to age and body size) or dissection and ectopia lentis allows the unequivocal diagnosis of Marfan syndrome, irrespective of the presence or absence of systemic features except where these are indicative of Shprintzen-Goldberg syndrome, Loeys-Dietz syn- drome, or vascular Ehlers-Danlos syndromeâ (Loeys et al., 2010, p. 478). 2. Aortic root dilatation (Z score â¥ 2) AND FBN1 = Marfan syndrome â¢ âThe presence of aortic root dilatation (Z â¥ 2) or dissection and the identification of a bona fide FBN1 mutation is sufficient to establish the diagnosis, even when ectopia lentis is absentâ (Loeys et al., 2010, p. 478). 3. Aortic root dilatation (Z score â¥ 2) AND systemic score [see Box 3-2] â¥ 7 points = Marfan syndrome* â¢ âWhere aortic root dilatation (Z â¥ 2) or dissection is present, but ectopia lentis is absent and the FBN1 status is either unknown or negative, a Marfan syndrome diagnosis is confirmed by the presence of sufficient systemic findings (â¥ 7 points, according to a scoring system). However, features suggestive of Shprintzen- Goldberg syndrome, Loeys-Dietz syndrome, or vascular Ehlers- Danlos syndrome must be excluded and appropriate alternative 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).
MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES 51 genetic testing (TGFBR1/2, collagen biochemistry, COL3A1, and other relevant genetic testing when indicated and available upon the discovery of other genes) should be performedâ (Loeys et al., 2010, p. 478). 4. Ectopia lentis AND an FBN1 mutation with known aortic root dilatation = Marfan syndrome â¢ âIn the presence of ectopia lentis, but absence of aortic root dilata- tion/dissection, the identification of an FBN1 mutation previously associated with aortic disease is required before making the diag- nosis of Marfan syndromeâ (Loeys et al., 2010, p. 478). In the presence of family history: 5. Ectopia lentis AND family history of Marfan syndrome (as defined above) = Marfan syndrome 6. A systemic score (â¥ 7 points) AND family history of Marfan syndrome (as defined above) = Marfan syndrome* 7. Aortic root dilatation (Z score â¥ 2 above 20 yrs. old, â¥ 3 below 20 yrs. old) + family history of Marfan syndrome (as defined above) = Marfan syndrome* * Caveat: without discriminating features of Shprintzen-Goldberg syndrome, Loeys-Dietz syndrome or vascular Ehlers-Danlos syndrome AND after TGFBR1/2, collagen biochemistry, COL3A1 testing if indicated. Other conditions/genes will emerge with time. SOURCE: Loeys et al., 2010. Adapted by permission from BMJ Publishing Group Limited. âThe revised Ghent nosology for the Marfan syndrome,â B. L. Loeys, H. C. Dietz, A. C. Braver- man, B. L. Callewaert, J. De Backer, R. B. Devereux, Y. Hilhorst-Hofstee, G. Jondeau, L. Faivre, D. M. Milewicz, R. E. Pyeritz, P. D. Sponseller, P. Wordsworth, and A. M. De Paepe, 47(1), p. 477, 2010. 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 âaverage ageâ of appearance of manifestations. In the most severe form of MFS (often termed âneonatal MFSâ), severe ocular, skeletal, and cardiovascular features are present at birth, and life expectancy is mark- edly reduced, even with early and aggressive treatment. In less severe forms, some features (e.g., aortic dilatation, disproportionately tall stature) may
52 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE BOX 3-2 Ghent II Criteria for Scoring of Systemic Features Systemic features excluding aortic disease, ectopia lentis and family history for the diagnosis of Marfan syndrome â¢ Wrist and thumb signs (3 points)Â â¢ Wrist or thumb sign (1 point)Â â¢ Anterior chest deformity (2 points)Â â¢ Hind foot deformity (2 points)Â â¢ Pneumothorax (2 points)Â â¢ Dural ectasia (2 points)Â â¢ Protrusio acetabuli (2 points)Â â¢ Reduced upper segment [to] lower segment and increased arm span to height ratio (1 point)Â â¢ Reduced elbow extension (1 point)Â â¢ Facial features: dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, and retrognathia (1 point if 3 out 5 features are present)Â â¢ Skin striae other than due to pregnancy or obesity (1 point)Â â¢ Myopia > 3 diopters (1 point)Â â¢ Mitral valve prolapse (1 point) The total score of the systemic features is used in the diagnostic criteria.Â SOURCE: Excerpted from Milewicz et al., 2021, p. 8. Reprinted by permission from Springer Nature: Springer Nature, Nature Reviews: Disease Primers, âMarfan syndrome,â M. D. Mile- wicz, A. C. Braverman, J. De Backer, S. A. Morris, C. Boileau, I. H. Maumenee, G. Jondeau, A. Evangelista, and R. E. Pyeritz, 2021. 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 second- ary impairments associated with and functional implications of MFS and related hereditary aortopathies (see Annex Tables 5-3â5-16 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
MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES 53 annulus, and pulmonary artery dilation (Loeys et al., 2010; Stuart and Williams, 2007). Echocardiography findings demonstrate aortic root dila- tion 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, al- though 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, some- times 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 el- evate 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 restric- tion 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, espe- cially with repetitive bending or carrying under strain. Ocular involvement is seen in the majority of MFS patients. Ectopia lentis is seen in 50â80 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), myo- pia, increased globe length, and corneal flattening (Loeys et al., 2010). An elongated globe contributes to severe myopia and a risk of retinal detach- ment, which may lead to visual impairment or permanent blindness. Early
54 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE cataract formation may also be observed (Dietz, 2022). In addition, the risk of developing glaucoma, a known complication of MFS, is signifi- cantly 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 enlarge- ment 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 car- diopulmonary 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 dis- ability (Sowho et al., 2020). Skin abnormalities include changes in the skin due to thinning of the underlying connective tissues, otherwise known as âstretch marksâ (striae atrophicae). Chronic pain is experienced by 47â92 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 physi- cal 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 com- mon 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, ner- vous, 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 edu- cation-related activities; Rao and colleagues (2016), for example, found that chronic fatigue was associated with reduced work capacity. Research has
MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES 55 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 function- ing (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 dif- ficulties, that diminish quality of life and affect a patientâs 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 com- pared 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 in- clude 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 cardiovas- cular 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).
