Severe Perinatal Marfan Syndrome

(1)

Severe

Perinatal

Marfan

Syndrome

Donald

M. Gross,

MD, CM,

Luther

K. Robinson,

MD,

Lynne

T. Smith,

PhD,

Nancy

Glass,

MD, Harvey

Rosenberg,

MD, and

Madeleine

Duvic,

MD

From the University of Texas Medical School at Houston, Departments of Pediatrics, Pathology, and Internal Medicine/Dermatology, Houston, and the University of Washington, Department of Biologic Structure, Seattle

ABSTRACT.

The cardiovascular manifestations of the

Marfan syndrome in older children and adults have been

well described. Clinical, radiographic, and

echocardi-ographic data regarding three patients with severe

pen-natal Marfan syndrome are descnibed. Two of these pa-tients had the syndrome at birth and died in infancy. The syndrome was diagnosed in the third patient at 6 months of age and the child is still alive at 3 years of age.

The possible relationship among the Marfan syndrome,

Ehiers-Danlos syndrome, and osteogenesis imperfecta is considered. Patients with Marfan syndrome and severe

cardiorespiratory problems early in life tend to have a limited life expectancy. Pediatrics 1989;84:83-89; Marfan

syndrome, cardiorespiratory problem, dermatologic

find-ings.

The Marfan syndrome is a heritable disorder of

connective tissue characterized by ocular,

muscu-loskeletal, cardiovascular and pulmonary abnor-malities.’ Most cases are diagnosed in adolescence

or adulthood because of the clinical appearance,

development of mitral valve prolapse, or sudden

death secondary to aortic rupture. However, a more

severe perinatal clinical appearance has been

de-scribed. Before the availability of

echocardi-ographic diagnosis, a single case of unequivocal

congenital Marfan syndrome was reported in an

infant who died at birth after taking a single

breath.2 In that case, pathologic changes in the

great vessels and cardiac valves were typical of

Marfan syndrome and assumed to be the cause of

death. Other early descriptions include the cases of a 4-month-old infant3 and 5-month-old twins4 who

Received for publication Feb 16, 1988; accepted Apr 26, 1988. Reprint requests to (D.M.G.) University of Texas Medical School at Houston, Dept of Pediatrics, Box 20708, Houston, TX

77225.

had congestive heart failure and typical cardiac findings documented at cardiac catheterization.

Since the advent of echocardiography, there have

been sporadic case reports of neonates5’6 and even

premature infants7 with evidence of Marfan

syn-drome. Phornphutkul et al8 described 36 children

with Marfan syndrome, 2 of whom were infants.

Sisk et al9 described the clinical, cardiac, and

ech-ocardiographic features of the Marfan syndrome in

15 children less than 4 years of age. Although

actuarial analysis has shown that mean life expect-ancy for affected men is 40 years and for affected

women 50 years, it seems clear that there is a subset

of patients in whom the disease is diagnosed early in life with severe cardiorespiratory problems and

a limited life expectancy.

Of the three patients recently described in the

literature in whom symptoms of Marfan syndrome

were diagnosed in the neonatal period,57 the age of

death ranged from 3 days to 3 years. Herein we

report two additional patients with severe cardiac

involvement on the first day of life who died of

combined cardiac and respiratory disease at 3

months and 2 years of age, respectively. An addi-tional patient with cardiac involvement at 6 months

of age is still alive, although with progressive car-diac deterioration.

METHODS

M mode and two-dimensional echocardiograms

were performed on Irex 2A (Irex Corporation)

im-aging equipment. Studies were performed in

non-standard patient positions and transducer

onienta-tions when necessitated by chest wall deformity.

Biopsies from skin of the chest wall and lung at

(2)

in 35-mm Costar dishes were labeled with

L(2,3,4,5)-3H-proline (Amersham 3.77 BciJmmol) in

0.5%

serum

Dulbecco’s minimum essential medium

with 100 g/mL L-ascorbate (Sigma).

For light and transmission electron microscopy,

the skin was fixed in half-strength Karnovsky’s

fixative’0 at 4#{176}Cfor at least 24 hours. The tissue

was stained en bloc with 1% 0504, dehydrated through graded alcohols, taken into propylene

ox-ide, and embedded in Epon.” Sections 1-sm thick

were stained according to Richardson et al’2 and

examined by light microscopy using a Zeiss

photo-microscope. Thin sections were collected onto

cop-per grids, stained with 1% phosphotungstic acid,

1%

uranyl acetate, and lead citrate,’3 and viewed

with a Philips 420 scanning transmission electron

microscope.

