Health Supervision for Children with Marfan Syndrome Abstract

FROM THE AMERICAN ACADEMY OF PEDIATRICS

Guidance for the Clinician in Rendering Pediatric Care

CLINICAL REPORT Health Supervision for Children With Marfan Syndrome

Brad T. Tinkle, MD, PhD, Howard M. Saal, MD, and the COMMITTEE ON GENETICS abstract KEY WORD Marfan syndrome is a systemic, heritable connective tissue disorder Marfan syndrome that affects many different organ systems and is best managed by us- This document is copyrighted and is property of the American ing a multidisciplinary approach. The guidance in this report is Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American designed to assist the pediatrician in recognizing the features of Mar- Academy of Pediatrics. Any conflicts have been resolved through fan syndrome as well as caring for the individual with this disorder. a process approved by the Board of Directors. The American Pediatrics 2013;132:e1059–e1072 Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication. The guidance in this report does not indicate an exclusive INTRODUCTION course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be Marfan syndrome is a heritable, multisystem disorder of connective appropriate. tissue with extensive clinical variability. It is a relatively common condition, with approximately 1 in 5000 people affected.1 Cardinal features involve the ocular, musculoskeletal, and cardiovascular systems. Because of the high degree of variability of this disorder, many of these clinical features can be present at birth or can manifest later in childhood or even adulthood. Marfan syndrome is an autosomal dominant disorder mainly caused by defects in FBN1, the gene that codes for the protein fibrillin, although patients with mutations in other genes, including TGFBR1 and TGFBR2, have also been reported, albeit rarely.2 Mutations in FBN1 are asso- www.pediatrics.org/cgi/doi/10.1542/peds.2013-2063 ciated with a wide phenotypic spectrum ranging from classic features doi:10.1542/peds.2013-2063 of Marfan syndrome presenting in childhood and early adulthood to All clinical reports from the American Academy of Pediatrics severe neonatal presentation with rapidly progressive disease. At the automatically expire 5 years after publication unless reaffirmed, other end of the spectrum, isolated phenotypic features, such as revised, or retired at or before that time. ectopia lentis or skeletal manifestations alone, may be the only pre- PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). senting signs. Mutations in FBN1 are found in up to 95% of those Copyright © 2013 by the American Academy of Pediatrics meeting diagnostic criteria.3,4 However, the diagnosis of Marfan syndrome is clinically based on well-defined criteria (revised Ghent diagnostic criteria [Tables 1 and 2]) and does not include the whole spectrum of FBN1-related disorders, especially the milder, isolated features.5 Thus, genetic testing of FBN1 is best reserved for those patients in whom there is a strong clinical suspicion of Marfan syndrome, including those with the “emerging” phenotype, using established guidelines of the interpretation of such results. Because many of the more specific clinical features are age dependent (eg, ectopia lentis, aortic dilation, dural ectasia, protrusio acetabuli), children and adolescents may not fulfill formal diagnostic criteria and are often described as having “potential” Marfan syndrome. Younger patients at risk for Marfan syndrome on the basis of clinical features or a positive family history should be evaluated periodically (eg, at 5, 10, 15, and 18 years of age) in lieu of genetic testing.