56 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE 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 (mid- face), 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 hypoten- sion, and spinal disorders (atlanto-occipital instability, atlanto-axial instabil- ity, 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 bruis- ing, 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 inflamma- tion, 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
MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES 57 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, rehabilita- tion 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 respondentsâ multiâorgan system burden, including chronic musculoskeletal pain, neck instability, joint prob- lems, 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 anoma- lies, 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 malfor- mation, and protruding sternum are often detected at birth (TunÃ§bilek 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
58 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE dilation has been reported in as many as 10â15 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 dis- ability, and severe skeletal muscle hypotonia (Greally, 2020). It is character- ized 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 preva- lence is unknown (Greally, 2020). Manifestations This disorder is often recognized early in life (AdÃ¨s et al., 1995). Clinical findings include marfanoid habitus, craniosynostosis, hydrocepha- lous, 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 aneu- rysms, 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 disabil- ity. This section addresses the management of MFS, LDS, CCA, and SGS. Chapter 5 addresses the relationship among secondary impairments associ- ated with these disorders, their potential effects on function, and consider- ations relevant to Social Security Administration disability.
MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES 59 Management of MFS and related hereditary aortopathies involves spe- cialists 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 man- age 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 treat- ment of manifestations in multiple organ systems, treatment of associated secondary impairments present at the time of diagnosis, and measures to re- duce or prevent problems that may occur with age. Management is lifelong (as summarized in Milewicz et al., 2021), including routine eye examina- tions 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 mus- culoskeletal 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 im- portant 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 pres- ent. Severe, progressive scoliosis, for example, requires early and aggressive bracing, as well as careful clinical and radiologic monitoring during child- hood 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.
60 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE 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 45â50 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 in- cludes diagnostic or baseline vascular imaging with magnetic resonance an- giography 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 tortuosityÂ (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 to- ward allergic and inflammatory diseases, appropriate management of those conditions should be included in care plans for these patients.Â 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 fol- lowed closely by physical examination and radiography. If it is severe or progressive, an orthopedist with special expertise in abnormal spinal curva- ture 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.
MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES 61 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, brac- ing 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 ongo- ing goal of research in MFS and related hereditary aortopathies; at pres- ent, 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 dis- section (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), congeni- tal contractural arachnodactyly (CCA; also known as Beals-Hecht syndrome), and Shprintzen-Goldberg syndrome (SGS) affect mul- tiple body systems, often with cardiovascular, skeletal, and ocular manifestations. 3-2. Diagnosis of MFS, LDS, CCA, and SGS is based on established clini- cal criteria and can be confirmed through genetic testing.
62 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE 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 as- sociated 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 im- provements 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 individualsâ 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 disabil- ity, 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 manifes- tations 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 mea- sures to reduce or prevent problems that may present with aging.
MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES 63 REFERENCES Aburawi, E. H., and J. OâSullivan. 2007. Relation of aortic root dilatation and age in Marfanâs syndrome.Â European Heart Journal 28(3):376-379.Â https://doi.org/10.1093/eurheartj/ ehl457. Adams, J. N., and R. J. Trent. 1998. Aortic complications of Marfanâs syndrome. Lancet 352(9142):1722-1723. https://doi.org/10.1016/s0140-6736(05)79822-6. AdÃ¨s, L. C., L. L. Morris, R. G. Power, M. Wilson, E. A. Haan, J. F. Bateman, D. M. Milewicz, and D. O. Sillence. 1995. Distinct skeletal abnormalities in four girls with Shprintzen- Goldberg syndrome. American Journal of Medical Genetics 57(4):565-572. https://doi. org/10.1002/ajmg.1320570410. Alpendurada, F., J. Wong, A. Kiotsekoglou, W. Banya, A. Child, S. K. Prasad, D. J. Pennell, and R. H. Mohiaddin. 2010. Evidence for Marfan cardiomyopathy. European Journal of Heart Failure 12(10):1085-1091. https://doi.org/10.1093/eurjhf/hfq127. Agarwal, A., and P. Narang. 2014. Ectopia lentis a major ocular manifestion of Marfan syndrome. Ocular Surgey News (September 10). https://www.healio.com/news/ophthal- mology/20140910/ectopia-lentis-a-major-ocular-manifestation-of-marfan-syndrome (ac- cessed May 5, 2022). Andonian, C., S. Freilinger, S. Achenbach, P. Ewert, U. Gundlach, H. Kaemmerer, N. Nagdyman, R. C. Neidenbach, L. Pieper, J. Schelling, M. Weyand, and J. Beckmann. 2021. Quality of life in patients with Marfan syndrome: A cross-sectional study of 102 adult patients. Cardiovascular Diagnosis and Therapy 11(2):602-610. https://cdt.amegroups.com/article/ view/63061. Baliga, R. R., C. A. Nienaber, E. Bossone, J. K. Oh, E. M. Isselbacher, U. Sechtem, R. Fattori, S. V. Raman, and K. A. Eagle. 2014. The role of imaging in aortic dissection and related syndromes. Journal of Cardiovascular Imaging 7(4):406-424. https://doi.org/10.1016/j. jcmg.2013.10.015. Bathen, T., G. Velvin, S. Rand-Hendriksen, and H. S. Robinson. 2014. Fatigue in adults with Marfan syndrome, occurrence and associations to pain and other factors. American Journal of Medical Genetics Part A 164(8):1931-1939. https://doi.org/10.1002/ ajmg.a.36574. Bertoli-Avella, A. M., E. Gillis, H. Morisaki, J. M. A. Verhagen, B. M. de Graaf, G. van de Beek, E. Gallo, B. P. T. Kruithof, H. Venselaar, L. A. Myers, S. Laga, A. J. Doyle, G. Oswald, G. W. A. van Cappellen, I. Yamanaka, R. M. van der Helm, B. Beverloo, A. de Klein, L. Pardo, M. Lammens, C. Evers, K. Devriendt, M. Dumoulein, J. Timmermans, H. T. Bruggenwirth, F. Verheijen, I. Rodrigus, G. Baynam, M. Kempers, J. Saenen, E. M. Van Craenenbroeck, K. Minatoya, R. Matsukawa, T. Tsukube, N. Kubo, R. Hofstra, M. J. Goumans, J. A. Bekkers, J. W. Roos-Hesselink, I. M. B. H. van de Laar, H. C. Dietz, L. Van Laer, T. Morisaki, M. W. Wessels, and B. L. Loeys. 2015. Mutations in a TGF-Î² ligand, TGFB3, causeÂ syndromic aortic aneurysms andÂ dissections. Journal of the American College of Cardiology 65(13):1324-1336. https://doi.org/10.1016/j.jacc.2015.01.040. Beaulieu R. J., J. Lue, B. A. Ehlert, J. C. Grimm, C. W. Hicks, and J. H. Black III. 2017. Surgical management of peripheral vascular manifestations of Loeys-Dietz syndrome. Annals of Vascular Surgery 38:10-16. https://doi.org/10.1016/j.avsg.2016.06.007. Bitterman, A. D., and P. D. Sponseller. 2017. Marfan syndrome: A clinical update. Journal of the American Academy of Orthopaedic Surgeons 25(9):603-609. https://doi.org/10.5435/ jaaos-d-16-00143.
64 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE Bruno, L., S. Tredici, M. Mangiavacchi, V. Colombo, G. F. Mazzotta, and C. R. Sirtori. 1984. Cardiac, skeletal, and ocular abnormalities in patients with Marfanâs syndrome and in their relatives. Comparison with the cardiac abnormalities in patients with kyphoscolio- sis. British Heart Journal 51(2):220-230. https://doi.org/10.1136/hrt.51.2.220. Callewaert, B. 2019. Congenital contractural arachnodactyly. In GeneReviewsÂ® [Internet], edited by M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. W. Gripp, G. M. Mirzaa, and A. Amemiya. Seattle, WA: University of Washington; 1993- 2022. https://www.ncbi.nlm.nih.gov/books/NBK1386/?report=classic. Callewaert, B. L., B. L. Loeys, A. Ficcadenti, S. Vermeer, M. Landgren, H. Y. Kroes, Y. Yaron, M. Pope, N. Foulds, O. Boute, F. GalÃ¡n, H. Kingston, N. Van der Aa, I. Salcedo, M. E. Swinkels, C. Wallgren-Pettersson, O. Gabrielli, J. De Backer, P. J. Coucke, and A. M. De Paepe. 2009. Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: Report of 14 novel mutations and review of the literature. Human Mutation 30(3):334-341. https://doi.org/10.1002/humu.20854. Chiu, H. H., M. H. Wu, H. C. Chen, F. Y. Kao, and S. K. Huang. 