Labeled procollagens were obtained from media

and pellet by ethanol precipitation and analyzed on

7.5% sodium dodecyl sulfate-polyacrylamide urea gels as described.14 Collagens were obtained by

pep-sin digestion of procollagen chains.’4 Gels were

visualized by autoradiography.

CASE REPORTS

Patient 1

Patient 1 was the product of an uncomplicated full-term pregnancy, labor, and delivery (Table 1). The father

was 26 years of age and there was no family history of connective tissue disease. The baby was a long, thin infant with marked arachnodactyly (Figs 1 to 4), a

de-creased upper to lower segment ratio, skin

hyperextensi-biity, joint contractures of the elbows, wrists, knees, and ankles, and bilateral ectopia lentis. His birth weight was

3.6 kg (75th percentile) and birth length was 58 cm

(>90th percentile). He was in no distress. There was an

apical nonejection click but no murmur or heart failure.

Electrocardiogram and chest radiogram results were

nor-mal. Echocardiographically, mild aortic root dilation was seen and a dysplastic, prolapsing mitral valve. The urine was negative for homocystine.

After discharge from the hospital, the baby had

inter-mittent respiratory distress and chest radiograms results

showed migratory pulmonary consolidation (Fig 1B). At

3 months of age, he had a mitral click and regurgitation

but no heart failure. Results of a second echocardiogram showed marked aortic root dilation, left atnial

enlarge-ment, and marked prolapse of both atnioventnicular

valves (Fig 1C). In spite of maximal medical therapy, progressive respiratory failure developed and the infant required a tracheostomy for home ventilation therapy by

7 months of age. Progressive dilation of the great

yes-sets also developed, leading to tracheal and bronchial

compression. Increasingly frequent and prolonged hos-pital admissions were needed for acute and chronic

res-piratory failure. He died at 21 months of age during an

acute episode of respiratory failure and pneumothorax. At postmortem examination (Table 2), numerous

em-physematous bullae were seen in the lungs, ranging in

size from 0.1 to 5 mm in diameter throughout all lobes.

TABLE 1. Clinical Features of Infants With Marfan Syndrome

Patient No/Sex Age at Diagnosis Family History Skin and Joints Eyes Cardiac Echogram Lung

1/M Newborn Negative Skin and joint hypermobil-ity, joint con-tractures,

an-achnodactyly,

beaked nose, decreased

up-per to lower segment

Ectopia lentis, myopia

Newborn: dilated aor-tic root, mitral valve prolapse

6 mo: atnial

enlarge-ment

11 mo: dilated aorta +

pulmonary artery

Pneumonia, emphysema, atelectasis

2/F Newborn

Mother-con-genital hip

dislocations; father-hy-perextensible joints

Loose skin,

an-achnodactyly, bilateral hip dislocations, hyperextensi-bility Droopy lids, myopia, ec-topia

3 mo: mitral valve pro-lapse, tricuspid valve prolapse, mitral re-gurgitation, tricuspid regurgitation, dilated aortic root, & ventni-des

Bilateral lower lobe infiltrates & heart failure

3/M 6 mo Negative Droopy, loose skin,

arach-nodactyly, joints not

by-perextensible, pectus exca-vatum, right hip disloca-tion, mild nerve hypo-tonia

Ectopia lentis Mitral valve prolapse, mitral regurgitation,

tricuspid valve pro-lapse, tricuspid

re-gurgitation, pul-monic insufficiency, aortic insufficiency,

atnial enlargement,

ventricular hypertro-phy, dilated aortic root

Bilateral lower lobe

(3)

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:#{149}#{149}#{149}#{149}#{149}#{149}

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Fig 1. A, Patient 1 as neonate. Note redundant skin and

arachnodactyly. B, Anteropostenior chest radiograph of patient 1. Note pulmonary hypeninflation, slightly in-creased heart size, and prominent aortic knob. C, Patient

1, M mode echocardiogram at 3 months of age. Both

mitral and tricuspid valves are seen. Note mid- to late

systolic prolapse of mitral valve and early systolic

pro-lapse of tricuspid valve (arrows). D, Postmortem

photo-graph of patient 2. Note contractures of elbow, and

an-achnodactyly, particularly suggestion of positive thumb

sign (extension of thumb beyond ulnar border when

confined within closed fist). E, Patient 2, anteropostenior chest radiograph at 3 months of age. Note wide superior mediastinum and markedly elongated heart (“Christmas stocking heart”). F, Patient 2, two-dimensional

echocar-diogram in apical four-chamber view showing systolic prolapse of both tricuspid and mitral valves. G, Patient

3 at initial evaluation at 6 months of age. Note pectus excavatum and arachnodactyly. H, Patient 3 at 20

months of age. Chest x-ray film in pulmonary artery

projection. Note marked cardiomegaly with elongation of

heart. There is eventration of left hemidiaphragm and prominence of left atnia appendage. Also note dilated

pulmonary artery branch above left main stem bronchus.