PEDIATRICS Volume 132, Number 4, October 2013 e1059 TABLE 1 Revised Ghent Diagnostic Criteria Approximately one-quarter of cases general population.9 Hormonal ther- for Marfan Syndrome occur as a result of a new mutation, apy to limit adult height is rarely used Diagnosis of definitive Marfan syndrome with the remainder inherited from an in males. Complications can include (any of the following) affected parent. Because of the broad accelerated growth, early puberty, • ≥ Aortic root 2 z score and ectopia lentis phenotypic variability, some parents and the undesirable consequences of • Aortic root ≥2 z score and FBN1 mutation • Aortic root ≥2 z score and systemic score ≥7 will not be readily recognized as hav- associated increased blood pressure, • Ectopia lentis and FBN1 mutation known to be ing Marfan syndrome.8 In such cases, which may increase the progression associated with Marfan syndrome both parents and at-risk first-degree of the aortic dilation. Prepubertal • Positive family history of Marfan syndrome and ectopia lentis relatives should have physical, oph- females have been treated with high- • Positive family history of Marfan syndrome thalmologic, and cardiac evaluation as dose estrogen therapy and pro- and systemic score ≥7 well, with consideration of genetic gesterone to reduce final adult height • Positive family history of Marfan syndrome and aortic root ≥3 z score in those <20 y of testing. in the past; however, this treatment age or ≥2 z score in those >20 y of age remains controversial in both its Diagnosis of potential Marfan syndrome GROWTH AND DEVELOPMENT psychosocial and medical benefits.10 • FBN1 mutation with aortic root with a z score <3 in those <20 y of age Overall growth is characterized by Lean muscle mass is also affected. excessive linear growth of the long Individuals with Marfan syndrome often show a paucity of muscle mass and Many features of Marfan syndrome are bones. Typically, most individuals with Marfan syndrome are tall for age fat stores despite adequate caloric seen in isolation as well as in other intake. Weight is often below the 50th 6 (Figs 1 and 2), but it is important to genetic syndromes (Table 3). Di- percentile for age.9 agnosis should be clearly established note that not all affected individuals Cognitive ability in patients with Marfan when possible. For those suspected to are tall by population standards; they syndrome is usually within the typical have Marfan syndrome based on are typically taller than predicted for range for the general population. How- clinical grounds after physical, car- their family (excluding others with 9 fi ever, poor vision and underlying medical diac, and ophthalmic evaluation but Marfan syndrome). Mean nal height ± problems may interfere with learning. Q:3 who may not meet full clinical criteria, was 191.3 9 cm (75 in) for males ± Similarly, many patients report chronic one can consider FBN1 testing.7 and 175.4 8.2 cm (69 in) for females. fatigue, which may affect education The growth of the tubular bones is and can manifest as inattention or 11 accelerated in Marfan syndrome, poor concentration. The etiology of TABLE 2 Systemic Scoring System for the resulting in disproportionate features. the fatigue is likely heterogeneous, Revised Ghent Diagnostic Criteria in part because of the underlying for Marfan Syndrome (Shown in The extremities are often dispropor- Table 1) tionately long in comparison with the chronic condition, medications such β Feature Value trunk (dolichostenomelia), altering the as -blockers, sleep disturbance (eg, Wrist and thumb sign 3 upper-to-lower segment and the arm- sleep apnea), and/or orthostatic in- 12 Wrist or thumb sign 1 span-to-height ratios. The arm-span-to- tolerance. Pectus carinatum 2 fi Pectus excavatum or chest asymmetry 1 height ratio is relatively xed during childhood, but the upper-to-lower Hindfoot deformity (eg, valgus) 2 SKELETAL Pes planus 1 segment ratio changes during growth Pneumothorax 2 (Fig 3). Use of such measurements Skeletal system involvement in Marfan Dural ectasia 2 Protrusio acetabulae 2 should take into account racial, gender, syndrome is characterized by bone Reduced upper-to-lower segment ratio and 1 and age differences. Similarly, the tu- overgrowth. Such overgrowth may be increased arm-span-to-height ratio bular bones of the hand and fingers noticeable at birth or can develop in Scoliosis or thoracolumbar kyphosis 1 Reduced elbow extension 1 are elongated, but the palm is not young children, with a tendency to Craniofacial features: 3 of the following— 1 proportionately wider, resulting in rel- progress more rapidly during periods dolichocephaly, downward-slanting ative arachnodactyly as measured by of rapid growth, necessitating close palpebral fissures, enophthalmos, retrognathia, and malar hypoplasia the thumb and wrist signs (Fig 4). monitoring at such times (Table 4). Skin striae 1 Excessive growth in Marfan syndrome Overgrowth of the ribs can push the Myopia 1 is attributable, in part, to a peak sternum inward (pectus excavatum) Mitral valve prolapse 1 growth velocity that typically occurs as or outward (pectus carinatum). Nearly Adapted from Loeys et al.3 Z score calculations are based on Roman et al.38 much as 2 years earlier than the two-thirds of patients with Marfan

