Syndrome of the Month J Med Genet: First Published As 10.1136/Jmg.33.5.403 on 1 May 1996

_t Med Genet 1996;33:403-408 403 Syndrome of the month J Med Genet: first published as 10.1136/jmg.33.5.403 on 1 May 1996. Downloaded from

Marfan syndrome

Jonathon R Gray, Sarah J Davies

It is almost a century since Dr Antoine Bernard Clinical features of Marfan syndrome Marfan (1858-1942) presented Gabrielle P to SKELETAL SYSTEM the Medical Society of Paris in 1896' and the Various analyses of affected patients have em- understanding of the condition which carries phasised the presence of dolichocephaly and his name continues to expand. Various de- elongation of the extremities (fig 1), most scriptions of similar syndromes predate that of marked in the fingers and toes (fig 2).7-9 Height Marfan. Williams2 and Conan-Doyle in his A and span have been measured by various work- study in scarlet3 may, in fact, have recognised ers,6 0 concluding that simple assessment of the disorder before Marfan. With the advantage span being greater than height is of no value, of retrospect, various figures including Paga- as this can be observed in approximately 59% nini4 and more recently Abraham Lincoln5 have ofnormal males and 21 % offemales."l Ofmore been proposed to have suffered from Marfan value is the observation that a span exceeding syndrome. McKusick6 gave a classic account height by greater than 8 cm is only observed in of the clinical features of the disorder in the 5-6% of normal patients."1 first edition of Heritable disorders of connective It is currently suggested by some workers tissue. that in the absence of confounding factors, (J Med Genet 1996;33:403-408) such as vertebral deformity causing a loss of height, a span to height ratio of greater than Key words: Marfan syndrome. 1-03 can be considered significant.'2 http://jmg.bmj.com/

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Institute of Medical Genetics, University Hospital of Wales, I...k ."'. Heath Park, Cardiff .::'i CF4 4XN, UK .. J R Gray ..:eg A S J Davies Figure 1 Clinical phenotype: dolichostenomelia, Correspondence to: abnormal upperllower segment ratio, and span greater Dr Davies. than height. Figure 2 Arachnodactyly of the hands and feet. 404 Gray, Davies J Med Genet: first published as 10.1136/jmg.33.5.403 on 1 May 1996. Downloaded from

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Figure 3 Typical facial features: dolichocephaly and malar hypoplasia. Figure 4 Kyphoscoliosis. Abnormal limb length is often estimated in terms of an upper segment to lower segment ratio, lower segment being measured from the top of the symphysis pubis to the floor, the crucial as subsequent amblyopia is a common upper segment being defined as total height cause of poor vision. Blindness may also be minus the lower segment. The upper segment caused by varying degrees of retinal de-

to lower segment ratio typically in the normal tachment. Approximately 60% of Marfan syn- http://jmg.bmj.com/ adult population is approximately 0 93 while drome patients'7 show lens dislocation to in an adult Marfan syndrome patient it would varying degrees and in the majority of cases approximate to 0.85. This ratio varies with age, this is bilateral. The lens may dislocate into the but for Marfan syndrome patients it is typically anterior chamber causing acute glaucoma in a at least two standard deviations below the mean minority of cases. for age, sex, and race.'3 The mean height is greater than unaffected on September 25, 2021 by guest. Protected copyright. sibs or the population average for sex, age, and CARDIOVASCULAR FEATURES race and tends to run slightly above and parallel Maximum stress is applied to the first part of to the 97th centile.'4 The skull is often ab- the ascending aorta. The first large increase in normally shaped, being long and narrow volume, and hence decrease in stress, beyond (dolichocephaly) (fig 3). A prominent brow, this point is at the innominate artery. As a retrognathic or hypognathic mandible, and a consequence of these haemodynamic factors hypoplastic malar region all may contribute to this is the area at which dissection and dilatation the lugubrious appearance described by McKu- usually occurs. Dilatation usually precedes the sick.'3 The palate is usually high arched and development of an aneurysm. Some degree of narrow leading to dental overcrowding often dilatation can be seen in approximately 50% necessitating orthodontic intervention. Ver- ofchildren and 70 to 80% ofadults with Marfan tebral and pectus deformities are a common syndrome. 8 The pattern of dilatation is of cause ofskeletal morbidity (fig 4) with scoliosis/ some value in predicting prognosis. 9 The more kyphoscoliosis occurring in between 30 and generalised, the more serious the probable out- 60% ofMarfan syndrome patients'5 at any time come, and the more generalised pattern tends before skeletal maturity. to occur more in males than in females. The Joint laxity is common but may coexist with advent of echocardiography has made a major normal mobility or even joint contractures. impact on the diagnosis and management of Recurrent joint dislocation may result from the cardiovascular features of Marfan syn- redundant weak joint capsules, ligaments, ten- drome. The diameter ofthe aortic root is meas- dons, and fascia.'6 ured at the level of the sinuses of Valsalva and compared to the body surface area nom- OCULAR FEATURES ograms."0 Approximately 5% of cases are not Myopia is frequent, appears early, and is often adequately assessed by echocardiography be- severe. Monitoring of vision in childhood is cause of pectus deformity. Marfan syndrome 405