I, Patient 3 at initial evaluation. Two-dimensional

echo-cardiogram in high parasternal oblique projection. Note normal pulmonary artery dimension (1.0 cm) and dilated

aortic root (2.1 cm). Abbreviations: RA, right atrium; LA,

left atrium; TV, tricuspid valve; Ao, aorta; PA, pulmonary artery.

Microscopically, there were markedly distended air

spaces with clubbing of the alveolar septa. Grossly, the

heart had a dilated left atrium and a thick, rubbery, redundant mitral valve that prolapsed into the left atrium. The aortic valve was thickened, opaque, and incompetent. The pulmonary valve was thickened and the sinuses of Valsalva were dilated and thin walled. The tricuspid valve appeared normal.

With light microscopy, the skin showed a thickened

Fig 2. Light microscopy (A) and transmission electron microscopy (B, C) of skin from patient 1. Reticular dermis had increased and densely packed collagen fibers and no apparent increase in elastic fibers (A). Within reticular collagen fiber bundles, fibnil diameters were variable in size and tended to have angular rather than round cross-sectional profiles (B). Elastic fibers were small and irreg-ular (B, C), and frequently appeared to merge with col-lagen fibers (C, arrowheads). Arrow indicates bundle of microfibnils associated with “moth-eaten” elastic fiber. A,

x340; B, x18 900; C, X12 300.

reticular dermis with densely packed collagen fiber

bun-dies and relatively little elastin (Fig 2A). Results of light microscopic examination of the endocardium, including the valves and great vessels, showed similar findings throughout with intimal sclerosis and increased

cellular-ity and blurring of the elastic lamina of the media. There were lakes of material that stained for mucopolysacchar-ide. By electron microscopy of the skin sample, collagen

fibers of the deep reticular dermis were seen to be a mixed population of large and small fibnils and slightly angular

in circumference (Fig 2B). The elastic fibers were

irreg-ular and moderately frayed around the edges (Fig 2B and C).

Analysis of 3H-proline-labeled procollagen chains in

skin appeared normal (Fig 3, lane D) compared with

control skin fibroblasts (Fig 3, lane C). Similarly, collagen

chains a-i and a-2 were not different than control chains (data not shown).

Patient 2

Patient 2 was the product of an uncomplicated full-term pregnancy, labor, and delivery (Table 1). Her birth weight was 4 kg (90th percentile) and birth length was

51 cm (>90th percentile). Because of a family history of

hypertrophic cardiomyopathy in the father (age 37 years),

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3A 1

-1

1-PCA1

PNAI

-PCA2

PNA2

I#{248}

.

.-, .

choscopy results showed a normal larynx but partial to complete closure of the trachea and both main stem bronchi during coughing. In spite of vigorous medical therapy, increasing respiratory failure developed and the baby had a cardiorespiratory arrest at 3#{189}months of age from which she could not be resuscitated. A postmortem

A

B

C

D

photograph of the patient is shown Fig 1D to F; chest

radiogram and echocardiogram were done shortly before death.

At postmortem examination (Table 2), the lungs were

hypeninflated. Microscopically, the baby had well-aerated alveoli with mild intraalveolar hemorrhage but no

em-physematous changes. By gross examination of the

car-diovascular system, she was shown to have dilation of both atnia, both ventricles, and both great arteries as well

as the coronary arteries near their origins. Both

atnioven-tnicular valves were large and redundant and prolapsed. The semilunar valves were thin and delicate but

redun-Fig 3. 3H-proline-labeled procollagens from cultured

fi-broblasts were separated by sodium dodecyl sulfate-poly-acrylamide gel and radioaudiographed. Lane A, skin fi-broblasts, patient 2; lane B, lung fibroblasts, patient 2;

lane C, skin fibroblasts of control subject; lane D, skin

fibroblasts, patient 1.