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TABLE 3 Differential Diagnoses: Syndromes With Overlapping Features of Marfan Syndrome Syndrome Manifestations Genetic Etiology Mitral valve prolapse syndrome Mitral valve prolapse; skeletal manifestations as seen in Marfan FBN1(in some) syndrome MASS phenotype Mitral valve prolapse; myopia; nonprogressive aortic dilation; FBN1 nonspecific skin and skeletal features Familial ectopia lentis Eye and skeletal findings of Marfan syndrome FBN1(in some) Shprintzen-Goldberg syndrome Skeletal and cardiac findings of Marfan syndrome; craniosynostosis; FBN1(in some) hypertelorism; proptosis; abdominal hernias; joint laxity; developmental delay/intellectual disability Weill-Marchesani syndrome (autosomal dominant form) Ectopia lentis; short stature; brachydactyly; characteristic facial FBN1 features Loeys-Dietz syndrome Skeletal and cardiovascular features of Marfan syndrome; no ectopia TGFBR1 lentis; aggressive dilation of large- and medium-sized arteries; most TGFBR2 common and unique features include hypertelorism, bifid uvula/cleft palate, blue sclerae, developmental delays, hydrocephalus, translucent skin, arterial tortuosity, and craniosynostosis Congenital contractural arachnodactyly Marfan-like skeletal features; “crumpled” ears; contractures of the FBN2 knees, ankles, and digits at birth; progressive kyphoscoliosis; arachnodactyly; cardiac valvular anomalies Familial thoracic aortic aneurysm Dilation of the aorta and dissections either at the level of the sinuses of Heterogeneous Valsalva or the ascending thoracic aorta without the other phenotypic features of Marfan syndrome Ehlers-Danlos syndrome, vascular type Thin skin with visible veins; easy bruising; small joint laxity; rupture of COL3A1 hollow organs as well as medium- and large-size arteries COL3A2 Ehlers-Danlos syndrome, kyphoscoliotic form (type VI) Marfanoid body habitus; kyphoscoliosis; joint laxity; mitral valve PLOD prolapse; hypotonia; blue sclerae; ocular fragility; at risk for rupture ZNF469 of medium-sized arteries Homocystinuria Ectopia lentis; skeletal abnormalities such as those seen in Marfan CBS syndrome; variable cognitive impairment; tendency for thrombotic events Stickler syndrome Severe myopia; retinal detachment; hearing loss; midface hypoplasia; COL2A1 cleft palate; spondyloepiphyseal dysplasia COL11A1 COL11A2 COL9A1 Fragile X syndrome Often tall; long face; joint laxity; mild dilation of the aorta; mitral valve FMR1 prolapse; pectus excavatum; variable intellectual disability syndrome will develop pectus excava- as well as atypically progressive.16,17 kyphoscoliosis). Postural education tum, which is often perceived as Close monitoring by using the and joint stabilization with core a disturbing physical feature by forward-bending test at yearly inter- strengthening may be of benefit but teenagers.13 The pectus deformity can vals and management by an ortho- are unproven for the treatment of be severe and, in extreme circum- pedist is preferred because surgical scoliosis in this population. Untreated stances, can interfere with pulmonary stabilization of the spine may be re- spinal deformities can lead to chronic functioning, warranting surgical in- quired.18 Bracing has a low success back pain and restrictive lung disease. tervention.14 Pectus excavatum may rate if the curves are greater than Spinal deformity correction is more also have a detrimental effect on 35° to 40° but may have some pre- prone to complications than in idio- cardiac function, especially during ventive value for smaller curves. pathic deformity and should be per- Those with spinal curvatures less submaximal exercising15 and is often formed by those with some experience than 30° have an excellent long-term repaired before cardiac surgery for in treating patients with Marfan syn- prognosis. Marked progression is aortic root replacement. Pectus de- drome.19 oftenseenbythosewithspinalcur- formity is often present before 10 vatures greater than 50°. The pro- The acetabulum of the hip can be years of age but may worsen during an gression of scoliosis can occur well abnormally deep (protrusio acetabuli) adolescent growth spurt. into adulthood. Thoracic kyphosis is in some patients with Marfan syn- Scoliosis is seen in slightly more than also common and can be postural or drome and can lead to pelvic or upper one-half of individuals with Marfan a further complication of bony over- leg pain. Protrusio acetabuli is seen syndrome and can be mild to severe growth and ligamentous laxity (eg, commonly in Marfan syndrome20;

PEDIATRICS Volume 132, Number 4, October 2013 e1061 FIGURE 1 Growth curves for males in Marfan syndrome. (A) 50th percentile and (B) 95th percentile for the general population used for comparison. Reprinted with permission from Erkula G, Jones KB, Sponseller PD, DietzHC,PyeritzRE.GrowthandmaturationinMarfansyndrome.Am J Med Genet. 2002;109 (2):103.9 however, it is not unique to this con- Some people with Marfan syndrome fatigue and overuse pain/injury.23 More dition and is seen in a number of will show reduced mobility of the el- typically, such individuals demonstrate infectious, inﬂammatory, metabolic, ge- bow, but other joints may demon- poor writing skills and complain of netic, neoplastic, and traumatic con- strate ligamentous laxity. Joint laxity hand pain/fatigue with prolonged use. ditions.21 In Marfan syndrome, the may be more signiﬁcant in young Physical and/or occupational therapy protrusio acetabuli is often asymptom- patients but rarely leads to motor can address these joint laxity issues by atic, and surgical intervention is rarely delays. True joint dislocations are using joint stabilization exercises, pos- indicated.22 rare. Joint laxity can lead to muscle tural support, education, alternative

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FIGURE 2 Growth curves for females in Marfan syndrome. (A) 50th percentile and (B) 95th percentile for the general population used for comparison. Reprinted with permission from Erkula G, Jones KB, Sponseller PD, DietzHC,PyeritzRE.GrowthandmaturationinMarfansyndrome.Am J Med Genet. 2002;109 (2):104.9 strategies (eg, use of a laptop for the use of shoe orthoses, such as an deeply set eyes (enophthalmos), taking notes), and bracing/resting splints arch support and more supportive downward slanting of the eyes, ﬂat if necessary. shoes. Surgical intervention is rarely cheek bones (malar hypoplasia), and Inward rotation of the medial aspect indicated or fully successful. Others a small chin (micrognathia) (Fig 6). of the ankle can result in pes planus will have highly arched feet but have However, facial features are often (Fig 5). This condition may lead to little or no symptoms. highly variable and may change with foot, ankle, knee, hip, and/or low back The facial features of Marfan syndrome age. In addition, these facial features pain.24 Some patients will beneﬁtfrom include a long and narrow face with are not highly sensitive for the