Aortic dissection Table 1 A summary of the Marfan syndrome criteria Aortic dissection has been described at aortic according to the Berlin Nosology 1987.29 In the absence of a definitely affected relative there should be skeletal diameters under 5 cm but the usual pattern is involvement plus involvement of two other systems, at

of gradual dilatation starting in the aortic root least one of which shows a cardinal feature (*) J Med Genet: first published as 10.1136/jmg.33.5.403 on 1 May 1996. Downloaded from and often extending up into the ascending Cardiovascular Dilatation of the ascending aorta* aorta.'2 There tends then to be a sudden onset Aortic dissection* Mitral regurgitation of aortic dissection with characteristic clinical Calcification of mitral annulus features of acute, anterior chest pain, often Mitral valve prolapse Abdominal aortic aneurysm described as being tearing in character. The Dysrhythmia pain may radiate through to the back or up to Ophthalmological Ectopia lentis* Flat cornea the jaw; very occasionally the dissection may be Elongated globe painless.2' The pattern ofdissection is usually of Retinal detachment Severe myopia distal progression, the minority that extend Neurological Dural ectasia* proximally may interfere with the coronary cir- Learning disability (verbal-performance discrepancy) culation with disastrous results. Respiratory skin/ Pneumothorax integument Striae Hernia Skeletal Chest wall deformity Mitral valve disease Dolichostenomelia not resulting from scoliosis Multivalvular abnormalities are the more fre- Arachnodactyly quent cardiac in children Vertebral column deformity pathology compared Tall stature, especially compared to to aortic complications in adults.22 Mitral valve first degree relatives is often the earliest ofthe cardiovascular High, narrow arched palate disease Protrusio acetabulae manifestations in Marfan syndrome. On echo- Abnormal joint mobility cardiographic assessment, 80% of patients re- gardless ofage or sex show evidence ofprolapse of at least the posterior mitral valve leaflet and often show evidence of valvular redundancy.22 Mitral valve prolapse occurring in Marfan syndrome is similar to the more commonly found isolated mitral valve prolapse in that they both Diagnostic criteria for Marfan syndrome show increased prevalence in females and an In the absence of an unequivocally affected increased prevalence with age. Differences be- first degree relative there should be involvement tween these two forms of mitral valve prolapse of the skeleton and at least two other systems, include the fact that over one-quarter ofMarfan at least one of those systems showing a major syndrome patients with mitral valve prolapse manifestation. progress to mitral regurgitation by adulthood.23 In the presence of at least one unequivocally affected first degree relative there should be at