Fig 4. Light microscopy (A) and transmission electron microscopy (B, C) of skin from patient 2. At light level,

collagen fibers appeared normal, but elastic fibers were

increased and apparently fragmented (A). Ultrastructure

of dermis confirmed many clusters of small, “moth-eaten”

elastic fibers (B). There was atypical fine, filamentous

material distributed in between collagen fibnils within

dermal collagen fiber bundies (arrowheads) (C). A, x340; B, x18 000; C, x43 200.

of hypertrophic cardiomyopathy. The infant was started on digoxin for congestive cardiomyopathy.

At 2 months of age, results of a dysmorphology evalu-ation revealed droopy eyes, lax skin, arachnodactyly,

hi-lateral hip dislocation, bilateral ectopia lentis, blue

sclerae, and pectus excavatum. According to further

fam-ily history, the mother had also had dislocated hips and

the father was thought to have hyperextensible joints.

The baby had mitral and tricuspid regurgitation without overt heart failure. The chest radiogram showed mild cardiomegaly and the electrocardiogram showed only ST and T wave changes consistent with digoxin effect. The urine was negative for homocystine.

Increasing respiratory failure developed and the infant

was readmitted to the hospital at 3 months of age with

bilateral pneumonia and mild heart failure. Antibiotics,

chest physiotherapy, and hydralazine were started.

Bron-dant.

Microscopically, the baby had focal intimal thickening ofthe great vessels with disruption of medial elastic fibers and lakes of amorphous, metachromatically staining ma-terial. Focal proliferation of the spongiosa was shown in

the atnioventnicular valves with areas of myxoid

degen-eration ofthe fibrous layer. Elastic tissue in the spongiosa

was well preserved.

By light microscopy, the skin showed abundant, small elastic fibers that appeared “fuzzy” with high

magnifica-tion (Fig 4A). By electron microscopy, the skin sample showed clusters of small elastin fibers with irregular

surface contours (Fig 4B). Collagen fibrils of the reticular

dermis had variable diameters with angular rather than

round cross sections (Fig 4B), and there was an additional filamentous material associated with collagen and elastic

fibers (Fig 4C).

Analysis of 3H-proline-labeled procollagen chains in

skin (Fig 3, lane A) showed increased amounts of PC a-1 (I), Pc a-2 (I), and a-i and -2 collagen chains relative

to control skin fibroblasts (Fig 3, lane C). The band above

pro a-2, type I, labeled “PNA 1,” the procollagen N-terminus a-2 (I) chain, appears more distinct in the

patient’s skin (lane A) than in the control cells (lane C). By two-dimensional map analysis, this appears to

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Al

A2

TABLE 2. Histologic Features of Marfan Syndrome

Patient Lung Heart and Endocardium Valves Skin

No.

1 Emphysema edema Internal sclerosis, increased cellularity, blurring of elastic lamina within media, muco-polysacchanides

Dense collagen in dermis in large & small bundles, decreased elastin

2 Focal hemorrhage L up- Focal thickening of intima, dis- Dense collagen in dermis, large

col-per lobe, hyperplastic rupted elastic fibers, in- lagen bundles, diminished elastin pseudostratified cili- creased mucopolysaccha- or microfibnillar material, dissolu-ated epithelium with rides, atnioventnicular tion of elastin

focal squamous meta- valves-myxoid degenera-plasia tion, focal proliferation of

spongiosa with preserved

elastin

mutant pro a-2, type I chain. In lung fibroblasts, two

bands of approximately 30 kd were seen (Fig 3, lane B)

that were not present in skin. Pepsin-treated samples

showed decreased amounts of a-i, type I and a-2, type I

collagen chains (Fig 5, lane B) relative to control skin (Fig 5, lane A) and to lung (Fig 5, lane C).

Patient 3

Patient 3 was the product of an uncomplicated, full-term pregnancy, labor, and delivery (Table 1). His birth weight was 3.6 kg (75th percentile) and birth length was

55cm (>90th percentile). During the neonatal period and

first 6 months of life, there was a notation of loose skin.

Paternal age was 31 years and there was no family history pointing to the disorder. At 6 months of age, the infant was admitted to the hospital with failure to thrive and a chronic cough. His weight had decreased to the fifth percentile. Prior chest radiogram results had been normal and the baby had not improved with administration of antibiotics.