PEDIATRICS Volume 132, Number 4, October 2013 e1063 drome.26,27 The etiology of this bone loss remains speculative, but no sig- niﬁcant increase in bone fracture rates has been seen.28

OCULAR Myopia is the most common ocular feature and often progresses rapidly during childhood.29 Displacement of the lens (ectopia lentis) is a hallmark feature of Marfan syndrome but is only seen in 1 or both eyes in approximately 60% of affected individuals.30 It is often the presenting feature FIGURE 3 and occurs much more commonly Normative upper-to-lower segment ratios for (A) white and (B) African-American subjects. Reprinted fi with permission from McKusick VA. Heritable Disorders of Connective Tissue. Philadelphia, PA: Mosby; before 10 years of age. This nding is 1972. most reliably diagnosed according to a slit-lamp examination after full pu- pillary dilation. presence of Marfan syndrome.25 The Decreased bone density has been palate is often highly arched and nar- documented in the lumbar and hip The globe is often elongated, and the rowed (Fig 7). regions in patients with Marfan syn- cornea may be flat or even cone- shaped (keratoconus). People with Marfan syndrome are at increased risk of retinal detachment, glaucoma, and early cataract formation, typically in adulthood. Flashes of light (pho- topsia) and new floaters are symptoms of posterior vitreous detachment, which may precede retinal detachment.31,32 Retinal detachment should be considered in any patient with acute onset of visual symptoms, and these patients should be evaluated and treated emergently. Most retinal detachments can be repaired suc- cessfully, but the key to optimum visual recovery is prompt diagnosis and treatment. Affected individuals should be followed up closely by an ophthalmologist familiar with Marfan syndrome at least yearly with slit lamp examinations for lens subluxation and evaluations for glaucoma and cataracts. Most often, eye problems can be controlled ade- quately with corrective lenses alone. Careful and aggressive refraction and FIGURE 4 visual correction are mandatory in (A) Positive thumb sign with the thumbnail extending past the ulnar side of the hand and (B) positive young children at risk for amblyopia. wrist sign with the overlap of the nail beds of the thumb and fifth finger. Lens dislocation can present a clinical

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TABLE 4 Anticipatory Guidance in Marfan Syndrome Option At Diagnosis 0–12 mo 1–5y 6–12 ya 13–18 ya 19–22 y Cardiac examinationb √ Each visit Each visit Each visit Yearly Yearly Echocardiogram √ As indicated Yearly Yearly Yearly Yearly Ocular (ophthalmology) √ Yearly Yearly Yearly Yearly Musculoskeletalb Scoliosis clinical examination √ Each visit Yearly Every 6 mo Every 6 mo Yearly Joint laxity √ Each visit Yearly Every 6 mo Every 6 mo Pectus deformity √ Each visit Yearly Every 6 mo Every 6 mo Bone age √c Review diagnosis √ PRN PRN PRNd PRNd PRNd Examine family members √ PRN PRN PRN PRN PRN Support group information √ PRN PRN PRN PRN PRN Genetic counseling √√e √e Lifestylef √√ √ Transition Discuss plans Begin transition Many systems should be reviewed regularly at developmentally appropriate stages. PRN, as needed. a Periods of rapid growth require closer supervision. b If abnormal results on examination, refer for further evaluation. Follow-up evaluations as indicated. c Bone age determination in preadolescence. If large discrepancy between bone age and height age, hormonal therapy should be considered. d Review symptoms of potential catastrophic events such as aortic dissection, vision changes, and pneumothorax. e Discuss reproductive and pregnancy risks. f Review physical activity restrictions/lifestyle modiﬁcations.