least two systems involved, preferably one of http://jmg.bmj.com/ those systems showing a major manifestation, Aortic valve but this depending somewhat on the family's Aortic regurgitation is common, progressive, phenotype.29 and found in up to 70% of adult Marfan syn- Table 1 shows the varied manifestations; drome patients.24 those designated "major" manifestations at the conference are indicated by an asterisk. on September 25, 2021 by guest. Protected copyright. OTHER SYSTEM INVOLVEMENT Striae atrophica have been reported in ap- Differential diagnosis of Marfan proximately two-thirds of patients.'2 The syndrome pathology of the striae in Marfan syndrome is It is important to consider both syndromes identical to stretch marks found in non-Marfan sharing a similar multisystem involvement to syndrome patients, the most obvious ab- Marfan syndrome and those which may present normality being elastic fibre fragmentation.25 26 with a single system showing Marfan-like char- Hernias are seen frequently, the most usual acteristics (table 2). being inguinal, either congenital or acquired. A recent population based study of Marfan The value of knowing the patient's diagnosis is syndrome in the UK derived a minimum pre- that reinforcement of a repair with prosthetic valence figure of 1 in 14 217 (7 03 per 100 000 mesh work reduces the significant risk of re- population) and an incidence of 1 in 9802.30 currence after surgery.'2 Marfan syndrome may cause death or severe The major respiratory problem in Marfan handicap through adulthood and it may be syndrome is spontaneous pneumothorax27 anticipated to reduce reproductive fitness. Cal- which may be recurrent owing to rupture of culated reproductive fitness was 0-647.30 Eight apical bullae. of 30 cases in the prevalence study group were The spinal canal is often abnormally wide, assumed to be new mutations. Mutation rate with laminal thinning secondary to dural ec- was estimated at between 1-5 + 6 7 x 10-5, and tasia.2' Dural ectasia is an abnormal protrusion 1-8+7-3 x 10-5 per haploid genome per gen- of the dural membranes which rarely may be eration.30 This figure agrees with other widely associated with pressure effects. It is diagnosed quoted estimates of between 25% and 35% of by CT scan, and hence not routinely assessed cases.22 There was no evidence of an advanced in the absence of suggestive symptoms such as paternal age effect as described by other work- nerve root irritation. ers.3' 406 Gray, Davies

Table 2 Differential diagnosis of Marfan syndrome and other such careers may not consider an Multisystem Homocystinuria, Stickler syndrome, Ehlers-Danlos syndrome (EDS) applicant with Marfan syndrome to be phys- Skeletal Homocystinuria, congenital contractural arachnodactyly (CCA), ically suitable. Contact sports are discouraged myotonic dystrophy, Sotos syndrome, Marfanoid hypermobility to and syndrome, Klinefelter syndrome, sickle cell anaemia, Stickler try reduce the risk oflens dislocation and J Med Genet: first published as 10.1136/jmg.33.5.403 on 1 May 1996. Downloaded from syndrome, multiple endocrine neoplasia type II (MEN type II), familial also associated shear forces across a potentially mitral valve prolapse syndrome, X linked mental retardation with a Marfan-like habitus dilated aortic root. Similarly discouraged are Ocular Homocystinuria, familial ectopia lentis, Weill-Marchesani syndrome, sports and occupations causing sudden in- EDS type VI, Stickler syndrome Cardiovascular EDS variants, familial bicuspid aortic valve, familial annuloaortic creases in blood pressure, for example, ex- ectasia, familial mitral valve prolapse plosive type sports and occupations requiring heavy manual labour.