2014. Epidemiological profile of Marfan syndrome in a general population: A national database study. Mayo Clinic Proceedings 89(1):34-42. https://doi.org/10.1016/j.mayocp.2013.08.022. Dietz, H. C. 2022. FBN1-related Marfan syndrome. In GeneReviewsÂ® [Internet], edited by M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. W. Gripp, G. M. Mirzaa and A. Amemiya. Seattle, WA: University of Washington; 1993-2022. https:// www.ncbi.nlm.nih.gov/books/NBK1335. Dietz, H. C., C. R. Cutting, R. E. Pyeritz, C. L. Maslen, L. Y. Sakai, G. M. Corson, E. G. Puffenberger, A. Hamosh, E. J. Nanthakumar, S. M. Curristin, G. Stetten, D. A. Meyers, and C. A. Francomano. 1991. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352(6333):337-339. https://doi. org/10.1038/352337a0. Doyle, A. J., J. J. Doyle, S. L. Bessling, S. Maragh, M. E. Lindsay, D. Schepers, E. Gillis, G. Mortier, T. Homfray, K. Sauls, R. A. Norris, N. D. Huso, D. Leahy, D. W. Mohr, M. J. Caulfield, A. F. Scott, A. DestrÃ©e, R. C. Hennekam, P. H. Arn, C. J. Curry, L. Van Laer, A. S. McCallion, B. L. Loeys, and H. C. Dietz. 2012. Mutations in the TGF-Î² repres- sor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nature Genetics 44(11):1249-1254. https://doi.org/10.1038/ng.2421. Dyhdalo, K., and C. Farver. 2011. Pulmonary histologic changes in Marfan syndrome: A case series and literature review. American Journal of Clinical Pathology 136(6):857-863. https://doi.org/10.1309/ajcp79sndhgkqfin. Erkula, G., P. D. Sponseller, L. C. Paulsen, G. L. Oswald, B. L. Loeys, and H. C. Dietz. 2010. Musculoskeletal findings of Loeys-Dietz syndrome. Journal of Bone and Joint Surgery (American Volume) 92(9):1876-1883. https://doi.org/10.2106/jbjs.I.01140. Esfandiari, H., S. Ansari, H. Mohammad-Rabei, and M. B. Mets. 2019. Management strate- gies of ocular abnormalities in patients with Marfan syndrome: Current perspective. Journal of Ophthalmic & Vision Research 14(1):71-77. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC6388525/. Frischmeyer-Guerrerio, P. A., A. L. Guerrerio, G. Oswald, K. Chichester, L. Myers, M. K. Halushka, M. Oliva-Hemker, R. A. Wood, and H. C. Dietz. 2013. TGFÎ² receptor muta- tions impose a strong predisposition for human allergic disease. Science Translational Medicine 5(195):195ra194. https://doi.org/10.1126/scitranslmed.3006448. Greally, M. T. 2020. Shprintzen-Goldberg syndrome. In GeneReviewsÂ® [Internet], edited by M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. Bean, K. W. Gripp, G. M. Mirzaa, and A. Amemiya. Seattle, WA: University of Washington; 1993-2022. https:// www.ncbi.nlm.nih.gov/books/NBK1277/.
MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES 65 Groth, K. A., H. Hove, K. Kyhl, L. Folkestad, M. Gaustadnes, N. Vejlstrup, K. Stochholm, J. R. Ãstergaard, N. H. Andersen, and C. H. Gravholt. 2015. Prevalence, incidence, and age at diagnosis in Marfan syndrome. Orphanet Journal of Rare Diseases 10(1):153. https:// doi.org/10.1186/s13023-015-0369-8. Gupta, P. A., E. A. Putnam, S. G. Carmical, I. Kaitila, B. Steinmann, A. Child, C. Danesino, K. Metcalfe, S. A. Berry, E. Chen, C. V. Delorme, M. K. Thong, L. C. AdÃ¨s, and D. M. Milewicz. 2002. Ten novel FBN2 mutations in congenital contractural arachnodactyly: Delineation of the molecular pathogenesis and clinical phenotype. Human Mutation 19(1):39-48. https://doi.org/10.1002/humu.10017. Hiratzka L. F., G. L. Bakris, J. A. Beckman, R. M. Bersin, V. F. Carr, D. E. Casey Jr, K. A. Eagle, L. K. Hermann, E. M. Isselbacher, E. A. Kazerooni, N. T. Kouchoukos, B. W. Lytle, D. M. Milewicz, D. L. Reich, S. Sen, J. A. Shinn, L. G. Svensson, and D. M. Williams, 2010. ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation 121(13):e266-e369. https://doi.org/10.1161/CIR.0b013e3181d4739e. Hoskoppal, A., S. Menon, F. Trachtenberg, K. M. Burns, J. De Backer, B. D. Gelb, M. Gleason, J. James, W. W. Lai, A. Liou, L. Mahony, A. K. Olson, R. E. Pyeritz, A. M. Sharkey, M. Stylianou, S. B. Wechsler, L. Young, J. C. Levine, E. S. S. Tierney, R. V. Lacro, and T. J. Bradley, on behalf of Pediatric Heart Network Investigators. 2018. Predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome. Pediatric Cardiology 39(7):1453-1461. https://doi.org/10.1007/s00246-018-1916-6. Huang, Y., H. Huang, Q. Li, R. F. Browning, S. Parrish, J. F. Turner, Jr., K. Zarogoulidis, I. Kougioumtzi, G. Dryllis, I. Kioumis, G. Pitsiou, N. Machairiotis, N. Katsikogiannis, N. Courcoutsakis, A. Madesis, K. Diplaris, T. Karaiskos, and P. Zarogoulidis. 