When he was admitted to the hospital, the infant had little subcutaneous fat, lax skin, arachnodactyly, and hypotonia with no joint contractures or

hyperextensibil-ity. There was a marked pectus excavatum and

disloca-tion of the right hip (Fig 1G). He had bilateral ectopia

lentis, mild hypotonia, and mild myopathy. Nerve

con-duction study results were normal and the urine was negative for homocystine. The baby had a mitral click and regurgitation but no heart failure. The chest radi-ogram showed normal heart size with a wide mediastinum

and bilateral lower lobe atelectasis.

Electrocardiographi-cally, he had left ventricular hypertrophy and left atnial

enlargement, and echocardiographically, he had mitral

and tricuspid prolapse and dilation of the aortic root (Fig 11).

The baby was treated with oral antibiotics and chest physiotherapy, which continued after discharge. He made initial improvement but had increasingly frequent

epi-sodes of cough and fever necessitating antibiotics and chest physiotherapy. A chest x-ray film at 1#{189}years of

age showed marked cardiomegaly with elongation of the heart and a prominent left atnial appendage (Fig 1H) and there was no pulmonary edema. Moderate to severe

mi-tral regurgitation without heart failure persisted and did

not improve with hydralazine treatment. At 4 years of

age his clinical cardiac status had changed little, but left atnial enlargement and left ventricular hypertrophy with

strain were seen on his electrocardiogram. By Doppler

echocardiography, moderate mitral and tricuspid

regur-gitation and mild to moderate pulmonic and aortic regur-gitation, were seen.

DISCUSSION

Although we refer to the Marfan syndrome as if

it were a distinct clinical entity, it seems clear in view of the variety in clinical appearance at a wide

range of ages that the underlying abnormality of

connective tissue must vary greatly, not only in

severity, but also in type. It is important to

recog-nize that no single biochemical abnormality has

been identified as the cause of the Marfan

pheno-type. In fact, it has been proposed that Marfan’s original patient probably had congenital

contrac-tuna! arachnodactyly rather than the condition we

now refer to as the Marfan syndrome.’5’16

Some patients are first diagnosed in the teenage years because of the development of the distinct

body habitus first described by Marfan in 1896.’ It

is of note that this original patient was not known

to have either cardiovascular or ocular

manifesta-tions, now considered to be typical of the Marfan

---

---A

B

C

Fig 5. ‘H-proline-labeled procollagens were digested

with pepsin, and collagen chains were separated by

so-chum dodecyl sulfate-polyacrylamide gel. Lane A, control subject, skin; lane B, patient 2, skin; lane C, patient 2,

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syndrome. Others are diagnosed earlier in

child-hood because of the finding of a murmur or valve

dysfunction, myopia or ectopia lentis, or a positive

family history of Marfan syndrome.8’9 Still others

are diagnosed in early infancy or even the neonatal period with musculoskeletal, ocular, cardiovascular,

and pulmonary manifestations.57 These last

pa-tients appear to have the worst prognosis, and it is

with them that this report is concerned.

Ironically, the first report, in 1912, of

cardiovas-cular abnormality in a patient with a Marfanoid

habitus was that of a 2-month-old infant with

car-diomegaly, attacks ofdyspnea, and death.’7 Autopsy

showed dilation of all cardiac chambers and both atrioventricular valves (patient 2). The pulmonary manifestations of the syndrome have been

de-scribed relatively recently’2#{176} and consist mainly

of pneumothorax and emphysematous changes in

the lung that are presumably due to inadequate

support by defective pulmonary connective tissue.

Again, it is clear that not all patients with the

Marfan syndrome have clinically apparent

pulmo-nary involvement.

Patient 1 had the clinical and autopsy findings

typical of the fully developed Marfan syndrome

with musculoskeletal, ocular, cardiovascular, and

pulmonary involvement. It might be reasonable to

speculate that his early demise was hastened by the

mechanical stress of chronic home ventilation on his inadequately supported lungs. However,

Bo-lande and Tucker’s report’8 of the lung findings in

the Marfan syndrome included four infants, 11

weeks to 10 months of age who died with marked

emphysematous changes in one or both lungs. None

of these patients had had chronic mechanical

yen-tilation.

The case of patient 2 is slightly more complex.

During life, she demonstrated many of the typical

findings of Marfan syndrome and died of refractory

cardiorespiratory failure at 3 months of age.