Natural history and management PUBERTY NEWBORN Cardiovascular features may be gross especially Rapid body growth brings the risk of pro- in "neonatal Marfan syndrome" cases where gressive aortic dilatation and annual or even various atypical features of skin laxity and con- six monthly echocardiograms may be necessary. tractures are associated with usually fatal Spinal abnormalities may accelerate and should cardiovascular complications and long, thin, be carefully checked for on each visit. The spindly physiques. In infancy dislocated lenses psychosocial aspects of the disorder may need are often the first diagnostic feature. Children to be addressed, with a careful discussion of are examined by echocardiography along with coping with issues such as anger or unkind the parents if it is the first case recognised in a comments from peers. Discussion ofthe genetic family. Skeletal examination allows the re- basis of the disorder will be necessary, both cording and assessment of length, weight, and individually and with partners in the later years. habitus which may be classical, and in some The extra care needed in managing pregnant infants marked pectus deformity can be de- Marfan patients should be explained. tected at an early stage. ADULTHOOD Annual echocardiography is usually PRESCHOOL TO PUBERTY adequate, Echocardiography is performed annually look- although more frequent assessment may be ing especially for valvular lesions which are the necessary if aortic dilatation is progressing rap- predominant cardiovascular idly. In the absence of abnormality, regular abnormalities in ophthalmological assessment is not necessary this age group. Antibiotic prophylaxis may be but indicated. P-blocker therapy may be considered emphasis must be placed on seeking urgent for children in this age group especially in the ophthalmic referral if vision deteriorates sud- presence of dilatation of the aorta, a severe denly. Annual clinic visits allow monitoring of cardiac family history, and in the absence of progress, discussion ofechocardiogram results, http://jmg.bmj.com/ the usual and continuing career/exercise advice, and are contraindications. very useful for pre- and postsurgical counselling Myopia may be progressive and severe and if aortic replacement is contemplated. a regular assessment is important. Regular assessment of potentially progressive skeletal abnormalities such as scoliosis, kyphosis, and Prenatal pectus deformity is vital for appropriate inter- With the availability oflinkage for analysis some on September 25, 2021 by guest. Protected copyright. vention. Joint laxity can be assessed, and meas- suitable families and mutation detection in a ures such as splinting introduced. Counselling minority, the issues of can be regarding appropriate careers and sports is vital. screening ad- It is valuable to discuss at an dressed. It is clear that families are keen to early stage how undertake presymptomatic and prenatal testing interview panels for the armed forces, police, for Marfan syndrome where feasible.32

Survival function 88 63 1.0 Life expectancy 117 97 34 Life expectancy has improved, most probably because of early diagnosis and appropriate sur- 0.8 iL ------7veillance and intervention.33 5-blockers seem to 429 11 likely to confer an improved prognosis34 al- 0.6 though the optimum age for beginning is un- 0) certain. In many centres, including our own, 03 L appropriate P-blockade would be started at the ._E) 0.4 first signs of aortic dilatation, as assessed using - Female standardised reference ranges for age and sex. 0.2 Other centres prefer to start P-blocker therapy Male at an earlier stage in the disease course, hoping to intervene before dilatation starts. Surgical 0 in 0 10 20 30 40 50 60 70 80 90 100 Lechniques appropriate specialised centres 304050 60 70 80 90 100have undoubtedly also contributed to the im- Ag10e20Age (years)r proved life expectancy. Our data (unpublished) Figure 5 Mortality curves for British Marfan syndrome patients. Kaplan Meir survival suggest that life expectancy has increased (fig curves for a cohort of Marfan syndrome patients with regard to gender (unpublished). 5) and for counselling purposes we suggest Marfan syndrome 407

RGD within the calcium binding EGF, TGF, and motifs. 1 3 8 1 1 12 24 26 33 38 hybrid The commonest mutations described to date are point mutations of these

