Marfan syndrome: is early diagnosis useful?

Current Paediatrics (1998)8, 121-125 © 1998Harcourt Brace& Co. Ltd

Mini-symposium: Rare and complex disorders

Marfan syndrome: is early diagnosis useful?

G. Stuart, D. Wilson microfibrils. Fibrillin has been found in a wide variety of organisms, from jellyfish to man, suggesting it is of fundamental structural importance. In 1990, abnormal fibrillin was identified in the skin and aorta of patients with Marfan syndrome. 2 In 1991, the Marfan and fibrillin genes were linked to chromosome 15 and by 1996 77 fibrillin deletions had been reported in families with Marfan syndrome. 3 Fibrillin-containing microfibrils provide a framework for elastic tissue deposition. They are found in many tissues including skin, tendons, muscle, blood vessels, pleura, periosteum, cartilage and the ciliary zonules. Abnormal fibrillin results in reduced tissue elasticity, which in the aorta predisposes to increased stiffness and can lead to dissection. 4

Marfan syndrome is an uncommon disorder of connective tissue characterized by abnormalities in the skeleton, eyes and cardiovascular system. It may present in infancy or childhood, although frequently the diagnosis is not made until adulthood. In recent years there have been major advances in our understanding of the aetiology, pathogenesis and diagnosis of Marfan syndrome. This has led to a rational strategy for diagnosis and management in the child. The purpose of this chapter is to discuss the diagnosis of Marfan syndrome in childhood and to address the question: 'Is early diagnosis useful?'

HISTORICAL NOTE Marfan syndrome was first described by the French paediatrician Dr Antoine-Bernard Marfan in 1896. He reported a 5-year-old girl who had spider legs ('pattes d'araignee'), joint contractures and a narrow skull.' He subsequently recognized the high incidence of cardiovascular and ophthalmic complications but it was not until one year after his death that the high mortality due to aortic abnormalities was recognized. Recent research has concentrated on identifying the genetic basis of Marfan syndrome and attempting to modify the poor prognosis associated with cardiovascular dysfunction.

GENETICS Marfan syndrome is an autosomal dominant condition with variable penetrance which affects both sexes equally. The condition has an incidence of 1:10 000 and has been described in all races. New mutations account for 25% of cases and the risk rises with increasing paternal age. 5The Marfan phenotype is usually associated with deletions of the fibrillin-1 (FBN1) gene on chromosome 15. 6 Each affected family carries a unique mutation making analysis difficult and expensive. Abnormalities in the FBN1 gene can be inferred by finding alterations in the fibrillin composition of cultured fibroblasts, but similar changes can occur in other connective tissue disorders, e.g. Ehlers-Danlos syndrome. 7 Thus, despite advances in molecular genetics, Marfan syndrome remains a clinical diagnosis.

AETIOLOGY In 1986, the protein 'fibrillin' was discovered and identified as an important constituent of extracellular

DIAGNOSIS OF M A R F A N S Y N D R O M E

Dr Graham Stuart, Dr Dirk Wilson, Congenital Heart Disease Centre, UniversityHospital of Wales NHS Trust, Heath Park, Cardiff CF4 4XW Wales, UK.

Internationally accepted criteria for the diagnosis of Marfan syndrome have been published and these are

Correspondenceand request for offprintsto GS. 121

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Table 1 Diagnostic criteria for Marfan syndrome System

Major criteria

Minor criteria

Comments

Skeletal

Presence of at least 4 of: • pectus carinatum • pectus excavatum requiring surgery • reduced upper to lower segment ratio or arm-height ratio > 1.05 • scoliosis > 20 degrees or spondolisthesis • reduced elbow extension < 170 degrees • pes planus • protrusio acetabulae on X-ray • dislocated lenses

• pectus excavatum • high arched palate with dental crowding • typical facial appearance (dolichcephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures)

Requires spinal X-ray

• flat cornea • increased axial length of globe • hypoplastic iris or ciliary muscle • mitral valve prolapse with / without mitral regurgitation • dilated main pulmonary artery with no stenosis or other cause < 40 years • calcification of the mitral annulus < 40 years • dilatation/dissection of descending aorta < 50 years • spontaneous pneumothorax and apical blebs • stretch marks, recurrent or incisional hernias

Requires detailed ophthalmology review

Ocular

Cardiovascular •

dilatation of the ascending aorta involving at least the simlses of Valsalva with or without aortic regurgitation aortic dissection

Pulmonary Skin/integument

Requires detailed echocardiography of aortic root dimensions An MRI or CT may also be necessary to visualize the descending aorta Chest X-ray required