2014. Approach of the treatment for pneumothorax. Journal of Thoracic Disease 6(Suppl 4):S416-S420. https://doi.org/10.3978/j.issn.2072-1439.2014.08.24. Izquierdo, N. J., E. I. Traboulsi, C. Enger, and I. H. Maumenee. 1994. Strabismus in the Marfan syndrome. American Journal of Ophthalmology 117(5):632-635. https://doi.org/10.1016/ S0002-9394(14)70069-8. Januzzi, J. L., E. M. Isselbacher, R. Fattori, J. V. Cooper, D. E. Smith, J. Fang, K. A. Eagle, R. H. Mehta, C. A. Nienaber, and L. A. Pape. 2004. Characterizing the young patient with aortic dissection: Results from the International Registry of Aortic Dissection (IRAD). Journal of the American College of Cardiology 43(4):665-669. https://doi.org/10.1016/j. jacc.2003.08.054. Jeremy, R. W., H. Huang, J. Hwa, H. McCarron, C. F. Hughes, and J. G. Richards. 1994. Relation between age, arterial distensibility, and aortic dilatation in the Marfan syndrome. American Journal of Cardiology 74(4):369-373. https://doi.org/10.1016/0002-9149(94)90405-7. Johansen, H., G. Velvin, and I. Lidal. 2020. Adults with LoeysâDietz syndrome and vas- cular EhlersâDanlos syndrome: A cross-sectional study of health burden perspectives. American Journal of Medical Genetics Part A 182(1):137-145. https://doi.org/10.1002/ ajmg.a.61396.
66 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE Jondeau, G., P. Boutouyrie, P. Lacolley, B. Laloux, O. Dubourg, J.-P. Bourdarias, and S. Laurent. 1999. Central pulse pressure is a major determinant of ascending aorta dilation in Marfan syndrome. Circulation 99(20):2677-2681. https://doi.org/10.1161/01.CIR.99.20.2677. Judge, D. P., and H. C. Dietz. 2005. Marfanâs syndrome. Lancet 366(9501):1965-1976. https:// doi.org/10.1016/s0140-6736(05)67789-6. Lee, B., M. Godfrey, E. Vitale, H. Hori, M.-G. Mattei, M. Sarfarazi, P. Tsipouras, F. Ramirez, and D. W. Hollister. 1991. Linkage of Marfan syndrome and a phenotypically re- lated disorder to two different fibrillin genes. Nature 352(6333):330-334. https://doi. org/10.1038/352330a0. Lindsay, M. E., D. Schepers, N. A. Bolar, J. J. Doyle, E. Gallo, J. Fert-Bober, M. J. Kempers, E. K. Fishman, Y. Chen, L. Myers, D. Bjeda, G. Oswald, A. F. Elias, H. P. Levy, B. M. Anderlid, M. H. Yang, E. M. Bongers, J. Timmermans, A. C. Braverman, N. Canham, G. R. Mortier, H. G. Brunner, P. H. Byers, J. Van Eyk, L. Van Laer, H. C. Dietz, and B. L. Loeys. 2012. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nature Genetics 44(8):922-927. https://doi.org/10.1038/ng.2349. Loeys, B. L., J. Chen, E. R. Neptune, D. P. Judge, M. Podowski, T. Holm, J. Meyers, C. C. Leitch, N. Katsanis, N. Sharifi, F. L. Xu, L. A. Myers, P. J. Spevak, D. E. Cameron, J. De Backer, J. Hellemans, Y. Chen, E. C. Davis, C. L. Webb, W. Kress, P. Coucke, D. B. Rifkin, A. M. De Paepe, and H. C. Dietz. 2005. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nature Genetics 37(3):275-281. https://doi.org/10.1038/ng1511. Loeys, B. L., H. C. Dietz, A. C. Braverman, B. L. Callewaert, J. De Backer, R. B. Devereux, Y. Hilhorst-Hofstee, G. Jondeau, L. Faivre, D. M. Milewicz, R. E. Pyeritz, P. D. Sponseller, P. Wordsworth, and A. M. De Paepe. 2010. The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics 47(7):476-485. https://doi.org/10.1136/jmg.2009. 072785. Loughborough, W. W., K. S. Minhas, J. C. L. Rodrigues, S. M. Lyen, H. E. Burt, N. E. Manghat, M. J. Brooks, G. Stuart, and M. C. K. Hamilton. 2018. Cardiovascular manifestations and complications of Loeys-Dietz syndrome: CT and MR imaging findings. Radiographics 38(1):275-286. https://doi.org/10.1148/rg.2018170120. MacCarrick, G., J. H. Black, 3rd, S. Bowdin, I. El-Hamamsy, P. A. Frischmeyer-Guerrerio, A. L. Guerrerio, P. D. Sponseller, B. Loeys, and H. C. Dietz, 3rd. 2014. Loeys-Dietz syndrome: A primer for diagnosis and management. Genetics in Medicine 16(8):576-587. https:// doi.org/10.1038/gim.2014.11. Matyas, G., P. Naef, M. Tollens, and K. Oexle. 2014. De novo mutation of the latency-associ- ated peptide domain of TGFB3 in a patient with overgrowth and Loeys-Dietz syndrome features. American Journal of Medical Genetics Part A 164a(8):2141-2143. https://doi. org/10.1002/ajmg.a.36593. Meester, J. A. N., A. Verstraeten, D. Schepers, M. Alaerts, L. Van Laer, and B. L. Loeys. 2017. Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Annals of Cardiothoracic Surgery 6(6):582-594. https://doi. org/10.21037/acs.2017.11.03. Milewicz, D. M., A. C. Braverman, J. De Backer, S. A. Morris, C. Boileau, I. H. Maumenee, G. Jondeau, A. Evangelista, and R. E. Pyeritz. 2021. Marfan syndrome. Nature Reviews: Disease Primers 7(1):64. https://doi.org/10.1038/s41572-021-00298-7.
MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES 67 Nielsen, C., I. Ratiu, M. Esfandiarei, A. Chen, and E. S. Selamet Tierney. 2019. A review of psychosocial factors of Marfan syndrome: Adolescents, adults, families, and providers. Journal of Pediatric Genetics 08(03):109-122. https://doi.org/10.1055/s-0039-1693663. NLM (U.S. National Library of Medicine). 2022. Clinicaltrails.gov. https://clinicaltrials.gov/ (accessed February 11, 2022). NORD (National Organization for Rare Disorders). 2017. Rare disease database: Shprintzen Goldberg syndrome. https://rarediseases.org/rare-diseases/marfan-syndrome/ (accessed May 11, 2022). NORD. 2021. Rare disease database: Marfan syndrome. https://rarediseases.org/rare-diseases/ marfan-syndrome/ (accessed February 9, 2022). Pyeritz, R. E. 2019. Marfan syndrome: Improved clinical history results in expanded natural his- tory. Genetics in Medicine 21(8):1683-1690. https://doi.org/10.1038/s41436-018-0399-4. Rand-Hendriksen, S., H. Johansen, S. O. Semb, O. Geiran, J. K. Stanghelle, and A. Finset. 2010. Health-related quality of life in Marfan syndrome: A cross-sectional study of short form 36 in 84 adults with a verified diagnosis. Genetics in Medicine 12(8):517-524. https:// doi.org/10.1097/GIM.0b013e3181ea4c1c. Rao, S. S., K. D. Venuti, H. C. Dietz, 3rd, and P. D. Sponseller. 2016. Quantifying health status and function in Marfan syndrome. Journal of Surgical Orthopaedic Advances 25(1):34-40. Ratiu, I., T. B. Virden, H. Baylow, M. Flint, and M. Esfandiarei. 2018. Executive function and quality of life in individuals with Marfan syndrome. Quality of Life Research 27(8):2057- 2065. https://doi.org/10.1007/s11136-018-1859-7. Regalado, E. S., D. C. Guo, C. Villamizar, N. Avidan, D. Gilchrist, B. McGillivray, L. Clarke, F. Bernier, R. L. Santos-Cortez, S. M. Leal, A. M. Bertoli-Avella, J. Shendure, M. J. Rieder, D. A. Nickerson, and D. M. Milewicz. 2011. Exome sequencing identifies SMAD3 muta- tions as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circulation Research 109(6):680-686. https://doi.org/10.1161/ circresaha.111.248161. Rienhoff, H. Y., Jr., C. Y. Yeo, R. Morissette, I. Khrebtukova, J. Melnick, S. Luo, N. Leng, Y. J. Kim, G. Schroth, J. Westwick, H. Vogel, N. McDonnell, J. G. Hall, and M. Whitman. 2013. A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome. American Journal of Medical Genetics Part A 161a(8):2040-2046. https://doi.org/10.1002/ajmg.a.36056. Robinson, P. N., L. M. Neumann, S. Demuth, H. Enders, U. Jung, R. KÃ¶nig, B. Mitulla, D. MÃ¼ller, P. Muschke, L. Pfeiffer, B. Prager, M. Somer, and S. Tinschert. 2005. Shprintzen- Goldberg syndrome: Fourteen new patients and a clinical analysis. American Journal of Medical Genetics Part A 135(3):251-262. https://doi.org/10.1002/ajmg.a.30431. Roman, M. J., R. B. Devereux, L. R. Preiss, F. M. Asch, K. A. Eagle, K. W. Holmes, S. A. LeMaire, C. L. Maslen, D. M. Milewicz, S. A. Morris, S. K. Prakash, R. E. Pyeritz, W. J. Ravekes, R. V. Shohet, H. K. Song, and J. W. Weinsaft. 2017. Associations of age and sex with Marfan phenotype: The National Heart, Lung, and Blood Institute GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry. Circulation: Cardiovascular Genetics 10(3). https://doi.org/10.1161/circgenetics.116.001647.