lens. Although this procedure is cur- vast majority of cases becoming evi- rently considered safe when per- dent before 18 years of age. The di- formed in specialized centers, major lation typically is at the level of the complications, including retinal de- sinuses of Valsalva, but dilation of any tachment, can occur. The long-term part of the aorta can be seen in these stability and safety of sew-in in- patients (Fig 8). Histologic examina- traocular lenses are unknown. Zon- tion reveals elastic fiber fragmenta- ular weakness in Marfan syndrome tion with total loss of elastin content may also result in complete lens and accumulation of amorphous ma- FIGURE 5 subluxation into the vitreous or result trix components in the aortic media. Elongated feet with collapse of the medial arch resulting in pes planus. in prolapse of the lens into the ante- This “cystic medial necrosis” does not rior chamber of the eye, which may distinguish Marfan syndrome from necessitate surgical removal. Corneal other causes of aortic aneurysm and, challenge. Typically, the lens will sublux refractive surgery for myopia is gen- therefore, is only a description, not superiorly with Marfan syndrome. If erally contraindicated in individuals a pathognomonic feature. the lens is subluxed but still within the with Marfan syndrome, given the risk The age of onset and rate of pro- visual axis, substantial lenticular of additional eye complications. astigmatism may result, which can gression of aortic dilation are highly variable. As the aneurysm enlarges, require powerful astigmatic spectacle CARDIOVASCULAR correction. If the lens edge has sub- the aortic annulus can be over- luxed at or beyond the center of the The cardiovascular system is the ma- stretched, leading to secondary aortic visual axis, aphakic spectacle or con- jor source of morbidity and mortality regurgitation. Valvular dysfunction can tact lens correction may improve vi- in Marfan syndrome. Cardiovascular lead to volume overload with second- sion. If there is sufficient optical manifestations include dilation of the ary left ventricular dilation and heart distortion from lens subluxation, sur- aorta, aortic valve insufficiency, a pre- failure. Indeed, mitral valve prolapse gical removal of the lens (aphakia) or disposition for aortic tear and rupture, with congestive heart failure is the lens replacement (pseudophakia) may mitral valve prolapse with or without leading cause of cardiovascular mor- be the treatment of choice.33 Because regurgitation, tricuspid valve prolapse, bidity and mortality in young children of inherently weak zonular support and enlargement of the proximal pul- with Marfan syndrome.35 for the Marfan lens, pseudophakia monary artery.34 A significant risk of aortic dissection may require supplemental means of The aortic dilation in Marfan syndrome or rupture occurs when the maximal attachment to affix the intraocular tends to progress over time, with the aortic dimension reaches approximately

PEDIATRICS Volume 132, Number 4, October 2013 e1065 FIGURE 6 Facial features of Marfan syndrome are highly variable, ranging from subtle ﬁndings to more “classic” facial features. Photo consents for publication on ﬁle.

paresthesia, and paralysis. Asymmet- 0.5 cm per year, or with the onset ric blood pressure may also be a sign of significant valvular or ventricular of dissection. dysfunction. Aortic root dimensions All individuals with a diagnosis of can also be determined by using com- Marfan syndrome should be followed puted tomography angiography or up by a cardiologist familiar with magnetic resonance angiography, and Marfan syndrome. An echocardiogram they potentially have the benefitof should be obtained at diagnosis. A evaluating beyond the aortic root. subsequent echocardiogram is often Because aortic dilation can occur at desired in 6 months to assess the rate any age, lifelong monitoring is war- of progression.37 Yearly echocardio- ranted. grams are sufficient when aortic Medications that reduce hemodynamic dimensions are small (<4.5 cm in stress on the aortic wall, such as adults) and rates of aortic dilation are β-blockers, are often prescribed.37 FIGURE 7 low (<0.5 cm per year). Aortic root Therapy should be considered at the High arched (“steepled”) palate. measurements should be interpreted time of diagnosis at any age or on on the basis of normal values for age appreciation of progressive aortic and body size.38 Nomograms are root dilation, even in the absence of 5.0 cm in adults, although rupture at available through the National Marfan adefinitive diagnosis.39 The dose 4.5 cm has been documented among Foundation (http://www.marfan.org/ needs to be titrated to effect, keeping women.36 Fortunately, aortic dissection marfan/2576/Aortic-Root-Dilatation- heart rate after submaximal exercise is exceedingly rare in early child- Nomogram). More frequent evalua- or agitation less than 110 beats per hood. Acute aortic dissection usually tions are indicated when the aortic minute in young children or less than presents as severe chest pain but root diameter exceeds 4.5 cm in adults, 100 beats per minute in older children can also include pallor, pulselessness, when the rate of aortic dilation exceeds or adults. In patients who cannot