Dura

•

lumbosacral dural ectasia

CT or MRI necessary

Genetic/ family history

• •

parent, child or sibling with Marfan syndrome presence of FBN1 mutation presence of an inherited haplotype linked around FBN1 associated with Marfan syndrome in family members

Requires full molecular diagnostic facilities

s u m m a r i z e d in Table 1.8 T h e d i a g n o s i s requires fulfillm e n t o f b o t h m a j o r a n d m i n o r criteria a n d is a i d e d by the availability o f gene studies. It can be difficult to be certain o f the diagnosis in a child. F o r example, a child with no f a m i l y h i s t o r y o f M a r f a n s y n d r o m e requires m a j o r criteria in two o r m o r e o r g a n systems with involvement o f a t h i r d system. I f a m u t a t i o n is k n o w n to cause M a r f a n s y n d r o m e in the family, the diagnosis requires one m a j o r criterion with a d d i t i o n a l involvement o f a s e c o n d system.

contractures, dolichocephaly, high a r c h e d palate, m i c r o g n a t h i a , hyperextensible joints, pes planus, chest deformity, m e g a l o c o r n e a , d i s l o c a t e d lenses a n d c h a r acteristic facies 'like an o l d m a n ' . M o r b i d i t y a n d m o r tality are high a n d u p to 40% die in infancy f r o m c a r d i a c failure. E a r l y diagnosis o f the severely affected infant allows a p p r o p r i a t e m a n a g e m e n t a n d counselling. M o s t familial cases t e n d to have a m i l d e r p r e s e n t a t i o n a n d are m o r e difficult to detect d u r i n g infancy.

Prenatal diagnosis

Diagnosis in the child

Two a p p r o a c h e s to p r e n a t a l diagnosis have been attempted. Standard ultrasonic measurements of skeletal length have been used b u t are insensitive a n d non-specific. 9 This is n o t surprising given the difficulty in m a k i n g a definitive clinical diagnosis in the newb o r n infant a n d y o u n g child. G e n e t i c l i n k a g e studies are possible in families with m o r e t h a n one affected member.

T h e p u b l i s h e d d i a g n o s t i c criteria have limitations in children. F o r example, it is i n a p p r o p r i a t e to p e r f o r m a C T scan to c o n f i r m d u r a l ectasia ( m a j o r criterion) in an a s y m p t o m a t i c child. Moreover, the growing child with M a r f a n s y n d r o m e has an evolving p h e n o t y p e . Thus, a l t h o u g h s o m e children fulfill the d i a g n o s t i c criteria in infancy, others m a y n o t until adolescence. This p r o b l e m was reviewed b y L i p s c o m e recently. 13 A t the initial assessment in o u r M a r f a n s y n d r o m e clinic we m a y c o n c l u d e that a child has ' p r o b a b l e ' o r 'possible' M a r f a n syndrome. T h e t e r m ' p r o b a b l e ' M a r f a n s y n d r o m e is used where several b u t n o t all d i a g n o s t i c criteria are met. These children are followed u p as if they h a d M a r f a n syndrome. The t e r m ' p o s s i b l e ' M a r f a n s y n d r o m e is used where child r e n are at 50% genetic risk a n d have some clinical

Diagnosis in the infant A rare t y p e o f severe infantile M a r f a n s y n d r o m e exists. 1°'~ M o s t are s p o r a d i c m u t a t i o n s a s s o c i a t e d with a deletion between exons 24 a n d 32 o f the fibritlin gene. 12 F e a t u r e s include severe c a r d i a c p r o b l e m s at b i r t h (especially m i t r a l a n d t r i c u s p i d regurgitation),

Marfan syndrome: is early diagnosis useful?

Central nervous system poor motor performance attention deficit disorder learning disability

(%) (30) ~ (17) (13)

/~

123

Ocular system ectopia tentis myopia detached retina

(%) (30) (20) (6)

Cardiovascular system aortic root dilatation mitral valve prolapse mitral regurgitation ECG abnormalities

(80) (25-50) (25-50) (55)

O

Skeletal system arm span > height arachnodactyly high/narrow arched palate typical facial features tall stature pectus deformity pes planus scoliosus

(93) (93) (90) (83) (80) (78) (78) (20-60)

f\

Skin and inte,qument striae with no obvious cause (55) hernias [inguinal, umbilical] (22)

Fig. 1 Commonfeaturesof Marfan syndromein children. The data are a compositefrom the Cardiff clinicfor children with Marfan syndromeand other recent studies.~3,'~,2°

features. They are reviewed infrequently (at 5, 10, 13 and 16 years old) until the diagnosis is confirmed or refuted. The most common features of Marfan syndrome in children are shown in Figure 1. In a survey of parents, the main areas of concern were problems with eyes (84%), joint or chest pain (66%), motor function (49%), behaviour (39%), speech, hearing or school (all 33%). 14The differential diagnosis is outlined in Table 2.