cysteine residues. J Med Genet: first published as 10.1136/jmg.33.5.403 on 1 May 1996. Downloaded from Protein biochemistry has shown alterations A B C D E in the synthesis, secretion, and processing of fibrillin in cell lines from patients with Marfan syndrome.42 These variations in patients with NH2 Terminus with Carboxy-terminal end; \ signal sequence 180 amino acids differing severity of phenotype have led to the 8CYS domains; suggestion of a dominant negative mechanism EGF-like domain 0 63-71 amino acids with severity of phenotype being dependent n pEGF-like domains; A Proline rich region; on the level of mutant product expressed.43 39-44 amino acids 47 amino acids However, the report of a null allele associated 4CYS domain Modified 8CYS domain with a severe phenotype is hard to equate with a dominant negative effect.44 Figure 6 Diagrammatic representation of the proposed amino acid structure of human Fibrillin (fig 6) is secreted as a 350 kDa fibrillin. profibrillin and processed extracellularly into fibrillin which forms higher molecular weight aggregates.45 It is the vital component of the in British populations the mean cumulat:ive ubiquitous 10 nm microfibril which interacts probability of survival for men is 53 years and with elastin in elastic fibres within tissues, such for women 72 years. The average age at de,ath as the aorta and ligaments, or serves an an- for our British patients is 44 years for men amd choring function in non-elastic tissues, such as 47 years for women. the ciliary zonules, bone periosteum, and tendon. Rotary shadowing electron micro- scopic studies of microfibrils assembled by tis- Genetics sue in cell culture confirms the extracellular The autosomal dominant inheritance of Miar- aggregation and assembly of fibrillin molecules fan syndrome has been well established writh into 10 nm diameter microfibrils with a beaded between 25 and 30% of cases being new mut- structure and a constant periodicity of ations.22 Initial evidence for the involvementt of 50-55 nm. Studies of cell lines from patients various collagens was discounted by linkEage with Marfan syndrome confirm abnormalities studies.3536 The discovery in 1986 of a niew in microfibrillar assembly.46 Subsequently, the glycoprotein named fibrillin37 and its uibi- fibrillin gene identified on chromosome 15 has quitous distribution within both elastic and been shown to be part of a larger "gene family". non-elastic tissues in the body led to the sius- At least three other fibrillin-like genes exist. A picion of the involvement of fibrillin in 1the second locus has been mapped to chromosome pathological process causing Marfan syndronne. 3,47 although there is some dispute whether http://jmg.bmj.com/ In 1991, in a good example of the convergerice the phenotype is truly consistent with Marfan of separate approaches, linkage of Marfan s)yn- syndrome. Fibrillin homologues have been drome was established to chromosome 15iq38 identified on chromosomes 5 and 17.4849 With at the same time as immunofluorescent imagiing the elucidation of respective sequences, poly- showed reduced levels of fibrillin to be prescent morphic intragenic markers have allowed dis- in fibroblast preparations from Marfan s~yn- ease entities similar to Marfan syndrome to be

drome patients.39 As sequence of the gene tbe- tested at these loci. Despite the difficulties of on September 25, 2021 by guest. Protected copyright. came available, mutations were described1.40 describing a family's phenotype as being "pure" The fibrillin gene itself is a complex mu]Iti- ectopia lentis, linkage for such families has been domain structure containing EGF (epidernnal described for chromosome 15.48 The disorder growth factor)-like repeats, TGF (transformiing congenital contractural arachnodactyly has growth factor)-like domains, and also uniqlue been linked to fibrillin-5.45 Recently the gene hybrid domains which bear resemblance to encoding microfibril associated glycoprotein both EGF and TGF motifs. The gene is lar~ge, (MAGP) has been mapped to 15q50 and it is 1lOkb with 56 exons and lOkb of codiing possible that mutations within this gene may sequence. The entire sequence is now (es- be responsible for phenocopies of Marfan syn- tablished and nonsense and missense mutatioins drome and explain the low mutation detection as well as deletions and insertions have been rate in Marfan families. detected. However, despite this knowledlge mutation analysis has proved disappointing a]nd time consuming with only a poor yield of I Marfan AB. Un cas de deformation congenitale des quatre mutations, most appearing unique. Genotyy:)e/ membres plus prononcee aux extremites caracterisee par phenotype correlation is proving difficult wiith allongement des os avec un certain degre d'amincissement. Bull Mem Soc Med Hop Paris 1896;13:220-6. only the occurrence of mutations clusterijng 2 Williams E. Rare cases with practical remarks. Trans Am within EGF motifs 24-264' in several seveire, Ophthalmol Soc 1879;2:291-301. 3 Conan-Doyle A. A study in scarlet. London: Penguin Books, sporadic, neonatal Marfan patients appeari:ng 1887. to show a consistent pattern. The EGF ats 4 Mantero R. The Marfan hands of Niccolo Paganini. Sem repei Hosp 1989;65:1606-1. have six crucial cysteine residues which appear 5 Gordon AM. Abraham Lincoln, the famous case ofMarfan's vital for disulphide bonding leading to stable syndrome. Deutsches Med_7 1967;18:256-60. 6 McKusick VA. Heritable disorders of connective tissue. Saint sheet formation and intracellular processing as Louis: C V Mosby, 1956. well as aiding calcium binding by the highily 7 Mery H, Babonneix L. Un cas de deformation congenitale des quatre membres: hyperchondroplasie. Bull Mem Soc conserved consensus calcium binding sittes Med Hop Paris 1902;19:671-6. 408 Gray, Davies