68 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE Rybczynski, M., T. S. Mir, S. Sheikhzadeh, A. M. Bernhardt, C. Schad, H. Treede, S. Veldhoen, E. F. Groene, K. KÃ¼hne, D. Koschyk, P. N. Robinson, J. Berger, H. Reichenspurner, T. Meinertz, and Y. von Kodolitsch. 2010. Frequency and age-related course of mitral valve dysfunction in the Marfan syndrome. American Journal of Cardiology 106(7):1048-1053. https://doi.org/10.1016/j.amjcard.2010.05.038. Sandvik, G. F., T. T. Vanem, S. Rand-Hendriksen, S. Cholidis, M. SÃ¦thre, and L. Drolsum. 2019. Ten-year reinvestigation of ocular manifestations in Marfan syndrome. Clinical & Experimental Ophthalmology 47(2):212-218. https://doi.org/10.1111/ceo.13408. Sowho, M. O., S. Patil, H. Schneider, G. MacCarrick, J. P. Kirkness, L. F. Wolfe, L. Sterni, P. A. Cistulli, and E. R. Neptune. 2020. Sleep disordered breathing in Marfan syndrome: Value of standard screening questionnaires. Molecular Genetics & Genomic Medicine 8(1):e1039. https://doi.org/10.1002/mgg3.1039. Speed, T. J., V. A. Mathur, M. Hand, B. Christensen, P. D. Sponseller, K. A. Williams, and C. M. Campbell. 2017. Characterization of pain, disability, and psychological burden in Marfan syndrome. American Journal of Medical Genetics Part A 173(2):315-323. https:// doi.org/10.1002/ajmg.a.38051. Stuart, A. G., and A. Williams. 2007. Marfanâs syndrome and the heart. Archives of Disease in Childhood 92(4):351-356. https://doi.org/10.1136/adc.2006.097469. Takeda, N., H. Morita, D. Fujita, R. Inuzuka, Y. Taniguchi, Y. Imai, Y. Hirata, and I. Komuro. 2015. Congenital contractural arachnodactyly complicated with aortic dilatation and dissection: Case report and review of literature. American Journal of Medical Genetics Part A 167a(10):2382-2387. https://doi.org/10.1002/ajmg.a.37162. Tan, E. W., R. U. Offoha, G. L. Oswald, R. L. Skolasky, A. K. Dewan, G. Zhen, J. R. Shapiro, H. C. Dietz, X. Cao, and P. D. Sponseller. 2013. Increased fracture risk and low bone mineral density in patients with Loeys-Dietz syndrome. American Journal of Medical Genetics Part A 161a(8):1910-1914. https://doi.org/10.1002/ajmg.a.36029. Tranos, P., R. Asaria, W. Aylward, P. Sullivan, and W. Franks. 2004. Long term outcome of secondary glaucoma following vitreoretinal surgery. British Journal of Ophthalmology 88(3):341. https://doi.org/10.1136/bjo.2003.028076. TunÃ§bilek, E., and Y. Alanay. 2006. Congenital contractural arachnodactyly (Beals syndrome). Orphanet Journal of Rare Diseases 1(1):20. https://doi.org/10.1186/1750-1172-1-20. Van Hemelrijk, C., M. Renard, and B. Loeys. 2010. The Loeys-Dietz syndrome: An update for the clinician. Current Opinion in Cardiology 25(6):546-551. https://doi.org/10.1097/ HCO.0b013e32833f0220. Vanem, T. T., S. Rand-Hendriksen, C. Brunborg, O. R. Geiran, and C. RÃ¸e. 2020. Health- related quality of life in Marfan syndrome: A 10-year follow-up. Health and Quality of Life Outcomes 18(1):376. https://doi.org/10.1186/s12955-020-01633-4. Velvin, G., T. Bathen, S. Rand-Hendriksen, and A. Ã. Geirdal. 2015. Work participation in adults with Marfan syndrome: Demographic characteristics, MFS related health symptoms, chronic pain, and fatigue. American Journal of Medical Genetics Part A 167(12):3082-3090. https://doi.org/10.1002/ajmg.a.37370. Velvin, G., T. Bathen, S. Rand-Hendriksen, and A. Geirdal. 2016a. Systematic review of chronic pain in persons with Marfan syndrome. Clinical Genetics 89(6):647-658. https://doi. org/10.1111/cge.12699.
MARFAN SYNDROME AND RELATED HEREDITARY AORTOPATHIES 69 Velvin, G., T. Bathen, S. Rand-Hendriksen, and A. Ã. Geirdal. 2016b. Satisfaction with life in adults with Marfan syndrome (MFS): Associations with health-related consequences of MFS, pain, fatigue, and demographic factors. Quality of Life Research 25(7):1779-1790. https://doi.org/10.1007/s11136-015-1214-1. Wang, X. J., M. Babameto, D. Babovic-Vuksanovic, J. M. Bowen, and M. Camilleri. 2021. Audit of gastrointestinal manifestations in patients with Loeys-Dietz syndrome and vas- cular Ehlers-Danlos syndrome. Digestive Diseases and Sciences 66(4):1142-1152. https:// doi.org/10.1007/s10620-020-06265-8.