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tolerate β-blockers (eg, individuals can improve cardiovascular func- should be restricted.50 However, all with asthma, depression, fatigue), ve- tion, but surgical intervention may people with Marfan syndrome can and rapamil is commonly used,40 although be warranted. should remain active, with aerobic recently, concerns have been raised Surgical repair of the aorta is in- activities performed in moderation. about calcium channel blockers and dicated once: (1) the maximal aortic Agents that stimulate the cardiovas- an increased risk of aortic complica- root measurement exceeds 5.0 cm; (2) cular system, including routine use of tions.41 Currently, randomized con- the rate of increase of the aortic di- decongestants, should be avoided. trolled trials are underway evaluating ameter approaches 1.0 cm per year; or Caffeine can aggravate a tendency for the response to the angiotensin re- (3) there is progressive aortic re- arrhythmia. The use of psychostimu- ceptor blocker losartan, in response gurgitation.44 More aggressive ther- lant medications for chronic fatigue or to earlier mouse model work42 and apy may be indicated in individuals attention-deficit/hyperactivity disorder a small cohort study.43 If congestive with a family history of early aortic should be used with caution and be heart failure is present as a result of dissection. Many individuals can re- approved by the cardiologist. valvular dysfunction, afterload-reducing ceive a valve-sparing procedure that Subacute bacterial endocarditis pro- agents (in combination with a β-blocker) precludes the need for chronic anti- phylaxis may be indicated for dental coagulation therapy.45,46 Children run work or other procedures expected to the highest risk of requiring repeated contaminate the bloodstream with cardiac operations, such as valve re- bacteria in the presence of significant placement.47 valvular insufficiency. With proper Aortic dilation can also be seen in the management, the life expectancy of descending aorta, although typically at someone with Marfan syndrome later ages. All people with Marfan syn- approximates that of the general drome should begin intermittent sur- population.51,52 veillance of the entire aorta with computed tomography angiography or PULMONARY AIRWAY magnetic resonance angiography scans Pulmonary issues encountered in 48,49 in young adulthood. Such imaging Marfan syndrome include spontane- FIGURE 8 should also be performed at least an- Dilation at the level of the aortic root as seen in ous pneumothorax, reduced pulmo- Marfan syndrome. 1, aortic valve annulus; 2, nually in anyone with a history of aortic nary reserve, and sleep apnea. In aortic root (sinuses of Valsalva); 3, sinotubular root replacement or dissection. neonatal Marfan syndrome, an em- junction; 4, ascending aorta; AO, aorta; LA, left atrium; LV, left ventricle. Rights to be retained by Participation in contact sports, com- physematous lung disease is uniformly author (B.T.T.). petitive sports, and isometric exercise present and also occurs in approximately 10% to 15% of those with “classic” Marfan syndrome. Lung bullae, which develop in 4% to 15% of patients with Marfan syndrome, can develop anywhere on the surface of the lungs but especially in the upper lobes.53 Such bullae (or blebs) can predispose to spontaneous pneumothorax. Symptoms of pneumothorax include sudden onset of chest pain, dyspnea, and/or cyanosis. Breathing against resistance (eg, playing a brass instrument), scuba diving, or high-altitude sports (eg, skydiving, mountaineering) should be avoided, FIGURE 9 especially among those with a family Dural ectasia of the lumbar spinal canal. MRI appearance of the dilated dural sac, which can erode the history of spontaneous pneumothorax. bone and entrap nerves. Those with recurrent pneumothorax

PEDIATRICS Volume 132, Number 4, October 2013 e1067 may require chemical or surgical Because of the defect in connective Often, these anomalies will cause sig- pleurodesis or surgical resection of tissue, individuals with Marfan syn- nificant dental crowding and malalignment. pulmonary blebs. drome are also at risk for hernias. Routine dental care is recommended; A restrictive lung disease pattern with Many will have inguinal herniation that however, many individuals with Mar- increased total and residual lung vol- will require surgical repair. However, fan syndrome require orthodontia for ume as well as exercise intolerance is recurrent hernias or hernias at the proper occlusion as well as appear- typically seen in the majority of those site of surgical incisions are a more ance. Oral and maxillofacial interven- affected.54 Often, this pattern is re- distinctive hallmark of a connective tions may also be indicated, such as lated to pectus deformity, chest wall tissue disorder, such as Marfan syn- palatal expansion and/or mandibular asymmetry, and/or scoliosis. Surgical drome. Primary hernia repair should distraction. use a synthetic mesh (or similar ar- repair of severe pectus excavatum or PHYSICAL ACTIVITY scoliosis may improve overall pulmo- tificial construct) in all known or nary lung function. Pulmonary func- suspected cases of Marfan syndrome Although all children are encouraged tion tests should be performed in any to minimize the risk of recurrence. to participate in physical activity for patient with pulmonary complaints or overall health, skill development, co- significant pectus deformity and can DURAL ECTASIA ordination, musculoskeletal health, and socialization, individuals with be monitored after surgical repair. Most individuals with Marfan syn- Marfan syndrome are at significant Obstructive sleep apnea is commonly drome often develop stretching of the risk of physical injury and medical seen in patients with Marfan syn- dural sac in the dependent lumbosa- complications. Of concern are activi- drome.55 Increased nasal resistance cral region, resulting in dural ectasia ties including contact sports and ac- attributable to craniofacial abnormal- (Fig 9).58 This development can lead to tivities involving “burst” exertion (eg, ities, such as a high arched palate, bony erosion and nerve entrapment. sprinting) and intense static (iso- micrognathia with possible glossop- Symptoms can include pain in the metric) exertion, such as weight lift- tosis, and laryngotracheomalacia, can lower back, hip/pelvic region, and ing.63 In general, patients with Marfan cause difficulty with intubation/ proximal leg, as well as weakness/ syndrome without aortic dilation or anesthesia as well as significant up- numbness above and below the significant mitral valve regurgitation per airway resistance.56 Sleep apnea knees.59 However, in most patients, are encouraged to participate in is underappreciated among adoles- the dural ectasia is asymptomatic.60 competitive and noncompetitive (rec- cents and young adults with Marfan Excessive accumulation or leakage of reational) activities, but this action is syndrome. Symptoms commonly seen cerebrospinal fluid from the dural sac still limited by the intensity level of the in Marfan syndrome that may be can cause postural hypotension and activity and the individual.50 Sports in partially attributable to sleep apnea “low-pressure” headaches.61,62 Dam- which ocular trauma is likely, such as include fatigue and loss of energy as age of the dura from spinal taps or boxing or full-contact karate, should well as impaired memory and cogni- epidurals may not sufficiently heal, be discouraged. Participation in any tion. Symptoms of sleep dysfunction, causing leakage, which also predis- activity should be evaluated and dis- such as fatigue, decreased sleep du- poses the patient to postural head- cussed before initiation of that activ- ration, nonrestorative sleep, and aches. In severe cases of dural ectasia, ity. Activities of most concern include snoring, should be reviewed at each spinal shunting and/or medication can basketball, body building/weight lift- visit. A formal sleep evaluation should be used. Complications after surgical ing, hockey, running, skiing, racquet- be considered in such cases. repair of the dura include cerebrospinal ball, surfing, scuba diving, and rock fluid leakage and recurrence. Detection climbing. More acceptable alter- INTEGUMENT of dural ectasia can be performed using natives include modest hiking, sta- Approximately two-thirds of people either MRI or computed tomography tionary cycling, bowling, golf, skating, with Marfan syndrome develop stretch scan. snorkeling, and brisk walking. Caution marks of the skin.57 Often, these are is needed for patients with low blood DENTAL located across the lower back as well pressure and orthostatic intolerance, as the inguinal and axillary regions. People with Marfan syndrome typically including those receiving β-blocker These stretch marks are signs of have oromaxillofacial anomalies. Most therapy, who may be more susceptible rapid growth and are usually per- have an elongated face, malar hypoplasia, to easy fatigue, near-syncopal/syncopal pendicular to the axes of growth. high-arched palate, and micrognathia. episodes, and falls.12