Be-cause the parents gave a history of hyperextensible

joint involvement and congenital hip dislocations,

this patient may represent a compound

heterozy-gote with features of both Ehlers-Danlos type VII

syndrome and Marfan syndrome. The biochemical

studies suggest that this patient may have a defect in one of her a-2, type I collagen chain genes and that her abnormal a-2 collagen chains may be more susceptible to proteolysis with trypsin. Byers et al21

previously described another patient with an

ab-normal a-2, type I collagen chain.

Structural abnormalities in collagen and elastin

have been shown in the dermis of skin biopsies

from patients with inherited disorders of connective tissue including the Marfan syndrome.22 At the

ultrastructural level, there is heterogeneity as well,

and a change in one matrix component may

influ-ence the structure of all others. Abnormal collagen fiber diameter, especially smaller diameter fibers,

has been described with the Marfan syndrome.22

The collagen may be dense with disassociated

bun-dies, angular fibrils, and excessive matrix material that is thought to be mucopolysaccharide. However, the specific abnormality usually associated with the

Marfan syndrome is abnormal elastin fiber with a

“moth-eaten” appearance, which has been found in

skin and aorta.2224

In the skin biopsies of patients 1 and 2, the

histologic features were similar (Table 2). In patient

1,

the dermal collagen was more dense and

com-pacted and there were diminished elastin fibers

relative to normal and to patient 2. In both patients,

the collagen fibnils were variable in size with

an-gular circumference. Elastic fibers were small and

fragmented or frayed around the edges. The biopsy

results of patient 2 showed the presence of fine

matrix material around both collagen fibrils and

elastic fibers. Mucopolysaccharide accumulation

was also seen in the endocardium and aorta of both

patients.

Patient 3 represents a diagnostic and prognostic

problem. Unfortunately, we have been unable to

obtain a skin biopsy for light and electron

micros-copy and collagen biochemical studies. This infant

clearly has had a less stormy course than the other two patients, but nonetheless has been ill for much of his life and is now deteriorating more rapidly. His major difficulty seems to be cardiac, with res-piratory symptoms secondary to compression by

dilated vascular structures.

If all of these children have the Marfan

syn-drome, then the syndrome must have a spectrum

not only of clinical expression (age of onset, cardiac

vs respiratory difficulty and early vs late death), but also of histochemical expression in connective

tissue (normal vs decreased collagen, amount of

disruption of elastin, and amount of acid

mucopo-lysaccharide in vascular endothelium). Although

Marfan described a patient with tall stature,

arach-nodactyly, and joint contractures in his original

report, it is now common to diagnose patients with these features as well as ocular, cardiovascular, and pulmonary manifestations as having the Marfan

syndrome. The underlying biochemical defect

caus-ing the Marfan syndrome is not yet known.

Clini-cally, however, it shares features with the

Ehlers-Danlos syndrome and osteogenesis imperfecta,24

and a single patient with the Marfan syndrome has

been shown to produce an abnormal pro-a-2 type I

collagen chain.2’ However, linkage with type I, II,

and III collagen chain genes has been excluded by

extensive restriction fragment length

polymor-phism linkage studies.25’26 Because the Marfan

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structural protein mutation. Sporadic cases occur 15% to 30% of the time and are more severe.9

Osteogenesis imperfecta is heterogeneous at the

clinical level, resulting from molecular

heterogene-ity in mutations affecting both type I collagen chains. The most severe perinatal form (type II) involves mutations affecting triple helix formation

of collagen, especially glycine substitutions.’4 Mild

osteogenesis imperfecta (type IV) involves muta-tions in the a-2, type I collagen chain.27 At the

genetic level, all osteogenesis imperfecta patients

thus far described have different mutations,

al-though linkage studies indicate that either a-i or

a-2 collagen chains are involved.28’29 Our three

pa-tients with infantile Marfan syndrome represent

the most severe form of heterogeneous Marfan

syn-drome. If Marfan syndrome patients were clinically

categorized, this subset would be analogous to

os-teogenesis imperfecta type II of the Sillence classi-fication system.24 Recognition of this severe,

pen-natal subset of the Marfan syndrome by

echocar-diographic and subsequent histologic techniques should permit better definition of this entity at the biochemical level.

ACKNOWLEDGMENTS

This work was supported, in part, by The March of Dimes Basil O’Connor grant 5-501.

The authors thank Yolanda Thomatis for her assist-ance with this manuscript.

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Pediatrics

and Madeleine Duvic

Donald M. Gross, Luther K. Robinson, Lynne T. Smith, Nancy Glass, Harvey Rosenberg