8 Achard C. Arachnodactylie. Bull Meni Soc Med Hop Paris 31 Murdoch JL, Walker BA, Halpern BL, et al. Life expectancy 1902;19:834-40. and causes of death in the Marfan syndrome. N EniglJ 9 Lambie CG, Shellshear KE, Shellshear JL. Arachnodactyly Med 1972;286:804-8. or Marfan syndrome. Med _7Aust 1950;1:213-23. 32 Bridges AB, Faed M, Boxer M, et al. Marfan syndrome in 10 Hamwi GJ. Marfan's syndrome (arachnodactyly). Am _7Med a large family: response of family members to a screening

1951;11:261-6. programme. _ Med Genet 1992;29:81-8. J Med Genet: first published as 10.1136/jmg.33.5.403 on 1 May 1996. Downloaded from 11 Pearson K, Lee A. On laws of inheritance in man. I. 33 Silverman DI, Burton KJ, Gray JR, et al. Life expectancy Inheritance ofphysical characters. Biometrika 1902;2:357- in the Marfan syndrome. Am.i7 Cardiol 1995;2:157-60. 462. 34 Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression 12 Pyeritz RE. The Marfan syndrome. In: Royce PM, Steinman of aortic dilatation and the benefit of long term beta of con- adrenergic-blockade in Marfans-syndrome. N Engl _7 Med B, eds. Extracellular matrix and inheritable disorders 1994;330:1335-41. nective tissue. New York: Wiley-Liss, 1993. 35 Dalgleish R, Hawkins JR, Keston M, et al. Exclusion of the 13 McKusick VA. Heritable disorders of connective tissue. Saint alpha 2(I) and alpha 1(III) collagen genes as the mutant Louis: C V Mosby, 1972. loci in a Marfan syndrome family. .7 Med Geniet 1987;24: 14 Pyeritz RE, Murphy EA, McKusick VA. Growth and an- 148-51. thropometrics in the Marfan syndrome. Prog Clin Biol Res 36 Tsipouras P, Borresen AL, Bamforth S, et al. Marfan syn- 1985;200:355-60. drome: exclusion of genetic linkage to the COL1A2 gene. 15 Ramirez F, Godfrey M. Marfan syndrome and related dis- Clin, Genet 1986;30:428. orders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, 37 Sakai LY, Keene DR, Engvall E, et al. Fibrillin, a new 350-kD eds. The metabolic and molecular bases of inherited disease. glycoprotein, is a component ofextracellular microfibrils.7 7th ed. New York: McGraw-Hill, 1993: 4079-94. Cell Biol 1986;103:2499-509. 16 Pennes DR, Braunstein EM, Shirazi KK, et al. Carpal 38 Kainulainen K, Pulkkinen L, Savollainen A, et al. Location ligamentous laxity with bilateral perilunate dislocation in on chromosome 15 of the gene defect causing Marfan Marfan syndrome. Skeletal Radiol 1985;13:62-4. syndrome. N Engl Med 1990;323:935-9. 17 Maumenee IH. The eye in the Marfan syndrome. Tranis Am 39 Hollister DW, Godfrey M, Sakai LY, et al. Immunohistologic Ophthalmol Soc 198 1;79:684-733. abnormalities ofthe microfibrillar-fiber system in the Mar- 18 Hwa J, Richards JG, Huang H, et al. The natural history of fan syndrome. N Enigl 3 Med 1990;323: 152-9. aortic dilatation in Marfan syndrome. Med J Aust 1993; 40 Dietz HC, Pyeritz RE, Puffenburger EG, et al. Marfan 158:558-62. syndrome caused by a recurrent de novo missense muta- 19 Roman MJ, Devereux RB, Kramer-Fox R, et al. Aortic root tion in the fibrillin gene. Nature 1991;352:337-9. dilatation in the Marfan syndrome: patterns, familiarity, 41 Kainulainen K, Karttunen L, Puhakka L, et al. Mutations and short term clinical course. j7Am Coll Cardiol 1988;11: in the fibrillin gene responsible for dominant ectopia lentis 74. and neonatal Marfan syndrome. Nature Genet 1994;6: et Two di- 64-9. 