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PSYCHOSOCIAL should be delayed if possible until after inheriting the genetic defect in definitive treatment of the aorta has Marfan syndrome affects each in- Marfan syndrome is 50%, consis- been completed. If already pregnant, dividual differently. Marfan syndrome tent with autosomal dominant in- consideration of immediate aortic re- has a significant effect on daily activ- heritance. Often, expectant parents placement, early delivery, or termination ities and perceived quality of life. are concerned about the severity of the pregnancy should be consid- However, in 2 small series, most af- of the disorder in the next genera- ered, given the potentially severe fected individuals older than 13 years tion. Variability of the Marfan phe- consequences. reported a positive general self-im- notype is extensive but is more age.64,65 A higher-than-expected rate of spon- similar among affected family taneous abortion has been reported members, suggesting that the ge- Many of those affected by Marfan in women with Marfan syndrome, netic defect is largely responsible syndrome benefit from networking although the etiology is unknown.69 In for the phenotype. Most people and peer relationships. The National addition, women with Marfan syn- with classic Marfan syndrome do Marfan Foundation (www.marfan.org) dromeexperienceahigherrateof not have children with a much is an excellent US resource for con- preterm deliveries, premature rup- more severe phenotype, such as nections as well as medical advice. ture of membranes, and increased 71 Most countries have similar organ- neonatal Marfan syndrome. One mortality of their offspring.69,70 Dural izations. should also be aware of the conse- ectasia should be considered in any quences that may affect the preg- TRANSITION/MEDICAL HOME affected individual, and avoidance of nancy outcome for women with spinal anesthesia may be necessary. Marfan syndrome. As mentioned Because Marfan syndrome can affect Epidural anesthesia is safe for most previously, women with an aortic the very young and continues women with Marfan syndrome, al- root greater than 4.5 cm in diame- throughout a patient’s lifetime, it is though it is not advised for those ter should avoid pregnancy or un- important that people with Marfan with moderately severe dural ecta- dergo elective aortic grafting syndrome be recognized and have sia. General anesthesia has the ben- before becoming pregnant.72 Aortic a medical home. Affected people are efit of avoiding complication of spinal dissection or rupture has occurred often followed up by cardiologists, anesthesia with dural ectasia and in women with an aorta less than ophthalmologists, and orthopedists.66 less stress on the aorta during de- 5.0 cm, which may result in signif- Care needs to be coordinated among livery. Optimally, pregnancy should icant morbidity and mortality of the various specialties, with a special be considered after appropriate coun- the fetus/infant and the expectant focus on the period of transition from seling from a geneticist or a cardiolo- mother. adolescence to adulthood. gist familiar with Marfan syndrome, 2. Parents of a child with Marfan syn- a genetic counselor, and a perinatol- drome may ask about recurrence ogist. PREGNANCY risk of Marfan syndrome in subsequent pregnancies. This issue may Pregnancy can lead to significant PRENATAL medical complications for women with best be explained by a geneticist. In Marfan syndrome and should be The pediatrician is sometimes called short, 1 of the parents may either approached with careful delibera- on to counsel a family prenatally with be unrecognized as having Marfan tion.67 If the aortic root is exceeds 4.0 regard to Marfan syndrome. The pe- syndrome (therefore, recurrence cm, complications can include rapid diatrician may have been previously risk is 50%) or both parents may progression of aortic root enlargement involved with this family through care be unaffected and, therefore, carry and/or aortic dissection or rupture of siblings or one of the expectant only a slight chance of having a low during pregnancy, delivery, and in the parents. Families may also seek pe- level of germline mosaicism (with postpartum period. Women whose diatric advice in the care and man- anticipated recurrence risk of 2%– aorta is greater than 4.5 cm or who agement of a fetus at risk. This 3%). Because of a high occurrence previously had an aortic dissection/ management may involve a few dif- of unrecognized Marfan syndrome rupture are at substantially higher ferent scenarios. in parents of a child with Marfan risk.68 Women with aortic dimensions 1. The pediatrician may be asked syndrome, it is advisable for both greater than 5.0 cm are at significant about the risk to a child of a parent parents to undergo further evalua- risk for aortic rupture, and pregnancy with Marfan syndrome. The risk of tion to establish their own personal