Annex Table 3-1â 70 Overview of Marfan Syndrome and Related Hereditary Aortopathies Documentation (e.g., laboratory tests, Selected HDCTs Description diagnostic criteria) Marfan syndrome Marfan syndrome is a heritable genetic disorder associated with Diagnostic criteria multiorgan syndrome dysfunctions and inherited in an autosomal 2010 Revised Ghent Nosology dominant manner. Abnormalities seen in this disorder include ectopia Laboratory genetic (mutation) testing lentis, myopia, corneal flatness, retinal detachment, early-onset glaucoma Fibrillin 1 (FBN1) 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. Loeys-Dietz syndrome Loeys-DietzÂ syndromeÂ isÂ anÂ autosomal dominant inherited arthropathy Diagnostic criteria syndrome with widespreadÂ systemicÂ involvement. Abnormalities Heterozygous mutation in one of the seen in this disorder include micrognathia, hypertelorism, exotropia, genes listed below and either of the blueÂ sclerae, proptosis, malarÂ hypoplasia, bifidÂ uvula, cleftÂ palate, following: atrialÂ septal defectÂ (uncommon), bicuspid aortic valve (uncommon), (1) aortic root enlargement (defined as bicuspidÂ pulmonaryÂ valve (rare), mitralÂ valveÂ prolapseÂ (uncommon), an aortic root z-score â¥2.0) or type A arterialÂ tortuosity (generalized), patentÂ ductusÂ arteriosus, ascending dissection, or aortic aneurysm andÂ dissection,Â pulmonaryÂ arteryÂ aneurysm, (2) compatible systemic features, descendingÂ aorticÂ aneurysm, cerebralÂ aneurysm, pectusÂ deformity, including characteristic craniofacial, jointÂ laxity, craniosynostosisÂ (uncommon),Â scoliosis, arachnodactyly, skeletal, cutaneous, and/or vascular camptodactyly, postaxialÂ polydactylyÂ (rare), talipesÂ equinovarus, manifestations found in combination, and velvetyÂ textured and translucent skin, mentalÂ retardationÂ (uncommon), particularly arterial tortuosity. developmentalÂ delayÂ (uncommon), ChiariÂ malformationÂ (uncommon), Laboratory genetic (mutation) testing hydrocephalusÂ (uncommon), headaches, asthma, food allergy, eczema, TGFBR1; TGFBR2; SMAD2; SMAD3; allergic rhinitis, increased incidence of eosinophilic gastrointestinal TGFB2; TGFB3 disease and other gastrointestinal complaints, pneumothorax and restrictive lung disease, and increased fracture risk.
Congenital Congenital contractural arachnodactyly is an autosomal dominant Diagnostic criteria contractural disorder characterized primarily by contractures and musculoskeletal Arachnodactyly (wrist and thumb sign) arachnodactyly (also and cardiac complications. Abnormalities seen in this disorder Marfanoid habitus (dolichostenomelia)â known as Beals-Hecht include marfanoid habitus (dolichostenomelia); dolichocephaly; decreased upper to lower segment ratio syndrome) micrognathia; crumpled appearing ears; ectopia lentis;Â myopia; (<0.85 in white adults; <0.78 in black high-arched palate; mitral valve prolapse;Â mitral regurgitation;Â atrial adults) andÂ ventricular septal defect;Â bicuspid aortic valve;Â patent ductus Laboratory genetic (mutation) testing arteriosus;Â aortic root dilatation;Â interrupted aortic arch; pectus Fibrillin 2 (FBN2) carinatum; duodenal or esophageal atresia (including intestinal malrotation);Â osteopenia;Â congenital kyphoscoliosis; hip, elbow, and knee contractures; subluxation of patella; arachnodactyly; camptodactyly;Â adducted thumbs; flexion contractures of proximal interphalangeal joints;Â metatarsus varus; talipes equinovarus; and motor developmental delay.Â Shprintzen Goldberg Shprintzen Goldberg syndrome is an ultrarare autosomal dominant Diagnostic criteria syndrome disorder characterized by craniofacial, skeletal, and cardiovascular No formal diagnostic criteria abnormalities. Clinical findings include craniosynostosis (premature fusion Considerable phenotypic overlap with of cranial bones in infancy), craniofacial features (maxillary hypoplasia, Marfan syndrome and Loeys-Dietz micrognathia, ptosis), mitral valve prolapse, aortic dilation, rare arterial syndrome with additional findings of tortuosity, obstructive apnea, pectus excavatum or carinatum, marfanoid intellectual disabilities and severe muscle habitus, joint laxity and/or contractures, umbilical and abdominal hernias, hypotonia scoliosis, osteopenia, talipes equinovarus, pes planus, hyperelastic skin, Laboratory genetic (mutation) testing lack of subcutaneous tissue, intellectual disability, Chiari malformation, SKI Protooncogene (SKI) hydrocephalus, and severe muscle hypotonia. 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. 71