20 Roman MJ, Devereux RB, Kramer-Fox R, al. 42 Milewicz DM, Pyeritz RE, Crawford ES, et al. Marfan mensional echocardiographic aortic root dimensions in syndrome: defective synthesis, secretion, and extracellular normal children and adults. Am_j Cardiol 1989;64:507-12. matrix formation offibrillin by cultured dermal fibroblasts. 21 Gott VL, Pyeritz RE, Magovern GJ, et al. Surgical treatment _7 Clini Invest 1992;89:79-86. of aneurysms of the ascending aorta in the Marfan syn- 43 Dietz HC, McIntosh I, Sakai LY, et al. Four novel FBN1 drome. Results of composite-graft repair in 50 patients. mutations: significance for mutant transcript level and N Engl 3 Med 1986;314:1070-4. EGF-like domain calcium binding in the pathogenesis of 22 Pyeritz RE, McKusick VA. The Marfan syndrome: diagnosis Marfan syndrome. Genonmics 1993; 17:468-75. and management. N Engl _J Med 1979;300:772-7. 44 Hewett DR, Lynch J, Child A, Firth H, Sykes B. Differential 23 Pyeritz RE, Wappel MA. Mitral valve dysfunction in the allele expression of a fibrillin gene (FBN 1) in patients Marfan syndrome. Clinical and echocardiographic study with Marfan syndrome. Anm Hunm Geniet 1994;52:447-52. of prevalence and natural history. Am 7 Med 1983;74: 45 Sakai LY, Keene DR, Glanville RW, et al. Purification 797-807. and partial characterization of fibrillin, a cysteine-rich 24 Lima SD, Lima JA, Pyeritz RE, et al. Relation of mitral structural component of connective tissue microfibrils. I valve prolapse to left ventricular size in Marfan's syndrome. Biol Chem 199 1;266:14763-70. Am _T Cardiol 1985;55:739-43. 46 Kielty CM, Davies SJ, Phillips JE, et al. Marfan syndrome: 25 Pinkus H, Keech MK, Mehregan AH, et al. Histopathology fibrillin expression and microfibrillar abnormalities in a of striae distensae, with special reference to striae and family with predominant ocular defects. _7Med Genet 1995; wound healing in the Marfan syndrome. _7 Invest Dermatol 32:1-6. 1966;46:283-92. 47 Collod G, Babron MC, Jondeau G, et al. A second locus 26 Cohen PR, Schneiderman P. Clinical manifestations of the for Marfan syndrome maps to chromosome 3p24.2-p25. Int J Nature Genet 1994;8:264-9. http://jmg.bmj.com/ Marfan syndrome. Dermatol 1989;28:291-9. 48 Tsipouras P, Del Mastro R, Sarfarazi M, et al. Genetic 27 Hall JR, Pyeritz RE, Dudgeon DL, et al. Pneumothorax in linkage of the Marfan syndrome, ectopia lentis, and con- the Marfan syndrome: prevalence and therapy. Ann Thorac genital contractural arachnodactyly to the fibrillin genes Surg 1984;37:500-4. on chromosomes 15 and 5. The International Marfan 28 Pyeritz RE, Fishman EK, Bemhardt BA, Siegelman SS. Syndrome Collaborative Study. N Engl _r Med 1992;326: Dural ectasia is a common feature ofthe Marfan syndrome. 905-9. Am3tHum Genet 1988;43:726. 49 Lee B, Godfrey M, Vitale E, et al. Linkage of Marfan 29 Beighton P, de Paepe A, Danks D, et al. International syndrome and a phenotypically related disorder to two nosology ofheritable disorders of connective tissue, Berlin, different fibrillin genes. Nature 1991 ;352:330-4. 1986. Am.7 Med Genet 1988;29:581-94. 50 Yeh H, Chow M, Abrams WR, et al. Structure of the

30 Gray JR, Bridges AB, Faed MW. Ascertainment and severity human gene encoding the associated microfibrillar protein on September 25, 2021 by guest. Protected copyright. of Marfan syndrome in a Scottish population. JMed Genet (MFAP1) and localisation to chromosome 15ql5-q21. 1994;31:51-4. Genonics 1994;23:443-9.