PEDIATRICS Volume 132, Number 4, October 2013 e1069 risk as well as the risk for subse- Cardiac abnormalities are severe and GU51 3NG, England quent pregnancies. include polyvalvular dysplasia and Phone: (0) 1252 810472 3. An expectant couple may have a fe- aortic dilation. Mortality is high within E-mail: [email protected] tus with concerning features of neo- the first year of life because of cardiac Web site: www.marfan.org.uk natal Marfan syndrome discovered failure secondary to severe mitral LEAD AUTHORS through prenatal ultrasonography valve regurgitation.75 Almost all cases of neonatal Marfan syndrome are Brad T. Tinkle, MD, PhD or even fetal MRI. Ultrasonographic Howard M. Saal, MD findings may include unusually long sporadic and are associated with limbs and congenital heart disease mutations clustering within exons 24 COMMITTEE ON GENETICS, 2011– and are often detected in the third through 32 of FBN1. 2012 trimester.73 Genetic testing for FBN1 Robert A. Saul, MD, Chairperson mutations by using amniocentesis SUPPORT GROUPS Stephen R. Braddock, MD Emily Chen, MD, PhD may be helpful to confirm the diag- National Marfan Foundation Debra L. Freedenberg, MD nosis of Marfan syndrome and to Marilyn C. Jones, MD 22 Manhasset Ave, reveal specific mutations in FBN1 James M. Perrin, MD Port Washington, NY 11050 that may be more typically associ- Beth Anne Tarini, MD Phone: 1-800-8-MARFAN ext 10 ated with neonatal Marfan syn- (1-800-862-7326); 1-516-883-8712 FORMER COMMITTEE ON GENETICS drome and, therefore, reduced Fax: 1-516-883-8040 MEMBERS survivability. E-mail: [email protected] Howard M. Saal, MD, Contributor Brad T. Tinkle, MD, PhD Web site: www.marfan.org NEONATAL MARFAN SYNDROME Canadian Marfan Association LIAISONS Neonatal Marfan syndrome is the most Centre Plaza Postal Outlet Sara Copeland, MD — Maternal and Child severe disorder attributable to a fibril- 128 Queen St South Health Bureau/Health Resources and Services linopathy. Features overlap significantly PO Box 42257 Administration with classic Marfan syndrome but are Mississauga, ONT, L5M4Z0, Canada Katrina M. Dipple, MD, PhD — American College Phone: of Medical Genetics more severe. Infants with neonatal 866-722-1722 (toll-free); 905- W. Allen Hogge, MD — American Congress of Marfan syndrome are long with simple/ 826-3223 Obstetricians and Gynecologists crumpled ears, aged-appearing face, Fax: 905-826-2125 Melissa A. Parisi, MD, PhD — Eunice Kennedy enlarged corneas, ectopia lentis, chest E-mail: [email protected] Shriver National Institute of Child Health and deformity, large feet, arachnodactyly, Web site: www.marfan.ca Human Development Stuart K. Shapira, MD, PhD — Centers for 74 and contractures. Respiratory insuf- Marfan Association UK Disease Control and Prevention ficiency is common as a result of an Rochester House abnormally pliant chest wall and em- 5 Aldershot Rd STAFF physematous changes in the lungs. Fleet, Hampshire Paul Spire

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