M A N A G E M E N T OF MARFAN S Y N D R O M E The management of Marfan syndrome in children has been reviewed recently and is outwith the scope of this article? 5 Useful advice for families, teachers and dentists can be obtained from the Marfan Association UK, 6 Queens Road, Farnborough, Hampshire GU14 6DH, UK.

can lead to a reduction in morbidity and mortality. For early diagnosis to be helpful in an asymptomatic child it is essential that: 1. The natural history should be known. 2. Treatment at the presymptomatic stage should improve outcome. The outlook in untreated Marfan syndrome is poor. In an early study of 257 patients there were 72 deaths at an average age of 32 years? 6 In over 90% this was due to cardiac complications, in particular, aortic dissection. Table 3 shows how early diagnosis can potentially improve outcome. Although sudden death is rare in children with Marfan syndrome, Shores has demonstrated that treatment with beta-blockers in childhood can significantly reduce the incidence of non-fatal dissection and cardiac death in early adulthood. 17 Moreover, early diagnosis enables elective replacement of the aortic root which has a lower mortality and better long-term outlook than emergency surgery for aortic dissection. TM

IS EARLY DIAGNOSIS USEFUL? In the symptomatic child, parents often feel relieved to have an explanation for their child's many problems. Early diagnosis enables prompt genetic counselling and family evaluation, including a search for asymptomatic adults who may be at risk of sudden death. The most important argument, however, is that early diagnosis in the child with Marfan syndrome

CONCLUSION Marfan syndrome is often diagnosed for the first time in young adults. Untreated the prognosis is poor. Diagnosis in childhood allows the early institution of optimal management and a significant improvement in long-term outcome.

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Table 2

Differential diagnosis of Marfan syndrome

Disorder

Characteristic features

Homocysteinuria

• • • • • • • • • • • • •

Kliuefelter syndrome

Stickler syndrome

Ehlers-Danlos Syndrome Beale's syndrome

Soto's syndrome Constitutional tall stature

Marfanoid phenotype Variable mental retardation Thrombotic vascular complications not dissection Lens dislocation in later years rather than early childhood Increased secretion of homocysteine in urine Marfanoid phenotype No cardiac or ocular features Small testicles and XXY genotype Marfanoid phenotype Sensorineural deafness Bony joint enlargement with progressive arthropathy Severe myopia with retinal detachmenffdegeneration Scoliosis and vascular dilatation including aortic dissection similar to Marfan syndrome but also hyperextensible skin easy bruising, extreme joint hypermobility • Marfanoid phenotype Multiple joint contractures - also known as congenital contracturat arachnodactyly Overlap with Marfan syndrome but cardiovascular features rare • Cerebral gigantism Cardiovascular features rare • No cardiac or eye features Facies not suggestive of Marfan syndrome

Other conditions to consider Similar cardiac features

Similar ocular features Similar skeletal features

Table 3

• • • • • • • • • •

Mitral valve prolapse syndrome Familial bicuspid valve with aortic dilatation Ankylosing spondylitis Familial ectopia lentis Weill Marchesani syndrome Pseudoxanthoma elasticum Trisomy 8 Myotonic dystrophy Campodactyly syndrome B Osteogenesis imperfecta

Examples where early medical treatment or advice might reduce morbidity

System

Feature

Treatment

Benefit

Ophthalmic

Asymptomatic retinal holes

Laser coagulopathy

Skeletal

Severe myopia Scoliosis

Prescription of spectacles orthopaedic brace/surgery

Excessive growth Lax tendons

Oestrogen treatment to induce early puberty Avoidance of contact sports

Avoidance of retinal detachment and blindness Improved vision/learning Improved long-term spinal function Reduced final height

Aortic dilatation

Beta blockade

Aortic dilatation

Avoidance of cigarette smoking

Valve regurgitation

Good dental hygiene, antibiotic prophylaxis during dental extraction/surgery Beta blockade

Cardiovascular

Mitral valve prolapse Other

Pregnancy associated aortic dissection

Contraceptive advice, echocardiographic monitoring and Beta blockade during pregnancy

Prevention of joint dislocation Reduced incidence of dissection Improved outcome after aortic root surgery Prevention of subacute bacterial endocarditis Reduced frequency of serious arrhythmias Reduction in maternal mortality

M a r f a n s y n d r o m e : is e a r l y d i a g n o s i s u s e f u l ?

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